Curriculum Vitae

Research Career

1987 – 1990

Experimental studies at the Justus-Liebig-University Giessen at the Institute of Anatomy and Cell Biology (Head: Prof. A. Oksche)

Feb. - March 1989

Visiting fellow at the laboratory of Dr. F. G. Wouterlood at the Free University of Amsterdam

Aug. - Okt. 1989

Visiting fellow at the laboratory of Prof. L.C.H. Wang, Dept. Zoology, Edmonton, Canada

Feb. - March 1990

Scholarship holder of the European Science Foundation at the laboratory of Dr. F. G. Wouterlood at the Free University of Amsterdam

Januar 1993

Graduation as MD (Dr. med.) at the Medical Faculty of the Justus-Liebig-University Giessen; grade: summa cum laude

1992 – 1994

Internship at the Department of Neurology at the University Düsseldorf(Head: Prof. Dr. H.-J. Freund)

Feb. - June 1994

Scholarship holder of the German Research Council at the laboratory of Dr. T. F. Freund, KOKI, Institute of Experimental Medicine, Dept. of Functional Neuroanatomy

June 1994 - present

Post-doc at the C. & O. Vogt-Institute for Brain Research, Düsseldorf, (Head: Prof. Dr. K. Zilles)

March 1998

Fachanatom – Anatomische Gesellschaft

December 2000

Habilitation and Venia legendi for Anatomy at the Medical Faculty of the Heinrich-Heine-University Düsseldorf

May 2002

Assistant Professor (C2-Hochschuldozenten)

November 2003

Junior Research Award of the Northrhine-Westfelian Academy of Science-initiative „Neurovisionen“

March 2006

Associate Professor of Cell Biology (Institute of Anatomy and Cell Biology, Department of Neuroanatomy) at the Albert-Ludwigs-University Freiburg

January 2007

Founding member of the Collaborative Research Center 780 Synaptic mechanisms of neural network function (Project C1: Topographic maps and their synaptic circuits in modular and nonmodular (disorganized) rodent barrel cortex)

April 2010

Full Professor of Neuroanatomy and Director of the Department of Neuroanatomy (Center Anatomy) at the Georg-August-University Göttingen

January 2011

Founding member of the Collaborative Research Center 889 Cellular mechanisms of sensory processing (Project C3: Integration of afferent sensory and cortical input by identified neurons of the rodent somatosensory cortex)

Research Overview

Overview

Ongoing projects of the Göttingen Barrel Group deal with the questions:

• How many layers are formed in the barrel cortex?
• Which canonical and non-canonical elementary circuits are implemented within and between these layers?
• What are the cellular and subcellular properties of a basket cell?
• What are the cellular and subcellular properties of a Martinotti cell?
• What are the cellular and subcellular properties of a (bipolar) interneuron-specific cell?
• What are the molecular foundations in the formation of cell type-specific innervation of cortical neurons by thalamic afferents?

Publications

2023

Direction selectivity of inhibitory interneurons in mouse barrel cortex differs between interneuron subtypes.
Julien Guy, Martin Möck, Jochen F. Staiger.
Cell Reports 42, 111936; https://doi.org/10.1016/j.celrep.2022.111936, 2023.
abstract link

GABAergic interneurons represent ∼15% to 20% of all cortical neurons, but their diversity grants them unique roles in cortical circuits. In the barrel cortex, responses of excitatory neurons to stimulation of facial whiskers are direction selective, whereby excitation is maximized over a narrow range of angular deflections. Whether GABAergic interneurons are also direction selective is unclear. Here, we use two-photon-guided whole-cell recordings in the barrel cortex of anesthetized mice and control whisker stimulation to measure direction selectivity in defined interneuron subtypes. Selectivity is ubiquitous in interneurons, but tuning sharpness varies across populations. Vasoactive intestinal polypeptide (VIP) interneurons are as selective as pyramidal neurons, but parvalbumin (PV) interneurons are more broadly tuned. Furthermore, a majority (2/3) of somatostatin (SST) interneurons receive direction-selective inhibition, with the rest receiving direction-selective excitation. Sensory evoked activity in the barrel cortex is thus cell-type specific, suggesting that interneuron subtypes make distinct contributions to cortical representations of stimuli.

2022

Repetitively burst-spiking neurons in reeler mice show conserved but also highly variable morphological features of layer Vb-fated “thick-tufted” pyramidal cells..
Jochen F. Staiger*, Alexandra Sachkova, Martin Möck, Julien Guy and Mirko Witte.
Front. Neuroanat. 16:1000107. doi: 10.3389/fnana.2022.1000107, 2022.
abstract link

Reelin is a large extracellular glycoprotein that is secreted by Cajal-Retziuscells during embryonic development to regulate neuronal migration andcell proliferation but it also seems to regulate ion channel distributionand synaptic vesicle release properties of excitatory neurons well intoadulthood. Mousemutants with a compromised reelin signaling cascade showa highly disorganized neocortex but the basic connectional features of thedisplaced excitatory principal cells seem to be relatively intact. Very little isknown, however, about the intrinsic electrophysiological and morphologicalproperties of individual cells in the reeler cortex. Repetitive burst-spiking (RB)is a unique property of large, thick-tufted pyramidal cells of wild-type layer Vbexclusively, which project to several subcortical targets. In addition, they areknown to possess sparse but far-reaching intracortical recurrent collaterals.Here, we compared the electrophysiological properties and morphologicalfeatures of neurons in the reeler primary somatosensory cortex with thoseof wild-type controls. Whereas in wild-type mice, RB pyramidal cells wereonly detected in layer Vb, and the vast majority of reeler RB pyramidal cellswere found in the superficial third of the cortical depth. There were noobvious di􀀀erences in the intrinsic electrophysiological properties and basicmorphological features (such as soma size or the number of dendrites) werealso well preserved. However, the spatial orientation of the entire dendritictree was highly variable in the reeler neocortex, whereas it was completelystereotyped in wild-typemice. It seems that basic quantitative features of layerVb-fated RB pyramidal cells are well conserved in the highly disorganizedmutant neocortex, whereas qualitative morphological features vary, possiblyto properly orient toward the appropriate input pathways, which are knownto show an atypical oblique path through the reeler cortex. The obliquedendritic orientation thus presumably reflects a re-orientation of dendriticinput domains toward spatially highly disorganized a􀀀erent projections.

BAF (mSWI/SNF) complex regulates mediolateral cortical patterning in the developing forebrain.
Huong Nguyen, Godwin Sokpor, Arpan Parichha, Linh Pham, Nidhi Saikhedkar, Yuanbin Xie, Pauline Antonie Ulmke, Joachim Rosenbusch, Mehdi Pirouz, Rüdiger Behr, Anastassia Stoykova, Beate Brand-Saberi, Huu Phuc Nguyen, Jochen F. Staiger, Shubha Tole and Tran Tuoc.
Front. Cell Dev. Biol. 10:1011109. doi: 10.3389/fcell.2022.1011109, 2022.
abstract

Early forebrain patterning entails the correct regional designation of theneuroepithelium, and appropriate specification, generation, and distributionof neural cells during brain development. Specific signaling and transcriptionfactors are known to tightly regulate patterning of the dorsal telencephalon toafford proper structural/functional cortical arealization and morphogenesis.Nevertheless, whether and how changes of the chromatin structure link to thetranscriptional program(s) that control cortical patterning remains elusive. Here,we report that the BAF chromatin remodeling complex regulates thespatiotemporal patterning of the mouse dorsal telencephalon. To determinewhether and how the BAF complex regulates cortical patterning, weconditionally deleted the BAF complex scaffolding subunits BAF155 andBAF170 in the mouse dorsal telencephalic neuroepithelium. Morphologicaland cellular changes in the BAF mutant forebrain were examined usingimmunohistochemistry and in situ hybridization. RNA sequencing, Coimmunoprecipitation,and mass spectrometry were used to investigate themolecular basis of BAF complex involvement in forebrain patterning. We foundthat conditional ablation of BAF complex in the dorsal telencephalonneuroepithelium caused expansion of the cortical hem and medial cortexbeyond their developmental boundaries. Consequently, the hippocampalprimordium is not specified, the mediolateral cortical patterning iscompromised, and the cortical identity is disturbed in the absence of BAFcomplex. The BAF complex was found to interact with the cortical hemsuppressor LHX2. The BAF complex suppresses cortical hem fate to permitproper forebrain patterning. We provide evidence that BAF complex modulatesmediolateral cortical patterning possibly by interacting with the transcriptionfactor LHX2 to drive the LHX2-dependent transcriptional program essential fordorsal telencephalon patterning. Our data suggest a putative mechanisticsynergy between BAF chromatin remodeling complex and LHX2 inregulating forebrain patterning and ontogeny.

2021

Theta activity paradoxically boosts gamma and ripple frequency sensitivity in prefrontal interneurons.
Ricardo Martins Merino, Leon-Pinzon, Walter Stühmer, Martin Möck, Jochen F. Staiger, Fred Wolf, Andreas Neef.
Proceedings of the National Academy of Science USA 2021 118 (51) e2114549118, 2021.
abstract link

Fast oscillations in cortical circuits critically depend on GABAergic interneurons. Which interneuron types and populations can drive different cortical rhythms, however, remains unresolved and may depend on brain state. Here, we measured the sensitivity of different GABAergic interneurons in prefrontal cortex under conditions mimicking distinct brain states. While fast-spiking neurons always exhibited a wide bandwidth of around 400 Hz, the response properties of spike-frequency adapting interneurons switched with the background input’s statistics. Slowly fluctuating background activity, as typical for sleep or quiet wakefulness, dramatically boosted the neurons’ sensitivity to gamma and ripple frequencies. We developed a time-resolved dynamic gain analysis and revealed rapid sensitivity modulations that enable neurons to periodically boost gamma oscillations and ripples during specific phases of ongoing low-frequency oscillations. This mechanism predicts these prefrontal interneurons to be exquisitely sensitive to high-frequency ripples, especially during brain states characterized by slow rhythms, and to contribute substantially to theta-gamma cross-frequency coupling.

Lactate is an energy substrate for rodent cortical neurons and enhances their firing activity.
Anastassios Karagiannis, Thierry Gallopin, Alexandre Lacroix, Fabrice Plaisier, Juliette Piquet, Hélène Geoffroy, Régine Hepp, Jérémie Naudé, Benjamin Le Gac, Richard Egger, Bertrand Lambolez, Dongdong Li, Jean Rossier, Jochen F Staiger, Hiromi Imamura, Susumu Seino, Jochen Roeper, Bruno Cauli.
eLife 2021;10:e71424, 2021.
abstract link

Glucose is the mandatory fuel for the brain, yet the relative contribution of glucose and lactate for neuronal energy metabolism is unclear. We found that increased lactate, but not glucose concentration, enhances the spiking activity of neurons of the cerebral cortex. Enhanced spiking was dependent on ATP-sensitive potassium (KATP) channels formed with KCNJ11 and ABCC8 subunits,which we show are functionally expressed in most neocortical neuronal types. We also demonstratethe ability of cortical neurons to take-upand metabolize lactate. We further reveal that ATP isproduced by cortical neurons largely via oxidative phosphorylation and only modestly by glycolysis.Our data demonstrate that in active neurons, lactate is preferred to glucose as an energy substrate,and that lactate metabolism shapes neuronal activity in the neocortex through KATP channels. Our results highlight the importance of metabolic crosstalk between neurons and astrocytes for brain function.

H3 acetylation selectively promotes basal progenitor proliferation and neocortex expansion.
Cemil Kerimoglu, Linh Pham, Anton B. Tonchev, M. Sadman Sakib, Yuanbin Xie, Godwin Sokpor, Pauline Antonie Ulmke, Lalit Kaurani, Eman Abbas, Huong Nguyen, Joachim Rosenbusch, Alexandra Michurina, Vincenzo Capece, Meglena Angelova, Nenad Maricic, Beate Brand-Saberi, Miriam Esgleas, Mareike Albert, Radoslav Minkov, Emil Kovachev, Ulrike Teichmann, Rho H. Seong, Wieland B. Huttner, Huu Phuc Nguyen, Anastassia Stoykova, Jochen F. Staiger, Andre Fischer, Tran Tuoc.
Science Advances 2021; 7 : eabc6792, 2021.
abstract link

Increase in the size of human neocortex―acquired in evolution―accounts for the unique cognitive capacity ofhumans. This expansion reflects the evolutionarily enhanced proliferative ability of basal progenitors (BPs), includingthe basal radial glia and basal intermediate progenitors (bIPs) in mammalian cortex, which may have been acquiredthrough epigenetic alterations in BPs. However, how the epigenome in BPs differs across species is not known.Here, we report that histone H3 acetylation is a key epigenetic regulation in bIP amplification and cortical expansion.Through epigenetic profiling of sorted bIPs, we show that histone H3 lysine 9 acetylation (H3K9ac) is low inmurine bIPs and high in human bIPs. Elevated H3K9ac preferentially increases bIP proliferation, increasing the sizeand folding of the normally smooth mouse neocortex. H3K9ac drives bIP amplification by increasing expressionof the evolutionarily regulated gene, Trnp1, in developing cortex. Our findings demonstrate a previously unknownmechanism that controls cortical architecture.

Conditional Loss of BAF (mSWI/SNF) Scaffolding Subunits Affects Specification and Proliferation of Oligodendrocyte Precursors in Developing Mouse Forebrain.
Eman Abbas, Mohamed A Hassan, Godwin Sokpor, Kamila Kiszka, Linh Pham, Cemil Kerimoglu, Andre Fischer, Huu Phuc Nguyen, Jochen F Staiger, Tran Tuoc.
Front Cell Dev Biol. 2021 Jul 15;9:619538., 2021.
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Loss of BAF Complex in Developing Cortex Perturbs Radial Neuronal Migration in a WNT Signaling-Dependent Manner.
Godwin Sokpor, Cemil Kerimoglu, Huong Nguyen, Linh Pham, Joachim Rosenbusch, Robin Wagener, Huu Phuc Nguy, Andre Fischer, Jochen F. Staiger and Tran Tuoc.
Front. Mol. Neurosci., 16 June 2021 | https://doi.org/10.3389/fnmol.2021.687581, 2021.
abstract link

Radial neuronal migration is a key neurodevelopmental event indispensable for proper cortical laminar organization. Cortical neurons mainly use glial fiber guides, cell adhesion dynamics, and cytoskeletal remodeling, among other discrete processes, to radially trek from their birthplace to final layer positions. Dysregulated radial migration can engender cortical mis-lamination, leading to neurodevelopmental disorders. Epigenetic factors, including chromatin remodelers have emerged as formidable regulators of corticogenesis. Notably, the chromatin remodeler BAF complex has been shown to regulate several aspects of cortical histogenesis. Nonetheless, our understanding of how BAF complex regulates neuronal migration is limited. Here, we report that BAF complex is required for neuron migration during cortical development. Ablation of BAF complex in the developing mouse cortex caused alteration in the cortical gene expression program, leading to loss of radial migration-related factors critical for proper cortical layer formation. Of note, BAF complex inactivation in cortex caused defective neuronal polarization resulting in diminished multipolar-to-bipolar transition and eventual disruption of radial migration of cortical neurons. The abnormal radial migration and cortical mis-lamination can be partly rescued by downregulating WNT signaling hyperactivity in the BAF complex mutant cortex. By implication, the BAF complex modulates WNT signaling to establish the gene expression program required for glial fiber-dependent neuronal migration, and cortical lamination. Overall, BAF complex has been identified to be crucial for cortical morphogenesis through instructing multiple aspects of radial neuronal migration in a WNT signaling-dependent manner.

Mapping of domain-mediated protein-protein interaction by SPOT peptide assay.
Xiaoyi Mao, Godwin Sokpor, Jochen F Staiger, Huu Phuc Nguyen, Tran Tuoc.
STAR Protocols, Volume 2, Issue 2, 100503, 2021.
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Ablation of Vti1a/1b Triggers Neural Progenitor Pool Depletion and Cortical Layer 5 Malformation in Late-embryonic Mouse Cortex.
Godwin Sokpor, Joachim Rosenbusch, Ajaya J Kunwar, Michael Rickmann, Tran Tuoc, Silvio O Rizzoli, Victor Tarabykin, Gabriele Fischer von Mollard, Kerstin Krieglstein, Jochen F Staiger.
Neuroscience . 2021 May 21;463:303-316. doi: 10.1016/j.neuroscience.2021.03.021. Epub 2021 Mar 26, 2021.
abstract link

Cortical morphogenesis entails several neurobiological events, including proliferation and differentiation of progenitors, migration of neuroblasts, and neuronal maturation leading to functional neural circuitry. These neurodevelopmental processes are delicately regulated by many factors. Endosomal SNAREs have emerged as formidable modulators of neuronal growth, aside their well-known function in membrane/vesicular trafficking. However, our understanding of their influence on cortex formation is limited. Here, we report that the SNAREs Vti1a and Vti1b (Vti1a/1b) are critical for proper cortical development. Following null mutation of Vti1a/1b in mouse, the late-embryonic mutant cortex appeared dysgenic, and the cortical progenitors therein were depleted beyond normal. Notably, cortical layer 5 (L5) is distinctively disorganized in the absence of Vti1a/1b. The latter defect, coupled with an overt apoptosis of Ctip2-expressing L5 neurons, likely contributed to the substantial loss of corticospinal and callosal projections in the Vti1a/1b-deficient mouse brain. These findings suggest that Vti1a/1b serve key neurodevelopmental functions during cortical histogenesis, which when mechanistically elucidated, can lend clarity to how endosomal SNAREs regulate brain development, or how their dysfunction may have implications for neurological disorders.

Molecular Profiling Reveals Involvement of ESCO2 in Intermediate Progenitor Cell Maintenance in the Developing Mouse Cortex.
Pauline Antonie Ulmke, M Sadman Sakib, Peter Ditte, Godwin Sokpor, Cemil Kerimoglu, Linh Pham, Yuanbin Xie, Xiaoyi Mao, Joachim Rosenbusch, Ulrike Teichmann, Huu Phuc Nguyen, Andre Fischer, Gregor Eichele, Jochen F Staiger, Tran Tuoc.
Stem Cell Reports 2021 Apr 13;16(4):968-984, 2021.
abstract link

Post-transcriptional regulation by the exosome complex is required for cell survival and forebrain development via repression of P53 signaling.
Pauline Antonie Ulmke, Yuanbin Xie, Godwin Sokpor, Linh Pham, Orr Shomroni, Tea Berulava, Joachim Rosenbusch, Uttiya Basu, Andre Fischer, Huu Phuc Nguyen, Jochen F. Staiger, Tran Tuoc.
Development 2021 148: dev188276 doi: 10.1242/dev.188276, 2021.
abstract link

Fine-tuned gene expression is crucial for neurodevelopment. The gene expression program is tightly controlled at different levels, including RNA decay. N6-methyladenosine (m6A) methylation-mediated degradation of RNA is essential for brain development. However, m6A methylation impacts not only RNA stability, but also other RNA metabolism processes. How RNA decay contributes to brain development is largely unknown. Here, we show that Exosc10, a RNA exonuclease subunit of the RNA exosome complex, is indispensable for forebrain development. We report that cortical cells undergo overt apoptosis, culminating in cortical agenesis upon conditional deletion of Exosc10 in mouse cortex. Mechanistically, Exosc10 directly binds and degrades transcripts of the P53 signaling-related genes, such as Aen and Bbc3. Overall, our findings suggest a crucial role for Exosc10 in suppressing the P53 pathway, in which the rapid turnover of the apoptosis effectors Aen and Bbc3 mRNAs is essential for cell survival and normal cortical histogenesis.

Spine dynamics of PSD-95-deficient neurons in the visual cortex link silent synapses to structural cortical plasticity.
Rashad Yusifov, Anja Tippmann, Jochen F. Staiger, Oliver M. Schlüter and Siegrid Löwel.
Proceedings of the National Academy of Science USA, 2021 118 (10) e2022701118, 2021.
abstract link

Critical periods (CPs) are timewindows of heightened brain plasticityduring which experience refines synaptic connections to achievemature functionality. At glutamatergic synapses on dendritic spinesof principal cortical neurons, the maturation is largely governed bypostsynaptic density protein-95 (PSD-95)-dependent synaptic incorporationof α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid(AMPA) receptors into nascent AMPA-receptor silent synapses. Consequently,in mouse primary visual cortex (V1), impaired silent synapsematuration in PSD-95-deficient neurons prevents the closure ofthe CP for juvenile ocular dominance plasticity (jODP). A structuralhallmark of jODP is increased spine elimination, induced by briefmonocular deprivation (MD). However, it is unknown whether impairedsilent synapse maturation facilitates spine elimination andalso preserves juvenile structural plasticity. Using two-photon microscopy,we assessed spine dynamics in apical dendrites of layer2/3 pyramidal neurons (PNs) in binocular V1 during ODP in awakeadult mice. Under basal conditions, spine formation and eliminationratios were similar between PSD-95 knockout (KO) and wild-type(WT) mice. However, a brief MD affected spine dynamics only inKO mice, where MD doubled spine elimination, primarily affectingnewly formed spines, and caused a net reduction in spine densitysimilar to what has been observed during jODP inWT mice. A similarincrease in spine elimination after MD occurred if PSD-95 wasknocked down in single PNs of layer 2/3. Thus, structural plasticityis dictated cell autonomously by PSD-95 in vivo in awake mice. Lossof PSD-95 preserves hallmark features of spine dynamics in jODP intoadulthood, revealing a functional link of PSD-95 for experiencedependentsynapse maturation and stabilization during CPs.

Sensory input drives rapid homeostatic scaling of the axon initial segment in mouse barrel cortex.
Nora Jamann, Dominik Dannehl, Nadja Lehmann, Robin Wagener, Corinna Thielemann, Christian Schultz, Jochen F. Staiger, Maarten H. P. Kole & Maren Engelhardt.
Nature Communications 12:23; https://doi.org/10.1038/s41467-020-20232-x, 2021.
abstract link

The axon initial segment (AIS) is a critical microdomain for action potential initiation and implicated in the regulation of neuronal excitability during activity-dependent plasticity. While structural AIS plasticity has been suggested to fine-tune neuronal activity when networkstates change, whether it acts in vivo as a homeostatic regulatory mechanism in behaviorally relevant contexts remains poorly understood. Using the mouse whisker-to-barrel pathway asa model system in combination with immunofluorescence, confocal analysis and electrophysiological recordings, we observed bidirectional AIS plasticity in cortical pyramidal neurons. Furthermore, we find that structural and functional AIS remodeling occurs in distinct temporal domains: Long-term sensory deprivation elicits an AIS length increase, accompanied with an increase in neuronal excitability, while sensory enrichment results in a rapidAIS shortening, accompanied by a decrease in action potential generation. Our findings highlight a central role of the AIS in the homeostatic regulation of neuronal input-output relations.

Neuronal Circuits in Barrel Cortex for Whisker Sensory Perception.
Staiger JF and Petersen CCH.
Physiological Reviews 101:353-415, 2021.
abstract link

The array of whiskers on the snout provides rodents with tactile sensory information relating to the size, shape and texture of objects in their immediate environment. Rodents can use their whiskers to detect stimuli, distinguish textures, locate objects and navigate. Important aspects of whisker sensation are thought to result from neuronal computations in the whisker somatosensory cortex (wS1). Each whisker is individually represented in the somatotopic map of wS1 by an anatomical unit named a ‘barrel’ (hence also called barrel cortex). This allows precise investigation of sensory processing in the context of a well-defined map. Here, we first review the signaling pathways from the whiskers to wS1, and then discuss current understanding of the various types of excitatory and inhibitory neurons present within wS1. Different classes of cells can be defined according to anatomical, electrophysiological and molecular features. The synaptic connectivity of neurons within local wS1 microcircuits, as well as their long-range interactions and the impact of neuromodulators, are beginning to be understood. Recent technological progress has allowed cell-type-specific connectivity to be related to cell-type-specific activity during whisker-related behaviors. An important goal for future research is to obtain a causal and mechanistic understanding of how selected aspects of tactile sensory information are processed by specific types of neurons in the synaptically connected neuronal networks of wS1 and signaled to downstream brain areas, thus contributing to sensory-guided decision-making.

2020

NKCC-1 mediated Cl− uptake in immature CA3 pyramidal neurons is sufficient to compensate phasic GABAergic inputs.
Sergey N. Kolbaev, Namrata Mohapatra, Rongqing Chen, Aniello Lombardi, Jochen F. Staiger, Heiko J. Luhmann, Peter Jedlicka & Werner Kilb.
Scientific Reports volume 10, Article number: 18399, 2020.
abstract link

Activation of GABAA receptors causes in immature neurons a functionally relevant decrease in the intracellular Cl− concentration ([Cl−]i), a process termed ionic plasticity. Amount and duration of ionic plasticity depends on kinetic properties of [Cl−]i homeostasis. In order to characterize the capacity of Cl− accumulation and to quantify the effect of persistent GABAergic activity on [Cl−]i, we performed gramicidin-perforated patch-clamp recordings from CA3 pyramidal neurons of immature (postnatal day 4–7) rat hippocampal slices. These experiments revealed that inhibition of NKCC1 decreased [Cl−]i toward passive distribution with a time constant of 381 s. In contrast, active Cl− accumulation occurred with a time constant of 155 s, corresponding to a rate of 15.4 µM/s. Inhibition of phasic GABAergic activity had no significant effect on steady state [Cl−]i. Inhibition of tonic GABAergic currents induced a significant [Cl−]i increase by 1.6 mM, while activation of tonic extrasynaptic GABAA receptors with THIP significantly reduced [Cl−]i.. Simulations of neuronal [Cl−]i homeostasis supported the observation, that basal levels of synaptic GABAergic activation do not affect [Cl−]i. In summary, these results indicate that active Cl−-uptake in immature hippocampal neurons is sufficient to maintain stable [Cl−]i at basal levels of phasic and to some extent also to compensate tonic GABAergic activity.

Increased Callosal Connectivity in Reeler Mice Revealed by Brain-Wide Input Mapping of VIP Neurons in Barrel Cortex.
Georg Hafner, Julien Guy, Mirko Witte, Pavel Truschow, Alina Rüppel, Nikoloz Sirmpilatze, Rakshit Dadarwal, Susann Boretius, Jochen F Staiger.
Cerebral Cortex, bhaa280, https://doi.org/10.1093/cercor/bhaa280, 2020.
abstract link

The neocortex is composed of layers. Whether layers constitute an essential framework for the formation of functional circuits is not well understood. We investigated the brain-wide input connectivity of vasoactive intestinal polypeptide (VIP) expressing neurons in the reeler mouse. This mutant is characterized by a migration deficit of cortical neurons so that no layers are formed. Still, neurons retain their properties and reeler mice show little cognitive impairment. We focused on VIP neurons because they are known to receive strong long-range inputs and have a typical laminar bias toward upper layers. In reeler, these neurons are more dispersed across the cortex. We mapped the brain-wide inputs of VIP neurons in barrel cortex of wild-type and reeler mice with rabies virus tracing. Innervation by subcortical inputs was not altered in reeler, in contrast to the cortical circuitry. Numbers of long-range ipsilateral cortical inputs were reduced in reeler, while contralateral inputs were strongly increased. Reeler mice had more callosal projection neurons. Hence, the corpus callosum was larger in reeler as shown by structural imaging. We argue that, in the absence of cortical layers, circuits with subcortical structures are maintained but cortical neurons establish a different network that largely preserves cognitive functions.

A community-based transcriptomics classification and nomenclature of neocortical cell types.
Rafael Yuste, Michael Hawrylycz, Nadia Aalling, Argel Aguilar-Valles, Detlev Arendt, Ruben Armananzas Arnedillo, Giorgio A. Ascoli, Concha Bielza, Vahid Bokharaie, Tobias Borgtoft Bergmann, Irina Bystron, Marco Capogna, Yoonjeung Chang, Ann Clemens, Christiaan P. J. de Kock, Javier DeFelipe, Sandra Esmeralda Dos Santos, Keagan Dunville, Dirk Feldmeyer, Richárd Fiáth, Gordon James Fishell, Angelica Foggetti, Xuefan Gao, Parviz Ghaderi, Natalia A. Goriounova, Onur Güntürkün, Kenta Hagihara, Vanessa Jane Hall, Moritz Helmstaedter, Suzana Herculano, Markus M. Hilscher, Hajime Hirase, Jens Hjerling-Leffler, Rebecca Hodge, Josh Huang, Rafiq Huda, Konstantin Khodosevich, Ole Kiehn, Henner Koch, Eric S. Kuebler, Malte Kühnemund, Pedro Larrañaga, Boudewijn Lelieveldt, Emma Louise Louth, Jan H. Lui, Huibert D. Mansvelder, Oscar Marin, Julio Martinez-Trujillo, Homeira Moradi Chameh, Alok Nath, Maiken Nedergaard, Pavel Němec, Netanel Ofer, Ulrich Gottfried Pfisterer, Samuel Pontes, William Redmond, Jean Rossier, Joshua R. Sanes, Richard Scheuermann, Esther Serrano-Saiz, Staiger JF, Peter Somogyi, Gábor Tamás, Andreas Savas Tolias, Maria Antonietta Tosches, Miguel Turrero García, Hermany Munguba Vieira, Christian Wozny, Thomas V. Wuttke, Liu Yong, Juan Yuan, Hongkui Zeng & Ed Lein.
Nature Neuroscience 23: 1456–1468, 2020.
abstract link

To understand the function of cortical circuits, it is necessary to catalog their cellular diversity. Past attempts to do so using anatomical, physiological or molecular features of cortical cells have not resulted in a unified taxonomy of neuronal or glial cell types, partly due to limited data. Single-cell transcriptomics is enabling, for the first time, systematic high-throughput measurements of cortical cells and generation of datasets that hold the promise of being complete, accurate and permanent. Statistical analyses of these data reveal clusters that often correspond to cell types previously defined by morphological or physiological criteria and that appear conserved across cortical areas and species. To capitalize on these new methods, we propose the adoption of a transcriptome-based taxonomy of cell types for mammalian neocortex. This classification should be hierarchical and use a standardized nomenclature. It should be based on a probabilistic definition of a cell type and incorporate data from different approaches, developmental stages and species. A community-based classification and data aggregation model, such as a knowledge graph, could provide a common foundation for the study of cortical circuits. This community-based classification, nomenclature and data aggregation could serve as an example for cell type atlases in other parts of the body.

Histological assessment of optogenetic tools to study fronto-visual and fronto-parietal cortical networks in the rhesus macaque.
Fortuna, M. G. Huer, J. Guo, H. Gruber, J. Gruber-Dujardin, E. Staiger, J. F. Scherberger, H. Treue, S. Gail, A..
Scientific Reports: 10(1)2020: DOI 10.1038/s41598-020-67752-6, 2020.
abstract link

Optogenetics ofers unprecedented possibilities to investigate cortical networks. Yet, the number of successful optogenetic applications in non-human primates is still low, and the consequences of opsin expression in the primate brain are not well documented. We assessed histologically if we can target cerebrocortical networks with three common optogenetic constructs (AAV2/5-CaMKIIα-eNpHR3.0mCherry, -ChR2-eYFP, -C1V1-mCherry). The frontal eye feld or the dorsal premotor area of rhesus macaques were virally injected, and the resulting transduction spread, expression specifcity, and opsin trafcking into axons projecting to parietal and visual areas were examined. After variable periods (2–24 months), expression was robust for all constructs at the injection sites. The CaMKIIα promoter driven-expression was predominant, but not exclusive, in excitatory neurons. In the case of eNpHR3.0-mCherry and ChR2-eYFP, opsins were present in axonal projections to target areas, in which sparse, retrogradely transduced neurons could also be found. Finally, the intracellular distribution of opsins difered: ChR2-eYFP had almost exclusive membrane localization, while eNpHR3.0-mCherry and C1V1-mCherry showed additional intracellular accumulations, which might afect neuronal survival in the long-term. Results indicate that all three constructs can be used for local neuronal modulation, but axonal stimulation and long-term use require additional considerations of construct selection and verifcation.

Recommendations for measuring whisker movements and locomotion in mice with sensory, motor and cognitive deficits.
Simanaviciute U, Ahmed J, Brown RE, Connor-Robson N, Farr TD, Fertan E, Gambles N, Garland H, Morton AJ, Staiger JF, Skillings EA, Trueman RC, Wade-Martins R, Wood NI, Wong AA, Grant RA.
J Neurosci Methods. 2020 Feb 1;331:108532. doi: 10.1016/j.jneumeth.2019.108532., 2020.
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2019

Selective Inactivation of Reelin in Inhibitory Interneurons Leads to Subtle Changes in the Dentate Gyrus But Leaves Cortical Layering and Behavior Unaffected.
Pahle J, Muhia M, Wagener RJ, Tippmann A, Bock HH, Graw J, Herz J, Staiger JF, Drakew A, Kneussel M, Rune GM, Frotscher M, Brunne B.
Cereb Cortex. 2019 Oct 30. pii: bhz196. doi: 10.1093/cercor/bhz196, 2019.
abstract link

Reelin is an extracellular matrix protein, known for its dual role in neuronal migration during brain development and in synaptic plasticity at adult stages. During the perinatal phase, Reelin expression switches from Cajal-Retzius (CR) cells, its main source before birth, to inhibitory interneurons (IN), the main source of Reelin in the adult forebrain. IN-derived Reelin has been associated with schizophrenia and temporal lobe epilepsy; however, the functional role of Reelin from INs is presently unclear. In this study, we used conditional knockout mice, which lack Reelin expression specifically in inhibitory INs, leading to a substantial reduction in total Reelin expression in the neocortex and dentate gyrus. Our results show that IN-specific Reelin knockout mice exhibit normal neuronal layering and normal behavior, including spatial reference memory. Although INs are the major source of Reelin within the adult stem cell niche, Reelin from INs does not contribute substantially to normal adult neurogenesis. While a closer look at the dentate gyrus revealed some unexpected alterations at the cellular level, including an increase in the number of Reelin expressing CR cells, overall our data suggest that Reelin derived from INs is less critical for cortex development and function than Reelin expressed by CR cells.

Pathway-, layer- and cell-type-specific thalamic input to mouse barrel cortex.
Sermet BS, Truschow P, Feyerabend M, Mayrhofer JM, Oram TB, Yizhar O, Staiger JF, Petersen CCH.
eLife 2019;8:e52665 , 2019.
abstract link

Mouse primary somatosensory barrel cortex (wS1) processes whisker sensory information, receiving input from two distinct thalamic nuclei. The first-order ventral posterior medial (VPM) somatosensory thalamic nucleus most densely innervates layer 4 (L4) barrels, whereas the higher-order posterior thalamic nucleus (medial part, POm) most densely innervates L1 and L5A. We optogenetically stimulated VPM or POm axons, and recorded evoked excitatory postsynaptic potentials (EPSPs) in different cell-types across cortical layers in wS1. We found that excitatory neurons and parvalbumin-expressing inhibitory neurons received the largest EPSPs, dominated by VPM input to L4 and POm input to L5A. In contrast, somatostatin-expressing inhibitory neurons received very little input from either pathway in any layer. Vasoactive intestinal peptide-expressing inhibitory neurons received an intermediate level of excitatory input with less apparent layer-specificity. Our data help understand how wS1 neocortical microcircuits might process and integrate sensory and higher-order inputs.

Mapping Brain-Wide Afferent Inputs of Parvalbumin-Expressing GABAergic Neurons in Barrel Cortex Reveals Local and Long-Range Circuit Motifs.
Hafner G, Witte M, Guy J, Subhashini N, Fenno LE, Ramakrishna C, Kim YS, Deisseroth K, Callaway EC, Oberhuber M, Conzelmann KK, Staiger JF.
Cell Reports 28 (13) P3450-3461.E8, 2019.
abstract link

Parvalbumin (PV)-expressing GABAergic neurons are the largest class of inhibitory neocortical cells. We visualize brain-wide, monosynaptic inputs to PV neurons in mouse barrel cortex. We develop intersectional rabies virus tracing to specifically target GABAergic PV cells and exclude a small fraction of excitatory PV cells from our starter population. Local inputs are mainly from layer (L) IV and excitatory cells. A small number of inhibitory inputs originate from LI neurons, which connect to LII/III PV neurons. Long-range inputs originate mainly from other sensory cortices and the thalamus. In visual cortex, most transsynaptically labeled neurons are located in LIV, which contains a molecularly mixed population of projection neurons with putative functional similarity to LIII neurons. This study expands our knowledge of the brain-wide circuits in which PV neurons are embedded and introduces intersectional rabies virus tracing as an applicable tool to dissect the circuitry of more clearly defined cell types.

Functional architecture and encoding of tactile sensorimotor behavior in rat posterior parietal cortex.
Mohan H, de Haan R, Broersen R, Pieneman AW, Helmchen F, Staiger JF, Mansvelder HD, de Kock CPJ.
Journal of Neuroscience 39:7332-7343, 2019.
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The posterior parietal cortex (PPC) in rodents is reciprocally connected to primary somatosensory and vibrissal motor cortices. The PPCneuronal circuitry could thus encode and potentially integrate incoming somatosensory information and whisker motor output. However,the information encoded across PPC layers during refined sensorimotor behavior remains largely unknown. To uncover thesensorimotor features represented in PPC during voluntary whisking and object touch, we performed loose-patch single-unit recordingsand extracellular recordings of ensemble activity, covering all layers of PPC in anesthetized and awake, behaving male rats. First, usingsingle-cell receptive field mapping, we revealed the presence of coarse somatotopy along the mediolateral axis in PPC. Second, we foundthat spiking activity was modulated during exploratory whisking in layers 2– 4 and layer 6, but not in layer 5 of awake, behaving rats.Population spiking activity preceded actual movement, and whisker trajectory endpoints could be decoded by population spiking,suggesting that PPC is involved in movement planning. Finally, population spiking activity further increased in response to activewhisker touch but only in PPC layers 2– 4. Thus, we find layer-specific processing, which emphasizes the computational role of PPCduring whisker sensorimotor behavior.

Characterizing the morphology of somatostatin‐expressing interneurons and their synaptic innervation pattern in the barrel cortex of the GFP‐expressing inhibitory neurons mouse.
Zhou X., Mansori I., Fischer T., Witte M., Staiger JF..
J Comp Neurol. 2019;1–17, 2019.
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Somatostatin‐expressing (SST+) cells form the second largest subpopulation of neocortical GABAergic neurons that contain diverse subtypes, which participate in layer‐specific cortical circuits. Martinotti cells, as the most abundant subtype of SST+ interneurons, are mainly located in layers II/III and V/VI, and are characterized by dense axonal arborizations in layer I. GFP‐expressing inhibitory neurons (GIN), representing a fraction of mainly upper layer SST+ interneurons in various cortical areas, were recently claimed to include both Martinotti cells and non‐Martinotti cells. This makes it necessary to examine in detail the morphology and synaptic innervation pattern of the GIN cells, in order to better predict their functional implications. In our study, we characterized the neurochemical specificity, somatodendritic morphology, synaptic ultrastructure as well as synaptic innervation pattern of GIN cells in the barrel cortex in a layer‐specific manner. We showed that GIN cells account for 44% of the SST+ interneurons in layer II/III and around 35% in layers IV and Va. There are 29% of GIN cells coexpressing calretinin with 54% in layer II/III, 8% in layer IV, and 13% in layer V. They have diverse somatodendritic configurations and form relatively small synapses across all examined layers. They almost exclusively innervate dendrites of excitatory cells, preferentially targeting distal apical dendrites and apical dendritic tufts of pyramidal neurons in layer I, and rarely target other inhibitory neurons. In summary, our study reveals unique features in terms of the morphology and output of GIN cells, which can help to better understand their diversity and structure–function relationships.

Neuromodulation Leads to a Burst-Tonic Switch in a Subset of VIP Neurons in Mouse Primary Somatosensory (Barrel) Cortex.
Prönneke A, Witte M, Möck M, Staiger JF.
Cerebral Cortex doi: 10.1093/cercor/bhz102, 2019.
abstract link

Neocortical GABAergic interneurons expressing vasoactive intestinal polypeptide (VIP) contribute to sensory processing,sensorimotor integration, and behavioral control. In contrast to other major subpopulations of GABAergic interneurons, VIPneurons show a remarkable diversity. Studying morphological and electrophysiological properties of VIP cells, we found apeculiar group of neurons in layer II/III of mouse primary somatosensory (barrel) cortex, which showed a highly dynamicburst firing behavior at resting membrane potential that switched to tonic mode at depolarized membrane potentials.Furthermore, we demonstrate that burst firing depends on T-type calcium channels. The burst-tonic switch could beinduced by acetylcholine (ACh) and serotonin. ACh mediated a depolarization via nicotinic receptors whereas serotoninevoked a biphasic depolarization via ionotropic and metabotropic receptors in 48% of the population and a purelymonophasic depolarization via metabotropic receptors in the remaining cells. These data disclose an electrophysiologicallydefined subpopulation of VIP neurons that via neuromodulator-induced changes in firing behavior is likely to regulate thestate of cortical circuits in a profound manner.

Distribution Patterns of Three Molecularly Defined Classes of GABAergic Neurons Across Columnar Compartments in Mouse Barrel Cortex.
Almási Z, Dávid C, Witte M, Staiger JF.
Frontiers in Neuroanatomy 13:45 doi: 10.3389/fnana.2019.00045, 2019.
abstract link

The mouse somatosensory cortex is an excellent model to study the structural basis ofcortical information processing, since it possesses anatomically recognizable domainsthat receive different thalamic inputs, which indicates spatial segregation of differentprocessing tasks. In this work we examined three genetically labeled, non-overlappingsubpopulations of GABAergic neurons: parvalbumin- (PVC), somatostatin- (SSTC), andvasoactive intestinal polypeptide-expressing (VIPC) cells. Each of these subpopulationsdisplayed a unique cellular distribution pattern across layers. In terms of columnarlocalization, the distribution of these three populations was not quantitatively differentbetween barrel-related versus septal compartments in most layers. However, in layer IV(LIV), SSTC, and VIPC, but not PVC neurons preferred the septal compartment overbarrels. The examined cell types showed a tendency toward differential distribution insupragranular and infragranular barrel-related versus septal compartments, too. Ourdata suggests that the location of GABAergic neuron cell bodies correlates with thespatial pattern of cortical domains receiving different kinds of thalamic input. Thus,at least in LIV, lemniscal inputs present a close spatial relation preferentially to PVCcells whereas paralemniscal inputs target compartments in which more SSTC andVIPC cells are localized. Our findings suggest pathway-specific roles for neocorticalGABAergic neurons.

RBM15 Modulates the Function of Chromatin Remodeling Factor BAF155 Through RNA Methylation in Developing Cortex.
Xie Y*, Hernandez RC*, Sokpor G, Pham L, Narayanan R, Rosenbusch J, Staiger JF, Tuoc T.
Molecular Neurobiology, https://doi.org/10.1007/s12035-019-1595-1, 2019.
abstract link

Chromatin remodeling factor BAF155 is an important regulator of many biological processes. As a core and scaffold subunit of the BAF (SWI/SNF-like) complex, BAF155 is capable of regulating the stability and function of the BAF complex. The spatiotemporal expression of BAF155 during embryogenesis is essential for various aspects of organogenesis, particularly in the brain development. However, our understanding of the mechanisms that regulate the expression and function of BAF155 is limited. Here, we report that RBM15, a subunit of the m6A methyltransferase complex, interacts with BAF155 mRNA and mediates BAF155 mRNA degradation through the mRNA methylation machinery. Ablation of endogenous RBM15 expression in cultured neuronal cells and in the developing cortex augmented the expression of BAF155. Conversely, RBM15 overexpression decreased BAF155 mRNA and protein levels, and perturbed BAF155 functions in vivo, including repression of BAF155-dependent transcriptional activity and delamination of apical radial glial progenitors as a hallmark of basal radial glial progenitor genesis. Furthermore, we demonstrated that the regulation of BAF155 by RBM15 depends on the activity of the mRNA methylation complex core catalytic subunit METTL3. Altogether, our findings reveal a new regulatory avenue that elucidates how BAF complex subunit stoichiometry and functional modulation are achieved in mammalian cells.

2018

Chromatin remodeling BAF155 subunit regulates the genesis of basal progenitors in developing cortex .
Narayanan R, Pham L, Kerimoglu C, Watanabe T, Hernandez RC, Sokpor G, Ulmke PA, Kiszka KA, Tonchev AB, Rosenbusch J, Seong RH, Teichmann U, Frahm J, Fischer F, Bonn S, Stoykova A, Staiger JF, Tuoc T.
iScience (Cell Press), DOI: https://doi.org/10.1016/j.isci.2018.05.014, 2018.
abstract link

The abundance of basal progenitors (BPs) - basal radial glia progenitors (bRGs) and basal intermediate progenitors (bIPs), in primate brain has been correlated to the high degree of cortical folding. Here we examined the role of BAF155, a subunit of the chromatin remodeling BAF complex, in generation of cortical progenitor heterogeneity. The conditional deletion of BAF155 led to diminished bIP pool and increased number of bRGs, due to delamination of apical RGs. We found that BAF155 is required for normal activity of neurogenic transcription factor PAX6, thus controlling expression of genes that are involved in bIP specification, cell-cell interaction and establishment of adherens junction. In PAX6-dependent manner, BAF155 regulates the expression of the CDC42 effector protein CEP4, thereby controlling progenitor delamination. Furthermore, BAF155-dependent chromatin remodeling seems to exert a specific role in the genesis of BPs through regulation of human RG-specific genes (such as Foxn4) that possibly acquired evolutionary significance.

Epigenetic regulation by BAF (mSWI/SNF) complexes limits neural stem cell proliferation by suppressing Wnt signaling in late embryonic development.
Nguyen H*, Kerimoglu C*, Pirouz M, Pham L, Kiszka KA, Sokpor G, Sakib MS, Rosenbusch J, Teichmann U, Seong RH, Stoykova A, Fischer A, Staiger JF, Tuoc T .
Stem Cell Reports, doi: 10.1016/j.stemcr.2018.04.014, 2018.
abstract link

During early cortical development, neural stem cells (NSCs) divide symmetrically to expand the progenitor pool, whereas in later stages, NSCs divide asymmetrically to self-renew and produce other cell types. The timely switch from such proliferative to differentiative division critically determines progenitor and neuron numbers. However, the mechanisms that limit proliferative division in late cortical development are not fully understood. Here, we show that the BAF (mSWI/SNF) complexes restrict proliferative competence and promote neuronal differentiation in late corticogenesis. Inactivation of BAF complexes leads to H3K27me3-linked silencing of neuronal differentiation-related genes, with concurrent H3K4me2-mediated activation of proliferation-associated genes via de-repression of Wnt signaling. Notably, the deletion of BAF complexes increased proliferation of neuroepithelial cell-like NSCs, impaired neuronal differentiation and exerted a Wnt-dependent effect on neocortical and hippocampal development. Thus, these results demonstrate that BAF complexes act as both activators and repressors to control global epigenetic and gene expression programs in late corticogenesis.

ATP-dependent chromatin remodeling during cortical neurogenesis.
Sokpor G*, Hernandez RC*, Rosenbusch J, Staiger JF, Tuoc T.
Front. Neurosci. | doi: 10.3389/fnins.2018.00226 , 2018.
abstract link

The generation of individual neurons (neurogenesis) during cortical development occurs in discrete steps that are subtly regulated and orchestrated to ensure normal histogenesis and function of the cortex. Notably, various gene expression programs are known to critically drive many facets of neurogenesis with a high level of specificity during brain development. Typically, precise regulation of gene expression patterns ensures that key events like proliferation and differentiation of neural progenitors, specification of neuronal subtypes, as well as migration and maturation of neurons in the developing cortex occur properly. ATP-dependent chromatin remodeling complexes regulate gene expression through utilization of energy from ATP hydrolysis to reorganize chromatin structure. These chromatin remodeling complexes are characteristically multimeric, with some capable of adopting functionally distinct conformations via subunit reconstitution to perform specific roles in major aspects of cortical neurogenesis. In this review, we highlight the functions of such chromatin remodelers during cortical development. We also bring together various proposed mechanisms by which ATP-dependent chromatin remodelers function individually or in concert, to specifically modulate vital steps in cortical neurogenesis.

Transcriptional and epigenetic control of mammalian olfactory epithelium development.
Sokpor G*, Abbas E*, Rosenbusch J, Staiger JF, Tuoc T..
Molecular Neurobiology (https://doi.org/10.1007/s12035-018-0987-y), 2018.
abstract link

The postnatal mammalian olfactory epithelium (OE) represents a major aspect of the peripheral olfactory system. It is a pseudostratified tissue that originates from the olfactory placode and is composed of diverse cells, some of which are specialized receptor neurons capable of transducing odorant stimuli to afford the perception of smell (olfaction). The OE is known to offer a tractable miniature model for studying the systematic generation of neurons and glia that typify neural tissue development. During OE development, stem/progenitor cells that will become olfactory sensory neurons and/or non-neuronal cell types, display fine spatiotemporal expression of neuronal and non-neuronal genes that ensures their proper proliferation, differentiation, survival, and regeneration. Many factors, including transcription and epigenetic factors have been identified as key regulators of the expression of such requisite genes to permit normal OE morphogenesis. Typically, specific interactive regulatory networks established between transcription and epigenetic factors/cofactors orchestrate histogenesis in the embryonic and adult OE. Hence, investigation of these regulatory networks critical for OE development promises to disclose strategies that may be employed in manipulating the stepwise transition of olfactory precursor cells to become fully differentiated and functional neuronal and non-neuronal cell types. Such strategies potentially offer formidable means of replacing injured or degenerated neural cells as therapeutics for nervous system perturbations. This review recapitulates the developmental cellular diversity of the olfactory neuroepithelium and discusses findings on how the precise and cooperative molecular control by transcriptional and epigenetic machinery is indispensable for OE ontogeny.

2017

Subcellular Targeting of VIP Boutons in Mouse Barrel Cortex is Layer-Dependent and not Restricted to Interneurons.
Zhou,X.; Rickmann,M.; Hafner,G.; Staiger,J.F..
Cerebral Cortex 27(11):5353-5368, 2017.
abstract link

Neocortical vasoactive intestinal polypeptide (VIP) expressing cells are a diverse subpopulation of GABAergic interneurons issuing distinct axonal projections. They are known to inhibit other types of interneurons as well as excitatory principal neurons and possess a disinhibitory net effect in cortical circuits. In order to elucidate their targeting specificity, the output connectivity of VIP interneurons was studied at the subcellular level in barrel cortex of interneuron-specific Cre-driver mice, using pre- and postembedding electron microscopy. Systematically sampling VIP boutons across all layers, we found a substantial proportion of the innervated subcellular structures were dendrites (80%), with somata (13%), and spines (7%) being much less targeted. In layer VI, a high proportion of axosomatic synapses was found (39%). GABA-immunopositive ratio was quantified among the targets using statistically validated thresholds: only 37% of the dendrites, 7% of the spines, and 26% of the somata showed above-threshold immunogold labeling. For the main target structure "dendrite", a higher proportion of GABAergic subcellular profiles existed in deep than in superficial layers. In conclusion, VIP interneurons innervate non-GABAergic excitatory neurons and interneurons at their subcellular domains with layer-dependent specificity. This suggests a diverse output of VIP interneurons, which predicts multiple functionality in cortical circuitry beyond disinhibition

Inhibitory interneurons and their circuit motifs in the many layers of the barrel cortex.
Feldmeyer D, Qi G, Emmenegger V, Staiger JF.
Neuroscience | http://dx.doi.org/10.1016/j.neuroscience.2017.05.027, 2017.
abstract link

Recent years have seen substantial progress instudying the structural and functional properties ofGABAergic interneurons and their roles in the neuronal networksof barrel cortex. Although GABAergic interneuronsrepresent only about 12% of the total number of neocorticalneurons, they are extremely diverse with respect to theirstructural and functional properties. It has become clear thatbarrel cortex interneurons not only serve the maintenanceof an appropriate excitation/inhibition balance but also aredirectly involved in sensory processing. In this review wepresent different interneuron types and their axonal projectionpattern framework in the context of the laminar andcolumnar organization of the barrel cortex. The main focusis here on the most prominent interneuron types, i.e. basketcells, chandelier cells, Martinotti cells, bipolar/bitufted cellsand neurogliaform cells, but interneurons with more unusualaxonal domains will also be mentioned. We describetheir developmental origin, their classification with respectto molecular, morphological and intrinsic membrane andsynaptic properties. Most importantly, we will highlight themost prominent circuit motifs these interneurons areinvolved in and in which way they serve feed-forward inhibition,feedback inhibition and disinhibition. Finally, this willbe put into context to their functional roles in sensory signalperception and processing in the whisker system andbeyond.

TRPV1 regulates excitatory innervation of OLM neurons in the hippocampus.
Hurtado-Zavala,J.I.; Ramachandran,B.; Ahmed,S.; Halder,R.; Bolleyer,C.; Awasthi,A.; Stahlberg,M.A.; Wagener,R.J.; Anderson,K.; Drenan,R.M.; Lester,H.A.; Miwa,J.M.; Staiger,J.F.; Fischer,A.; Dean,C..
Nature Communications 8:15878, 2017. DOI: 10.1038/ncomms15878
abstract link

TRPV1 is an ion channel activated by heat and pungent agents including capsaicin, and has been extensively studied in nociception of sensory neurons. However, the location and function of TRPV1 in the hippocampus is debated. We found that TRPV1 is expressed in oriens-lacunosum-moleculare (OLM) interneurons in the hippocampus, and promotes excitatory innervation. TRPV1 knockout mice have reduced glutamatergic innervation of OLM neurons. When activated by capsaicin, TRPV1 recruits more glutamatergic, but not GABAergic, terminals to OLM neurons in vitro. When TRPV1 is blocked, glutamatergic input to OLM neurons is dramatically reduced. Heterologous expression of TRPV1 also increases excitatory innervation. Moreover, TRPV1 knockouts have reduced Schaffer collateral LTP, which is rescued by activating OLM neurons with nicotine—via α2β2-containing nicotinic receptors—to bypass innervation defects. Our results reveal a synaptogenic function of TRPV1 in a specific interneuron population in the hippocampus, where it is important for gating hippocampal plasticity.

The functioning of a cortex without layers.
Guy J, Staiger JF.
Frontiers in Neuroanatomy 11:54, 2017.
abstract link

A major hallmark of cortical organization is the existence of a variable number of layers, i.e., sheets of neurons stacked on top of each other, in which neurons have certain commonalities. However, even for the neocortex, variable numbers of layers have been described and it is just a convention to distinguish six layers from each other. Whether cortical layers are a structural epiphenomenon caused by developmental dynamics or represent a functionally important modularization of cortical computation is still unknown. Here we present our insights from the reeler mutant mouse, a model for a developmental, “molecular lesion”-induced loss of cortical layering that could serve as ground truth of what an intact layering adds to the cortex in terms of functionality. We could demonstrate that the reeler neocortex shows no inversion of cortical layers but rather a severe disorganization that in the primary somatosensory cortex leads to the complete loss of layers. Nevertheless, the somatosensory system is well organized. When exploring an enriched environment with specific sets of whiskers, activity-dependent gene expression takes place in the corresponding modules. Precise whisker stimuli lead to the functional activation of somatotopically organized barrel columns as visualized by intrinsic signal optical imaging. Similar results were obtained in the reeler visual system. When analyzing pathways that could be responsible for preservation of tactile perception, lemniscal thalamic projections were found to be largely intact, despite the smearing of target neurons across the cortical mantle. However, with optogenetic experiments we found evidence for a mild dispersion of thalamic synapse targeting on layer IV-spiny stellate cells, together with a general weakening in thalamocortical input strength. This weakening of thalamic inputs was compensated by intracortical mechanisms involving increased recurrent excitation and/or reduced feedforward inhibition. In conclusion, a layer loss so far only led to the detection of subtle defects in sensory processing by reeler mice. This argues in favor of a view in which cortical layers are not an essential component for basic perception and cognition. A view also supported by recent studies in birds, which can have remarkable cognitive capacities despite the lack of a neocortex with multiple cortical layers. In conclusion, we suggest that future studies directed toward understanding cortical functions should rather focus on circuits specified by functional cell type composition than mere laminar location.

2016

Intracortical Network Effects Preserve Thalamocortical Input Efficacy in a Cortex Without Layers.
Guy,J.; Sachkova,A.; Möck,M.; Witte,M.; Wagener,R.J.; Staiger,J.F..
Cerebral Cortex DOI 10.1093/cercor/bhw281, 2016.
abstract

Layer IV (LIV) of the rodent somatosensory cortex contains the somatotopic barrel field. Barrels receive much of the sensory input to the cortex through innervation by thalamocortical axons from the ventral posteromedial nucleus. In the reeler mouse, the absence of cortical layers results in the formation of mispositioned barrel-equivalent clusters of LIV fated neurons. Although functional imaging suggests that sensory input activates the cortex, little is known about the cellular and synaptic properties of identified excitatory neurons of the reeler cortex. We examined the properties of thalamic input to spiny stellate (SpS) neurons in the reeler cortex with in vitro electrophysiology, optogenetics, and subcellular channelrhodopsin-2-assisted circuit mapping (sCRACM). Our results indicate that reeler SpS neurons receive direct but weakened input from the thalamus, with a dispersed spatial distribution along the somatodendritic arbor. These results further document subtle alterations in functional connectivity concomitant of absent layering in the reeler mutant. We suggest that intracortical amplification mechanisms compensate for this weakening in order to allow reliable sensory transmission to the mutant neocortex

Parvalbumin- and vasoactive intestinal polypeptide-expressing neocortical interneurons impose differential inhibition on Martinotti cells.
Walker F, Möck M, Feyerabend M, Guy J, Wagener RJ, Schubert D, Staiger JF, Witte M.
Nature Comunications 7:13664 (DOI: 10.1038/ncomms13664, 2016.
abstract link

Disinhibition of cortical excitatory cell gate information flow through and between corticalcolumns. The major contribution of Martinotti cells (MC) is providing dendritic inhibition toexcitatory neurons and therefore they are a main component of disinhibitory connections.Here we show by means of optogenetics that MC in layers II/III of the mouse primarysomatosensory cortex are inhibited by both parvalbumin (PV)- and vasoactive intestinalpolypeptide (VIP)-expressing cells. Paired recordings revealed stronger synaptic inputonto MC from PV cells than from VIP cells. Moreover, PV cell input showed frequencyindependentdepression, whereas VIP cell input facilitated at high frequencies. Thesedifferences in the properties of the two unitary connections enable disinhibition with distincttemporal features.

Morphological Characteristics of Electrophysiologically Characterized Layer Vb Pyramidal Cells in Rat Barrel Cortex.
Jochen F. Staiger, Alexandre J. C. Loucif, Dirk Schubert, Martin Möck.
PLoS ONE 11 (10): e0164004, 2016. doi:10.1371/journal. pone.0164004
abstract link

Layer Vb pyramidal cells are the major output neurons of the neocortex and transmit theoutcome of cortical columnar signal processing to distant target areas. At the same time they contribute to local tactile information processing by emitting recurrent axonal collateralsinto the columnar microcircuitry. It is, however, not known how exactly the two types of pyramidal cells, called slender-tufted and thick-tufted, contribute to the local circuitry.Here, we investigated in the rat barrel cortex the detailed quantitative morphology of biocytin-filled layer Vb pyramidal cells in vitro, which were characterized for their intrinsicelectrophysiology with special emphasis on their action potential firing pattern. Since westained the same slices for cytochrome oxidase, we could also perform layer- and columnrelated analyses. Our results suggest that in layer Vb the unambiguous action potential firing patterns "regular spiking (RS)" and "repetitive burst spiking (RB)" (previously called intrinsically burst spiking) correlate well with a distinct morphology. RS pyramidal cells are somatodendritically of the slender-tufted type and possess numerous local intralaminarand intracolumnar axonal collaterals, mostly reaching layer I. By contrast, their transcolumnar projections are less well developed. The RB pyramidal cells are somatodendritically of the thick-tufted type and show only relatively sparse local axonal collaterals, whichare preferentially emitted as long horizontal or oblique infragranular collaterals. However,contrary to many previous slice studies, a substantial number of these neurons alsoshowed axonal collaterals reaching layer I. Thus, electrophysiologically defined pyramidalcells of layer Vb show an input and output pattern which suggests RS cells to be more"locally segregating" signal processors whereas RB cells seem to act more on a "global integrative" scale.

Comment on “Principles of connectivity among morphologically defined cell types in adult neocortex”.
Barth, A.; Burkhalter, A.; Callaway, E.M.; Connors, B.W.; Cauli, B.; DeFelipe, J.; Feldmeyer, D.; Freund, T.; Kawaguchi, Y.; Kisvarday, Z.; Kubota, Y.; McBain, C.;Oberlaender, M.; Rossier, J.;Rudy, B.; Staiger, J.F.; Somogyi, P.; Tamas, G.;Yuste, R..
Science 353 (6304):1108-a, 2016.
abstract link

Jiang et al. (Research Article, 27 November 2015, aac9462) describe detailed experimentsthat substantially add to the knowledge of cortical microcircuitry and are unique in the numberof connections reported and the quality of interneuron reconstruction.The work appeals toexperts and laypersons because of the notion that it unveils new principles and provides acomplete description of cortical circuits.We provide a counterbalance to the authors’ claimsto give those less familiar with the minutiae of cortical circuits a better sense of thecontributions and the limitations of this study.

mSWI/SNF (BAF) complexes are indispensable for the neurogenesis and development of embryonic olfactory epithelium.
Bachmann C*, Nguyen H*, Rosenbusch J*, Pham L, Rabe T, Patwa M, Sokpor G, Seong RH, Ashery-Padan R, Mansouri A, Stoykova A, Staiger JF, Tuoc T..
Plos Genetics, 2016. 12(9), *equally contributed authors
abstract link

Neurogenesis is a key developmental event through which neurons are generated from neural stem/progenitor cells. Chromatin remodeling BAF (mSWI/SNF) complexes have been reported to play essential roles in the neurogenesis of the central nervous system. However, whether BAF complexes are required for neuron generation in the olfactory system is unknown. Here, we identified onscBAF and ornBAF complexes, which are specifically present in olfactory neural stem cells (oNSCs) and olfactory receptor neurons (ORNs), respectively. We demonstrated that BAF155 subunit is highly expressed in both oNSCs and ORNs, whereas high expression of BAF170 subunit is observed only in ORNs. We report that conditional deletion of BAF155, a core subunit in both onscBAF and ornBAF complexes, causes impaired proliferation of oNSCs as well as defective maturation and axonogenesis of ORNs in the developing olfactory epithelium (OE), while the high expression of BAF170 is important for maturation of ORNs. Interestingly, in the absence of BAF complexes in BAF155/BAF170 double-conditional knockout mice (dcKO), OE is not specified. Mechanistically, BAF complex is required for normal activation of Pax6-dependent transcriptional activity in stem cells/progenitors of the OE. Our findings unveil a novel mechanism mediated by the mSWI/SNF complex in OE neurogenesis and development.

Intracortical polyimide electrodes with a bioresorbable coating.
Hassler,C.; Guy,J.; Nietzschmann,M.; Plachta,D.T.; Staiger,J.F.; Stieglitz,T..
Biomed.Microdevices 18 (5):81, 2016.
abstract link

Polyimide based shaft electrodes were coated with a bioresorbable layer to stiffen them for intracortical insertion and to reduce the mechanical mismatch between the target tissue and the implanted device after degradation of the coating. Molten saccharose was used as coating material. In a proof-of-concept study, the electrodes were implanted into the cortex of Wistar rats and the insertion forces during implantation were recorded. Electrochemical impedance spectroscopy was performed immediately after implantation and up to 13 weeks after implantation to monitor the tissue response to the implanted electrodes. The recorded spectra were modeled with an equivalent circuit to differentiate the influence of the single components. In one rat, a peak in the encapsulation resistance was observable after two weeks of implantation, indicating the peak of the acute inflammatory response. In another rat, the lowest resistances were observed after four weeks, indicating the termination of the acute inflammatory response. Multiunit activity was recorded with an adequate signal to noise ratio to allow spike sorting. Histology was performed after 7, 45 and 201 days of implantation. The results showed the highest tissue reaction after 45 days and confirmed impedance data that acute inflammatory reactions terminate over time

Ablation of BAF170 in Developing and Postnatal Dentate Gyrus Affects Neural Stem Cell Proliferation, Differentiation, and Learning.
Tuoc T, Dere E, Radyushkin K, Pham L, Nguyen H, Tonchev AB, Sun G, Ronnenberg A, Shi Y, Staiger JF, Ehrenreich H, Stoykova A.
Molecular Neurobiology, 2016. doi:10.1007/s12035-016-9948-5
abstract link

The BAF chromatin remodeling complex plays an essential role in brain development. However its function in postnatal neurogenesis in hippocampus is still unknown. Here, we show that in postnatal dentate gyrus (DG), the BAF170 subunit of the complex is expressed in radial glial-like (RGL) progenitors and in cell types involved in subsequent steps of adult neurogenesis including mature astrocytes. Conditional deletion of BAF170 during cortical late neurogenesis as well as during adult brain neurogenesis depletes the pool of RGL cells in DG, and promotes terminal astrocyte differentiation. These derangements are accompanied by distinct behavioral deficits, as reflected by an impaired accuracy of place responding in the Morris water maze test, during both hidden platform as well as reversal learning. Inducible deletion of BAF170 in DG during adult brain neurogenesis resulted in mild spatial learning deficits, having a more pronounced effect on spatial learning during the reversal test. These findings demonstrate involvement of BAF170-dependent chromatin remodeling in hippocampal neurogenesis and cognition and suggest a specific role of adult neurogenesis in DG in adaptive behavior.

Epigenetic regulation by BAF (mSWI/SNF) chromatin remodeling complexes is indispensable for embryonic development.
Nguyen H*, Sokpor G*, Pham L, Rosenbusch J, Stoykova A, Staiger JF, Tuoc T.
Cell Cycle, 2016. 2016, 18;15(10):1317-24, equally contributed authors
abstract link

The multi-subunit chromatin-remodeling SWI/SNF (known as BAF for Brg/Brm-associated factor) complexes play essential roles in development. Studies have shown that the loss of individual BAF subunits often affects local chromatin structure and specific transcriptional programs. However, we do not fully understand how BAF complexes function in development because no animal mutant had been engineered to lack entire multi-subunit BAF complexes. Importantly, we recently reported that double conditional knock-out (dcKO) of the BAF155 and BAF170 core subunits in mice abolished the presence of the other BAF subunits in the developing cortex. The generated dcKO mutant provides a novel and powerful tool for investigating how entire BAF complexes affect cortical development. Using this model, we found that BAF complexes globally control the key heterochromatin marks, H3K27me2 and -3, by directly modulating the enzymatic activity of the H3K27 demethylases, Utx and Jmjd3. Here, we present further insights into how the scaffolding ability of the BAF155 and BAF170 core subunits maintains the stability of BAF complexes in the forebrain and throughout the embryo during development. Furthermore, we show that the loss of BAF complexes in the above-described model up-regulates H3K27me3 and impairs forebrain development and embryogenesis. These findings improve our understanding of epigenetic mechanisms and their modulation by the chromatin-remodeling SWI/SNF complexes that control embryonic development.

2015

Thalamocortical Connections Drive Intracortical Activation of Functional Columns in the Mislaminated Reeler Somatosensory Cortex .
Robin J. Wagener, Mirko Witte, Julien Guy, Nieves Mingo-Moreno, Sebastian Kügler, Jochen F. Staiger.
Cerebral Cortex, 2015.
abstract link

Neuronal wiring is key to proper neural information processing. Tactile information from the rodent's whiskers reaches the cortex via distinct anatomical pathways. The lemniscal pathway relays whisking and touch information from the ventral posteromedial thalamic nucleus to layer IV of the primary somatosensory "barrel" cortex. The disorganized neocortex of the reeler mouse is a model system that should severely compromise the ingrowth of thalamocortical axons (TCAs) into the cortex. Moreover, it could disrupt intracortical wiring. We found that neuronal intermingling within the reeler barrel cortex substantially exceeded previous descriptions, leading to the loss of layers. However, viral tracing revealed that TCAs still specifically targeted transgenically labeled spiny layer IV neurons. Slice electrophysiology and optogenetics proved that these connections represent functional synapses. In addition, we assessed intracortical activation via immediate-early-gene expression resulting from a behavioral exploration task. The cellular composition of activated neuronal ensembles suggests extensive similarities in intracolumnar information processing in the wild-type and reeler brains. We conclude that extensive ectopic positioning of neuronal partners can be compensated for by cell-autonomous mechanisms that allow for the establishment of proper connectivity. Thus, genetic neuronal fate seems to be of greater importance for correct cortical wiring than radial neuronal position.

Loss of BAF (mSWI/SNF) complexes causes global transcriptional and chromatin state changes in forebrain development.
Ramanathan Narayanan, Mehdi Pirouz, Cemil Kerimoglu, Linh Pham, Robin J. Wagener, Kamila A. Kiszka, Joachim Rosenbusch, Michael Kessel, Andre Fischer, Anastassia Stoykova, Jochen F. Staiger, and Tran Tuoc.
Cell Reports, 2015. 13, 1–13
abstract link

BAF (Brg/Brm-associated factors) complexes play important roles in development and are linked to chromatin plasticity at selected genomic loci. Nevertheless, a full understanding of their role in development and chromatin remodeling has been hindered by the absence of mutants completely lacking BAF complexes. Here, we report that the loss of BAF155/BAF170 in double-conditional knock-out (dcKO) mice eliminates all known BAF subunits, resulting in an overall reduction in active chromatin marks (H3K9Ac), a global increase in repressive marks (H3K27me2/3), and down-regulation of gene expression. We demonstrate that BAF complexes interact with H3K27 demethylases (JMJD3, UTX) and potentiate their activity. Importantly BAF complexes are indispensable for forebrain development, including proliferation, differentiation and cell survival of neural progenitor cells. Our findings reveal a molecular mechanism mediated by BAF complexes that controls global transcriptional program and chromatin state in development.

The disorganized visual cortex in reelin-deficient mice is functional and allows for enhanced plasticity.
Justyna Pielecka-Fortuna, Robin Jan Wagener, Ann-Kristin Martens, Bianka Goetze, Karl-Friedrich Schmidt, Jochen F. Staiger, Siegrid Löwel.
Brain Structure and Function; DOI: 10.1007/s00429-014-0866-x, 2015. 220(6):3449-67
abstract link

A hallmark of neocortical circuits is the segregation of processing streams into six distinct layers. The importance of this layered organization for cortical processing and plasticity is little understood. We investigated the structure, function and plasticity of primary visual cortex (V1) of adult mice deficient for the glycoprotein reelin and their wild-type littermates. In V1 of rl-/- mice, cells with different laminar fates are present at all cortical depths. Surprisingly, the (vertically) disorganized cortex maintains a precise retinotopic (horizontal) organization. Rl-/- mice have normal basic visual capabilities, but are compromised in more challenging perceptual tasks, such as orientation discrimination. Additionally, rl-/- animals learn and memorize a visual task as well as their wild-type littermates. Interestingly, reelin deficiency enhances visual cortical plasticity: juvenile-like ocular dominance plasticity is preserved into late adulthood. The present data offer an important insight into the capabilities of a disorganized cortical system to maintain basic functional properties.

Characterizing VIP Neurons in the Barrel Cortex of VIPcre/tdTomato Mice Reveals Layer-Specific Differences.
Prönneke A, Scheuer B, Wagener RJ, Möck M, Witte M, and Staiger JF.
Cereb. Cortex (2015) 25 (12): 4854-4868. doi: 10.1093/cercor/bhv202 , 2015.
abstract pdf link

Neocortical GABAergic interneurons have a profound impact on cortical circuitry and its information processing capacity. Distinct subgroups of inhibitory interneurons can be distinguished by molecular markers, such as parvalbumin, somatostatin, and vasoactive intestinal polypeptide (VIP). Among these, VIP-expressing interneurons sparked a substantial interest since these neurons seem to operate disinhibitory circuit motifs found in all major neocortical areas. Several of these recent studies used transgenic Vip-ires-cre mice to specifically target the population of VIP-expressing interneurons. This makes it necessary to elucidate in detail the sensitivity and specificity of Cre expression for VIP neurons in these animals. Thus, we quantitatively compared endogenous tdTomato with Vip fluorescence in situ hybridization and αVIP immunohistochemistry in the barrel cortex of VIPcre/tdTomato mice in a layer-specific manner. We show that VIPcre/tdTomato mice are highly sensitive and specific for the entire population of VIP-expressing neurons. In the barrel cortex, approximately 13% of all GABAergic neurons are VIP expressing. Most VIP neurons are found in layer II/III (∼60%), whereas approximately 40% are found in the other layers of the barrel cortex. Layer II/III VIP neurons are significantly different from VIP neurons in layers IV-VI in several morphological and membrane properties, which suggest layer-dependent differences in functionality.

Persistence of Functional Sensory Maps in the Absence of Cortical Layers in the Somatosensory Cortex of Reeler Mice.
Guy J, Wagener R, Möck M and Staiger JF.
Cerebral Cortex; doi: 10.1093/cercor/bhu052, 2015. 25(9):2517-28
abstract link

In rodents, layer IV of the primary somatosensory cortex contains the barrel field, where individual, large facial whiskers are represented as a dense cluster of cells. In the reeler mouse, a model of disturbed cortical development characterized by a loss of cortical lamination, the barrel field exists in a distorted manner. Little is known about the consequences of such a highly disturbed lamination on cortical function in this model. We used in vivo intrinsic signal optical imaging together with piezo-controlled whisker stimulation to explore sensory map organization and stimulus representation in the barrel field. We found that the loss of cortical layers in reeler mice had surprisingly little incidence on these properties. The overall topological order of whisker representations is highly preserved and the functional activation of individual whisker representations is similar in size and strength to wild-type controls. Because intrinsic imaging measures hemodynamic signals, we furthermore investigated the cortical blood vessel pattern of both genotypes, where we also did not detect major differences. In summary, the loss of the reelin protein results in a widespread disturbance of cortical development which compromises neither the establishment nor the function of an ordered, somatotopic map of the facial whiskers.

S1 laminar specialization.
Staiger JF.
Scholarpedia of touch, 2015. ISBN: 978-94-6239-132-1
link

What types of neocortical GABAergic neurons do really exist?.
Jochen F. Staiger, Martin Möck, Alvar Prönneke, Mirko Witte .
e-Neuroforum (Springer), 2015.
abstract link

The neocortex is regarded as the brain structure responsible for mediating higher brain functions, like conscious perception of sensory signals, learning and memory or programming of goal-directed behavior. Cortical circuits that enable these functions are formed by, first, a larger population of excitatory so-called principal cells (i.e., glutamatergic pyramidal cells; ca. 80–85 %), which issue long-distance projections, in addition to local recurrent collaterals, which form the major part of local cortical excitatory circuits. A second, smaller population of inhibitory also called local or short-axoned interneurons (i.e., GABAergic neurons; ca. 15–20 %), however, contribute heavily to intracortical microcircuits too. They can be subdivided by their location in specific areas, layers, or columns, which possess specific input–output relationships, but also in terms of morphology, electrophysiology, molecular expression profiles, and subcellular target specificity. Here it is proposed that, at present, in the rodent neocortex this population of GABAergic neurons can be reasonably divided into six different types, mainly due to their unique axonal patterns and subcellular target specificity: (i) axo-axonic cells, (ii) basket cells, (iii) Martinotti cells, (iv) bipolar/bitufted cells, (v) neurogliaform cells, and (vi) projection neurons. These different types of GABAergic neurons strongly govern the working of cortical circuits for meaningful behavior by feed-forward and feedback inhibition as well as disinhibition. Thus, they keep excitation in check, perform gain modulation, and open temporal or spatial windows for input control or output generation.

A gradual depth-dependent change in connectivity features of supragranular pyramidal cells in rat barrel cortex.
Staiger JF, Bojak I, Miceli S, Schubert D..
Brain Struct Funct., 2015.
abstract link

Recent experimental evidence suggests a finer genetic, structural and functional subdivision of the layers which form a cortical column. The classical layer II/III (LII/III) of rodent neocortex integrates ascending sensory information with contextual cortical information for behavioral read-out. We systematically investigated to which extent regular-spiking supragranular pyramidal neurons, located at different depths within the cortex, show different input-output connectivity patterns. Combining glutamate uncaging with whole-cell recordings and biocytin filling, we revealed a novel cellular organization of LII/III: (1) "Lower LII/III" pyramidal cells receive a very strong excitatory input from lemniscal LIV and much fewer inputs from paralemniscal LVa. They project to all layers of the home column, including a feedback projection to LIV, whereas transcolumnar projections are relatively sparse. (2) "Upper LII/III" pyramidal cells also receive their strongest input from LIV, but in addition, a very strong and dense excitatory input from LVa. They project extensively to LII/III as well as LVa and Vb of their home and neighboring columns. (3) "Middle LII/III" pyramidal cell shows an intermediate connectivity phenotype that stands in many ways in between the features described for lower versus upper LII/III. "Lower LII/III" intracolumnarly segregates and transcolumnarly integrates lemniscal information, whereas "upper LII/III" seems to integrate lemniscal with paralemniscal information. This suggests a fine-grained functional subdivision of the supragranular compartment containing multiple circuits without any obvious cytoarchitectonic, other structural or functional correlate of a laminar border in rodent barrel cortex.

Cortical GABAergic neurons.
Staiger JF.
Brain Mapping: An encyclopedic reference, 2015.
abstract link

The neocortex is regarded as the brain structure responsible for mediating higher brain functions, like conscious perception of sensory signals, learning and memory, and programming of goal-directed behavior. Cortical circuits are formed by, first, a larger population of excitatory so-called principal cells (i.e., glutamatergic pyramidal cells; ca. 80–88%), which issue long-distance projections, in addition to local recurrent collaterals, which form the major part of local cortical excitatory circuits (Douglas, R. J., & Martin, K. A. C. (2007). Mapping the matrix: The ways of neocortex. Neuron 56, 226–238; Feldmeyer, D., Brecht, M., Helmchen, F., Petersen, C. C. H., Poulet, J. F. A., Staiger, J. F. (2013). Barrel cortex function. Progress in Neurobiology 103, 3–27; Schubert, D., Kötter, R., & Staiger, J. F. (2007). Mapping functional connectivity in barrel-related columns reveals layer- and cell type-specific microcircuits. Brain Structure and Function 212, 107–119). A second, smaller population of inhibitory also called local or short-axoned interneurons (i.e., GABAergic neurons; ca. 12–20%), however, contribute heavily to intracortical microcircuits, too. They can be subdivided by their location not only in specific areas, layers, or columns, which possess specific input–output relationships, but also in terms of morphology, electrophysiology, molecular expression profiles, and subcellular target specificity (Ascoli, G. A., Alonso-Nanclares, L., Anderson, S. A., Barrionuevo, G., & Benavides-Piccione, R. (2008). Petilla terminology: nomenclature of features of GABAergic interneurons of the cerebral cortex. Nature Reviews Neuroscience 9, 557–568; Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A., Silberberg, G., Wu, C. Z. (2004). Interneurons of the neocortical inhibitory system. Nature Reviews Neuroscience 5, 793–807). Here, it is proposed that, at present, in the rodent neocortex, this population of GABAergic neurons can be reasonably divided into six different types: (i) axo-axonic cells, (ii) basket cells, (iii) Martinotti cells, (iv) bipolar/bitufted cells, (v) neurogliaform cells, and (vi) projection neurons. A major topic for future research will be to determine how much within-type diversity does exist, that is, how many subtypes can reasonably be distinguished and what are their genuine functions in the cortical circuitry.

2014

Revisiting enigmatic cortical calretinin-expressing interneurons.
Cauli B., Zhou X., Tricoire L., Toussay X. and Staiger JF.
Frontiers in Neuroanatomy, 2014.
abstract link

Cortical calretinin (CR)-expressing interneurons represent a heterogeneous subpopulation of about 10–30% of GABAergic interneurons, which altogether total ca. 12–20% of all cortical neurons. In the rodent neocortex, CR cells display different somatodendritic morphologies ranging from bipolar to multipolar but the bipolar cells and their variations dominate. They are also diverse at the molecular level as they were shown to express numerous neuropeptides in different combinations including vasoactive intestinal polypeptide (VIP), cholecystokinin (CCK), neurokinin B (NKB) corticotrophin releasing factor (CRF), enkephalin (Enk) but also neuropeptide Y (NPY) and somatostatin (SOM) to a lesser extent. CR-expressing interneurons exhibit different firing behaviors such as adapting, bursting or irregular. They mainly originate from the caudal ganglionic eminence (CGE) but a subpopulation also derives from the dorsal part of the medial ganglionic eminence (MGE). Cortical GABAergic CR-expressing interneurons can be divided in two main populations: VIP-bipolar interneurons deriving from the CGE and SOM-Martinotti-like interneurons originating in the dorsal MGE. Although bipolar cells account for the majority of CR-expressing interneurons, the roles they play in cortical neuronal circuits and in the more general metabolic physiology of the brain remained elusive and enigmatic. The aim of this review is, firstly, to provide a comprehensive view of the morphological, molecular and electrophysiological features defining this cell type. We will, secondly, also summarize what is known about their place in the cortical circuit, their modulation by subcortical afferents and the functional roles they might play in neuronal processing and energy metabolism.

2013

Barrel cortex function.
Feldmeyer D, Brecht M, Helmchen F, Petersen CCH, Poulet JFA, Staiger JF, Luhmann HJ, Schwarz C.
Prog Neurobiol 103:3-27 , 2013.
abstract link

eocortex, the neuronal structure at the base of the remarkable cognitive skills of mammals, is a layered sheet of neuronal tissue composed of juxtaposed and interconnected columns. A cortical column is considered the basic module of cortical processing present in all cortical areas. It is believed to contain a characteristic microcircuit composed of a few thousand neurons. The high degree of cortical segmentation into vertical columns and horizontal layers is a boon for scientific investigation because it eases the systematic dissection and functional analysis of intrinsic as well as extrinsic connections of the column. In this review we will argue that in order to understand neocortical function one needs to combine a microscopic view, elucidating the workings of the local columnar microcircuits, with a macroscopic view, which keeps track of the linkage of distant cortical modules in different behavioral contexts. We will exemplify this strategy using the model system of vibrissal touch in mice and rats. On the macroscopic level vibrissal touch is an important sense for the subterranean rodents and has been honed by evolution to serve an array of distinct behaviors. Importantly, the vibrissae are moved actively to touch GÇô requiring intricate sensorimotor interactions. Vibrissal touch, therefore, offers ample opportunities to relate different behavioral contexts to specific interactions of distant columns. On the microscopic level, the cortical modules in primary somatosensory cortex process touch inputs at highest magnification and discreteness GÇô each whisker is represented by its own so-called barrel column. The cellular composition, intrinsic connectivity and functional aspects of the barrel column have been studied in great detail. Building on the versatility of genetic tools available in rodents, new, highly selective and flexible cellular and molecular tools to monitor and manipulate neuronal activity have been devised. Researchers have started to combine these with advanced and highly precise behavioral methods, on par with the precision known from monkey preparations. Therefore, the vibrissal touch model system is exquisitely positioned to combine the microscopic with the macroscopic view and promises to be instrumental in our understanding of neocortical function.

Characterization and Distribution of Reelin-Positive Interneuron Subtypes in the Rat Barrel Cortex..
Pohlkamp T, Dávid C, Cauli B, Gallopin T, Bouché E, Karagiannis A, May P, Herz J, Frotscher M, Staiger JF, Bock HH..
Cerebral Cortex (doi: 10.1093/cercor/bht161), 2013.
abstract link

GABAergic inhibitory interneurons (IN) represent a heterogeneous population with different electrophysiological, morphological, and molecular properties. The correct balance between interneuronal subtypes is important for brain function and is impaired in several neurological and psychiatric disorders. Here we show the data of 123 molecularly and electrophysiologically characterized neurons of juvenile rat barrel cortex acute slices, 48 of which expressed Reelin (Reln). Reln mRNA was exclusively detected in Gad65/67-positive cells but was found in interneuronal subtypes in different proportions: all cells of the adapting-Somatostatin (SST) cluster expressed Reln, whereas 63% of the adapting-neuropeptide Y (NPY, 50% of the fast-spiking Parvalbumin (PVALB), and 27% of the adapting/bursting-Vasoactive Intestinal Peptide (VIP) cluster were Reln-positive. Silhouette analysis revealed a high impact of the parameter Reln on cluster quality. By analyzing the co-localization of RELN immunoreactivity with those of different IN-markers, we found that RELN is produced layer-independently in SST-, NPY-, and NOS1-expressing INs, whereas co-localization of RELN and VIP was mostly absent. Of note, RELN co-localized with PVALB, predominantly in INs of layers IV/V (>30%). Our findings emphasize RELN's role as an important IN-marker protein and provide a basis for the functional characterization of Reln-expressing INs and its role in the regulation of inhibitory IN networks.

Mapping remodeling of thalamocortical projections in the living reeler mouse brain by diffusion tractography.
Harsan LA, Dávid C, Reisert M, Schnell S, Hennig J, von Elverfeldt D, Staiger JF.
Proc Natl Acad Sci USA 110: E1797-E1806, 2013.
abstract link

A major challenge in neuroscience is to accurately decipher in vivo the entire brain circuitry (connectome) at a microscopic level. Currently, the only methodology providing a global noninvasive window into structural brain connectivity is diffusion tractography. The extent to which the reconstructed pathways reflect realistic neuronal networks depends, however, on data acquisition and postprocessing factors. Through a unique combination of approaches, we designed and evaluated herein a framework for reliable fiber tracking and mapping of the living mouse brain connectome. One important wiring scheme, connecting gray matter regions and passing fiber-crossing areas, was closely examined: the lemniscal thalamocortical (TC) pathway. We quantitatively validated the TC projections inferred from in vivo tractography with correlative histological axonal tracing in the same wild-type and reeler mutant mice. We demonstrated noninvasively that changes in patterning of the cortical sheet, such as highly disorganized cortical lamination in reeler, led to spectacular compensatory remodeling of the TC pathway.

Optopatcher-An electrode holder for simultaneous intracellular patch-clamp recording and optical manipulation.
Katz Y, Yizhar O, Staiger,JF, Lampl I.
Journal of Neuroscience Methods 214:113-117, 2013.
abstract link

Optogenetics has rapidly become a standard method in neuroscience research. Although significant progress has been made in the development of molecular tools, refined techniques for combined light delivery and recording in vivo are still lacking. For example, simultaneous intracellular recording and light stimulation have only been possible by using two separate positioning systems. To overcome this limitation, we have developed a glass pipette holder which contains an additional port for the insertion of an optical fiber into the pipette. This device, which we called "optopatcher" allows whole cell patch-clamp recording simultaneously with direct projection of light from the recording pipette. The holder spares the use of an additional manipulator and, importantly, enables accurate, stable and reproducible illumination. In addition, replacement of standard pipettes is done as easily as with the available commercial holders. Here we used the optopatcher in vivo to record the membrane potential of neurons from different cortical layers in the motor cortex of transgenic mice expressing channelrhodopsin-2 under the Thy1 promoter. We demonstrate the utility of the optopatcher by recording LFP and intracellular responses to light stimulation.

New insights into the classification and nomenclature of cortical GABAergic interneurons.
De Felipe J, Lopez-Cruz PL, Benavides-Piccione R, Bielza C, Larranaga P, Anderson S, Burkhalter A, Cauli B, Fairen A, Feldmeyer D, Fishell G, Fitzpatrick D, Freund TF, Gonzalez-Burgos G, Hestrin S, Hill S, Hof PR, Huang J, Jones EG, Kawaguchi Y, Kisvarday Z, Kubota Y, Lewis, DA, Marin O, Markram H, McBain CJ, Meyer HS, Monyer H, Nelson SB, Rockland K, Rossier J, Rubenstein JL, Rudy B, Scanziani M, Shepherd GM, Sherwood CC, Staiger JF, Tamas G, Thomson A, Wang Y, Yuste R, Ascoli GA.
Nature Reviews Neuroscience 14: 202-16, 2013.
abstract link

A systematic classification and accepted nomenclature of neuron types is much needed but is currently lacking. This article describes a possible taxonomical solution for classifying GABAergic interneurons of the cerebral cortex based on a novel, web-based interactive system that allows experts to classify neurons with pre-determined criteria. Using Bayesian analysis and clustering algorithms on the resulting data, we investigated the suitability of several anatomical terms and neuron names for cortical GABAergic interneurons. Moreover, we show that supervised classification models could automatically categorize interneurons in agreement with experts' assignments. These results demonstrate a practical and objective approach to the naming, characterization and classification of neurons based on community consensus.

2012

Unique functional properties of somatostatin-expressing GABAergic neurons in mouse barrel cortex.
Gentet LJ, Kremer Y, Taniguchi H, Huang ZJ, Staiger J, Petersen CCH.
Nat Neurosci 15:607-612, 2012.
abstract link

Neocortical GABAergic neurons have diverse molecular, structural and electrophysiological features, but the functional correlates of this diversity are largely unknown. We found unique membrane potential dynamics of somatostatin-expressing (SOM) neurons in layer 2/3 of the primary somatosensory barrel cortex of awake behaving mice. SOM neurons were spontaneously active during periods of quiet wakefulness. However, SOM neurons hyperpolarized and reduced action potential firing in response to both passive and active whisker sensing, in contrast with all other recorded types of nearby neurons, which were excited by sensory input. Optogenetic inhibition of SOM neurons increased burst firing in nearby excitatory neurons. We hypothesize that the spontaneous activity of SOM neurons during quiet wakefulness provides a tonic inhibition to the distal dendrites of excitatory pyramidal neurons. Conversely, the inhibition of SOM cells during active cortical processing likely enhances distal dendritic excitability, which may be important for top-down computations and sensorimotor integration.

2011

Chronic intracortical implantation of saccharose-coated flexible shaft electrodes into the cortex of rats.
Hassler C, Guy J, Nietzschmann M, Staiger JF, Stieglitz T.
Conf Proc IEEE Eng Med Biol Soc 2011: 644-47, 2011.
abstract link

Within this study, polyimide based shaft electrodes were fabricated and dip-coated in molten saccharose to stiffen them for insertion into the brain tissue. These electrodes were then implanted successfully into the cortex of whistar rats and the insertion force during implantation was recorded. Electrochemical impedance spectroscopy was performed immediately after implantation and in regular time intervals up to 201 days after implantation to monitor the tissue response to the implanted electrodes. Depending on the measured electrode pairs and the rats, the impedance spectra behaved different over time. Either they showed a constant decrease in impedance at 1 kHz, or they showed an initial decrease to increase again later. Furthermore, physiological signal recording was performed by stimulating the rats with acoustic signals and simultaneously recording the response on the different electrode sites. Multi-unit activity was detected until 37 days after implantation with an averaged signal-to-noise ratio of 2 to 4.

2010

Electrophysiological and morphological properties of Cajal-Retzius cells with different ontogenetic origins.
Sava BA, David CS, Teissier A, Pierani A, Staiger JF, Luhmann HJ, Kilb W.
Neuroscience 167:724-734, 2010.
abstract link

The different origins of Cajal-Retzius cells (CRc) as well as their diverse molecular profile suggest that this cell type may represent different neuronal subpopulations. In order to investigate whether CRc from different origins show distinct functional or morphological characteristics we used transgenic Dbx1(cre);ROSA26(YFP) mice in which two subpopulations of CRc, originating from the septum and ventral pallium (VP) at the pallial-subpallial border (PSB), were permanently labeled by yellow fluorescent protein (YFP) expression. Electrophysiological properties of YFP(+) and YFP(-) CRc were investigated by whole-cell patch-clamp recordings, while a thorough somatodendritic and axonal reconstruction of the biocytin labeled CRc was subsequently performed using a Neurolucida system. Our experiments revealed that no significant differences in resting membrane potential, input resistance or capacitance, hyperpolarization activated currents and most action potentials properties could be observed between YFP(+) and YFP(-) CRc. Both YFP(+) and YFP(-) CRc displayed spontaneous and carbachol-induced GABAergic postsynaptic currents with similar properties and comparable NMDA-receptor mediated glutamatergic inward currents that were equally affected by the NR2B specific antagonist ifenprodil. Morphological reconstructions revealed that dendritic and axonal parameters are similar between YFP(+) and YFP(-) CRc, while the dendritic compartment of YFP(+) CRc was slightly larger. In summary, no considerable differences in functional and morphological properties between YFP(+) and YFP(-) CRc could be observed in this study. These observations suggest that CRc of different ontogenic origins display comparable functional properties in the early postnatal cortex and therefore perform similar functions within the transient neuronal networks of the developing cortex.

Membrane potential dynamics of GABAergic neurons in the barrel cortex of behaving mice.
Gentet LJ, Avermann M, Matyas F, Staiger JF, Petersen CCH.
Neuron 65:422-435, 2010.
abstract link

Computations in cortical circuits are mediated by synaptic interactions between excitatory and inhibitory neurons, and yet we know little about their activity in awake animals. Here, through single and dual whole-cell recordings combined with two-photon microscopy in the barrel cortex of behaving mice, we directly compare the synaptically driven membrane potential dynamics of inhibitory and excitatory layer 2/3 neurons. We find that inhibitory neurons depolarize synchronously with excitatory neurons, but they are much more active with differential contributions of two classes of inhibitory neurons during different brain states. Fast-spiking GABAergic neurons dominate during quiet wakefulness, but during active wakefulness Non-fast-spiking GABAergic neurons depolarize, firing action potentials at increased rates. Sparse uncorrelated action potential firing in excitatory neurons is driven by fast, large, and cell-specific depolarization. In contrast, inhibitory neurons fire correlated action potentials at much higher frequencies driven by slower, smaller, and broadly synchronized depolarization.

In vivo diffusion tensor magnetic resonance imaging and fiber tracking of the mouse brain.
Harsan LA, Paul D, Schnell S, Kreher B, Hennig J, Staiger JF, von Elverfeldt D.
NMR in Biomedicine DOI:10.1002/nbm.1496, 2010.
abstract link

Until very recently, the study of neural architecture using fixed tissue has been a major scientific focus of neurologists and neuroanatomists. A non-invasive detailed insight into the brain's axonal connectivity in vivo has only become possible since the development of diffusion tensor magnetic resonance imaging (DT-MRI). This unique approach of analyzing axonal projections in the living brain was used in the present study to describe major white matter fiber tracts of the mouse brain and also to identify for the first time non-invasively the rich connectivity between the amygdala and different target regions. To overcome the difficulties associated with high spatially and temporally resolved DT-MRI measurements a 4-shot diffusion weighted spin echo (SE) echo planar imaging (EPI) protocol was adapted to mouse brain imaging at 9.4T. Diffusion tensor was calculated from data sets acquired by using 30 diffusion gradient directions while keeping the acquisition time at 91 min. Two fiber tracking algorithms were employed. A deterministic approach (fiber assignment by continuous tracking - FACT algorithm) allowed us to identify and generate the 3D representations of various neural pathways. A probabilistic approach was further used for the generation of probability maps of connectivity with which it was possible to investigate - in a statistical sense - all possible connecting pathways between selected seed points. We show here applications to determine the connection probability between regions belonging to the visual or limbic systems. This method does not require a priori knowledge about the projections' trajectories and is shown to be efficient even if the investigated pathway is long or three-dimensionally complex. Additionally, high resolution images of rotational invariant parameters of the diffusion tensor, such as fractional anisotropy, volume ratio or main eigenvalues allowed quantitative comparisons in-between regions of interest (ROIs) and showed significant differences between various white matter regions.

The somatosensory cortex of reeler mutant mice shows absent layering but intact formation and behavioral activation of columnar somatotopic maps.
Wagener RJ, David C, Zhao S, Haas CA, Staiger JF .
J Neurosci 30:15700-15709, 2010.
abstract link

Sensory information acquired via the large facial whiskers is processed and relayed in the whisker-to-barrel pathway, which shows multiple somatotopic maps of the receptor periphery. These maps consist of individual structural modules, the development of which may require intact cortical lamination. In the present study we examined the whisker-to-barrel pathway in the reeler mouse and thus used a model with disturbed cortical organization. A combination of histological (fluorescent Nissl and cytochrome oxidase staining) as well as molecular methods (c-Fos and laminar markers Rgs8, RORB, and ER81 expression) revealed wild type-equivalent modules in reeler. At the neocortical level, however, we found extensive alterations in the layout of the individual modules of the map. Nevertheless, they showed a columnar organization that included compartments equivalent to those of their wild-type counterparts. Moreover, all examined modules showed distinct activation as a consequence of behavioral whisker stimulation. Analysis of the magnitude of the cortical lamination defect surprisingly revealed an extensive disorganization, rather than an inversion, as assumed previously. Striking developmental plasticity of thalamic innervation, as suggested by vGluT2 immunohistochemistry, seems to ensure the proper formation of columnar modules and topological maps even under highly disorganized conditions.

2009

Local circuits targeting parvalbumin-containing interneurons in layer IV of rat barrel cortex.
Staiger JF, Zuschratter W, Luhmann HJ, Schubert D.
Brain Struct Func 214:1-13; DOI 10.1007/s00429-009-0225-5, 2009.
abstract link

Interactions between inhibitory interneurons and excitatory spiny neurons and also other inhibitory cells represent fundamental network properties which cause the so-called thalamo-cortical response transformation and account for the well-known receptive field differences of cortical layer IV versus thalamic neurons. We investigated the currently largely unknown morphological basis of these interactions utilizing acute slice preparations of barrel cortex in P19-21 rats. Layer IV spiny (spiny stellate, star pyramidal and pyramidal) neurons or inhibitory (basket and bitufted) interneurons were electrophysiologically characterized and intracellularly biocytin-labeled. In the same slice, we stained parvalbumin-immunoreactive (PV-ir) interneurons as putative target cells after which the tissue was subjected to confocal image acquisition. Parallel experiments confirmed the existence of synaptic contacts in these types of connection by correlated light and electron microscopy. The axons of the filled neurons differentially targeted barrel PV-ir interneurons: (1) The relative number of all contacted PV-ir cells within the axonal sphere was 5–17% for spiny (n = 10), 32 and 58% for basket (n = 2) and 12 and 13% for bitufted (n = 2) cells. (2) The preferential subcellular site which was contacted on PV-ir target cells was somatic for four and dendritic for five spiny cells; for basket cells, there was a somatic and for bitufted cells a dendritic preference in each examined case. (3) The highest number of contacts on a single PV-ir cell was 9 (4 somatic and 5 dendritic) for spiny neurons, 15 (10 somatic and 5 dendritic) for basket cells and 4 (1 somatic and 3 dendritic) for bitufted cells. These patterns suggest a cell type-dependent communication within layer IV microcircuits in which PV-ir interneurons provide not only feed-forward but also feedback inhibition thus triggering the thalamo-cortical response transformation.

Classification of NPY-expressing neocortical interneurons.
Karagiannis A, Gallopin T, David C, Battaglia D, Geoffroy H, Rossier J, Hillman EMC, Staiger JF, Cauli B.
J Neurosci 29:3642-3659, 2009.
abstract link

Neuropeptide Y (NPY) is an abundant neuropeptide of the neocortex involved in numerous physiological and pathological processes. Because of the large electrophysiological, molecular, and morphological diversity of NPY-expressing neurons their precise identity remains unclear. To define distinct populations of NPY neurons we characterized, in acute slices of rat barrel cortex, 200 cortical neurons of layers I-IV by means of whole-cell patch-clamp recordings, biocytin labeling, and single-cell reverse transcriptase-PCR designed to probe for the expression of well established molecular markers for cortical neurons. To classify reliably cortical NPY neurons, we used and compared different unsupervised clustering algorithms based on laminar location and electrophysiological and molecular properties. These classification schemes confirmed that NPY neurons are nearly exclusively GABAergic and consistently disclosed three main types of NPY-expressing interneurons. (1) Neurogliaform-like neurons exhibiting a dense axonal arbor, were the most frequent and superficial, and substantially expressed the neuronal isoform of nitric oxide synthase. (2) Martinotti-like cells characterized by an ascending axon ramifying in layer I coexpressed somatostatin and were the most excitable type. (3) Among fast-spiking and parvalbumin-positive basket cells, NPY expression was correlated with pronounced spike latency. By clarifying the diversity of cortical NPY neurons, this study establishes a basis for future investigations aiming at elucidating their physiological roles.

2008

Efficient recruitment of layer 2/3 interneurons by excitatory layer 4 input in single columns of rat somatosensory cortex.
Helmstaedter M, Staiger JF, Sakmann B, Feldmeyer D.
J Neurosci 28:8273-8284, 2008.
abstract link

Interneurons in layers 2/3 are excited by pyramidal cells within the same layer (Reyes et al., 1998; Gupta et al., 2000), but little is known about translaminar innervation of these interneurons by spiny neurons in the main cortical input layer 4 (L4). Here, we investigated (1) how efficiently L4 spiny neurons excite L2/3 interneurons via monosynaptic connections, (2) whether glutamate release from axon terminals of L4 spiny neurons depends on the identity of the postsynaptic interneuron, and (3) how L4-to-L2/3 interneuron connections compare with L4-to-L2/3 pyramidal neuron connections. We recorded from pairs of L4 spiny neurons and L2/3 interneurons in acute slices of rat barrel cortex of postnatal day 20 (P20) to P29 rats. The L4-to-L2/3 interneuron connections had an average unitary EPSP of 1.2 ± 1.1 mV. We found an average of 2.3 ± 0.8 contacts per connection, and the L4-to-L2/3 interneuron innervation domains were mostly column restricted. Unitary EPSP amplitudes and paired-pulse ratios in the L4-to-L2/3 interneuron connections depended on the “group” of the postsynaptic interneuron. Averaged over all L4-to-L2/3 interneuron connections, unitary EPSP amplitudes were 1.8-fold higher than in the translaminar L4-to-L2/3 pyramidal cell connections. Our results suggest that L4 spiny neurons may more efficiently recruit L2/3 interneurons than L2/3 pyramidal neurons, and that glutamate release from translaminar boutons of L4 spiny neuron axons is target cell specific.

Petilla Terminology: Nomenclature of features of GABAergic interneurons of the cerebral cortex.
Ascoli GA, Alonso-Nanclares L, Anderson SA, Barrionuevo G, Benavides-Piccione R, Burkhalter A, Buzsaki G, Cauli B, DeFelipe J, Fairén A, Feldmeyer D, Fishell G, Fregnac Y, Freund TF, Karube F, Gardner D, Gardner EP, Goldberg JH, Helmstaedter M, Hestrin S, Kisvarday Z, Lambolez B, Lewis D, Marin O, Markram H, Muñoz A, Packer A, Petersen C, Rockland K, Rossier J, Rudy B, Somogyi P, Staiger JF, Tamas G, Thomson AM, Toledo-Rodriguez M, Wang Y, West DC, and Yuste R.
Nat Rev Neurosci 9:557-568, 2008.
abstract link

Neuroscience produces a vast amount of data from an enormous diversity of neurons. A neuronal classification system is essential to organize such data and the knowledge that is derived from them. Classification depends on the unequivocal identification of the features that distinguish one type of neuron from another. The problems inherent in this are particularly acute when studying cortical interneurons. To tackle this, we convened a representative group of researchers to agree on a set of terms to describe the anatomical, physiological and molecular features of GABAergic interneurons of the cerebral cortex. The resulting terminology might provide a stepping stone towards a future classification of these complex and heterogeneous cells. Consistent adoption will be important for the success of such an initiative, and we also encourage the active involvement of the broader scientific community in the dynamic evolution of this project.

2007

Cholinergic control of spindle bursts in neonatal rat visual cortex.
Hanganu IL, Staiger JF, Ben-Ari Y, Khazipov R.
J Neurosci 27:5694-5705, 2007.
abstract link

Acetylcholine (ACh) is known to shape the adult neocortical activity related to behavioral states and processing of sensory information. However, the impact of cholinergic input on the neonatal neuronal activity remains widely unknown. Early during development, the principal activity pattern in the primary visual (V1) cortex is the intermittent self-organized spindle burst oscillation that can be driven by the retinal waves. Here, we assessed the relationship between this early activity pattern and the cholinergic drive by either blocking or augmenting the cholinergic input and investigating the resultant effects on the activity of the rat visual cortex during the first postnatal week in vivo. Blockade of the muscarinic receptors by intracerebroventricular, intracortical, or supracortical atropine application decreased the occurrence of V1 spindle bursts by 50%, both the retina-independent and the optic nerve-mediated spindle bursts being affected. In contrast, blockade of acetylcholine esterase with physostigmine augmented the occurrence, amplitude, and duration of V1 spindle bursts. Whereas direct stimulation of the cholinergic basal forebrain nuclei increased the occurrence probability of V1 spindle bursts, their chronic immunotoxic lesion using 192 IgG-saporin decreased the occurrence of neonatal V1 oscillatory activity by 87%. Thus, the cholinergic input facilitates the neonatal V1 spindle bursts and may prime the developing cortex to operate specifically on relevant early (retinal waves) and later (visual input) stimuli.

The innervation of parvalbumin containing interneurons by VIP immunopositive interneurons in the primary somatosensory cortex of the adult rat.
David C, Schleicher A, Zuschratter W, Staiger JF.
Eur J Neurosci 25:2329-2340, 2007.
abstract link

Gamma-Aminobutyric acid (GABA)ergic interneurons of neocortex consist of many subgroups with extremely heterogeneous morphological, physiological and molecular properties. To explore the putative effect of the vasoactive intestinal polypeptide-immunopositive (VIP +) neurons on neocortical circuitry, the number and distribution of VIP + boutons were analysed on somatodendritic domains of 272 parvalbumin immunopositive (PV +) 3D-reconstructed neurons. The synaptic nature of 91% of somatic and 76% of dendritic contacts was verified by electron microscopy. The target PV + neurons were separated in two significantly different groups by means of cluster analysis. The first group (Cluster 1, 26%) received on average five times more VIP + synapses than those of the second group. The second group (Cluster 2, 74%) contained cells that were poorly innervated by VIP + boutons or did not have either somatic or dendritic or any VIP innervation at all. The cells of Cluster 1 had a soma size and total dendritic length significantly smaller than that of Cluster 2, however, they received three times more dendritic synapses, which resulted in a five times higher VIP + synaptic density on dendrites. Our results showed that although most of the PV + cells are innervated by VIP + boutons at a varying degree, some 6% of PV + cells received no input from VIP + interneurons. This suggests a refined morphological basis to influence the majority of the PV + interneurons, which are very effectively controlling pyramidal cell firing. Together with metabolic and neuromodulatory effects of VIP, this would probably result in an enhanced responsiveness of the latter cell type to tactile stimuli.

Mapping functional connectivity in barrel-related columns reveals layer- and cell type-specific microcircuits.
Schubert D, Kötter R, Staiger JF.
Brain Struct Funct 212: 107-119, 2007.
abstract link

Synaptic circuits bind together functional modules of the neocortex. We aim to clarify in a rodent model how intra- and transcolumnar microcircuits in the barrel cortex are laid out to segregate and also integrate sensory information. The primary somatosensory (barrel) cortex of rodents is the ideal model system to study these issues because there, the tactile information derived from the large facial whiskers on the snout is mapped onto so called barrel-related columns which altogether form an isomorphic map of the sensory periphery. This allows to functionally interpret the synaptic microcircuits we have been analyzing in barrel-related columns by means of whole-cell recordings, biocytin filling and mapping of intracortical functional connectivity with sublaminar specificity by computer-controlled flash-release of glutamate. We find that excitatory spiny neurons (spiny stellate, star pyramidal, and pyramidal cells) show a layer-specific connectivity pattern on top of which further cell type-specific circuits can be distinguished. The main features are: (a) strong intralaminar, intracolumnar connections are established by all types of excitatory neurons with both, excitatory and (except for layer Vb- intrinsically burst-spiking-pyramidal cells) inhibitory cells; (b) effective translaminar, intracolumnar connections become more abundant along the three main layer compartments of the canonical microcircuit, and (c) extensive transcolumnar connectivity is preferentially found in specific cell types in each of the layer compartments of a barrel-related column. These multiple sequential and parallel circuits are likely to be suitable for specific cortical processing of "what" "where" and "when" aspects of tactile information acquired by the whiskers on the snout.

2006

Immediate-early gene expression in the barrel cortex.
Staiger JF.
Somatosens Mot Res 23:135-146., 2006.
abstract link

Since their detection in the early 1980s immediate-early genes (most of them being inducible transcription factors) have been regarded as molecular keys to the orchestration of late-effector genes that ultimately would enable functional and structural adaptation of the brain to changing external and internal demands. This is called neuronal plasticity and it has been intensively studied in the somatosensory (barrel) cortex of rodents. This brain region is intimately involved in the processing and probably also the storage of tactile information, stemming from the large facial whiskers, necessary for object detection or spatial navigation in the environment. On the other hand, several of the inducible transcription factors have been found to function as neuronal activity markers providing a cellular resolution, thus, enabling the cell-type specific mapping of activated neuronal circuits. Some recent data on both topics in the rodent barrel cortex will be presented in this topical review.

Morphology, electrophysiology and functional input connectivity of pyramidal neurons characterizes a genuine layer Va in the primary somatosensory cortex.
Schubert D, Kötter R, Luhmann HJ, Staiger JF.
Cereb Cortex 16:223-236., 2006.
abstract link

Cortical layer V classically has been subdivided into sublayers Va and Vb on cytoarchitectonic grounds. In the analysis of cortical microcircuits, however, layer Va has largely been ignored. The purpose of this study was to investigate pyramidal neurons of layer Va in view of their potential role in integrating information from lemniscal and paralemniscal sources. For this we combined detailed electrophysiological and morphological characterization with mapping of intracortical functional connectivity by caged glutamate photolysis in layer Va of rat barrel cortex in vitro. Electrophysiological characterization revealed pyramidal cells of the regular spiking as well as the intrinsically burst firing type. However, all layer Va pyramidal neurons displayed uniform morphological properties and comparable functional input connectivity patterns. They received most of their excitatory and inhibitory inputs from intracolumnar sources, especially from layer Va itself, but also from layer IV. Those two layers were also the main origin for transcolumnar excitatory inputs. Layer Va pyramidal neurons thus may predominantly integrate information intralaminarly as well as from layer IV. The functional connectivity maps clearly distinguish layer Va from layer Vb pyramidal cells, and suggest that layer Va plays a unique role in intracortical processing of sensory information.

2005

Optical release of caged glutamate for stimulation of neurons in the in vitro slice preparation.
Kötter R, Schubert D, Dyhrfjeld-Johnsen J, Luhmann HJ, Staiger JF.
J Biomed Optics 10: 1-15., 2005.
abstract link

Optical stimulation techniques prove useful to map functional inputs in the in vitro brain slice preparation: Glutamate released by a focused beam of UV light induces action potentials, which can be detected in postsynaptic neurons. The direct activation effect is influenced by factors such as compound concentration, focus depth, light absorption in the tissue, and sensitivity of different neuronal domains. We analyze information derived from direct stimulation experiments in slices from rat barrel cortex and construct a computational model of a layer V pyramidal neuron that reproduces the experimental findings. The model predictions concerning the influence of focus depth on input maps and action potential generation are investigated further in subsequent experiments where the focus depth of a high-numerical-aperture lens is systematically varied. With our setup flashes from a xenon light source can activate neuronal compartments to a depth of 200 mum below the surface of the slice. The response amplitude is influenced both by tissue depth and focus plane. Specific somatodendritic structures can be targeted as the probability of action potential induction falls off exponentially with distance. Somata and primary apical dendrites are most sensitive to uncaged glutamate with locally increased sensitivity on proximal apical dendrites. We conclude that optical stimulation can be targeted with high precision.

CoCoDat: a database system for organizing and selecting quantitative data on single neurons and neuronal microcircuitry.
Dyhrfjeld-Johnsen J, Maier J, Schubert D, Staiger JF, Luhmann HJ, Stephan KE, Kötter R.
J Neurosci Methods 141:291-308., 2005.
abstract link

We present a novel database system for organizing and selecting quantitative experimental data on single neurons and neuronal microcircuitry that has proven useful for reference-keeping, experimental planning and computational modelling. Building on our previous experience with large neuroscientific databases, the system takes into account the diversity and method-dependence of single cell and microcircuitry data and provides tools for entering and retrieving published data without a priori interpretation or summarizing. Data representation is based on the framework suggested by biophysical theory and enables flexible combinations of data on membrane conductances, ionic and synaptic currents, morphology, connectivity and firing patterns. Innovative tools have been implemented for data retrieval with optional relaxation of search criteria along the conceptual dimensions of brain region, cortical layer, cell type and subcellular compartment. The relaxation procedures help to overcome the traditional trade-off between exact, non-interpreted data representation in the original nomenclature and convenient data retrieval. We demonstrate the use of these tools for the construction, tuning and validation of a multicompartmental model of a layer V pyramidal cell from the rat barrel cortex. CoCoDat is freely available at . Its application is scalable from offline use by individual researchers via local laboratory networks to a federation of distributed web sites in platform-independent XML format using Axiope tools.

2004

Calbindin-containing interneurons are a target for VIP-immunoreactive synapses in rat primary somatosensory cortex.
Staiger JF, Masanneck C, Schleicher A, Zuschratter W.
J Comp Neurol 468: 179-189., 2004.
abstract link

Inhibitory interneurons in cerebral cortex are morphologically and physiologically extremely heterogeneous. This greatly interferes with an understanding of their functions. Progress has been made by classifying these neurons with the aid of molecular markers, e.g., neuropeptides or calcium-binding proteins, which are reliably expressed by certain subpopulations. We have used this approach to demonstrate an output of a subpopulation of cortical interneurons which express vasoactive intestinal polypeptide (VIP). By double immunostaining and correlated light and electron microscopy, we show that calbindin (CB)-containing interneurons located in layers II-VI of rat barrel cortex are targets of symmetric VIP-immunoreactive synapses. All CB-immunoreactive interneurons showed numerous contacts of VIP boutons on proximal and distal dendritic segments. A great majority of CB-immunoreactive interneurons (214/222) displayed such close appositions with VIP boutons on their soma as well. Quantification revealed that the number of VIP-immunoreactive boutons on CB-immunoreactive somata and dendrites of specified order is comparable for the different cortical layers. In conclusion, all calbindin-containing cortical interneurons seem to be under direct influence of other GABAergic interneurons expressing the peptide VIP. An indirect functional consequence of this may be disinhibition of pyramidal cells, which are considered the major target of calbindin interneurons. However, since the examined types of interneurons are intricately embedded in networks of yet different interneurons, the outcome of these multiple inhibitory interactions is likely to be less simplistic. It may be related to the timing of pyramidal cell discharge within and across layers of cortical columns.

Functional diversity of layer IV spiny neurons in rat somatosensory cortex: quantitative morphology of electrophysiologically characterized and biocytin labeled cells.
Staiger JF, Flagmeyer I, Schubert D, Zilles K, Kötter R, Luhmann HJ.
Cereb Cortex 14: 690-701., 2004.
abstract link

Previous analyses of the spiny layer IV neurons have almost exclusively focused on spiny stellate cells. Here we provide detailed morphological data characterizing three subpopulations of spiny neurons in slices of adolescent rats: (i) spiny stellate cells (58%), (ii) star pyramidal cells (25%) and (iii) pyramidal cells (17%), which can be distinguished objectively by the preferential orientation of their dendritic stems. Spiny stellate cells lacked an apical dendrite and frequently confined their dendritic and axonal arbors to the respective column. Star pyramidal and pyramidal cells possessed an apical dendrite, which reached the supragranular layers. Their axonal arbors were similar, showing both a columnar component and transcolumnar branches with direct transbarrel projections. However, a small fraction of star pyramidal cells possessed few or even no transcolumnar branches. Electrophysiologically, all three types of neurons were either regular-spiking or intrinsically burst-spiking without a significant relation to the morphological subtypes. The basic synaptic properties of thalamic inputs were also independent of the type of target layer IV spiny neuron. All remained subthreshold and showed paired-pulse depression. In conclusion, the columnar axonal arborization of spiny stellate cells is supplemented by a significant oblique to horizontal projection pattern in pyramidal-like neurons. This offers a structural basis for either segregation or early context-dependent integration of tactile information, in a cell-type specific manner.

2003

Distinct local circuits between neocortical pyramidal cells and fast-spiking interneurons in young adult rats.
Angulo MC, Staiger JF, Rossier J, Audinat A.
J Neurophysiol 89: 943-953., 2003.
abstract link

Connections between layer V pyramidal cells and GABAergic fast-spiking interneurons (pyramidal-FS) were studied by paired recordings combined with morphological analyses in acute neocortical slices from 28- to 52-day-old rats. Pairs of spikes elicited in pyramidal cells at a stimulation rate of 0.2 Hz induced unitary excitatory postsynaptic currents (EPSCs) in FS interneurons that displayed facilitation (48%), depression (38.5%), or neither depression nor facilitation (13.5%). Analyses of the EPSC amplitude distributions indicate that depressing connections always showed multiple functional release sites. On the contrary, facilitating connections consisted either of one or several release sites. At a holding potential of -72 mV, the quantal size (q) and the release probability (p) of facilitating connections with a single release site were -21.9 +/- 7.5 pA and 0.49 +/- 0.19 (SD), respectively. The mean q and the estimated number of release sites (n) at connections showing multiple sites were obtained by decreasing the release probability and did not differ between depressing and facilitating synapses (depressing connections: q = -15.3 +/- 2.5 pA, n = 5.1 +/- 3, facilitating connections: q = -23.9 +/- 9.8 pA, n = 7.8 +/- 5.4). However, the quantal content at facilitating synapses with multiple sites (1.9 +/- 1.5) was significantly different from that at depressing connections (4.1 +/- 3.9). Finally, quantitative morphological analyses revealed that most of the pyramidal cells displaying facilitation can be differentiated from those displaying depression by a more densely branched apical dendritic tree. Therefore two types of morphologically distinct pyramidal cells form excitatory connections with FS interneurons that differ in their short-term plasticity characteristics. Facilitating and depressing connections may provide a differential control of the temporal information processing of FS cells and thus finely regulate the inhibitory effect of these interneurons in neocortical networks of young adult rats.

Cell type-specific circuitry of cortical layer IV spiny neurons.
Schubert D, Kötter R, Zilles K, Luhmann HJ, Staiger JF.
J Neurosci 23: 2961-2970., 2003.
abstract link

Sensory signal processing in cortical layer IV involves two major morphological classes of excitatory neurons: spiny stellate and pyramidal cells. It is essentially unknown how these two cell types are integrated into intracortical networks and whether they play different roles in cortical signal processing. We mapped their cell-specific intracortical afferents in rat somatosensory cortex through a combination of whole-cell patch-clamp recordings and caged glutamate photolysis. Spiny stellate cells received monosynaptic excitation and inhibition originating almost exclusively from neurons located within the same barrel. Pyramidal cells, by contrast, displayed additional excitatory inputs from nongranular layers and from neighboring barrels. Their inhibitory inputs originated, as for spiny stellate cells, mainly from neurons located in the same barrel. These results indicate that spiny stellate cells act predominantly as local signal processors within a single barrel, whereas pyramidal cells globally integrate horizontal and top-down information within a functional column and between neighboring barrels.

2002

Excitatory and inhibitory neurons express c-Fos in barrel-related columns after exploration of a novel environment.
Staiger JF, Masanneck C, Bisler S, Zuschratter W, Zilles K.
Neuroscience 109: 687-699., 2002.
abstract link

Recent work has shown that behaviorally meaningful sensory information processing is accompanied by the induction of several transcription factors in the barrel cortex of rodents. It is now generally accepted that stimulus-transcription coupling is an important step in the sequence of events leading to long-term plastic changes in neuronal structure and function. Nevertheless, so far few data are available as to what types of neurons are involved in such a genomic response. Here, we determined the morphological and neurochemical identity of neurons in rat barrel cortex showing a c-Fos-immunoreactive nucleus after exploration of an enriched environment. Double stainings of c-Fos and glial fibrillary acidic protein excluded astrocytes as a possible cell type expressing this transcription factor. By morphological phenotyping with intracellular Lucifer Yellow injections, it was found that a large majority were probably excitatory pyramidal cells, but inhibitory interneurons were also found to contain c-Fos-immunoreactive nuclei. By neurochemical phenotyping of GABAergic interneurons with specific antibodies, a significant induction was found, in a layer-dependent manner, for the populations of glutamic acid decarboxylase-, parvalbumin-, calbindin- and vasoactive intestinal polypeptide-immunoreactive neurons but not for calretinin-immunoreactive cells in experimental compared to control columns. From these data we conclude that thalamic afferents effectively drive cortical excitatory as well as inhibitory intracortical circuits. Thus, the adaptations of receptive field properties of cortical neurons after different manipulations of the sensory periphery are likely to be caused by plastic changes in excitatory and inhibitory networks.

Expression of Fos, ICER, Krox-24 and JunB in the whisker-to-barrel-pathway of rats: time course of induction upon whisker-pairing and exploration of an enriched environment.
Bisler S, Schleicher A, Gass P, Stehle JH, Zilles K, Staiger JF.
J Chem Neuroanat 23: 187-198., 2002.

Innervation of interneurons immunoreactive for VIP by intrinsically bursting pyramidal cells and fast-spiking interneurons in infragranular layers of juvenile rat neocortex.
Staiger JF, Schubert D, Zuschratter W, Kötter R, Luhmann HJ, Zilles K.
Eur J Neurosci 16: 11-20., 2002.

Two types of nicotinic receptors mediate an excitation of neocortical layer I interneurons.
Christophe E, Roebuck A, Staiger JF, Lavery DJ, Charpak S, Audinat E.
J Neurophysiol 88: 1318-1327., 2002.

2001

Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex.
Ali AB, Rossier J, Staiger JF, Audinat E.
J Neurosci 21: 2992-2999., 2001.

Layer-specific intracolumnar and transcolumnar functional connectivity of layer V pyramidal cells in rat barrel cortex.
Schubert D, Staiger JF, Cho N, Kötter R, Zilles K, Luhmann HJ.
J Neurosci 21: 3580-3592., 2001.

2000

Neurons immunoreactive for vasoactive intestinal polypeptide in the rat primary somatosensory cortex: morphology and spatial relationship to barrel-related columns.
Bayraktar T, Welker E, Freund TF, Zilles K, Staiger JF.
J Comp Neurol 420: 291-304., 2000.

Exploration of a novel environment leads to the expression of inducible transcription factors in barrel-related columns.
Staiger JF, Bisler S, Schleicher A, Gass P, Stehle JH, Zilles K.
Neuroscience 99: 7-16., 2000.
abstract link

Tactile information acquired through the vibrissae is of high behavioral relevance for rodents. Numerous physiological studies have shown adaptive plasticity of cortical receptive field properties due to stimulation and/or manipulation of the whiskers. However, the cellular mechanisms leading to these plastic processes remain largely unknown. Although genomic responses are anticipated to take place in this sequel, virtually no data so far exist for freely behaving animals concerning this issue. Thus, adult rats were placed overnight in an enriched environment and most of them were also subjected to clipping of different sets of whiskers. This type of stimulation led to a specific and statistically significant increase in the expression of the protein products of the inducible transcription factors c-Fos, JunB, inducible cyclic-AMP early repressor and Krox-24 (also frequently named Zif268 or Egr-1), but not c-Jun. The response was found in columns of the barrel cortex corresponding to the stimulated vibrissae; it displayed a layer-specific pattern. However, no induction of transcription factors was observed in the subcortical relay stations of the whisker-to-barrel pathway, i.e. the trigeminal nuclei and the ventrobasal complex. These results strongly suggest that a coordinated transcriptional response is initiated in the barrel cortex as a consequence of processing of novel environmental stimuli.

Laminar characteristics of functional connectivity in rat barrel cortex revealed by stimulation with caged-glutamate.
Staiger JF, Kötter R, Zilles K, Luhmann HJ.
Neurosci Res 37: 49-58., 2000.

1999

Developmental synaptic changes increase the range of integrative capabilities of an identified excitatory neocortical connection.
Angulo MC, Staiger JF, Rossier J, Audinat E.
J Neurosci 19: 1566-1576., 1999.

Cellular morphology and physiology of the perinatal rat cerebral cortex.
Luhmann HJ, Schubert D, Kötter R, Staiger JF.
Dev Neurosci 21: 298-309., 1999.

Enlargement of cortical vibrissa representation in the surround of an ischemic cortical lesion.
Schiene K, Staiger JF, Bruehl C, Witte OW.
J Neurol Sci 162: 6-13. , 1999.

Connectivity in the somatosensory cortex of the adolescent rat: an in vitro biocytin study.
Staiger JF, Kötter R, Zilles K, Luhmann HJ.
Anat Embryol 199: 357-365. , 1999.

1998

Disturbance of the cortical cholinergic innervation in Borna disease prior to encephalitis.
Gies U, Bilzer T, Stitz L, Staiger JF.
Brain Pathol 8: 39-48., 1998.

Analysing functional connectivity in brain slices by a combination of infrared video microscopy, flash photolysis of caged compounds and scanning methods.
Kötter R, Staiger JF, Zilles K, Luhmann HJ.
Neuroscience 86: 265-277., 1998.

Immunohistochemical evidence for dysregulation of the GABAergic system ipsilateral to photochemically induced cortical infarcts in rats.
Neumann-Haefelin T, Staiger JF, Redecker C, Zilles K, Fritschy JM, Mohler H, Witte OW.
Neuroscience 87: 871-879., 1998.

Unsolved problems in comparing brain sizes in Homo sapiens.
Peters M, Jäncke L, Staiger JF, Schlaug G, Huang Y, Steinmetz H.
Brain and Cognition 37: 254-285., 1998.

Properties of bipolar VIPergic interneurons and their excitation by pyramidal neurons in the rat neocortex.
Porter JT, Cauli B, Staiger JF, Lambolez B, Rossier J, Audinat E.
Eur J Neurosci 10: 3617-3628., 1998.

1997

Co-localization of vasoactive intestinal polypeptide, gamma-aminobutyric acid and choline acetyltransferase in neocortical interneurons of the adult rat.
Bayraktar T, Staiger JF, Acsady L, Cozzari C, Freund TF, Zilles K.
Brain Res 757: 209-217., 1997.

Geniculo-cortical afferents form synaptic contacts with vasoactive intestinal polypeptide (VIP) immunoreactive neurons of the rat visual cortex.
Hajos F, Staiger JF, Halasy K, Freund TF, Zilles K.
Neurosci Lett 228: 179-182., 1997.

The relationship between corpus callosum size and forebrain volume.
Jäncke L, Staiger JF, Schlaug G, Huang YX, Steinmetz H.
Cereb Cortex 7: 48-56., 1997.

Interneurons immunoreactive for vasoactive intestinal polypeptide (VIP) are extensively innervated by parvalbumin-containing boutons in rat primary somatosensory cortex.
Staiger JF, Freund TF, Zilles K.
Eur J Neurosci 9: 2259-2268., 1997.

1996

Recurrent axon collaterals of corticothalamic projection neurons in rat primary somatosensory cortex contribute to excitatory and inhibitory feedback-loops.
Staiger JF, Zilles K, Freund TF.
Anat Embryol 194: 533-543., 1996.

Innervation of VIP-immunoreactive neurons by the ventroposteromedial thalamic nucleus in the barrel cortex of the rat.
Staiger JF, Zilles K, Freund TF.
J Comp Neurol 367: 194-204., 1996.

Distribution of GABAergic elements postsynaptic to ventroposteromedial thalamic projections in layer IV of rat barrel cortex.
Staiger JF, Zilles K, Freund TF.
Eur J Neurosci 8: 2273-2285., 1996.

Inverse relationship between brain size and callosal connectivity.
Steinmetz H, Staiger JF, Schlaug G, Huang YX, Jäncke L.
Naturwissenschaften 83: 221., 1996.

1995

Increased corpus callosum size in musicians.
Schlaug G, Jäncke L, Huang YX, Staiger JF, Steinmetz H.
Neuropsychologia 33: 1047., 1995.

Corpus callosum and brain volume in women and men.
Steinmetz H, Staiger JF, Schlaug G, Huang Y, Jäncke L.
Neuroreport 6: 1002-1004., 1995.

1992

Restricted origin and distribution of projections from the lateral to the medial septal complex in rat and guinea pig.
Witter MP, Daelmans HEM, Jorritsma-Byham B, Staiger JF, Wouterlood FG.
Neurosci Lett 148: 164-168., 1992.

1991

The efferent connections of the lateral septal nucleus in the guinea pig: intrinsic connectivity of the septum and projections to other telencephalic areas.
Staiger JF, Nürnberger F.
Cell Tissue Res 264: 415-426., 1991.

The efferent connections of the lateral septal nucleus in the guinea pig: projections to the diencephalon and brainstem.
Staiger JF, Nürnberger F.
Cell Tissue Res 264: 391-413., 1991.

1990

Efferent projections from the lateral septal nucleus to the anterior hypothalamus in the rat: a study combining Phaseolus vulgaris-leucoagglutinin tracing with vasopressin immunocytochemistry.
Staiger JF, Wouterlood FG.
Cell Tissue Res 261: 17-23., 1990.

Columnar arrangement of lumbar motoneurons innervating a pair of antagonistically acting leg muscles in the rat.
Staiger JF, Nürnberger F.
Z mikrosk -anat Forsch 104: 79-86., 1990.

1989

Pattern of afferents to the lateral septum in the guinea pig.
Staiger JF, Nürnberger F.
Cell Tissue Res 257: 471-490., 1989.

Teachings

WS 2017/18:

IMPRES- Neuroscience (Lecture)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Martin Möck,

IMPRES- Neuroscience (Course)

Prof. Dr. Jochen Staiger, PD Dr. Michael Rickmann, Dr. Martin Möck, Dr. Mirko Witte, Dr. Alvar Prönneke, Dr. Julien Guy,

Neuroanatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, Dr. Mirko Witte, Dr. Ivo Chao,

SS 2017:

Kurs der Mikroskopischen Anatomie (Histologie II) (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, Dr. Tran Tuoc, Dr. Alvar Prönneke,

Neuroanatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, Dr. Mirko Witte, Dr. Ivo Chao,

Grundlagen der Anatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch,

WS 2015/16:

Kurs der Makroskopischen Anatomie (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, ,

Neuroanatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, Dr. Mirko Witte, ,

IMPRS Neuroscience (Course)

Prof. Dr. Jochen Staiger, PD Dr. Michael Rickmann, Dr. Martin Möck, Dr. Mirko Witte, Robin Wagener ,

IMPRS Neuroscience (Lecture)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Martin Möck,

Begleitvorlesung Makroskopische Anatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Jörg Wilting, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Ivo Chao,

SS 2015:

Neuroanatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, Dr. Mirko Witte,

Mikroskopischen Anatomie (Spezielle Histologie) (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, ,

Kurs der Mikroskopischen Anatomie (Histologie II) (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, Dr. Robin Wagener, Dr. Tran Tuoc,

Kurs der Mikroskopischen Anatomie (Histologie I) (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, Dr. Robin Wagener, Dr. Tran Tuoc ,

Grundlagen der Anatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch,

WS 2014/15:

Neuroanatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, Dr. Mirko Witte,

IMPRS Neuroscience (Lecture)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Martin Möck,

IMPRS Neuroscience (Course)

Prof. Dr. Jochen Staiger, PD Dr. Michael Rickmann, Dr. Martin Möck, Dr. Mirko Witte, Robin Wagener,

Kurs der Makroskopischen Anatomie (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, Robin Wagener,

Begleitvorlesung Makroskopische Anatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Jörg Wilting, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Ivo Chao,

SS 2014:

Mikroskopischen Anatomie (Spezielle Histologie) (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann,

Neuroanatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann,

Kurs der Mikroskopischen Anatomie (Histologie II) (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, Dr. Robin Wagener, Dr. Tran Tuoc,

Kurs der Mikroskopischen Anatomie (Histologie I) (Kurs)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch, Dr. Martin Möck, Dr. Mirko Witte, Dr. Robin Wagener, Dr. Tran Tuoc,

Grundlagen der Anatomie (Vorlesung)

Prof. Dr. Jochen Staiger, Prof. Dr. Bernhard Reuss, PD Dr. Michael Rickmann, Dr. Joachim Rosenbusch,