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Prof. Dr. Jochen Staiger

Prof. Dr. Bernhard Reuss

Gabriele Schmidt

Dr. rer. nat. Julien Guy

Dr. rer. nat. Martin Möck

Dr. med. Rebeka Andrea Palicz

Dr. Stefan Pommer

Dr. rer. nat. Joachim Rosenbusch

Dr. rer. nat. Mirko Witte

Merve Özgür Erat

Aybeniz Ece Cetin

Xiaoyi Mao

Felix Preuss

Jenifer Rachel

Harun Akkoyun

Felicita Fischer

Philipp Kolligs

Lukas Müller

Flore Schork

Sophia Heidenreich

Ima Mansori

Leander Matthes

Paul Molis

Sandra Heinzl

Sabrina Hübner

Patricia Sprysch

Pavel Truschow

Dr. rer. nat. Csaba Dávid

Dr. rer. nat. Alvar Prönneke

PD Dr. Michael Rickmann

Dr. Marcel Ruiz Mejias

Dr. rer. nat. Dirk Schubert

Dr. Godwin Sokpor

Dr. rer. nat. Nidhi Subhashini

Dr. rer. nat. Tran Tuoc

Dr. med. Robin Wagener

Dr. rer. nat. Yuanbin Xie

Xiaojuan Zhou

Eman Abbas

Weilin Chen

Michael Feyerabend

Georg Hafner

Kamila Kiszka

Anouk Meeuwissen

Nieves Mingo Moreno

Ramanathan Narayanan

Huong Nguyen

Pauline Antonie Ulmke

Florian Walker

Khatuna Aslanishvili

Christina Bachmann

Simon Badura

Thore Behrendt

Jürgen Delchmann

Esther Alexandra Dockhorn

Tatjana Fischer

Anna Garcia Galera

Kristina Glöckner

Janis Hülsemann

Dilbrin Khelo

Stephen Olt

Bettina Pater

Alina Rüppel

Alexandra Sachkova

Bianca Scheuer

Lisa Thiecke

Joris Brehmer

Dennis Dalügge

Julia Dziubek

Ricardo Castro Hernandez

Fernando Gonzalez Ibanez

Christin Korb

Anette Mertens

Megha Patwa

Adrián Villalobos

Simon Weiler

Maxim Wintergoller

Nicolas Zdun

Anna Dudek

Heike Faust

Sabrina Heide

Ansgar Jahn

Linh Pham


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Mirko

Witte


Last Name: Witte Position: Wissenschaftlicher Mitarbeiter
First Name: Mirko Ort: Göttingen
Akademischer Titel: Dr. rer. nat. Tel.: +49-(0)551/39-66876
Tel.: +49-(0)551/39-7992
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Lebenslauf

  •  Seit August 2010
Postdoc an der Universitätsmedizin Göttingen der Georg-August-Universität, Zentrum Anatomie, Institut Neuroanatomie unter der Leitung von Prof. Dr. J. Staiger
  • 2010 Promotion
in der Arbeitsgruppe Neurobiologie an der Universität Leipzig unter Leitung von Prof. Dr. R. Rübsamen, Thema: "Differenzierung und Reifung GABAerger und glycinerger Neurotransmission im anteroventralen Cochleariskern der Wüstenrennmaus (Meriones unguiculatus)"
  • 2008 - 2009
wissenschaftl. Mitarbeiter an der Universität Leipzig in der Arbeitsgruppe Neurobiologie von Prof. Dr. R. Rübsamen
  • April 2005 - April 2010
Mitglied im Internationales Promotionsprogramm (IPP)  "Von der Signalverarbeitung zum Verhalten"http://www.uni-leipzig.de/zhs/ipp/
  • April 2005 - April 2010
Mitglied im Graduiertenkolleg GRK 1097/1 "Interneuro"  http://www.uni-leipzig.de/~ineuro/
  • 2005 Diplomarbeit
in der Arbeitsgruppe Neurobiologie an der Universität Leipzig unter Leitung von Prof. Dr. R. Rübsamen, Thema:"Entwicklung inhibitorischer Einflüsse im Cochleariskern: eine Patch-clamp Studie"
  • 2003 Projektarbeit
in der Arbeitsgruppe Verhaltensbiologie an der Universität Leipzig unter Leitung von PD Dr. P. A. Stevenson und Prof. Dr. K. Schildberger, Thema: "Die aminerge Modulation des Mandibel-Schließermuskels bei der Grille (Gryllus bimaculatus)"
  • 2001 - 2005
Hauptstudium im Fach Biologie an der Universität Leipzig mit den Hauptfächern: Neurobiologie, Genetik, Verhaltensphysiologie, Spezielle Zoologie und Biochemie
  • 1999 - 2001
 Grundstudium im Fach Biologie an der Universität Leipzig














Forschung

Funktionelle Analyse der Netzwerke von GABAergen Interneuronen im primären somatosensorischen (Barrel) Kortex

GABA-freisetzende Interneurone sind wesentlich an der Informationsverarbeitung im Neokortex beteiligt und unmittelbar in den somatosensorischen Verschaltungskreislauf eingebunden. Martinotti-Zellen, ein gut identifizierbarer Typ GABAerger Interneurone, wird aufgrund ihrer morphologischen Struktur eine zentrale Rolle in der Modulation dendritischer Exzitation von Pyramidenzellen zugesprochen. Sie besitzen somit einen unmittelbaren Einfluss auf die neokortikalen Ausgangstrukturen des Barrel Kortex. Neben exzitatorischen Eingängen von umgebenden Pyramidenzellen sind Martinotti-Zellen das Ziel einer ausgeprägten verhaltensabhängigen Inhibition, deren neokortikaler Ursprung ungeklärt ist. In dieser Studie sollen die Ursprungszellen der inhibitorischen Projektionen auf die Martinotti-Zellen der neokortikalen Schichten 2/3 und 5 im Barrel Kortex mittels kombinierter whole-cell Patch-Clamp-Ableitungen und lokaler Photolyse von caged-Glutamat im akuten Hirnschnitt untersucht werden. Anschließend werden "gepaarte" Patch-Clamp-Ableitungen von Martinotti-Zellen und den mit ihnen direkt verbundenen GABAergen Interneuronen genutzt, um diese Interneurone eindeutig zu identifizieren und charakterisieren. Die gewonnenen Erkenntnisse sollen einen Beitrag zum Modell zur Verarbeitung sensorischer Information im Barrel Kortex leisten und das Verständnis der Netzwerke GABAerger Interneurone verbessern.

Forschungsziele:

(I) Patch-Clamp-Ableitungen von Martinotti-Zellen und die Identifikation der neokortikalen Schichten, aus denen Neurone inhibitorisch auf die Martinotti-Zellen projizieren, mit Hilfe der "caged-Glutamat" Photolyse.

(II) Etablierung der Methode zur Identifizierung von verbundenen GABAergen Interneuronen in den ausgewählten (I) neokortikalen Schichten im akuten Hirnschnitt

(III) Simultane "gepaarte" Patch-Clamp-Ableitungen von Martinotti-Zellen und den vorgeschalteten inhibitorischen Interneuronen, sowie deren Charakterisierung nach der Petilla Terminologie

Publikationen

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.

2020

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.

2019

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.

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.
abstract link

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.

2017

Nicotine reverses hypofrontality in animal models of addiction and schizophrenia.
Koukouli,F.; Rooy,M.; Tziotis,D.; Sailor,K.A.; O'Neill,H.C.; Levenga,J.; Witte,M.; Nilges,M.; Changeux,J.P.; Hoeffer,C.A.; Stitzel,J.A.; Gutkin,B.S.; DiGregorio,D.A.; Maskos,U..
Nature Medicine, 2017.
abstract link

The prefrontal cortex (PFC) underlies higher cognitive processes that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs. PFC spontaneous default activity is altered in neuropsychiatric disorders, including schizophrenia-a disorder that can be accompanied by heavy smoking. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking.

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.

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.

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.

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.

2014

Depolarizing chloride gradient in developing cochlear nucleus neurons: Underlying mechanism and implication for calcium signaling.
Witte M, Reinert T., Dietz B., Nerlich J., Rübsamen R., Milenkovic I..
Neuroscience 261: 207-222 , 2014.
abstract link

Precise regulation of the chloride homeostasis crucially determines the action of inhibitory transmitters GABA and glycine and thereby endows neurons or even discrete neuronal compartments with distinct physiological responses to the same transmitters. In mammals, the signaling mediated by GABAA/glycine receptors shifts during early postnatal life from depolarization to hyperpolarization, due to delayed maturation of the chloride homeostasis system. While the activity of the secondary active, K+-Cl--extruding cotransporter KCC2, renders GABA/glycine hyperpolarizing in auditory brainstem nuclei of altricial rodents, the mechanisms contributing to the initially depolarizing transmembrane gradient for Cl- in respective neurons remained unknown. Here we used gramicidin-perforated patch recordings, non-invasive Cl- and Ca2+ imaging, and immunohistochemistry to identify the Cl--loading transporter that renders depolarizing effects of GABA/glycine in early postnatal life of spherical bushy cells in the cochlear nucleus of gerbil. Our data identify the 1Na+:1K+:2Cl- cotransporter 1 (NKCC1) as the major Cl--loader responsible for depolarizing action of GABA/glycine at postnatal days 3-5 (P3-5). Extracellular GABA/muscimol elicited calcium signaling through R-, L-, and T-type channels, which was dependent on bumetanide- and [Na+]e-sensitive Cl- accumulation. The "adult like", low intracellular Cl- concentration is established during the second postnatal week, through a mechanism engaging the NKCC1-down regulation between P5 and P15 and ongoing KCC2-mediated Cl--extrusion.

2010

Presynaptic and postsynaptic origin of multicomponent extracellular spike waveforms at the endbulb of held/spherical bushy cell synapse..
Typlt M., Haustein M., Dietz B., Steinert J., Witte M., Englitz B., Milenkovic I., Kopp-Scheinpflug C., Forsythe I., Rübsamen R..
Eur J Neuroscience 31(9):1574-81 , 2010.
abstract link

Extracellular signals from the endbulb of Held-spherical bushy cell (SBC) synapse exhibit up to three component waves ('P', 'A' and 'B'). Signals lacking the third component (B) are frequently observed but as the origin of each of the components is uncertain, interpretation of this lack of B has been controversial: is it a failure to release transmitter or a failure to generate or propagate an action potential? Our aim was to determine the origin of each component. We combined single- and multiunit in vitro methods in Mongolian gerbils and Wistar rats and used pharmacological tools to modulate glutamate receptors or voltage-gated sodium channels. Simultaneous extra- and intracellular recordings from single SBCs demonstrated a presynaptic origin of the P-component, consistent with data obtained with multielectrode array recordings of local field potentials. The later components (A and B) correspond to the excitatory postsynaptic potential (EPSP) and action potential of the SBC, respectively. These results allow a clear interpretation of in vivo extracellular signals. We conclude that action potential failures occurring at the endbulb-SBC synaptic junction largely reflect failures of the EPSP to trigger an action potential and not failures of synaptic transmission. The data provide the basis for future investigation of convergence of excitatory and inhibitory inputs in modulating transmission at a fully functional neuronal system using physiological stimulation.

2009

P2 receptor-mediated signaling in spherical bushy cells of the mammalian cochlear nucleus..
Milenkovic, I., Rinke I, Witte M, Dietz, B., Rübsamen R..
J Neurophysiol. 102(3):1821-1833, 2009.
abstract link

Purinoreceptors of the P2 family contribute strongly to signaling in the cochlea, but little is known about the effects of purinergic neurotransmission in the central auditory system. Here we examine P2 receptor-mediated signaling in the large spherical bushy cells (SBCs) of Mongolian gerbils around the onset of acoustically evoked signal processing (P9-P14). Brief adenosine 5'-O-(3-thiotriphosphate) (ATPgammaS) application evoked inward current, membrane depolarization, and somatic Ca2+ signals. Moreover, ATPgammaS changed the SBCs firing pattern from phasic to tonic, when the application was synchronized with depolarizing current injection. This bursting discharge activity was dependent on [Ca2+]i and Ca2+-dependent protein kinase (PKC) activity and is presumably caused by modulation of low-threshold K+ conductance. Activation of P2Y1 receptors could not evoke these changes per se, thus it was concluded that the involvement of P2X receptors seems to be necessary. Ca2+ imaging data showed that both P2X and P2Y1 receptors mediate Ca2+ signals in SBCs where P2Y1 receptors most likely activate the PLC-IP3 (inositol trisphosphate) pathway and release Ca2+ from internal stores. Immunohistochemical staining confirmed the expression of P2X2 and P2Y1 receptor proteins in SBCs, providing additional evidence for the involvement of both receptors in signal transduction in these neurons. Purinergic signaling might modulate excitability of SBCs and thereby contribute to regulation of synaptic strength. Functionally, the increase in firing rate mediated by P2 receptors could reduce temporal precision of the postsynaptic firing, e.g., phase locking, which has an immediate effect on signal processing related to sound localization. This might provide a mechanism for adaptation to the ambient acoustic environment.

2007

Development of chloride-mediated inhibition in neurons of the anteroventral cochlear nucleus of gerbil (Meriones unguiculatus).
Milenkovic I., Witte M., Turecek R., Heinrich M., Reinert T., Rübsamen R..
J Neurophysiol 98: 1634-1644, 2007.
abstract link

At the initial stages in neuronal development, GABAergic and glycinergic neurotransmission exert depolarizing responses, assumed to be of importance for maturation, which in turn shift to hyperpolarizing in early postnatal life due to development of the chloride homeostasis system. Spherical bushy cells (SBC) of the mammalian cochlear nucleus integrate excitatory glutamatergic inputs with inhibitory (GABAergic and glycinergic) inputs to compute signals that contribute to sound localization based on interaural time differences. To provide a fundamental understanding of the properties of GABAergic neurotransmission in mammalian cochlear nucleus, we investigated the reversal potential of the GABA-evoked currents (E GABA) by means of gramicidin-perforated-patch recordings in developing SBC. The action of GABA switches from depolarizing to hyperpolarizing by the postnatal day 7 due to the negative shift in E GABA. Furthermore, we studied the expression pattern of the K+-Cl(-)-extruding cotransporter KCC2, previously shown to induce a switch from neonatal Cl(-) efflux to the mature Cl(-) influx in various neuron types, thereby causing a shift from depolarizing to hyperpolarizing GABA action. The KCC2 protein is expressed in SBC already at birth, yet its activity is attained toward the end of the first postnatal week as indicated by pharmacological inhibition. Interruption of the Cl(-) extrusion by [(dihydroindenyl)oxy] alkanoic acid or furosemide gradually shifted E(GABA) in positive direction with increasing maturity, suggesting that KCC2 could be involved in maintaining low [Cl(-)]i after the postnatal day 7 thereby providing the hyperpolarizing Cl(-)-mediated inhibition in SBC.

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