Publications by authors named "Hannah Monyer"

131 Publications

Neurogenesis in the adult brain functionally contributes to the maintenance of chronic neuropathic pain.

Sci Rep 2021 Sep 17;11(1):18549. Epub 2021 Sep 17.

Institute of Pharmacology, Heidelberg University, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

Maladaptive adult neurogenesis in the mammalian brain has been associated with diverse behaviors including disrupted learning, negative mood disorders and psychiatric conditions. However, its functional role in the generation and maintenance of chronic pathological pain has not yet been elucidated. Using an inducible genetic deletion in vivo mouse model, different behavioural paradigms and home cage monitoring systems, we show that an absence of adult neurogenesis does not impact the development of neuropathic injury-induced peripheral nociceptive hypersensitivity, but rather promotes the recovery of pathological pain as well as improves parameters associated with the state of well-being of the injured mice. These results provide a mechanistic insight into the mechanisms of chronic pain and implicate neurogenic processes as a potential therapeutic target for reducing pain and improving the quality of life for patients.
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http://dx.doi.org/10.1038/s41598-021-97093-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8448753PMC
September 2021

Two septal-entorhinal GABAergic projections differentially control coding properties of spatially tuned neurons in the medial entorhinal cortex.

Cell Rep 2021 03;34(9):108801

Department of Clinical Neurobiology at the Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Septal parvalbumin-expressing (PV) and calbindin-expressing (CB) projections inhibit low-threshold and fast-spiking interneurons, respectively, in the medial entorhinal cortex (MEC). We investigate how the two inputs control neuronal activity in the MEC in freely moving mice. Stimulation of PV and CB terminals causes disinhibition of spatially tuned MEC neurons, but exerts differential effects on temporal coding and burst firing. Thus, recruitment of PV projections disrupts theta-rhythmic firing of MEC neurons, while stimulation of CB projections increases burst firing of grid cells and enhances phase precession in a cell-type-specific manner. Inactivation of septal PV or CB neurons differentially affects context, reference, and working memory. Together, our results reveal how specific connectivity of septal GABAergic projections with MEC interneurons translates into differential modulation of MEC neuronal coding.
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http://dx.doi.org/10.1016/j.celrep.2021.108801DOI Listing
March 2021

Layer 3 Pyramidal Cells in the Medial Entorhinal Cortex Orchestrate Up-Down States and Entrain the Deep Layers Differentially.

Cell Rep 2020 12;33(10):108470

Charité-Universitätsmedizin Berlin, Neuroscience Research Center, 10117 Berlin, Germany; Berlin Institute of Health, 10178 Berlin, Germany; German Center for Neurodegenerative Diseases (DZNE) Berlin, 10117 Berlin, Germany; Cluster of Excellence NeuroCure, 10117 Berlin, Germany; Einstein Center for Neurosciences Berlin, 10117 Berlin, Germany. Electronic address:

Up-down states (UDS) are synchronous cortical events of neuronal activity during non-REM sleep. The medial entorhinal cortex (MEC) exhibits robust UDS during natural sleep and under anesthesia. However, little is known about the generation and propagation of UDS-related activity in the MEC. Here, we dissect the circuitry underlying UDS generation and propagation across layers in the MEC using both in vivo and in vitro approaches. We provide evidence that layer 3 (L3) MEC is crucial in the generation and maintenance of UDS in the MEC. Furthermore, we find that the two sublayers of the L5 MEC participate differentially during UDS. Our findings show that L5b, which receives hippocampal output, is strongly innervated by UDS activity originating in L3 MEC. Our data suggest that L5b acts as a coincidence detector during information transfer between the hippocampus and the cortex and thereby plays an important role in memory encoding and consolidation.
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http://dx.doi.org/10.1016/j.celrep.2020.108470DOI Listing
December 2020

Septal GABAergic inputs to CA1 govern contextual memory retrieval.

Sci Adv 2020 Oct 30;6(44). Epub 2020 Oct 30.

Pharmacology Unit, Department of Clinical Foundations, University of Barcelona, Barcelona 08036, Spain.

The CA1 output region of the hippocampus plays an essential role in the retrieval of episodic memories. γ-Aminobutyric acid-releasing (GABAergic) long-range projections from the medial septum (MS) densely innervate the hippocampus, but whether septal inputs regulate memory expression remains elusive. We found that the MS to CA1 connection is recruited during recall of a contextual fear memory. Chemogenetic silencing of CA1-projecting MS neurons or septal GABAergic terminals within CA1 blocked memory retrieval. Photostimulation of septal GABAergic terminals in CA1 selectively inhibited interneurons. Abrogating septal GABAergic cells during retrieval disinhibited parvalbumin-rich (PV+) cells in CA1. Direct activation of CA1 PV+ cells impaired memory and prevented the induction of extracellular signal-regulated kinase/mitogen-activated kinase signaling in postsynaptic pyramidal neurons. Opposing disinhibition of hippocampal PV+ cells reversibly restored memory. Our data indicate that suppression of feed-forward inhibition onto CA1 by septal GABAergic neurons is an important mechanism in gating contextual fear behavior.
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http://dx.doi.org/10.1126/sciadv.aba5003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608800PMC
October 2020

Diversity and function of corticopetal and corticofugal GABAergic projection neurons.

Nat Rev Neurosci 2020 09 3;21(9):499-515. Epub 2020 Aug 3.

Department of Clinical Neurobiology of the Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.

It is still widely thought that cortical projections to distant brain areas derive by and large from glutamatergic neurons. However, an increasing number of reports provide evidence that cortical GABAergic neurons comprise a smaller population of 'projection neurons' in addition to the well-known and much-studied interneurons. GABAergic long-range axons that derive from, or project to, cortical areas are thought to entrain distant brain areas for efficient information transfer and processing. Research conducted over the past 10 years has revealed that cortical GABAergic projection neurons are highly diverse in terms of molecular marker expression, synaptic targeting (identity of targeted cell types), activity pattern during distinct behavioural states and precise temporal recruitment relative to ongoing neuronal network oscillations. As GABAergic projection neurons connect many cortical areas unidirectionally or bidirectionally, it is safe to assume that they participate in the modulation of a whole series of behavioural and cognitive functions. We expect future research to examine how long-range GABAergic projections fine-tune activity in distinct distant networks and how their recruitment alters the behaviours that are supported by these networks.
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http://dx.doi.org/10.1038/s41583-020-0344-9DOI Listing
September 2020

Neurogenesis of medium spiny neurons in the nucleus accumbens continues into adulthood and is enhanced by pathological pain.

Mol Psychiatry 2020 Jul 1. Epub 2020 Jul 1.

Department of Clinical Neurobiology, University Hospital Heidelberg and German Cancer Research Center, Heidelberg, Germany.

In mammals, most adult neural stem cells (NSCs) are located in the ventricular-subventricular zone (V-SVZ) along the wall of the lateral ventricles and they are the source of olfactory bulb interneurons. Adult NSCs exhibit an apico-basal polarity; they harbor a short apical process and a long basal process, reminiscent of radial glia morphology. In the adult mouse brain, we detected extremely long radial glia-like fibers that originate from the anterior-ventral V-SVZ and that are directed to the ventral striatum. Interestingly, a fraction of adult V-SVZ-derived neuroblasts dispersed in close association with the radial glia-like fibers in the nucleus accumbens (NAc). Using several in vivo mouse models, we show that newborn neurons integrate into preexisting circuits in the NAc where they mature as medium spiny neurons (MSNs), i.e., a type of projection neurons formerly believed to be generated only during embryonic development. Moreover, we found that the number of newborn neurons in the NAc is dynamically regulated by persistent pain, suggesting that adult neurogenesis of MSNs is an experience-modulated process.
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http://dx.doi.org/10.1038/s41380-020-0823-4DOI Listing
July 2020

Neuronal signatures in cancer.

Int J Cancer 2020 12 19;147(12):3281-3291. Epub 2020 Jun 19.

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany.

Despite advances in the treatment of solid tumors, the prognosis of patients with many cancers remains poor, particularly of those with primary and metastatic brain tumors. In the last years, "Cancer Neuroscience" emerged as novel field of research at the crossroads of oncology and classical neuroscience. In primary brain tumors, including glioblastoma (GB), communicating networks that render tumor cells resistant against cytotoxic therapies were identified. To build these networks, GB cells extend neurite-like protrusions called tumor microtubes (TMs). Synapses on TMs allow tumor cells to retrieve neuronal input that fosters growth. Single cell sequencing further revealed that primary brain tumors recapitulate many steps of neurodevelopment. Interestingly, neuronal characteristics, including the ability to extend neurite-like protrusions, neuronal gene expression signatures and interactions with neurons, have now been found not only in brain and neuroendocrine tumors but also in some cancers of epithelial origin. In this review, we will provide an overview about neurite-like protrusions as well as neurodevelopmental origins, hierarchies and gene expression signatures in cancer. We will also discuss how "Cancer Neuroscience" might provide a framework for the development of novel therapies.
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http://dx.doi.org/10.1002/ijc.33138DOI Listing
December 2020

Emerging intersections between neuroscience and glioma biology.

Nat Neurosci 2019 12 12;22(12):1951-1960. Epub 2019 Nov 12.

Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, INF 400, Heidelberg, Germany.

The establishment of neuronal and glial networks in the brain depends on the activities of neural progenitors, which are influenced by cell-intrinsic mechanisms, interactions with the local microenvironment and long-range signaling. Progress in neuroscience has helped identify key factors in CNS development. In parallel, studies in recent years have increased our understanding of molecular and cellular factors in the development and growth of primary brain tumors. To thrive, glioma cells exploit pathways that are active in normal CNS progenitor cells, as well as in normal neurotransmitter signaling. Furthermore, tumor cells of incurable gliomas integrate into communicating multicellular networks, where they are interconnected through neurite-like cellular protrusions. In this Review, we discuss evidence that CNS development, organization and function share a number of common features with glioma progression and malignancy. These include mechanisms used by cells to proliferate and migrate, interact with their microenvironment and integrate into multicellular networks. The emerging intersections between the fields of neuroscience and neuro-oncology considered in this review point to new research directions and novel therapeutic opportunities.
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http://dx.doi.org/10.1038/s41593-019-0540-yDOI Listing
December 2019

Dynamic Changes in Ultrastructure of the Primary Cilium in Migrating Neuroblasts in the Postnatal Brain.

J Neurosci 2019 12 4;39(50):9967-9988. Epub 2019 Nov 4.

Department of Developmental and Regenerative Neurobiology, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan,

New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventricular zone of the brain throughout an animal's life. These neuroblasts are characterized by their unique potential for proliferation, formation of chain-like cell aggregates, and long-distance and high-speed migration through the rostral migratory stream (RMS) toward the olfactory bulb (OB), where they decelerate and differentiate into mature interneurons. The dynamic changes of ultrastructural features in postnatal-born neuroblasts during migration are not yet fully understood. Here we report the presence of a primary cilium, and its ultrastructural morphology and spatiotemporal dynamics, in migrating neuroblasts in the postnatal RMS and OB. The primary cilium was observed in migrating neuroblasts in the postnatal RMS and OB in male and female mice and zebrafish, and a male rhesus monkey. Inhibition of intraflagellar transport molecules in migrating neuroblasts impaired their ciliogenesis and rostral migration toward the OB. Serial section transmission electron microscopy revealed that each migrating neuroblast possesses either a pair of centrioles or a basal body with an immature or mature primary cilium. Using immunohistochemistry, live imaging, and serial block-face scanning electron microscopy, we demonstrate that the localization and orientation of the primary cilium are altered depending on the mitotic state, saltatory migration, and deceleration of neuroblasts. Together, our results highlight a close mutual relationship between spatiotemporal regulation of the primary cilium and efficient chain migration of neuroblasts in the postnatal brain. Immature neurons (neuroblasts) generated in the postnatal brain have a mitotic potential and migrate in chain-like cell aggregates toward the olfactory bulb. Here we report that migrating neuroblasts possess a tiny cellular protrusion called a primary cilium. Immunohistochemical studies with zebrafish, mouse, and monkey brains suggest that the presence of the primary cilium in migrating neuroblasts is evolutionarily conserved. Ciliogenesis in migrating neuroblasts in the rostral migratory stream is suppressed during mitosis and promoted after cell cycle exit. Moreover, live imaging and 3D electron microscopy revealed that ciliary localization and orientation change during saltatory movement of neuroblasts. Our results reveal highly organized dynamics in maturation and positioning of the primary cilium during neuroblast migration that underlie saltatory movement of postnatal-born neuroblasts.
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http://dx.doi.org/10.1523/JNEUROSCI.1503-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6978947PMC
December 2019

Localization of Retinal Ca/Calmodulin-Dependent Kinase II-β (CaMKII-β) at Bipolar Cell Gap Junctions and Cross-Reactivity of a Monoclonal Anti-CaMKII-β Antibody With Connexin36.

Front Mol Neurosci 2019 28;12:206. Epub 2019 Aug 28.

Animal Navigation/Neurosensorics, Institute for Biology and Environmental Sciences, University of Oldenburg, Oldenburg, Germany.

Neuronal gap junctions formed by connexin36 (Cx36) and chemical synapses share striking similarities in terms of plasticity. Ca/calmodulin-dependent protein kinase II (CaMKII), an enzyme known to induce memory formation at chemical synapses, has recently been described to potentiate electrical coupling in the retina and several other brain areas phosphorylation of Cx36. The contribution of individual CaMKII isoforms to this process, however, remains unknown. We recently identified CaMKII-β at electrical synapses in the mouse retina. Now, we set out to identify cell types containing Cx36 gap junctions that also express CaMKII-β. To ensure precise description, we first tested the specificity of two commercially available antibodies on CaMKII-β-deficient retinas. We found that a polyclonal antibody was highly specific for CaMKII-β. However, a monoclonal antibody (CB-β-1) recognized CaMKII-β but also cross-reacted with the C-terminal tail of Cx36, making localization analyses with this antibody inaccurate. Using the polyclonal antibody, we identified strong CaMKII-β expression in bipolar cell terminals that were secretagogin- and HCN1-positive and thus represent terminals of type 5 bipolar cells. In these terminals, a small fraction of CaMKII-β also colocalized with Cx36. A similar pattern was observed in putative type 6 bipolar cells although there, CaMKII expression seemed less pronounced. Next, we tested whether CaMKII-β influenced the Cx36 expression in bipolar cell terminals by quantifying the number and size of Cx36-immunoreactive puncta in CaMKII-β-deficient retinas. However, we found no significant differences between the genotypes, indicating that CaMKII-β is not necessary for the formation and maintenance of Cx36-containing gap junctions in the retina. In addition, in wild-type retinas, we observed frequent association of Cx36 and CaMKII-β with synaptic ribbons, i.e., chemical synapses, in bipolar cell terminals. This arrangement resembled the composition of mixed synapses found for example in Mauthner cells, in which electrical coupling is regulated by glutamatergic activity. Taken together, our data imply that CaMKII-β may fulfill several functions in bipolar cell terminals, regulating both Cx36-containing gap junctions and ribbon synapses and potentially also mediating cross-talk between these two types of bipolar cell outputs.
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http://dx.doi.org/10.3389/fnmol.2019.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6724749PMC
August 2019

GluA4-Targeted AAV Vectors Deliver Genes Selectively to Interneurons while Relying on the AAV Receptor for Entry.

Mol Ther Methods Clin Dev 2019 Sep 23;14:252-260. Epub 2019 Jul 23.

Division of Medical Biotechnology, Paul-Ehrlich-Institut, 63225 Langen, Germany.

Selective gene delivery into subtypes of interneurons remains an important challenge in vector development. Adeno-associated virus (AAV) vector particles are especially promising for intracerebral injections. For cell entry, AAV2 particles are supposed to attach to heparan-sulfate proteoglycans (HSPGs) followed by endocytosis via the AAV receptor (AAVR). Here, we assessed engineered AAV particles deficient in HSPG attachment but competent in recognizing the glutamate receptor 4 (GluA4, also known as GluRD or GRIA4) through a displayed GluA4-specific DARPin (designed ankyrin repeat protein). When injected into the mouse brain, histological evaluation revealed that in various regions, more than 90% of the transduced cells were interneurons, mainly of the parvalbumin-positive subtype. Although part of the selectivity was mediated by the DARPin, the chosen spleen focus-forming virus (SFFV) promoter had contributed as well. Further analysis revealed that the DARPin mediated selective attachment to GluA4-positive cells, whereas gene delivery required expression of AAVR. Our data suggest that cell selectivity of AAV particles can be modified rationally and efficiently through DARPins, but expression of the AAV entry receptor remains essential.
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http://dx.doi.org/10.1016/j.omtm.2019.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706527PMC
September 2019

Gamma oscillations in somatosensory cortex recruit prefrontal and descending serotonergic pathways in aversion and nociception.

Nat Commun 2019 02 28;10(1):983. Epub 2019 Feb 28.

Pharmacology Institute, Medical Faculty Heidelberg, Im Neuenheimer Feld 366, 69120, Heidelberg, Germany.

In humans, gamma-band oscillations in the primary somatosensory cortex (S1) correlate with subjective pain perception. However, functional contributions to pain and the nature of underlying circuits are unclear. Here we report that gamma oscillations, but not other rhythms, are specifically strengthened independently of any motor component in the S1 cortex of mice during nociception. Moreover, mice with inflammatory pain show elevated resting gamma and alpha activity and increased gamma power in response to sub-threshold stimuli, in association with behavioral nociceptive hypersensitivity. Inducing gamma oscillations via optogenetic activation of parvalbumin-expressing inhibitory interneurons in the S1 cortex enhances nociceptive sensitivity and induces aversive avoidance behavior. Activity mapping identified a network of prefrontal cortical and subcortical centers whilst morphological tracing and pharmacological studies demonstrate the requirement of descending serotonergic facilitatory pathways in these pain-related behaviors. This study thus describes a mechanistic framework for modulation of pain by specific activity patterns in the S1 cortex.
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http://dx.doi.org/10.1038/s41467-019-08873-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395755PMC
February 2019

Identification of Embryonic Neural Plate Border Stem Cells and Their Generation by Direct Reprogramming from Adult Human Blood Cells.

Cell Stem Cell 2019 01 20;24(1):166-182.e13. Epub 2018 Dec 20.

Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ), and DKFZ-ZMBH Alliance, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. Electronic address:

We report the direct reprogramming of both adult human fibroblasts and blood cells into induced neural plate border stem cells (iNBSCs) by ectopic expression of four neural transcription factors. Self-renewing, clonal iNBSCs can be robustly expanded in defined media while retaining multilineage differentiation potential. They generate functional cell types of neural crest and CNS lineages and could be used to model a human pain syndrome via gene editing of SCN9A in iNBSCs. NBSCs can also be derived from human pluripotent stem cells and share functional and molecular features with NBSCs isolated from embryonic day 8.5 (E8.5) mouse neural folds. Single-cell RNA sequencing identified the anterior hindbrain as the origin of mouse NBSCs, with human iNBSCs sharing a similar regional identity. In summary, we identify embryonic NBSCs and report their generation by direct reprogramming in human, which may facilitate insights into neural development and provide a neural stem cell source for applications in regenerative medicine.
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http://dx.doi.org/10.1016/j.stem.2018.11.015DOI Listing
January 2019

Deciphering the Contributions of CRH Receptors in the Brain and Pituitary to Stress-Induced Inhibition of the Reproductive Axis.

Front Mol Neurosci 2018 30;11:305. Epub 2018 Aug 30.

Schaller Group on Neuropeptides, German Cancer Research Center, Heidelberg - Central Institute of Mental Health, Mannheim, Germany.

Based on pharmacological studies, corticotropin-releasing hormone (CRH) and its receptors play a leading role in the inhibition of the hypothalamic-pituitary-gonadal (HPG) axis during acute stress. To further study the effects of CRH receptor signaling on the HPG axis, we generated and/or employed male mice lacking CRH receptor type 1 (CRHR1) or type 2 (CRHR2) in gonadotropin-releasing hormone neurons, GABAergic neurons, or in all central neurons and glia. The deletion of CRHRs revealed a preserved decrease of plasma luteinizing hormone (LH) in response to either psychophysical or immunological stress. However, under basal conditions, central infusion of CRH into mice lacking CRHR1 in all central neurons and glia, or application of CRH to pituitary cultures from mice lacking CRHR2, failed to suppress LH release, unlike in controls. Our results, taken together with those of the earlier pharmacological studies, suggest that inhibition of the male HPG axis during acute stress is mediated by other factors along with CRH, and that CRH suppresses the HPG axis at the central and pituitary levels via CRHR1 and CRHR2, respectively.
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http://dx.doi.org/10.3389/fnmol.2018.00305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6125327PMC
August 2018

Target selectivity of septal cholinergic neurons in the medial and lateral entorhinal cortex.

Proc Natl Acad Sci U S A 2018 03 27;115(11):E2644-E2652. Epub 2018 Feb 27.

Department of Clinical Neurobiology, German Cancer Research Center, 69120 Heidelberg, Germany;

The entorhinal cortex (EC) plays a pivotal role in processing and conveying spatial information to the hippocampus. It has long been known that EC neurons are modulated by cholinergic input from the medial septum. However, little is known as to how synaptic release of acetylcholine affects the different cell types in EC. Here we combined optogenetics and patch-clamp recordings to study the effect of cholinergic axon stimulation on distinct neurons in EC. We found dense cholinergic innervations that terminate in layer I and II (LI and LII). Light-activated stimulation of septal cholinergic projections revealed differential responses in excitatory and inhibitory neurons in LI and LII of both medial and lateral EC. We observed depolarizing responses mediated by nicotinic and muscarinic receptors primarily in putative serotonin receptor (p5HTR)-expressing interneurons. Hyperpolarizing muscarinic receptor-mediated responses were found predominantly in excitatory cells. Additionally, some excitatory as well as a higher fraction of inhibitory neurons received mono- and/or polysynaptic GABAergic inputs, revealing that medial septum cholinergic neurons have the capacity to corelease GABA alongside acetylcholine. Notably, the synaptic effects of acetylcholine were similar in neurons of both medial and lateral EC. Taken together, our findings demonstrate that EC activity may be differentially modulated via the activation or the suppression of distinct subsets of LI and LII neurons by the septal cholinergic system.
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http://dx.doi.org/10.1073/pnas.1716531115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5856533PMC
March 2018

Eliminating Glutamatergic Input onto Horizontal Cells Changes the Dynamic Range and Receptive Field Organization of Mouse Retinal Ganglion Cells.

J Neurosci 2018 02 19;38(8):2015-2028. Epub 2018 Jan 19.

Departments of Neurobiology,

In the mammalian retina, horizontal cells receive glutamatergic inputs from many rod and cone photoreceptors and return feedback signals to them, thereby changing photoreceptor glutamate release in a light-dependent manner. Horizontal cells also provide feedforward signals to bipolar cells. It is unclear, however, how horizontal cell signals also affect the temporal, spatial, and contrast tuning in retinal output neurons, the ganglion cells. To study this, we generated a genetically modified mouse line in which we eliminated the light dependency of feedback by deleting glutamate receptors from mouse horizontal cells. This genetic modification allowed us to investigate the impact of horizontal cells on ganglion cell signaling independent of the actual mode of feedback in the outer retina and without pharmacological manipulation of signal transmission. In control and genetically modified mice (both sexes), we recorded the light responses of transient OFF-α retinal ganglion cells in the intact retina. Excitatory postsynaptic currents (EPSCs) were reduced and the cells were tuned to lower temporal frequencies and higher contrasts, presumably because photoreceptor output was attenuated. Moreover, receptive fields of recorded cells showed a significantly altered surround structure. Our data thus suggest that horizontal cells are responsible for adjusting the dynamic range of retinal ganglion cells and, together with amacrine cells, contribute to the center/surround organization of ganglion cell receptive fields in the mouse. Horizontal cells represent a major neuronal class in the mammalian retina and provide lateral feedback and feedforward signals to photoreceptors and bipolar cells, respectively. The mode of signal transmission remains controversial and, moreover, the contribution of horizontal cells to visual processing is still elusive. To address the question of how horizontal cells affect retinal output signals, we recorded the light responses of transient OFF-α retinal ganglion cells in a newly generated mouse line. In this mouse line, horizontal cell signals were no longer modulated by light. With light response recordings, we show that horizontal cells increase the dynamic range of retinal ganglion cells for contrast and temporal changes and contribute to the center/surround organization of their receptive fields.
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http://dx.doi.org/10.1523/JNEUROSCI.0141-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705883PMC
February 2018

Differential Distribution of Retinal Ca/Calmodulin-Dependent Kinase II (CaMKII) Isoforms Indicates CaMKII-β and -δ as Specific Elements of Electrical Synapses Made of Connexin36 (Cx36).

Front Mol Neurosci 2017 19;10:425. Epub 2017 Dec 19.

Animal Navigation/Neurosensorics, Institute for Biology and Environmental Sciences, University of Oldenburg, Oldenburg, Germany.

AII amacrine cells are essential interneurons of the primary rod pathway and transmit rod-driven signals to ON cone bipolar cells to enable scotopic vision. Gap junctions made of connexin36 (Cx36) mediate electrical coupling among AII cells and between AII cells and ON cone bipolar cells. These gap junctions underlie a remarkable degree of plasticity and are modulated by different signaling cascades. In particular, Ca/calmodulin-dependent protein kinase II (CaMKII) has been characterized as an important regulator of Cx36, capable of potentiating electrical coupling in AII cells. However, it is unclear which CaMKII isoform mediates this effect. To obtain a more detailed understanding of the isoform composition of CaMKII at retinal gap junctions, we analyzed the retinal distribution of all four CaMKII isoforms using confocal microscopy. These experiments revealed a differential distribution of CaMKII isoforms: CaMKII-α was strongly expressed in starburst amacrine cells, which are known to lack electrical coupling. CaMKII-β was abundant in OFF bipolar cells, which form electrical synapses in the outer and the inner retina. CaMKII-γ was diffusely distributed across the entire retina and could not be assigned to a specific cell type. CaMKII-δ labeling was evident in bipolar and AII amacrine cells, which contain the majority of Cx36-immunoreactive puncta in the inner retina. We double-labeled retinas for Cx36 and the four CaMKII isoforms and revealed that the composition of the CaMKII enzyme differs between gap junctions in the outer and the inner retina: in the outer retina, only CaMKII-β colocalized with Cx36-containing gap junctions, whereas in the inner retina, CaMKII-β and -δ colocalized with Cx36. This finding suggests that gap junctions in the inner and the outer retina may be regulated differently although they both contain the same connexin. Taken together, our study identifies CaMKII-β and -δ as Cx36-specific regulators in the mouse retina with CaMKII-δ regulating the primary rod pathway.
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http://dx.doi.org/10.3389/fnmol.2017.00425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5742114PMC
December 2017

Mouse Is Dispensable for Hearing Acquisition and Auditory Function.

Front Mol Neurosci 2017 28;10:379. Epub 2017 Nov 28.

CNR Institute of Cell Biology and Neurobiology, Monterotondo, Italy.

Panx1 forms plasma membrane channels in brain and several other organs, including the inner ear. Biophysical properties, activation mechanisms and modulators of Panx1 channels have been characterized in detail, however the impact of on auditory function is unclear due to conflicts in published results. To address this issue, hearing performance and cochlear function of the -/- mouse strain, the first with a reported global ablation of , were scrutinized. Male and female homozygous (-/-), hemizygous (+/-) and their wild type (WT) siblings (+/+) were used for this study. Successful ablation of was confirmed by RT-PCR and Western immunoblotting in the cochlea and brain of -/- mice. Furthermore, a previously validated Panx1-selective antibody revealed strong immunoreactivity in WT but not in -/- cochleae. Hearing sensitivity, outer hair cell-based "cochlear amplifier" and cochlear nerve function, analyzed by auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) recordings, were normal in +/- and -/- mice. In addition, we determined that global deletion of impacts neither on connexin expression, nor on gap-junction coupling in the developing organ of Corti. Finally, spontaneous intercellular Ca signal (ICS) activity in organotypic cochlear cultures, which is key to postnatal development of the organ of Corti and essential for hearing acquisition, was not affected by ablation. Therefore, our results provide strong evidence that, in mice, is dispensable for hearing acquisition and auditory function.
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http://dx.doi.org/10.3389/fnmol.2017.00379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5712377PMC
November 2017

Impaired path integration in mice with disrupted grid cell firing.

Nat Neurosci 2018 01 11;21(1):81-91. Epub 2017 Dec 11.

Department of Clinical Neurobiology, Medical Faculty of University of Heidelberg and DKFZ, Heidelberg, Germany.

Path integration (PI) is a highly conserved, self-motion-based navigation strategy. Since the discovery of grid cells in the medial entorhinal cortex, neurophysiological data and computational models have suggested that these neurons serve PI. However, more direct empirical evidence supporting this hypothesis has been missing due to a lack of selective manipulations of grid cell activity and suitable behavioral assessments. Here we report that selective disruption of grid cell activity in mice can be achieved by removing NMDA glutamate receptors from the retro-hippocampal region and that disrupted grid cell firing accounts for impaired PI performance. Notably, the genetic manipulation did not affect the activity of other spatially selective cells in the medial entorhinal cortex and the hippocampus. By directly linking grid cell activity to PI, these results contribute to a better understanding of how grid cells support navigation and spatial memory.
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http://dx.doi.org/10.1038/s41593-017-0039-3DOI Listing
January 2018

Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival.

Elife 2017 06 13;6. Epub 2017 Jun 13.

Wolfson Institute for Biomedical Research, University College London, London, United Kingdom.

Myelin, made by oligodendrocytes, is essential for rapid information transfer in the central nervous system. Oligodendrocyte precursors (OPs) receive glutamatergic synaptic input from axons but how this affects their development is unclear. Murine OPs in white matter express AMPA receptor (AMPAR) subunits GluA2, GluA3 and GluA4. We generated mice in which OPs lack both GluA2 and GluA3, or all three subunits GluA2/3/4, which respectively reduced or abolished AMPAR-mediated input to OPs. In both double- and triple-knockouts OP proliferation and number were unchanged but ~25% fewer oligodendrocytes survived in the subcortical white matter during development. In triple knockouts, this shortfall persisted into adulthood. The oligodendrocyte deficit resulted in ~20% fewer myelin sheaths but the average length, number and thickness of myelin internodes made by individual oligodendrocytes appeared normal. Thus, AMPAR-mediated signalling from active axons stimulates myelin production in developing white matter by enhancing oligodendrocyte survival, without influencing myelin synthesis per se.
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http://dx.doi.org/10.7554/eLife.28080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484614PMC
June 2017

Serotonergic Projections Govern Postnatal Neuroblast Migration.

Neuron 2017 May;94(3):534-549.e9

Department of Clinical Neurobiology, Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address:

In many vertebrates, postnatally generated neurons often migrate long distances to reach their final destination, where they help shape local circuit activity. Concerted action of extrinsic stimuli is required to regulate long-distance migration. Some migratory principles are evolutionarily conserved, whereas others are species and cell type specific. Here we identified a serotonergic mechanism that governs migration of postnatally generated neurons in the mouse brain. Serotonergic axons originating from the raphe nuclei exhibit a conspicuous alignment with subventricular zone-derived neuroblasts. Optogenetic axonal activation provides functional evidence for serotonergic modulation of neuroblast migration. Furthermore, we show that the underlying mechanism involves serotonin receptor 3A (5HT3A)-mediated calcium influx. Thus, 5HT3A receptor deletion in neuroblasts impaired speed and directionality of migration and abolished calcium spikes. We speculate that serotonergic modulation of postnatally generated neuroblast migration is evolutionarily conserved as indicated by the presence of serotonergic axons in migratory paths in other vertebrates.
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http://dx.doi.org/10.1016/j.neuron.2017.04.013DOI Listing
May 2017

Distinct Corticostriatal GABAergic Neurons Modulate Striatal Output Neurons and Motor Activity.

Cell Rep 2017 05;19(5):1045-1055

Department of Clinical Neurobiology at the Medical Faculty of Heidelberg University and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

The motor cortico-basal ganglion loop is critical for motor planning, execution, and learning. Balanced excitation and inhibition in this loop is crucial for proper motor output. Excitatory neurons have been thought to be the only source of motor cortical input to the striatum. Here, we identify long-range projecting GABAergic neurons in the primary (M1) and secondary (M2) motor cortex that target the dorsal striatum. This population of projecting GABAergic neurons comprises both somatostatin-positive (SOM) and parvalbumin-positive (PV) neurons that target direct and indirect pathway striatal output neurons as well as cholinergic interneurons differentially. Notably, optogenetic stimulation of M1 PV and M2 SOM projecting neurons reduced locomotion, whereas stimulation of M1 SOM projecting neurons enhanced locomotion. Thus, corticostriatal GABAergic projections modulate striatal output and motor activity.
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http://dx.doi.org/10.1016/j.celrep.2017.04.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437725PMC
May 2017

Diazepam Binding Inhibitor Promotes Stem Cell Expansion Controlling Environment-Dependent Neurogenesis.

Neuron 2017 Apr 23;94(1):125-137.e5. Epub 2017 Mar 23.

Department of Clinical Neurobiology at the German Cancer Research Center (DKFZ) and the Medical Faculty of the Heidelberg University, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address:

Plasticity of adult neurogenesis supports adaptation to environmental changes. The identification of molecular mediators that signal these changes to neural progenitors in the niche has remained elusive. Here we report that diazepam binding inhibitor (DBI) is crucial in supporting an adaptive mechanism in response to changes in the environment. We provide evidence that DBI is expressed in stem cells in all neurogenic niches of the postnatal brain. Focusing on the hippocampal subgranular zone (SGZ) and employing multiple genetic manipulations in vivo, we demonstrate that DBI regulates the balance between preserving the stem cell pool and neurogenesis. Specifically, DBI dampens GABA activity in stem cells, thereby sustaining the proproliferative effect of physical exercise and enriched environment. Our data lend credence to the notion that the modulatory effect of DBI constitutes a general mechanism that regulates postnatal neurogenesis.
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http://dx.doi.org/10.1016/j.neuron.2017.03.003DOI Listing
April 2017

Electrotonic Coupling in the Pituitary Supports the Hypothalamic-Pituitary-Gonadal Axis in a Sex Specific Manner.

Front Mol Neurosci 2016 18;9:65. Epub 2016 Aug 18.

Department of Clinical Neurobiology, Medical Faculty of Heidelberg, German Cancer Research Center, University of Heidelberg Heidelberg, Germany.

Gap junctions are present in many cell types throughout the animal kingdom and allow fast intercellular electrical and chemical communication between neighboring cells. Connexin-36 (Cx36), the major neuronal gap junction protein, synchronizes cellular activity in the brain, but also in other organs. Here we identify a sex-specific role for Cx36 within the hypothalamic-pituitary-gonadal (HPG) axis at the level of the anterior pituitary gland (AP). We show that Cx36 is expressed in gonadotropes of the AP sustaining their synchronous activity. Cx36 ablation affects the entire downstream HPG axis in females, but not in males. We demonstrate that Cx36-mediated coupling between gonadotropes in the AP supports gonadotropin-releasing hormone-induced secretion of luteinizing hormone. Furthermore, we provide evidence for negative feedback regulation of Cx36 expression in the AP by estradiol. We thus, conclude that hormonally-controlled plasticity of gap junction communication at the level of the AP constitutes an additional mechanism affecting female reproduction.
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http://dx.doi.org/10.3389/fnmol.2016.00065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4988985PMC
September 2016

Central Role of P2Y6 UDP Receptor in Arteriolar Myogenic Tone.

Arterioscler Thromb Vasc Biol 2016 08 2;36(8):1598-606. Epub 2016 Jun 2.

From the MITOVASC Institute, CNRS UMR 6214, INSERM U1083 (G.K., C.R., A.A., B.T., L.G., L.L., P.A., V.P., D.H.) and EA 3860 Cardioprotection Remodelage et Thrombose, University of Angers, Angers, France (S.T., F.P.); Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville (M.B., B.E.I.); University Hospital Angers, Angers, France (G.K., P.R., P.A., V.P.); Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg, Heidelberg, Germany (H.M.); Institut für Physiologie, Universität zu Lübeck and Deutsches Zentrum für Herz-Kreislauf-Forschung, Lübeck, Germany (C.d.W.); Institute of Interdisciplinary Research, IRIBHM, Université Libre de Bruxelles, Gosselies, Belgium (J.-M.B., B.R.); and Departments of Pathology and Immunology and Medical Specializations - Cardiology, University of Geneva, Geneva, Switzerland (B.R.K.).

Objective: Myogenic tone (MT) of resistance arteries ensures autoregulation of blood flow in organs and relies on the intrinsic property of smooth muscle to contract in response to stretch. Nucleotides released by mechanical strain on cells are responsible for pleiotropic vascular effects, including vasoconstriction. Here, we evaluated the contribution of extracellular nucleotides to MT.

Approach And Results: We measured MT and the associated pathway in mouse mesenteric resistance arteries using arteriography for small arteries and molecular biology. Of the P2 receptors in mouse mesenteric resistance arteries, mRNA expression of P2X1 and P2Y6 was dominant. P2Y6 fully sustained UDP/UTP-induced contraction (abrogated in P2ry6(-/-) arteries). Preventing nucleotide hydrolysis with the ectonucleotidase inhibitor ARL67156 enhanced pressure-induced MT by 20%, whereas P2Y6 receptor blockade blunted MT in mouse mesenteric resistance arteries and human subcutaneous arteries. Despite normal hemodynamic parameters, P2ry6(-/-) mice were protected against MT elevation in myocardial infarction-induced heart failure. Although both P2Y6 and P2Y2 receptors contributed to calcium mobilization, P2Y6 activation was mandatory for RhoA-GTP binding, myosin light chain, P42-P44, and c-Jun N-terminal kinase phosphorylation in arterial smooth muscle cells. In accordance with the opening of a nucleotide conduit in pressurized arteries, MT was altered by hemichannel pharmacological inhibitors and impaired in Cx43(+/-) and P2rx7(-/-) mesenteric resistance arteries.

Conclusions: Signaling through P2 nucleotide receptors contributes to MT. This mechanism encompasses the release of nucleotides coupled to specific autocrine/paracrine activation of the uracil nucleotide P2Y6 receptor and may contribute to impaired tissue perfusion in cardiovascular diseases.
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http://dx.doi.org/10.1161/ATVBAHA.116.307739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350073PMC
August 2016

Spatially segregated feedforward and feedback neurons support differential odor processing in the lateral entorhinal cortex.

Nat Neurosci 2016 07 16;19(7):935-44. Epub 2016 May 16.

Department of Clinical Neurobiology at the Medical Faculty of Heidelberg University, Heidelberg, Germany.

The lateral entorhinal cortex (LEC) computes and transfers olfactory information from the olfactory bulb to the hippocampus. Here we established LEC connectivity to upstream and downstream brain regions to understand how the LEC processes olfactory information. We report that, in layer II (LII), reelin- and calbindin-positive (RE(+) and CB(+)) neurons constitute two major excitatory cell types that are electrophysiologically distinct and differentially connected. RE(+) neurons convey information to the hippocampus, while CB(+) neurons project to the olfactory cortex and the olfactory bulb. In vivo calcium imaging revealed that RE(+) neurons responded with higher selectivity to specific odors than CB(+) neurons and GABAergic neurons. At the population level, odor discrimination was significantly better for RE(+) than CB(+) neurons, and was lowest for GABAergic neurons. Thus, we identified in LII of the LEC anatomically and functionally distinct neuronal subpopulations that engage differentially in feedforward and feedback signaling during odor processing.
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http://dx.doi.org/10.1038/nn.4303DOI Listing
July 2016

Experimental Cerebral Malaria Spreads along the Rostral Migratory Stream.

PLoS Pathog 2016 Mar 10;12(3):e1005470. Epub 2016 Mar 10.

Department of Neuroradiology, Heidelberg University Hospital, Heidelberg, Germany.

It is poorly understood how progressive brain swelling in experimental cerebral malaria (ECM) evolves in space and over time, and whether mechanisms of inflammation or microvascular sequestration/obstruction dominate the underlying pathophysiology. We therefore monitored in the Plasmodium berghei ANKA-C57BL/6 murine ECM model, disease manifestation and progression clinically, assessed by the Rapid-Murine-Coma-and-Behavioral-Scale (RMCBS), and by high-resolution in vivo MRI, including sensitive assessment of early blood-brain-barrier-disruption (BBBD), brain edema and microvascular pathology. For histological correlation HE and immunohistochemical staining for microglia and neuroblasts were obtained. Our results demonstrate that BBBD and edema initiated in the olfactory bulb (OB) and spread along the rostral-migratory-stream (RMS) to the subventricular zone of the lateral ventricles, the dorsal-migratory-stream (DMS), and finally to the external capsule (EC) and brainstem (BS). Before clinical symptoms (mean RMCBS = 18.5±1) became evident, a slight, non-significant increase of quantitative T2 and ADC values was observed in OB+RMS. With clinical manifestation (mean RMCBS = 14.2±0.4), T2 and ADC values significantly increased along the OB+RMS (p = 0.049/p = 0.01). Severe ECM (mean RMCBS = 5±2.9) was defined by further spread into more posterior and deeper brain structures until reaching the BS (significant T2 elevation in DMS+EC+BS (p = 0.034)). Quantitative automated histological analyses confirmed microglial activation in areas of BBBD and edema. Activated microglia were closely associated with the RMS and neuroblasts within the RMS were severely misaligned with respect to their physiological linear migration pattern. Microvascular pathology and ischemic brain injury occurred only secondarily, after vasogenic edema formation and were both associated less with clinical severity and the temporal course of ECM. Altogether, we identified a distinct spatiotemporal pattern of microglial activation in ECM involving primarily the OB+RMS axis, a distinct pathway utilized by neuroblasts and immune cells. Our data suggest significant crosstalk between these two cell populations to be operative in deeper brain infiltration and further imply that the manifestation and progression of cerebral malaria may depend on brain areas otherwise serving neurogenesis.
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http://dx.doi.org/10.1371/journal.ppat.1005470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4786214PMC
March 2016

Age-Dependent Degeneration of Mature Dentate Gyrus Granule Cells Following NMDA Receptor Ablation.

Front Mol Neurosci 2015 12;8:87. Epub 2016 Jan 12.

Department of Clinical Neurobiology, University Hospital and German Cancer Research Center Heidelberg Heidelberg, Germany.

N-methyl-D-aspartate receptors (NMDARs) in all hippocampal areas play an essential role in distinct processes of memory formation as well as in sustaining cell survival of postnatally generated neurons in the dentate gyrus (DG). In contrast to the beneficial effects, over-activation of NMDARs has been implicated in many acute and chronic neurological diseases, reason why therapeutic approaches and clinical trials involving receptor blockade have been envisaged for decades. Here we employed genetically engineered mice to study the long-term effect of NMDAR ablation on selective hippocampal neuronal populations. Ablation of either GluN1 or GluN2B causes degeneration of the DG. The neuronal demise affects mature neurons specifically in the dorsal DG and is NMDAR subunit-dependent. Most importantly, the degenerative process exacerbates with increasing age of the animals. These results lead us to conclude that mature granule cells in the dorsal DG undergo neurodegeneration following NMDAR ablation in aged mouse. Thus, caution needs to be exerted when considering long-term administration of NMDAR antagonists for therapeutic purposes.
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http://dx.doi.org/10.3389/fnmol.2015.00087DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4709453PMC
January 2016
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