TY - JOUR A1 - Strekalova, Tatyana A1 - Pavlov, Dmitrii A1 - Trofimov, Alexander A1 - Anthony, Daniel C. A1 - Svistunov, Andrei A1 - Proshin, Andrey A1 - Umriukhin, Aleksei A1 - Lyundup, Alexei A1 - Lesch, Klaus-Peter A1 - Cespuglio, Raymond T1 - Hippocampal over-expression of cyclooxygenase-2 (COX-2) is associated with susceptibility to stress-induced anhedonia in mice JF - International Journal of Molecular Sciences N2 - The phenomenon of individual variability in susceptibility/resilience to stress and depression, in which the hippocampus plays a pivotal role, is attracting increasing attention. We investigated the potential role of hippocampal cyclooxygenase-2 (COX-2), which regulates plasticity, neuroimmune function, and stress responses that are all linked to this risk dichotomy. We used a four-week-long chronic mild stress (CMS) paradigm, in which mice could be stratified according to their susceptibility/resilience to anhedonia, a key feature of depression, to investigate hippocampal expression of COX-2, a marker of microglial activation Iba-1, and the proliferation marker Ki67. Rat exposure, social defeat, restraints, and tail suspension were used as stressors. We compared the effects of treatment with either the selective COX-2 inhibitor celecoxib (30 mg/kg/day) or citalopram (15 mg/kg/day). For the celecoxib and vehicle-treated mice, the Porsolt test was used. Anhedonic (susceptible) but not non-anhedonic (resilient) animals exhibited elevated COX-2 mRNA levels, increased numbers of COX-2 and Iba-1-positive cells in the dentate gyrus and the CA1 area, and decreased numbers of Ki67-positive cells in the subgranular zone of the hippocampus. Drug treatment decreased the percentage of anhedonic mice, normalized swimming activity, reduced behavioral despair, and improved conditioned fear memory. Hippocampal over-expression of COX-2 is associated with susceptibility to stress-induced anhedonia, and its pharmacological inhibition with celecoxib has antidepressant effects that are similar in size to those of citalopram. KW - major depression KW - inducible cyclooxygenase-2 (COX-2) KW - hippocampus KW - anhedonia KW - chronic stress KW - stress resilience KW - fear conditioning KW - celecoxib KW - citalopram KW - mouse Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284056 SN - 1422-0067 VL - 23 IS - 4 ER - TY - JOUR A1 - Graf, Jürgen A1 - Rahmati, Vahid A1 - Majoros, Myrtill A1 - Witte, Otto W. A1 - Geis, Christian A1 - Kiebel, Stefan J. A1 - Holthoff, Knut A1 - Kirmse, Knut T1 - Network instability dynamics drive a transient bursting period in the developing hippocampus in vivo JF - eLife N2 - Spontaneous correlated activity is a universal hallmark of immature neural circuits. However, the cellular dynamics and intrinsic mechanisms underlying network burstiness in the intact developing brain are largely unknown. Here, we use two-photon Ca\(^{2+}\) imaging to comprehensively map the developmental trajectories of spontaneous network activity in the hippocampal area CA1 of mice in vivo. We unexpectedly find that network burstiness peaks after the developmental emergence of effective synaptic inhibition in the second postnatal week. We demonstrate that the enhanced network burstiness reflects an increased functional coupling of individual neurons to local population activity. However, pairwise neuronal correlations are low, and network bursts (NBs) recruit CA1 pyramidal cells in a virtually random manner. Using a dynamic systems modeling approach, we reconcile these experimental findings and identify network bi-stability as a potential regime underlying network burstiness at this age. Our analyses reveal an important role of synaptic input characteristics and network instability dynamics for NB generation. Collectively, our data suggest a mechanism, whereby developing CA1 performs extensive input-discrimination learning prior to the onset of environmental exploration. KW - hippocampus KW - spontaneous network activity KW - transient bursting Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300906 VL - 11 ER - TY - JOUR A1 - Schmitt, Andrea A1 - Tatsch, Laura A1 - Vollhardt, Alisa A1 - Schneider-Axmann, Thomas A1 - Raabe, Florian J. A1 - Roell, Lukas A1 - Heinsen, Helmut A1 - Hof, Patrick R. A1 - Falkai, Peter A1 - Schmitz, Christoph T1 - Decreased oligodendrocyte number in hippocampal subfield CA4 in schizophrenia: a replication study JF - Cells N2 - Hippocampus-related cognitive deficits in working and verbal memory are frequent in schizophrenia, and hippocampal volume loss, particularly in the cornu ammonis (CA) subregions, was shown by magnetic resonance imaging studies. However, the underlying cellular alterations remain elusive. By using unbiased design-based stereology, we reported a reduction in oligodendrocyte number in CA4 in schizophrenia and of granular neurons in the dentate gyrus (DG). Here, we aimed to replicate these findings in an independent sample. We used a stereological approach to investigate the numbers and densities of neurons, oligodendrocytes, and astrocytes in CA4 and of granular neurons in the DG of left and right hemispheres in 11 brains from men with schizophrenia and 11 brains from age- and sex-matched healthy controls. In schizophrenia, a decreased number and density of oligodendrocytes was detected in the left and right CA4, whereas mean volumes of CA4 and the DG and the numbers and density of neurons, astrocytes, and granular neurons were not different in patients and controls, even after adjustment of variables because of positive correlations with postmortem interval and age. Our results replicate the previously described decrease in oligodendrocytes bilaterally in CA4 in schizophrenia and point to a deficit in oligodendrocyte maturation or a loss of mature oligodendrocytes. These changes result in impaired myelination and neuronal decoupling, both of which are linked to altered functional connectivity and subsequent cognitive dysfunction in schizophrenia. KW - schizophrenia KW - hippocampus KW - CA4 KW - dentate gyrus KW - postmortem KW - stereology KW - oligodendrocyte KW - neuron Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290360 SN - 2073-4409 VL - 11 IS - 20 ER - TY - THES A1 - Rüdt von Collenberg, Cora Freifrau T1 - The role of Ciliary Neurotrophic Factor in hippocampal synaptic plasticity and learning T1 - Die Rolle von Ciliary Neurotrophic Factor bei hippocampaler synaptischer Plastizität und Lernen N2 - Ciliary neurotrophic factor (Cntf) acts as a differentiation and survival factor for different types of neurons and glial cells. It is expressed by peripheral Schwann cells and astrocytes in the central nervous system and mediates its effects via a receptor complex involving CntfRα, LifRß and gp130, leading to downstream activation of Stat3. Recent studies by our group have shown that Cntf modulates neuronal microtubule dynamics via Stat3/stathmin interaction. In a mouse model for motor neuron disease, i.e. pmn, Cntf is able to rescue axonal degeneration through Stat3/stathmin signaling. While these findings suggest a role of Cntf in controlling axonal functions in the neuromuscular system, additional data indicate that Cntf might also play a role in synaptic plasticity in the hippocampus. Electrophysiological recordings in hippocampal organotypic cultures and acute slices revealed a deficit in long-term potentiation (LTP) in Cntf -/- mice. This deficit was rescued by 24 h stimulation with Cntf, combined with an acute application of Cntf during LTP-measurements indicating that Cntf is both necessary and sufficient for hippocampal LTP, and possibly synaptic plasticity. Therefore, Cntf knockout mice were investigated to elucidate this possible role of Cntf in hippocampal LTP and synaptic plasticity. First, we validated the presence of Cntf in the target tissue: in the hippocampus, Cntf was localized in Gfap-positive astrocytes surrounding small blood vessels in the fissure and in meningeal areas close to the dentate gyrus. Laser micro-dissection and qPCR analysis showed a similar distribution of Cntf-coding mRNA validating the obtained immunofluorescent results. Despite the strong LTP deficit in organotypic cultures, in vivo behavior of Cntf -/- mice regarding hippocampus-dependent learning and anxiety-related paradigms was largely inconspicuous. However, western blot analysis of hippocampal organotypic cultures revealed a significant reduction of pStat3 levels in Cntf -/- cultures under baseline conditions, which in turn were elevated upon Cntf stimulation. In order to resolve and examine synaptic structures we turned to in vitro analysis of cultured hippocampal neurons which indicated that pStat3 is predominantly located in the presynapse. In line with these findings, presynapses of Cntf -/- cultures were reduced in size and when in contact to astrocytes, contained less pStat3 immunoreactivity compared to presynapses in wildtype cultures. In conclusion, our findings hypothesize that despite of a largely inconspicuous behavioral phenotype of Cntf -/- mice, Cntf appears to have an influence on pStat3 levels at hippocampal synapses. In a next step these two key questions need to be addressed experimentally: 1) is there a compensatory mechanism by members of the Cntf family, possibly downstream of pStat3, which explains the in vivo behavioral results of Cntf -/- mice and can likewise account for the largely inconspicuous phenotype in CNTF-deficient humans? 2) How exactly does Cntf influence LTP through Stat3 signaling? To unravel the underlying mechanism further experiments should therefore investigate whether microtubule dynamics downstream of Stat3 and stathmin signaling are involved in the Cntf-induced modulation of hippocampal synaptic plasticity, similar to as it was shown in motoneurons. N2 - Ciliary neurotrophic factor (Cntf) wirkt als Differenzierungs- und Überlebensfaktor für verschiedene Arten von Neuronen und Gliazellen. Es wird von peripheren Schwann´schen Zellen und Astrozyten des zentralen Nervensystems exprimiert und vermittelt seine Effekte über einen Rezeptorenkomplex, der aus CntfRα, LifRß und gp130 besteht, und zu einer nachfolgenden Aktivierung von Stat3 führt. Jüngste Studien unserer Arbeitsgruppe haben gezeigt, dass Cntf neuronale Mikrotubulidynamik über Stat3/stathmin Interaktion modulieren kann. In pmn Mäusen, einem Mausmodell für Motoneuronenerkrankungen, ist Cntf in der Lage, durch Stat3/Stathmin Signaltransduktion die zugrundeliegende axonale Degeneration wieder aufzuheben. Während diese Ergebnisse eine Rolle von Cntf bei der Kontrolle axonaler Funktionen im neuromuskulären System postulieren, deuten zusätzliche Daten darauf hin, dass Cntf ebenfalls eine Funktion bei synaptischer Plastizität im Hippocampus ausübt. Elektrophysiologische Messungen in hippocampalen organotypischen Kulturen und akuten Schnitten zeigen ein Defizit in der Langzeitpotenzierung (LTP) bei Cntf -/- Mäusen. Dieses Defizit konnte durch eine 24 stündige Stimulation mit Cntf, in Kombination mit akuter Zugabe von Cntf während der LTP Messungen, kompensiert werden. Dies weist darauf hin, dass Cntf sowohl notwendig als auch ausreichend für hippocampale LTP und möglicherweise synaptische Plasizität ist. Deshalb wurden Cntf knockout Mäuse untersucht, um diese putative Rolle von Cntf bei hippocampaler LTP und synaptischer Plastizität zu untersuchen. Zunächst haben wir die Lokalisation von Cntf in unserem Zielgewebe bestätigt: im Hippocampus war Cntf sowohl in Gfap-positiven Astrocyten lokalisiert, die kleine Blutgefäße in der Fissur umschließen, als auch in Gfap-positiven Astrocyten nahe des Gyrus dentatus. Lasermikrodissektion und qPCR-Analysen zeigten eine ähnliche Verteilung von Cntf kodierender mRNA, und bestätigten somit die durch Immunoflureszenz-Färbung erworbenen Ergebnisse. Trotz des starken LTP Defizits in organotypischen Kulturen zeigten jedoch Cntf -/- Mäuse in Hippocampus-abhängigen lern- und angstbedingten Verhaltensparadigmen keinen offensichtlichen Phänotyp. Allerdings zeigten Western Blot Analysen hippocampaler Kulturen eine signifikante Reduktion der pStat3 Level in Cntf -/- Kulturen unter Kontrollbedingungen, die nach Cntf Zugabe wieder erhöht werden konnten. Um synaptische Strukturen besser darstellen und evaluieren zu können, wurden hippocampale Neurone in vitro kultiviert, in denen Stat3 überwiegend in Präsynapsen lokalisiert war. In Übereinstimmung mit diesen Beobachtungen zeigten Cntf -/- Präsynapsen eine geringere Größe und enthielten, verglichen zu Präsynapsen in Wildtypkulturen, weniger pStat3 Immunreaktivität, gerade dann, wenn sie sich in Kontakt mit Astrozyten befanden. Zusammenfassend weisen unsere Befunde darauf hin, dass Cntf – trotz eines weitgehend unaufälligen Verhaltensphänotyps bei Cntf -/- Mäusen – einen Einfluss auf den Level von pStat3 an hippokampalen Synapsen zu haben scheint. In einem nächsten Schritt sollten die folgenden zwei Schlüsselfragen experimentell geklärt werden: 1) gibt es einen kompensierenden Mechanismus, über welchen Mitglieder der Cntf Familie wirken könnten – möglicherweise nachfolgend von pStat3 – und welcher das Verhalten der Cntf -/- Mäuse, sowie den größtenteils unauffälligen Phänotyp bei CNTF defizienten Menschen erklären könnte? 2) Wie genau wirkt sich Cntf induziertes pStat3 auf LTP aus? Um diesen zugrundeliegenden Mechanismus aufzuklären, sollten weitere Experimente untersuchen, ob pStat3 und Stathmin abhängige Mikrotubulidynamik in der durch Cntf induzierten Modulation hippocampaler Plastizität eine Rolle spielt – ähnlich, wie es in Motoneuronen bereits gezeigt wurde. KW - Hippocampus KW - Ciliary neurotrophic factor KW - hippocampus KW - synaptic plasticity KW - learning KW - Hippocampus KW - synaptische Plastizität KW - Lernen Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-206646 ER - TY - JOUR A1 - Rivero, Olga A1 - Alhama-Riba, Judit A1 - Ku, Hsing-Ping A1 - Fischer, Matthias A1 - Ortega, Gabriela A1 - Álmos, Péter A1 - Diouf, David A1 - van den Hove, Daniel A1 - Lesch, Klaus-Peter T1 - Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation JF - Frontiers in Genetics N2 - Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity. KW - sialyltransferase KW - sialic acid KW - psychiatric disorders KW - attention-deficit/hyperactivity disorder (ADHD) KW - prefrontal cortex KW - hippocampus KW - mouse model Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-246855 SN - 1664-8021 VL - 12 ER - TY - THES A1 - Sasi, Manju T1 - A mouse model for genetic deletion of presynaptic BDNF from adult hippocampal mossy fiber terminals T1 - Mausmodell für genetische Deletion von präsynaptischem BDNF aus adulten hippokampalen Moosfaserterminalen N2 - Brain-derived neurotrophic factor (BDNF) is a modulator and mediator of structural and functional plasticity at synapses in the central nervous system. Despite our profound knowledge about the synaptic function of BDNF at synapses, it is still controversially discussed whether synaptic BDNF acts primarily from pre- or postsynaptic sites. In the central nervous system, several studies show that mossy fiber (MF) projections formed by hippocampal granule neurons store the highest amount of BDNF. However, immunofluorescence and RNA labelling studies suggest that MF BDNF is primarily produced by granule neurons. Multiple other studies prefer the view that BDNF is primarily produced by postsynaptic neurons such as CA3 pyramidal neurons. Here, we question whether the BDNF, which is stored in the mossy fiber synapse, is primarily produced by granule neurons or whether by other cells in the MF-CA3 microcircuit. After standardization of immunolabelling of BDNF, confocal imaging confirmed the localization of BDNF in presynaptic MF terminals. This anterograde location of synaptic BDNF was also found in distinct regions of the fear and anxiety circuit, namely in the oval nucleus of the bed nucleus stria terminals (ovBNST) and in the central amygdala. To find out whether the presynaptic BDNF location is due to protein translation in the corresponding presynaptic dentate gyrus (DG) granule neuron, we developed and characterized a mouse model that exhibits BDNF deletion specifically from adult DG granule neurons. In this mouse model, loss of presynaptic BDNF immunoreactivity correlated with the specific Creactivity in granule neurons, thus confirming that MF BDNF is principally released by granule neurons. After BDNF deletion from granule neurons, we observed more immature neurons with widely arborized dendritic trees. This indicated that local BDNF deletion also affects the local adult neurogenesis, albeit Cre-mediated BDNF deletion only occur in adult granule neurons. Since BDNF is a master regulator of structural synaptic plasticity, it was questioned whether it is possible to visualize presynaptic, synapse-specific, structural plasticity in mossy fiber synapses. It was established that a combination of Cre-techniques together with targeting of GFP to membranes with the help of palmitoylation / myristoylation anchors was able to distinctly outline the synaptic structure of the BDNF-containing MF synapse. In summary, the mouse model characterized in here is suited to investigate the synaptic signalling function of presynaptic BDNF at the mossy fiber terminal, a model synapse to investigate microcircuit information processing from molecule to behaviour. N2 - Der neurotrophe Wachstumsfaktor BDNF (brain-derived neurotrophic factor) ist ein Regulator und Vermittler von struktureller und funktionaler Plastizität in Synapsen des zentralen Nervensystems. Trotz des umfassenden Wissens über die synaptische Funktion von BDNF an Synapsen wird immer noch kontrovers diskutiert, ob synaptisches BDNF vorrangig von der prä- oder von der postsynaptischen Seite her agiert. Zahlreiche Studien zeigen, dass die größten BDNF Mengen des Zentralnervensystems in den Projektionen der hippocampalen Körnerzellen, den sogenannten Moosfasern (MF), enthalten sind. Während manche Studien basierend auf der Markierung von RNA und Immunofloureszenz nahelegen, dass MF BDNF in erster Linie von Körnerzellen produziert wird, bevorzugen zahlreiche andere Studien wiederum die Sicht, dass BDNF primär von postsynaptischen Neuronen wie beispielsweise den CA3 Pyramidenneuronen gebildet wird. In dieser Arbeit wurde die Fragestellung untersucht, ob das BDNF, welches in den Moosfasersynapsen enthalten ist, in erster Linie von Körnerzellen hergestellt wird, oder ob es hauptsächlich von anderen Zellen aus dem MF-CA3 Mikronetzwerk gebildet wird. Nachdem eine Standardisierung der Immunfluoreszenzmarkierung von BDNF etabliert wurde, konnte anhand von konfokaler Bildgebung die Lokalisierung von BDNF in den präsynaptischen MF Terminalen bestätiget werden. Diese anterograde Lokalisierung synaptischen BDNFs konnte außerdem in zwei weiteren Regionen des Furcht- und Angstnetzwerkes, genauer gesagt im ovalen Kern des bed nucleus stria terminalis (ovBNST) und in der zentralen Amygdala, nachgewiesen werden. Um Herauszufinden, ob die präsynaptische Lokalisation von BDNF von der Proteintranslation in den zugehörigen präsynaptischen Körnerzellen des Gyrus Dentatus abhängig ist, entwickelten und charakterisierten wir ein Mausmodel , welches die spezifische Deletion von BDNF aus den ausgereiften Körnerzellen des Gyrus Dentatus ermöglicht. In diesem Mausmodell korrelierte der Verlust präsynaptischer BDNF Immunreaktivität mit der spezifischen Cre-Aktivität in Körnerzellen, was bestätigt, dass MF BDNF hauptsächlich von den Körnerzellen ausgeschüttet wird. Nach BDNF Deletion aus den Körnerzellen konnten mehr unreife Neurone mit sich weit verzweigenden, dendritischen Strukturen beobachtet werden. Dies weist darauf hin, dass die lokale Deletion von BDNF auch die lokale adulte Neurogenese beeinflusst, obwohl die Crevermittelte BDNF Deletion nur in adulten Körnerzellen stattfindet. Da BDNF ein Hauptregulator von struktureller synaptischer Plastizität ist, kam die Frage auf, ob es möglich ist, diese präsynaptische, synapsenspezifische strukturelle Plastizität in Moosfasersynapsen zu visualisieren. Es wurde festgestellt, dass eine Kombination aus der Cre- Technik zusammen mit der gezielten Verankerung von GFP in der Zellmembran durch Palmitoylierungs-/Myristoylierungsmotive in der Lage ist, die synaptische Struktur von BDNF enthaltenden MF Synapsen darzustellen. Zusammenfassend konnte gezeigt werden, dass das hier entwickelte und charakterisierte Mausmodell dafür geeignet ist, die synaptische Signalfunktion präsynaptischen BDNFs in der Moosfaserterminale, einer Modellsynapse für die Erforschung der Informationsverarbeitung in Mikronetzwerken vom Molekül bis hin zum Verhalten, zu untersuchen. KW - Wachstumsfaktor KW - Brain derived neurotorphic factor KW - Hippokampus KW - Moosfaserterminalen KW - hippocampus KW - mossy fiber terminal Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-186250 ER - TY - JOUR A1 - Weselek, Grit A1 - Keiner, Silke A1 - Fauser, Mareike A1 - Wagenführ, Lisa A1 - Müller, Julia A1 - Kaltschmidt, Barbara A1 - Brandt, Moritz D. A1 - Gerlach, Manfred A1 - Redecker, Christoph A1 - Hermann, Andreas A1 - Storch, Alexander T1 - Norepinephrine is a negative regulator of the adult periventricular neural stem cell niche JF - Stem Cells N2 - The limited proliferative capacity of neuroprogenitor cells (NPCs) within the periventricular germinal niches (PGNs) located caudal of the subventricular zone (SVZ) of the lateral ventricles together with their high proliferation capacity after isolation strongly implicates cell‐extrinsic humoral factors restricting NPC proliferation in the hypothalamic and midbrain PGNs. We comparatively examined the effects of norepinephrine (NE) as an endogenous candidate regulator of PGN neurogenesis in the SVZ as well as the periventricular hypothalamus and the periaqueductal midbrain. Histological and neurochemical analyses revealed that the pattern of NE innervation of the adult PGNs is inversely associated with their in vivo NPC proliferation capacity with low NE levels coupled to high NPC proliferation in the SVZ but high NE levels coupled to low NPC proliferation in hypothalamic and midbrain PGNs. Intraventricular infusion of NE decreased NPC proliferation and neurogenesis in the SVZ‐olfactory bulb system, while pharmacological NE inhibition increased NPC proliferation and early neurogenesis events in the caudal PGNs. Neurotoxic ablation of NE neurons using the Dsp4‐fluoxetine protocol confirmed its inhibitory effects on NPC proliferation. Contrarily, NE depletion largely impairs NPC proliferation within the hippocampus in the same animals. Our data indicate that norepinephrine has opposite effects on the two fundamental neurogenic niches of the adult brain with norepinephrine being a negative regulator of adult periventricular neurogenesis. This knowledge might ultimately lead to new therapeutic approaches to influence neurogenesis in hypothalamus‐related metabolic diseases or to stimulate endogenous regenerative potential in neurodegenerative processes such as Parkinson's disease. KW - adult neurogenesis KW - hippocampus KW - noradrenaline KW - norepinephrine KW - olfactory bulb neurogenesis KW - subventricular zone Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-218250 VL - 38 IS - 9 SP - 1188 EP - 1201 ER - TY - JOUR A1 - Waider, Jonas A1 - Popp, Sandy A1 - Mlinar, Boris A1 - Montalbano, Alberto A1 - Bonfiglio, Francesco A1 - Aboagye, Benjamin A1 - Thuy, Elisabeth A1 - Kern, Raphael A1 - Thiel, Christopher A1 - Araragi, Naozumi A1 - Svirin, Evgeniy A1 - Schmitt-Böhrer, Angelika G. A1 - Corradetti, Renato A1 - Lowry, Christopher A. A1 - Lesch, Klaus-Peter T1 - Serotonin deficiency increases context-dependent fear learning through modulation of hippocampal activity JF - Frontiers in Neuroscience N2 - Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses. KW - tryptophan hydroxylase 2 KW - knockout KW - fear learning KW - extinction KW - long-term potentiation KW - hippocampus KW - immediate-early gene KW - serotonin deficiency Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196077 SN - 1662-453X VL - 13 IS - 245 ER - TY - JOUR A1 - Bahmer, Andreas A1 - Gupta, Daya Shankar T1 - Role of Oscillations in Auditory Temporal Processing: A General Model for Temporal Processing of Sensory Information in the Brain? JF - Frontiers in Neuroscience N2 - We review the role of oscillations in the brain and in the auditory system showing that the ability of humans to distinguish changes in pitch can be explained as a precise analysis of temporal information in auditory signals by neural oscillations. The connections between auditory brain stem chopper neurons construct neural oscillators, which discharge spikes at various constant intervals that are integer multiples of 0.4 ms, contributing to the temporal processing of auditory cochlear output. This is subsequently spatially mapped in the inferior colliculus. Electrophysiological measurements of auditory chopper neurons in different species show oscillations with periods which are integer multiples of 0.4 ms. The constant intervals of 0.4 ms can be attributed to the smallest synaptic delay between interconnected simulated chopper neurons. We also note the patterns of similarities between microcircuits in the brain stem and other parts of the brain (e.g., the pallidum, reticular formation, locus coeruleus, oculomotor nuclei, limbic system, amygdala, hippocampus, basal ganglia and substantia nigra), dedicated to the processing of temporal information. Similarities in microcircuits across the brain reflect the importance of one of the key mechanisms in the information processing in the brain, namely the temporal coupling of different neural events via coincidence detection. KW - canonical microcircuits KW - cochlear nucleus KW - locus coerulus KW - limbic system KW - amygdala KW - hippocampus KW - basal ganglia KW - substantia nigra Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-196087 SN - 1662-453X VL - 12 IS - 793 ER - TY - JOUR A1 - Grünewald, Benedikt A1 - Lange, Maren D A1 - Werner, Christian A1 - O'Leary, Aet A1 - Weishaupt, Andreas A1 - Popp, Sandy A1 - Pearce, David A A1 - Wiendl, Heinz A1 - Reif, Andreas A1 - Pape, Hans C A1 - Toyka, Klaus V A1 - Sommer, Claudia A1 - Geis, Christian T1 - Defective synaptic transmission causes disease signs in a mouse model of juvenile neuronal ceroid lipofuscinosis JF - eLife N2 - Juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease) caused by mutations in the CLN3 gene is the most prevalent inherited neurodegenerative disease in childhood resulting in widespread central nervous system dysfunction and premature death. The consequences of CLN3 mutation on the progression of the disease, on neuronal transmission, and on central nervous network dysfunction are poorly understood. We used Cln3 knockout (Cln3\(^{Δex1-6}\)) mice and found increased anxiety-related behavior and impaired aversive learning as well as markedly affected motor function including disordered coordination. Patch-clamp and loose-patch recordings revealed severely affected inhibitory and excitatory synaptic transmission in the amygdala, hippocampus, and cerebellar networks. Changes in presynaptic release properties may result from dysfunction of CLN3 protein. Furthermore, loss of calbindin, neuropeptide Y, parvalbumin, and GAD65-positive interneurons in central networks collectively support the hypothesis that degeneration of GABAergic interneurons may be the cause of supraspinal GABAergic disinhibition. KW - CLN3 KW - mutation KW - mouse model KW - synaptic transmission KW - amygdala KW - hippocampus Y1 - 2017 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170004 VL - 6 IS - e28685 ER - TY - JOUR A1 - Düzel, Emrah A1 - van Praag, Henriette A1 - Sendtner, Michael T1 - Can physical exercise in old age improve memory and hippocampal function? JF - Brain N2 - Physical exercise can convey a protective effect against cognitive decline in ageing and Alzheimer’s disease. While the long-term health-promoting and protective effects of exercise are encouraging, it’s potential to induce neuronal and vascular plasticity in the ageing brain is still poorly understood. It remains unclear whether exercise slows the trajectory of normal ageing by modifying vascular and metabolic risk factors and/or consistently boosts brain function by inducing structural and neurochemical changes in the hippocampus and related medial temporal lobe circuitry—brain areas that are important for learning and memory. Hence, it remains to be established to what extent exercise interventions in old age can improve brain plasticity above and beyond preservation of function. Existing data suggest that exercise trials aiming for improvement and preservation may require different outcome measures and that the balance between the two may depend on exercise intensity and duration, the presence of preclinical Alzheimer’s disease pathology, vascular and metabolic risk factors and genetic variability. KW - hippocampus KW - exercise KW - cerebral blood flow KW - Alzheimer's disease KW - memory Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-190721 VL - 139 IS - 3 ER - TY - JOUR A1 - Pfeiffer, Verena A1 - Götz, Rudolf A1 - Xiang, Chaomei A1 - Camarero, Guadelupe A1 - Braun, Attila A1 - Zhang, Yina A1 - Blum, Robert A1 - Heinsen, Helmut A1 - Nieswandt, Bernhard A1 - Rapp, Ulf R. T1 - Ablation of BRaf Impairs Neuronal Differentiation in the Postnatal Hippocampus and Cerebellum JF - PLoS ONE N2 - This study focuses on the role of the kinase BRaf in postnatal brain development. Mice expressing truncated, non-functional BRaf in neural stem cell-derived brain tissue demonstrate alterations in the cerebellum, with decreased sizes and fuzzy borders of the glomeruli in the granule cell layer. In addition we observed reduced numbers and misplaced ectopic Purkinje cells that showed an altered structure of their dendritic arborizations in the hippocampus, while the overall cornus ammonis architecture appeared to be unchanged. In male mice lacking BRaf in the hippocampus the size of the granule cell layer was normal at postnatal day 12 (P12) but diminished at P21, as compared to control littermates. This defect was caused by a reduced ability of dentate gyrus progenitor cells to differentiate into NeuN positive granule cell neurons. In vitro cell culture of P0/P1 hippocampal cells revealed that BRaf deficient cells were impaired in their ability to form microtubule-associated protein 2 positive neurons. Together with the alterations in behaviour, such as autoaggression and loss of balance fitness, these observations indicate that in the absence of BRaf all neuronal cellular structures develop, but neuronal circuits in the cerebellum and hippocampus are partially disturbed besides impaired neuronal generation in both structures. KW - granule cells KW - hippocampus KW - neurons KW - neuronal dendrites KW - embryos KW - dentate gyrus KW - neuronal differentiation KW - cerebellum Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130304 VL - 8 IS - 3 ER - TY - JOUR A1 - Karabeg, Margherita M. A1 - Grauthoff, Sandra A1 - Kollert, Sina Y. A1 - Weidner, Magdalena A1 - Heiming, Rebecca S. A1 - Jansen, Friederike A1 - Popp, Sandy A1 - Kaiser, Sylvia A1 - Lesch, Klaus-Peter A1 - Sachser, Norbert A1 - Schmitt, Angelika G. A1 - Lewejohann, Lars T1 - 5-HTT Deficiency Affects Neuroplasticity and Increases Stress Sensitivity Resulting in Altered Spatial Learning Performance in the Morris Water Maze but Not in the Barnes Maze JF - PLoS ONE N2 - The purpose of this study was to evaluate whether spatial hippocampus-dependent learning is affected by the serotonergic system and stress. Therefore, 5-HTT knockout (-/-), heterozygous (+/-) and wildtype (+/+) mice were subjected to the Barnes maze (BM) and the Morris water maze (WM), the latter being discussed as more aversive. Additionally, immediate early gene (IEG) expression, hippocampal adult neurogenesis (aN), and blood plasma corticosterone were analyzed. While the performance of 5-HTT-/- mice in the BM was undistinguishable from both other genotypes, they performed worse in the WM. However, in the course of the repeated WM trials 5-HTT-/- mice advanced to wildtype level. The experience of a single trial of either the WM or the BM resulted in increased plasma corticosterone levels in all genotypes. After several trials 5-HTT-/- mice exhibited higher corticosterone concentrations compared with both other genotypes in both tests. Corticosterone levels were highest in 5-HTT-/- mice tested in the WM indicating greater aversiveness of the WM and a greater stress sensitivity of 5-HTT deficient mice. Quantitative immunohistochemistry in the hippocampus revealed increased cell counts positive for the IEG products cFos and Arc as well as for proliferation marker Ki67 and immature neuron marker NeuroD in 5-HTT-/- mice compared to 5-HTT+/+ mice, irrespective of the test. Most differences were found in the suprapyramidal blade of the dentate gyrus of the septal hippocampus. Ki67-immunohistochemistry revealed a genotype x environment interaction with 5-HTT genotype differences in naïve controls and WM experience exclusively yielding more Ki67-positive cells in 5-HTT+/+ mice. Moreover, in 5-HTT-/- mice we demonstrate that learning performance correlates with the extent of aN. Overall, higher baseline IEG expression and increased an in the hippocampus of 5-HTT-/- mice together with increased stress sensitivity may constitute the neurobiological correlate of raised alertness, possibly impeding optimal learning performance in the more stressful WM. KW - immediate early genes KW - learning curves KW - animal performance KW - animal behavior KW - serotonin KW - learning KW - mice KW - hippocampus Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-129978 VL - 8 IS - 10 ER - TY - THES A1 - Kroker, Katja T1 - Establishment and validation of hippocampal LTP for characterization of memory enhancing drugs as potential treatment of Alzheimer’s disease T1 - Etablierung und Validierung hippocampalen LTPs zur Charakterisierung gedächtnissteigernde Substanzen zur potentiellen Behandlung der Alzheimer’schen Erkrankung N2 - Die Alzheimer’sche Erkrankung ist eine neurodegenerative Erkrankung des Gehirns. Um geeignete Medikamente für die Behandlung der Alzheimer’schen Erkrankung zu finden, werden experimentelle Modellsysteme zur Erforschung von Substanzkandidaten verwendet. Ein solches experimentelles System ist die hippocampale Langzeitpotenzierung (LTP), welche ein anerkanntes in vitro Modell für die Erforschung der zugrundeliegenden zellulären Prozesse der Gedächtnisbildung ist. Die vorliegende Arbeit beschäftigt sich mit der Etablierung und Validierung von LTP in hippocampalen Hirnschnitten der Ratte um gedächtnissteigernde Substanzen zur potentiellen Behandlung der Alzheimer’schen Erkrankung zu charakterisieren. Dazu wurde zunächst ein Messsystem zur parallelen Charakterisierung mehrerer Schnitte aufgebaut, das Messungen bis zu sieben Stunden erlaubt (Kapitel 2). Dann wurden unterschiedliche Protokolle etabliert um Früh- und Spätphasen-LTP zu generieren. Dabei würde Frühphasen-LTP konzeptionell eher mit dem Kurzzeitgedächtnis einhergehen, während Spätphasen-LTP dem Langzeitgedächtnis gleichkommen würde (Kapitel 3). Da in Alzheimer-Patienten hauptsächlich ein Defizit cholinerger und glutamaterger Neurone vorliegt, wurden die validierten LTP Formen benutzt, um solche Substanzen zu analysieren, die potentiell cholinerge und/oder glutamaterge neuronale Funktion erhöhen. Die Effekte zweier ausschließlich cholinerge Funktion erhöhender Substanzen wurden analysiert: Der α4β2 nicotinische Acetylcholin-Rezeptor Agonist TC-1827 (Kapitel 4) und der Acetylcholinesterase-Inhibitor Donepezil (Kapitel 5). Beide Substanzen erhöhten Frühphasen-LTP, aber hatten keinen Effekt auf Spätphasen-LTP. Desweiteren wurden zwei Substanzen getestet, die ausschließlich mit glutamaterger Funktion interferieren: Der metabotrope Glutamatrezeptor 5 positiv allosterische Modulator ADX-47273 (Kapitel 3) und der Phosphodiesterase (PDE) 9A-Inhibitor BAY 73-6691 (Kapitel 5). ADX-47273 erhöhte Spätphasen-LTP, aber hatte keinen Effekt auf Frühphasen-LTP, wohingegen BAY 73-6691 eine erhöhende Wirkung auf beide LTP Formen aufwies und sogar Früh- in Spätphasen-LTP umwandelte. Die gleichen Effekte, wie bei dem PDE9A-Inhibitor, konnten auch mit dem partiellen α7 nicotinische Acetylcholin-Rezeptor Agonisten SSR180711 (Kapitel 4) demonstriert werden. SSR180711 wirkt sowohl auf cholinerge, als auch auf glutamaterge neuronale Funktion. Dann wurde die Fähigkeit der Substanzen überprüft, durch lösliche Aβ Oligomere verschlechtertes LTP zu verbessern (Kapitel 6). Lösliche Aβ Oligomere, auch als amyloid-β derived diffusible ligands (ADDLs) bezeichnet, werden zurzeit als eine mutmaßliche Ursache der Alzheimer’schen Erkrankung angesehen. In der vorliegenden Arbeit wurde gezeigt, dass ADDLs Früh- und Spätphasen-LTP in verschiedenem Ausmaß vermindern. Donepezil und TC-1827 konnten die durch ADDLs induzierten Defizite bei Frühphasen-LTP geringfügig wiederherstellen, aber sie hatten keinen Einfluss auf das durch ADDLs verschlechterte Spätphasen-LTP. Im Gegensatz dazu, konnten sowohl SSR180711 als auch BAY 73-6691 ein durch ADDLs verschlechtertes Früh- und Spätphasen-LTP komplett wiederherstellen. ADX-47273 hatte keinen positiven Effekt auf Frühphasen-LTP, welches durch ADDLs verschlechtert worden war, konnte aber ein durch ADDLs verschlechtertes Spätphasen-LTP teilweise wiederherstellen. Somit wurde der vorherige Befund der Arbeit bestätigt: Substanzen, welche die glutamaterge Funktion verbessern, scheinen nicht nur wirksamer im Bezug auf LTP-Erhöhung zu sein als Substanzen die ausschließlich cholinerge Funktion erhöhen, sondern sie sind auch in der Lage, durch lösliche Aβ Oligomere verursachte Defizite bei LTP zu verbessern. Aus einem präklinischen Blickwinkel und basierend auf den Ergebnissen der vorliegenden Arbeit weisen demnach Substanzen, die glutamaterge Funktionen verbessern, ein hohes therapeutisches Potential als alternative Ansätze bezüglich kognitiver Defizite auf. Möglicherweise könnten sie sogar wirksamere Ansätze für die symptomatische Behandlung der Alzheimer’schen Erkrankung darstellen, als derzeitige Behandlungen, die ausschließlich cholinerge Funktion verbessern. N2 - Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain. Today AD is the most common form of dementia in elderly people. It is clinically characterized by a progressive loss of memory and later on a decline in higher cognitive functions. The pathological hallmarks of AD, consistently demonstrated in brain tissue of patients, are extracellular amyloid-β (Aβ plaques, intracellular neurofibrillary tangles of tau protein and a profound loss of mainly cholinergic and glutamatergic synapses and ultimatively neurons. Estimates foresee that more than 80 million individuals will be affected by the disease by 2040 due to population aging worldwide underlining the high medical need for this disease. In order to find suitable drugs for the treatment of AD, experimental model systems are utilized to explore potential drug candidates. Such an experimental system is hippocampal long-term potentiation (LTP), which is widely accepted as an in vitro model of cellular processes fundamentally involved in memory formation. The present thesis focuses on the establishment and validation of LTP in rat hippocampal slices to characterize memory enhancing drugs as a potential treatment of AD. First, a multi-slice recording system was set up enabling stable measurements of LTP for up to seven hours from several slices simultaneously (chapter 2). Then, distinct protocols to induce early and late CA1 LTP, resembling short-term and long-term memory, were established. They were validated by addressing the hallmarks accepted for these forms of LTP: protein-synthesis independence and NMDA receptor dependence without contribution of L-VDCCs for early LTP, as opposed to protein-synthesis and NMDA / L-VDCCs dependence for late LTP (chapter 3). As in AD patients a loss of mainly cholinergic and glutamatergic synapses is obvious, these validated forms of LTP were used to study drugs potentially being able to enhance cholinergic and/or glutamatergic neuronal functions. The effects of two drugs exclusively interfering with cholinergic function on LTP were tested: the α4β2 nicotinic acetylcholinergic receptor agonist TC-1827 (chapter 4) and the acetylcholine esterase inhibitor donepezil (chapter 5). Both drugs were found to increase early LTP, but to not affect late LTP. Furthermore, two drugs exclusively interfering with glutamatergic function were analyzed: the metabotropic glutamate 5 receptor postive allosteric modulator ADX-47273 (chapter 3) and the phosphodiesterase (PDE) 9A inhibitor BAY 73-6691 (chapter 5). ADX-47273 increased late LTP, but had no effect on early LTP, whereas BAY 73-6691 showed enhancing effects on both early and late LTP and even transformed early into late LTP. The same effects like for the PDE9A inhibitor were observed for the α7 nicotinic acetylcholinergic receptor partial agonist SSR180711 (chapter 4), which interferes with both, cholinergic and glutamatergic function. Thus, drugs facilitating glutamatergic function or both glutamatergic and cholinergic function seem to be more efficacious in enhancing LTP than drugs facilitating solely cholinergic function. To evaluate whether this finding also proves true for experimental circumstances mimicking decreased cognitive function together with pathophysiology in AD patients, the ability of the drugs to ameliorate LTP impaired by soluble Aβ oligomer was analyzed (chapter 6). Soluble Aβ oligomers, also referred to as amyloid-β derived diffusible ligands (ADDLs), are thought to a putative cause of AD. Here, they were demonstrated to impair early and late LTP to different extents by exclusively targeting NMDA receptors and/or their signaling. These results further contribute to the hypothesis that soluble Aβ oligomers cause synaptic dysfunction which might lead to cognitive decline seen in AD patients. Regarding drug effects, donepezil and TC-1827 slightly restored ADDLs induced impairment of early LTP, but had no effect on late LTP impaired by ADDLs. In contrast, both, SSR180711 and BAY 73-6691 completely rescued early as well as late LTP impaired by ADDLs. ADX-47273 had no restoring effect on ADDLs induced early LTP impairment, but partially restored late LTP impaired by ADDLs. Thus, the earlier finding of the present thesis was confirmed: drugs facilitating glutamatergic function not only seem to be more efficacious in enhancing LTP than drugs facilitating solely cholinergic function, but are also superior in ameliorating soluble Aβ oligomer induced LTP deficits. Therefore, from a preclinical perspective and based on the results of the present thesis, drugs interfering with glutamatergic function seem to have a high therapeutic potential as alternative treatment concerning cognitive deficits. Probably, they represent more efficacious approaches for the symptomatic treatment of AD than current treatments solely facilitating cholinergic function. KW - Alzheimerkrankheit KW - Long-term potentiation KW - hippocampus KW - rat KW - learning and memory KW - Langzeitpotenzierung KW - Hippocampus KW - Ratte KW - Wirkstoff Y1 - 2011 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-85412 ER -