Publications by authors named "Peter Gass"

192 Publications

Robustly High Hippocampal BDNF levels under Acute Stress in Mice Lacking the Full-length p75 Neurotrophin Receptor.

Pharmacopsychiatry 2021 Feb 16. Epub 2021 Feb 16.

Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Berlin, Germany.

Background: Brain-derived neurotrophic factor (BDNF) exerts its effects on neural plasticity via 2 distinct receptor types, the tyrosine kinase TrkB and the p75 neurotrophin receptor (p75NTR). The latter can promote inflammation and cell death while TrkB is critically involved in plasticity and memory, particularly in the hippocampus. Acute and chronic stress have been associated with suppression of hippocampal BDNF expression and impaired hippocampal plasticity. We hypothesized that p75NTR might be involved in the hippocampal stress response, in particular in stress-induced BDNF suppression, which might be accompanied by increased neuroinflammation.

Method: We assessed hippocampal BDNF protein concentrations in wild-type mice compared that in mice lacking the long form of the p75NTR (p75NTR) with or without prior exposure to a 1-hour restraint stress challenge. Hippocampal BDNF concentrations were measured using an optimized ELISA. Furthermore, whole-brain mRNA expression of pro-inflammatory interleukin-6 () was assessed with RT-PCR.

Results: Deletion of full-length p75NTR was associated with higher hippocampal BDNF protein concentration in the stress condition, suggesting persistently high hippocampal BDNF levels in p75NTR-deficient mice, even under stress. Stress elicited increased whole-brain mRNA expression irrespective of genotype; however, p75NTR mice showed elevated baseline expression and thus a lower relative increase.

Conclusions: Our results provide evidence for a role of p75NTR signaling in the regulation of hippocampal BDNF levels, particularly under stress. Furthermore, p75NTR signaling modulates baseline but not stress-related gene expression in mice. Our findings implicate p75NTR signaling as a potential pathomechanism in BDNF-dependent modulation of risk for neuropsychiatric disorders.
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http://dx.doi.org/10.1055/a-1363-1680DOI Listing
February 2021

Microglia activation and adult neurogenesis in the hippocampus: New clues about the antidepressant effect of minocycline.

Brain Behav Immun 2021 Feb 9. Epub 2021 Feb 9.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim/Heidelberg University, Germany.

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http://dx.doi.org/10.1016/j.bbi.2021.01.031DOI Listing
February 2021

Voltage-independent GluN2A-type NMDA receptor Ca signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

Commun Biol 2021 Jan 8;4(1):59. Epub 2021 Jan 8.

Departments Molecular Neurobiology and Physiology at the Max Planck Institute for Medical Research, Jahnstr. 29, 69120, Heidelberg, Germany.

The NMDA receptor-mediated Ca signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2a), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.
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http://dx.doi.org/10.1038/s42003-020-01538-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794508PMC
January 2021

Hippocampal synaptoproteomic changes of susceptibility and resilience of male rats to chronic social isolation.

Brain Res Bull 2021 Jan 22;166:128-141. Epub 2020 Nov 22.

Molecular Biology and Endocrinology MBE-090, "VINČA", Institute of Nuclear Sciences - National Institute of thе Republic of Serbia, University of Belgrade, Belgrade, Serbia. Electronic address:

The susceptibility of an individual to chronic social isolation (CSIS) stress may cause major depression (MD) whereby some individuals are resistant to the stress. Recent studies relate MD with altered expression of synaptic proteins in specific brain regions. To explore the neurobiological underpinnings and identify candidate biomarkers of susceptibility or resilience to CSIS, a comparative proteomic approach was used to map hippocampal synaptic protein alterations of rats exposed to 6 weeks of CSIS, an animal model of depression. This model generates two stress-response phenotypes: CSIS-sensitive (depressive-like behaviour) and CSIS-resilience assessed by means of sucrose preference and forced swim tests. Our aim was to characterize the synaptoproteome changes representative of potential long-term changes in protein expression underlying susceptibility or resilience to stress. Proteomic data showed increased expression of glycolytic enzymes, the energy-related mitochondrial proteins, actin cytoskeleton, signalling transduction and synaptic transmission proteins in CSIS-sensitive rats. Protein levels of glutamate-related enzymes such as glutamate dehydrogenase and glutamine synthetase were also increased. CSIS-resilient rats showed similar proteome changes, however with a weaker increase compared to CSIS-sensitive rats. The main difference was observed in the level of protein expression of vesicle-mediated transport proteins. Nonetheless, only few proteins were uniquely up-regulated in the CSIS-resilient rats, whereby Cytochrome b-c1 complex subunit 2, mitochondrial (Uqcrc2) and Voltage-dependent anion-selective channel protein 1 (Vdac1) were uniquely down-regulated. Identified altered activated pathways and potential protein biomarkers may help us better understand the molecular mechanisms underlying synaptic neurotransmission in MD or resilience, crucial for development of new therapeutics.
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http://dx.doi.org/10.1016/j.brainresbull.2020.11.013DOI Listing
January 2021

Social isolation in rats: Effects on animal welfare and molecular markers for neuroplasticity.

PLoS One 2020 27;15(10):e0240439. Epub 2020 Oct 27.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany.

Early life stress compromises brain development and can contribute to the development of mental illnesses. A common animal model used to study different facets of psychiatric disorders is social isolation from early life on. In rats, this isolation can induce long-lasting alterations in molecular expression and in behavior. Since social isolation models severe psychiatric symptoms, it is to be expected that it affects the overall wellbeing of the animals. As also promoted by the 3Rs principle, though, it is pivotal to decrease the burden of laboratory animals by limiting the number of subjects (reduce, replace) and by improving the animals' wellbeing (refine). The aim of this study was therefore to test possible refinement strategies such as resocialization and mere adult social isolation. We examined whether the alternatives still triggered the necessary phenotype while minimizing the stress load on the animals. Interestingly, we did not find reduced wellbeing-associated burrowing performance in isolated rats. The hyperactive phenotype seen in socially isolated animals was observed for rats undergoing the adult-only isolation, but resocializing ameliorated the locomotor abnormality. Isolation strongly affected markers of neuroplasticity in the prefrontal cortex independent of timing: mRNA levels of Arc, Bdnf and the pool of Bdnf transcripts with the 3' long UTR were reduced in all groups. Bdnf splice variant IV expression was reduced in lifelong-isolated animals. Some of these deficits normalized after resocialization; likewise, exon VI Bdnf mRNA levels were reduced only in animals persistently isolated. Conversely, social deprivation did not affect the expression of Gad67 and Pvb, two GABAergic markers, whereas changes occurred in the expression of dopamine d1 and d2 receptors. As adult isolation was sufficient to trigger the hyperactive phenotype and impaired neuroplasticity in the prefrontal cortex, it could be a candidate for a refinement strategy for certain research questions. To fully grade the severity of post-weaning social isolation and the alternatives, adult isolation and resocialization, a more profound and multimodal assessment approach is necessary.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240439PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7591026PMC
December 2020

Measuring endogenous corticosterone in laboratory mice - a mapping review, meta-analysis, and open source database.

ALTEX 2021 6;38(1):111-122. Epub 2020 Oct 6.

Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.

Evaluating stress in laboratory animals is a key principle in animal welfare. Measuring corticosterone is a common method to assess stress in laboratory mice. There are, however, numerous methods to measure glucocorticoids with differences in sample matrix (e.g., plasma, urine) and quantification techniques (e.g., enzyme immunoassay or radioimmunoassay). Here, the authors present a mapping review and a searchable database, giving a complete overview of all studies mea­suring endogenous corticosterone in mice up to February 2018. For each study, information was recorded regarding mouse strain and sex; corticosterone sample matrix and quantification technique; and whether the study covered the research theme animal welfare, neuroscience, stress, inflammation, or pain (the themes of specific interest in our con­sortium). Using all database entries for the year 2012, an exploratory meta-regression was performed to determine the effect of predictors on basal corticosterone concentrations. Seventy-five studies were included using the predictors sex, time-since-lights-on, sample matrix, quantification technique, age of the mice, and type of control. Sex, time-since-lights-on, and type of control significantly affected basal corticosterone concentrations. The resulting database can be used, inter alia, for preventing unnecessary duplication of experiments, identifying knowledge gaps, and standardizing or heterogenizing methodologies. These results will help plan more efficient and valid experiments in the future and can answer new questions in silico using meta-analyses.
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http://dx.doi.org/10.14573/altex.2004221DOI Listing
October 2020

Tianeptine Enhances Energy-related Processes in the Hippocampal Non-synaptic Mitochondria in a Rat Model of Depression.

Neuroscience 2020 12 14;451:111-125. Epub 2020 Oct 14.

Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences - National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia. Electronic address: https://www.vinca.rs/.

Tianeptine (Tian) has been widely used in treating mood and anxiety disorders, and recently as a nootropic to improve cognitive performance. However, its mechanisms of action are insufficiently clear. We used a comparative proteomic approach to identify sub-proteome changes in hippocampal cytosol and non-synaptic mitochondria (NSM) following chronic Tian treatment (3 weeks, 10 mg/kg/day) of adult male Wistar rats and rats exposed to chronic social isolation stress (CSIS) (6 weeks), an animal model of depression. Behavioural assessment of depressive and anxiety-like behaviours was based on sucrose preference, forced swim test and marble burying. Selected differently expressed proteins were validated by Western blot and/or immunohistochemical analysis. Tian normalized the behavioural alternations induced by CSIS, indicating its antidepressant and anxiolytic efficacy. Proteomic data showed that Tian increased the expression of proteasome system elements and redox system enzymes, enhanced energy metabolism and increased glyceraldehyde-3-phosphate dehydrogenase expression bound to NSM in control rats. Tian-treatment of CSIS-stressed rats resulted in a minor suppression of the increase in proteasome elements and antioxidative enzymes, except for an increase in Cu-Zn superoxide dismutase, and increased the level of Lactate dehydrogenase. Our results indicate on an increased NSM functionality in controls and suppression of the CSIS-induced impairment of NSM functionality by Tian treatment as well as on the CSIS-caused discrepancy in Tian effects relative to controls.
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http://dx.doi.org/10.1016/j.neuroscience.2020.09.061DOI Listing
December 2020

The impact of handling technique and handling frequency on laboratory mouse welfare is sex-specific.

Sci Rep 2020 10 14;10(1):17281. Epub 2020 Oct 14.

RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Handling is a well-known source of stress to laboratory animals and can affect variability of results and even compromise animal welfare. The conventional tail handling in mice has been shown to induce aversion and anxiety-like behaviour. Recent findings demonstrate that the use of alternative handling techniques, e.g. tunnel handling, can mitigate negative handling-induced effects. Here, we show that technique and frequency of handling influence affective behaviour and stress hormone release of subjects in a sex-dependent manner. While frequent tail handling led to a reduction of wellbeing-associated burrowing and increased despair-like behaviour in male mice, females seemed unaffected. Instead, they displayed a stress response to a low handling frequency, which was not detectable in males. This could suggest that in terms of refinement, the impact in handling could differ between the sexes. Independently from this observation, both sexes preferred to interact with the tunnel. Mice generally explored the tunnel more often than the tail-handling hands of the experimenter and showed more positively rated approaches, e.g. touching or climbing, and at the same time, less defensive burrowing, indicating a strong preference for the tunnel.
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http://dx.doi.org/10.1038/s41598-020-74279-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560820PMC
October 2020

[Mental Health Status in the Community During the COVID-19-Pandemic].

Psychiatr Prax 2020 Oct 21;47(7):361-369. Epub 2020 Aug 21.

Abteilung Psychiatrie und Psychotherapie, Zentralinstitut für Seelische Gesundheit, Mannheim, Medizinische Fakultät Mannheim der Universität Heidelberg.

Objective: Analysis of associations between perceived daily life strain during the COVID-19-crisis and personality aspects with current psychological wellbeing in the general population and comparison of mental health indicators with those from a previous survey in 2018.

Methods: Written survey in a random sample from the general population (n = 721) on Corona-related assessments, personality aspects and current mental health (WHO-5, PHQ-D).

Results: Fear for the health of close persons, strain regarding going out restrictions, increased substance use and psychological risk- and resilience factors were independently related to current mental health. Extent and frequencies of mental health symptomatology did not differ between 2018 and 2020.

Conclusion: This is a first study in Germany reporting results from a population-based random sample on determinants of mental health during the COVID-19-crisis and a comparison of mental health symptomatology with prepandemic data from the same population.
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http://dx.doi.org/10.1055/a-1222-9067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7664009PMC
October 2020

Rapastinel alleviates the neurotoxic effect induced by NMDA receptor blockade in the early postnatal mouse brain.

Eur Arch Psychiatry Clin Neurosci 2020 Aug 13. Epub 2020 Aug 13.

RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Medical Faculty Mannheim, Central Institute of Mental Health Mannheim, Heidelberg University, J 5, 68159, Mannheim, Germany.

Rapastinel is a novel psychoactive substance that acts as an N-methyl-D-aspartate-receptor (NMDAR) agonist and triggers antidepressant- and antipsychotic-like effects in animal models. However, it is unknown if rapastinel possesses a better side-effect profile than fast-acting glutamatergic antidepressants, like ketamine, which trigger neurotoxicity in the perinatal rodent cortex and protracted schizophrenia-like alterations. Here we found a remarkable neuroprotective effect of rapastinel against apoptosis induced by the NMDAR antagonist MK-801 in comparison to that elicited by clozapine and the mGlu2/3 agonist LY354740. These results suggest the potential therapeutic/prophylactic effect of rapastinel in ameliorating deleterious effects induced by NMDAR blockade during neurodevelopment.
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http://dx.doi.org/10.1007/s00406-020-01180-5DOI Listing
August 2020

Fluoxetine modulates neuronal activity in stress-related limbic areas of adult rats subjected to the chronic social isolation.

Brain Res Bull 2020 10 28;163:95-108. Epub 2020 Jul 28.

Department of Molecular Biology and Endocrinology, "VINČA" Institute of Nuclear Sciences National Institute of thе Republic of Serbia, University of Belgrade, Belgrade, Serbia. Electronic address:

Antidepressant fluoxetine (Flx) is the first therapeutic choice for the treatment of major depression (MD), however neuroanatomical spots of its action remain unclear. Immunohistochemical detection of c-Fos protein expression has been used for mapping activated neuronal circuits upon various stressors and drugs. We investigated the effect of 3 weeks of Flx treatment (15 mg/kg/day) on changes in neuronal activity, by mapping the number of c-Fos cells, in several brain subregions in adult male rats of control and following 3 weeks of chronic social isolation (CSIS), an animal model of depression. The aim was to identify brain subregions activated by vehicle or Flx treatment in both controls or simultaneously applied with CSIS. Flx prevented depressive- and anxiety-like behaviors in CSIS rats. In controls, Flx increased the number of c-Fos cells in the anterior/posterior piriform cortex (aPirCx, pPirCx), retrosplenial cortex dysgranular (RSD) and granular, c region (RSGc), dorsal hippocampal subregions (CA1d, CA2, CA3d, DGd), lateral habenula (LHB), paraventricular thalamic nucleus, posterior part (PVP) and lateral/basolateral complex of amygdala (LA/BL). CSIS-induced neuronal activation was observed in brain subregions implicated in mood and other mental disorders such as aPirCx, pPirCx, caudate putamen (CPu), acumbens nucleus shell (AcbSh), RSD, RSGc, DGd, PVP and LA/BL. Flx increased neuronal activation in both controls and CSIS rats in the CA1d, CA2, CA3d, PVP, LA/BL, while in striatum increased neuronal activation was observed only in CSIS. Our data identify activated CSIS-related brain subregions and/or Flx treatment, in which Flx increased c-Fos protein expression in CSIS rats.
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http://dx.doi.org/10.1016/j.brainresbull.2020.07.021DOI Listing
October 2020

The Prevalence and Effects of Stalking.

Dtsch Arztebl Int 2020 05;117(20):347-353

Department of Psychiatry and Psychotherapy, Central Institute for Mental Health, Medical Faculty Mannheim, University of Heidelberg.

Background: In 2003, we carried out the first epidemiological study on the frequency and effects of stalking in Germany that was based on a random population sample. We repeated the study with the same design in 2018 in order to assess any potential alterations over time in the frequency of stalking and of psychological problems in the affected persons. As far as we know, this is the first replication study of this kind to be carried out anywhere.

Methods: 1000 women and 1000 men were randomly chosen from the residents' registration data of Mannheim, Germany. Each one of them received, by mail, a comprehensive questionnaire about stalking, as well as the WHO-5 Well-Being Index and the German version of the Patient Health Questionnaire (PHQ-D).

Results: In the Mannheim population samples (2003: N = 675; 2018: N = 444), the lifetime prevalence of being stalked was 11.6% in 2003 (95% confidence interval, [9.2; 14.4]) and 10.8% in 2018 [8.1; 13.7]. In both 2003 and 2018, persons who had been stalked had significantly worse mental well-being than unaffected persons (WHO-5 summated score 2003: 11.2 [9.7; 12.6] vs. 15.5 [15.1; 16.0], WHO-5 summated score 2018: 11.8 [10.1; 13.6] vs. 14.5 [13.9; 15.0]). A markedly higher percentage of persons who had been stalked also fulfilled the syndrome criteria for at least one mental disorder (PHQ-D 2003: 50.0% vs. 22.5%; odds ratio [OR]: 3.5 [2.1; 5.6], PHQ-D 2018: 46.5% vs. 24.4%; OR: 2.7 [1.4; 5.1]). In 2018, as in 2003, persons who had been stalked were dissatisfied with, or unaware of, the opportu - nities that they had to get help from the police and the judicial system.

Conclusion: Stalking remains a major problem that must be taken seriously. Physicians and psychologists should be well informed about it in order to help affected persons who turn to them for medical and psychological assistance.
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http://dx.doi.org/10.3238/arztebl.2020.0347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373813PMC
May 2020

Social isolation stress-resilient rats reveal energy shift from glycolysis to oxidative phosphorylation in hippocampal nonsynaptic mitochondria.

Life Sci 2020 Aug 19;254:117790. Epub 2020 May 19.

Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, 68159 Mannheim, Germany.

Aims: To examine the differences in the hippocampal proteome profiles of resilience or susceptibility to chronic social isolation (CSIS), animal model of depression, and to identify biomarkers that can distinguish the two.

Main Methods: Comparative subproteomic approach was used to identify changes in hippocampal cytosol and nonsynaptic mitochondria (NSM) of CSIS-resilient compared to CSIS-sensitive or control rats. The resilient and sensitive phenotypes of CSIS rats were distinguished based on their sucrose preference values. Selected proteins were validated by Western blot or immunofluorescence.

Key Findings: Predominantly down-regulated processes such as cytosolic cytoskeleton organization, the calcium signaling pathway, ubiquitin proteasome degradation, redox system, malate/aspartate shuttling and glutamate metabolism in CSIS-resilient compared to CSIS-sensitive rats were found. Decreased protein expression of glycolytic enzymes with simultaneous increased expression of Aco2 involved in tricarboxylic acid cycle and expression of several subunits composing oxidative phosphorylation involved enzymes (Uqcrc2, Atp5f1a, Atp5f1b) were found, indicating shift in energy production from glycolysis to oxidative phosphorylation in NSM. The four-fold higher level of mitochondrial glyceraldehyde-3-phosphate dehydrogenase of resilient rats indicated its transfer from the cytosol to the NSM. An increased level of transketolase along with the reduced pyruvate kinase level suggested an activated pentose phosphate pathway in CSIS-resilient relative to control rats. Cytosolic up-regulated CSIS proteins were implicated in antioxidative and proteasomal systems, while down-regulated NSM protein was involved in oxidative phosphorylation.

Significance: The identified altered activated pathways and potential biomarkers enhance understanding of molecular mechanisms underlying resilience or susceptibility to CSIS, crucial in developing new therapeutic strategies.
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http://dx.doi.org/10.1016/j.lfs.2020.117790DOI Listing
August 2020

Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice.

Proc Natl Acad Sci U S A 2020 01 2;117(3):1753-1761. Epub 2020 Jan 2.

Institute for Experimental and Clinical Pharmacology and Toxicology, University of Lübeck, 23562 Lübeck, Germany;

Carbon dioxide (CO), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H receptor, and endothelial Gα proteins mediate the CO/H effect on cerebrovascular reactivity in mice. CO/H leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO effect on anxiety. Even at atmospheric CO concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.
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http://dx.doi.org/10.1073/pnas.1907467117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983400PMC
January 2020

Measurement of corticosterone in mice: a protocol for a mapping review.

Lab Anim 2020 Feb 26;54(1):26-32. Epub 2019 Oct 26.

Institute for Laboratory Animal Science, Hannover Medical School, Germany.

Severity assessment for experiments conducted with laboratory animals is still based mainly on subjective evaluations; evidence-based methods are scarce. Objective measures, amongst which determination of the concentrations of stress hormones, can be used to aid severity assessment. Short-term increases in glucocorticoid concentrations generally reflect healthy responses to stressors, but prolonged increases may indicate impaired welfare. As mice are the most commonly used laboratory animal species, we performed a systematic mapping review of corticosterone measurements in , to provide a full overview of specimen types (e.g. blood, urine, hair, saliva, and milk) and analysis techniques. In this publication, we share our protocol and search strategy, and our rationale for performing this systematic analysis to advance severity assessment. So far, we have screened 13,520 references, and included 5337 on primary studies with measurements of endogenous corticosterone in . Data extraction is currently in progress. When finished, this mapping review will be a valuable resource for scientists interested in corticosterone measurements to aid severity assessment. We plan to present the data in a publication and a searchable database, which will allow for even easier retrieval of the relevant literature. These resources will aid implementation of objective measures into severity assessment.
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http://dx.doi.org/10.1177/0023677219868499DOI Listing
February 2020

Systematic analysis of severity in a widely used cognitive depression model for mice.

Lab Anim 2020 Feb 1;54(1):40-49. Epub 2019 Oct 1.

RG Animal Models in Psychiatry, Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany.

Animal models in psychiatric research are indispensable for insights into mechanisms of behaviour and mental disorders. Distress is an important aetiological factor in psychiatric diseases, especially depression, and is often used to mimic the human condition. Modern bioethics requires balancing scientific progress with animal welfare concerns. Therefore, scientifically based severity assessment of procedures is a prerequisite for choosing the least compromising paradigm according to the 3Rs principle. Evidence-based severity assessment in psychiatric animal models is scarce, particularly in depression research. Here, we assessed severity in a cognitive depression model by analysing indicators of stress and well-being, including physiological (body weight and corticosterone metabolite concentrations) and behavioural (nesting and burrowing behaviour) parameters. Additionally, a novel approach for objective individualised severity grading was employed using clustering of voluntary wheel running (VWR) behaviour. Exposure to the paradigm evoked a transient elevation of corticosterone, but neither affected body weight, nesting or burrowing behaviour. However, the performance in VWR was impaired after recurrent stress exposure, and the individual severity level increased, indicating that this method is more sensitive in detecting compromised welfare. Interestingly, the direct comparison to a somatic, chemically induced colitis model indicates less distress in the depression model. Further objective severity assessment studies are needed to classify the severity of psychiatric animal models in order to balance validity and welfare, reduce the stress load and thus promote refinement.
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http://dx.doi.org/10.1177/0023677219874831DOI Listing
February 2020

Effects of Soy in Laboratory Rodent Diets on the Basal, Affective, and Cognitive Behavior of C57BL/6 Mice.

J Am Assoc Lab Anim Sci 2019 09 29;58(5):532-541. Epub 2019 Aug 29.

Department of Psychiatry and Psychotherapy Research Group Animal Models in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

Soy is one of the most common sources of protein in many commercial formulas for laboratory rodent diets. Soy contains isoflavones, which are estrogenic. Therefore, soy-containing animal diets might influence estrogen-regulated systems, including basal behavioral domains, as well as affective behavior and cognition. Furthermore, the isoflavone content of soy varies, potentially unpredictably confounding behavioral results. Therefore researchers are increasingly considering completely avoiding dietary soy to circumvent this problem. Several animal studies have investigated the effects of soy free diets but produced inconsistent results. In addition, most of these previous studies were performed in outbred rat or mouse strains. In the current study, we assessed whether a soy-free diet altered locomotion, exploration, nesting, anxiety-related behaviors, learning, and memory in C57BL/6 mice, the most common inbred strain used in biomedical research. The parameters evaluated address measures of basic health, natural behavior, and affective state that also are landmarks for animal welfare. We found minor differences between feeding groups but no indications of altered welfare. We therefore suggest that a soy-free diet can be used as a standard diet to prevent undesirable side effects of isoflavones and to further optimize diet standardization, quality assurance, and ultimately increase the reproducibility of experiments.
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http://dx.doi.org/10.30802/AALAS-JAALAS-18-000129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774457PMC
September 2019

Differential Neuroinflammatory Response in Male and Female Mice: A Role for BDNF.

Front Mol Neurosci 2019 17;12:166. Epub 2019 Jul 17.

Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.

A growing body of evidence supports the close relationship between major depressive disorder (MDD), a severe psychiatric disease more common among women than men, and alterations of the immune/inflammatory system. However, despite the large number of studies aimed at understanding the molecular bases of this association, a lack of information exists on the potential cross-talk between systems known to be involved in depression and components of the inflammatory response, especially with respect to sex differences. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a well-established role in MDD etiopathology: it is altered in depressed patients as well as in animal models of the disease and its changes are restored by antidepressant drugs. Interestingly, this neurotrophin is also involved in the inflammatory response. Indeed, it can be secreted by microglia, the primary innate immune cells in the central nervous system whose functions may be in turn regulated by BDNF. With these premises, in this study, we investigated the reciprocal impact of BDNF and the immune system by evaluating the neuroinflammatory response in male and female BDNF-heterozygous mutant mice acutely treated with the cytokine-inducer lipopolysaccharide (LPS). Specifically, we assessed the potential onset of an LPS-induced sickness behavior as well as changes of inflammatory mediators in the mouse hippocampus and frontal cortex, with respect to both genotype and sex. We found that the increased inflammatory response induced by LPS in the brain of male mice was independent of the genotype, whereas in the female, it was restricted to the heterozygous mice with no changes in the wild-type group, suggestive of a role for BDNF in the sex-dependent effect of the inflammatory challenge. Considering the involvement of both BDNF and neuroinflammation in several psychiatric diseases and the diverse incidence of such pathologies in males and females, a deeper investigation of the mechanisms underlying their interaction may have a critical translational relevance.
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http://dx.doi.org/10.3389/fnmol.2019.00166DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658805PMC
July 2019

Clozapine increased c-Fos protein expression in several brain subregions of socially isolated rats.

Brain Res Bull 2019 10 9;152:35-44. Epub 2019 Jul 9.

Laboratory of Molecular Biology and Endocrinology, Institute of Nuclear Sciences "Vinča", University of Belgrade, 11001 Belgrade, Serbia. Electronic address:

Chronic social stress and/or pharmacological treatments differentially modulate the expression of c-Fos, a marker of neuronal activity, in subregions of the rat brain. Here, we examined the effect of the atypical antipsychotic Clozapine (Clz) (20 mg/kg/day for 3 weeks) on the neuronal activation pattern of c-Fos protein expression in stress-relevant brain subregions of adult male Wistar rats exposed to chronic social isolation (CSIS: 3 weeks), an animal model of depression and schizophrenia, and controls. The protein expression of c-Fos was also used to map neuronal populations in brain subregions activated by CSIS alone. Subregions which showed significantly increased c-Fos protein expression following CSIS included the retrosplenial cortex (RSC), (subregions:RSC granular cortex, c region (RSGc) and dysgranular (RSD)), dentate gyrus, dorsal (DGd), paraventricular thalamic nucleus, posterior part (PVP), lateral (LA)/basolateral (BL) complex of amygdala, caudate putamen (CPu) and accumbens nucleus, shell (AcbSh). Increases in c-Fos protein expression in the RSGc, RSD, DGd, PVP, LA/BL complex of amygdala and striatum (CPu, Acb Core (AcbC) and AcbSh) following Clz treatment in controls were found. Clz applied simultaneously with CSIS modulated neuronal activity in CPu, AcbC and AcbSh subregions compared to CSIS alone, increasing c-Fos protein expression. Furthermore, Clz revealed synergistic effects with CSIS in the CA1d and PVP. These identified neural circuits reflect brain subregions activated following CSIS and/or Clz administration. These data further contribute to the understanding of the effectiveness of Clz in the modulation of brain subregion activation in response to CSIS.
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http://dx.doi.org/10.1016/j.brainresbull.2019.07.005DOI Listing
October 2019

Two Sides of the Same Coin: A Case Report of First-Episode Catatonic Syndrome in a High-Functioning Autism Patient.

Front Psychiatry 2019 12;10:224. Epub 2019 Apr 12.

Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Catatonic phenomena such as stupor, mutism, stereotypy, echolalia, echopraxia, affective flattening, psychomotor deficits, and social withdrawal are characteristic symptoms of both schizophrenia and autism spectrum disorders (ASD), suggesting overlapping pathophysiological similarities such as altered glutamatergic and dopaminergic synaptic transmission and common genetic mutations. In daily clinical practice, ASD can be masked by manifest catatonic or psychotic symptoms and represent a diagnostic challenge, especially in patients with unknown or empty medical history. Unclear diagnosis is one of the main factors for delayed treatment. However, we are still missing diagnostic recommendations when dealing with ASD patients suffering from catatonic syndrome. A 31-year-old male patient without history of psychiatric disease presented with a severe catatonic syndrome and was admitted to our closed psychiatric ward. After the treatment with high-dose lorazepam and intramuscular olanzapine, catatonic symptoms largely remitted, but autistic traits persisted. Following a detailed anamnesis and a thorough neuropsychological testing, we diagnosed the patient with high-functioning autism and catatonic schizophrenia. The patient was discharged in a remitted state with long-acting injectable olanzapine. This case represents an example of diagnostic and therapeutic challenges of catatonic schizophrenia in high-functioning autism due to clinical and neurobiological overlaps of these conditions. We discuss clinical features together with pathophysiological concepts of both conditions. Furthermore, we tackle social and legal hurdles in Germany that naturally arise in these patients. Finally, we present diagnostic "red flags" that can be used to rationally select and conduct current recommended diagnostic assessments if there is a suspicion of ASD in patients with catatonic syndrome in order to provide them with the most appropriate treatment.
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http://dx.doi.org/10.3389/fpsyt.2019.00224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473553PMC
April 2019

Learned helplessness reveals a population at risk for depressive-like behaviour after myocardial infarction in mice.

ESC Heart Fail 2019 08 26;6(4):711-722. Epub 2019 Apr 26.

Department of General Internal Medicine and Psychosomatics, University of Heidelberg, Heidelberg, Germany.

Aims: Myocardial infarction (MI) and heart failure (HF) are risk factors for the development of depression, additionally worsening the quality of life and patient outcome. How HF causes depression and how depression promotes HF remain mechanistically unclear, which is at least partly caused by the difficulty of in vivo modelling of psychosomatic co-morbidity. We aimed to study the potential sequence of events with respect to different depression aspects upon HF.

Methods And Results: Male C57BL6 mice underwent MI, followed by behavioural and echocardiographic characterization. Motility, exploration, and anxiety-like behaviour were unaffected in mice after MI. We did not observe increased depressive-like behaviour in the sucrose preference, tail suspension, or Porsolt forced swim test. Mice did not display signs of learned helplessness (LH) when compared to sham. Accordingly, cluster analysis revealed only a slightly higher quota of LH in HF (38%) vs. sham mice (32%). But strikingly, three-group cluster analysis revealed an additional intermediate subpopulation at risk for LH after HF (29%). Interestingly, this population featured elevated cardiac expression of nr4a1.

Conclusions: The LH paradigm uncovered a subtle predisposition to depressive-like behaviour after MI, whereas testing for anhedonia and despair was insufficient to show a behavioural shift in mice. Therefore, we suggest an accumulating risk profile and a multiple-hits hypothesis regarding the pathogenesis of co-morbid depression after MI. Symptoms of LH may present a marker of subclinical depression after MI, the impact of which remains to be investigated. The proposed sequence of behavioural testing enables the mechanistic dissection of cardio-psychogenic signalling in the future.
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http://dx.doi.org/10.1002/ehf2.12440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6676303PMC
August 2019

Effect of three different forms of handling on the variation of aggression-associated parameters in individually and group-housed male C57BL/6NCrl mice.

PLoS One 2019 12;14(4):e0215367. Epub 2019 Apr 12.

University of Heidelberg, Interfaculty Biomedical Research Facility (IBF), Heidelberg, Germany.

Mice are social animals hence group-housing of mice is preferred over individual housing. However, aggression in group-housed male mice under laboratory housing conditions is a well-known problem leading to serious health issues, including injury or death. Therefore, group-housed mice are frequently separated for welfare reasons. In this study, we investigated the effect of 3 different handling methods (tail, forceps, tube) in 2 different housing conditions (single vs. group) on the variance of aggression-associated parameters in male C57BL/6NCrl mice over 8 weeks. Blood glucose concentration, body weight, body temperature, plus number and severity of bite wounds and barbering intensity in group-housed mice were recorded. An assessment of nest complexity was also performed weekly. Feces were collected in week 3 and 7 for analysis of corticosterone metabolites. We also monitored the level of aggression by recording the behavior of group-housed animals after weekly cage cleaning. An open field test followed by a social novel object test, a light/dark box test, a hotplate and a resident-intruder test were performed at the end of the 8-week handling period. Post-mortem, we assessed organ weights. We found that forceps-handled mice, independent of the housing condition, had significantly higher levels of stress-induced-hyperthermia and enhanced aggression after cage cleaning, and they performed worse in the nest complexity test. In addition, handling male mice by the tail seems to be most effective to reduce aggressiveness after transferring animals into new cages, thereby representing an appropriate refinement.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215367PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461241PMC
February 2020

[The CIMH track concept in the treatment of psychotic disorders].

Nervenarzt 2020 Mar;91(3):233-242

Klinik für Psychiatrie und Psychotherapie, Zentralinstitut für Seelische Gesundheit, Medizinische Fakultät Mannheim, Universität Heidelberg, J5, 68159, Mannheim, Deutschland.

The treatment of psychotic disorders and illnesses is a challenge for therapists and institutions due to the heterogeneity of the cause and course, refractory symptoms, lack of therapy adherence and high rates of relapse. These circumstances can be effectively counteracted by the flexibility of therapeutic approaches and settings. A useful but rarely used concept is the treatment of psychoses within the so-called track unit. A track unit is defined as a syndrome-oriented, decentralized, modular unit, adjusted to the patient's individual stage-specific needs across both inpatient and outpatient sectors. The track concept offers a fully integrated sector-spanning model of treatment at all stages of psychotic illnesses as well as a continuity of treatment. Another important goal is the early availability of timely treatment for as many psychotic patients as possible so that the symptoms can be alleviated as soon as possible and the quality of life can be sustainably improved or preserved. The track concept not only improves the current situation of treatment for acutely or chronically psychotic patients but also represents a necessary investment in the future. This treatment model aims to ensure that the good but complex and costly treatment options are available to patients even if inpatient treatment is not favored by the patient.
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http://dx.doi.org/10.1007/s00115-019-0711-9DOI Listing
March 2020

Fetal glucocorticoid receptor (Nr3c1) deficiency alters the landscape of DNA methylation of murine placenta in a sex-dependent manner and is associated to anxiety-like behavior in adulthood.

Transl Psychiatry 2019 01 17;9(1):23. Epub 2019 Jan 17.

Department of Pharmacology & Therapeutics, McGill University, Montreal, QC, H3G 1Y6, Canada.

Prenatal stress defines long-term phenotypes through epigenetic programming of the offspring. These effects are potentially mediated by glucocorticoid release and by sex. We hypothesized that the glucocorticoid receptor (Gr, Nr3c1) fashions the DNA methylation profile of offspring. Consistent with this hypothesis, fetal Nr3c1 heterozygosity leads to altered DNA methylation landscape in fetal placenta in a sex-specific manner. There was a significant overlap of differentially methylated genes in fetal placenta and adult frontal cortex in Nr3c1 heterozygotes. Phenotypically, Nr3c1 heterozygotes show significantly more anxiety-like behavior than wildtype. DNA methylation status of fetal placental tissue is significantly correlated with anxiety-like behavior of the same animals in adulthood. Thus, placental DNA methylation might predict behavioral phenotypes in adulthood. Our data supports the hypothesis that Nr3c1 influences DNA methylation at birth and that DNA methylation in placenta correlates with adult frontal cortex DNA methylation and anxiety-like phenotypes.
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http://dx.doi.org/10.1038/s41398-018-0348-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6336883PMC
January 2019

Brain Sub/Region-Specific Effects of Olanzapine on c-Fos Expression of Chronically Socially Isolated Rats.

Neuroscience 2019 01 17;396:46-65. Epub 2018 Nov 17.

Vinča Institute of Nuclear Sciences, Laboratory for Molecular Biology and Endocrinology, University of Belgrade, Serbia. Electronic address:

Olanzapine (Olz) is an atypical antipsychotic used to treat depression, anxiety and schizophrenia, which can be caused by chronic psychosocial stress. c-Fos protein expression has been used as an indirect marker of neuronal activity in response to various forms of stress or pharmacological treatments. We examined the effects of a 3-week treatment of Olz (7.5 mg/kg/day) on c-Fos protein expression in stress-relevant brain sub/regions, its relationship with isolation-induced behavioral changes, and potential sites of Olz action on control and male rats exposed to 6 weeks of chronic social isolation (CSIS), an animal model of depression. Olz treatment reversed depression- and anxiety-like behaviors induced by CSIS and suppressed a CSIS-induced increase in the number of c-Fos-positive cells in subregions of the dorsal hippocampus, ventral (v) DG, retrosplenial cortex, and medial prefrontal cortex. In contrast, no change in c-Fos expression was seen in the CA3v, amygdala and thalamic, hypothalamic or striatal subregions in Olz-treated CSIS rats, suggesting different brain sub/regions' susceptibility to Olz. An increased number of c-Fos-positive cells in the CA1v, amygdala and thalamic, hypothalamic and striatal subregions in controls as well as in the CA1v and subregion of the hypothalamus and nucleus accumbens in Olz-treated CSIS rats was found. Results suggest the activation of brain sub/regions following CSIS that may be involved in depressive and anxiety-like behaviors. Olz treatment showed region-specific effects on neuronal activation. Our data contribute to a better understanding of the mechanisms underlying the CSIS response and potential brain targets of Olz in socially isolated rats.
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http://dx.doi.org/10.1016/j.neuroscience.2018.11.015DOI Listing
January 2019

Imaging biomarkers of behavioral impairments: A pilot micro-positron emission tomographic study in a rat electrical post-status epilepticus model.

Epilepsia 2018 12 28;59(12):2194-2205. Epub 2018 Oct 28.

Institute of Pharmacology, Toxicology, and Pharmacy, Ludwig Maximilian University of Munich, Munich, Germany.

Objective: In patients with epilepsy, psychiatric comorbidities can significantly affect the disease course and quality of life. Detecting and recognizing these comorbidities is central in determining an optimal treatment plan. One promising tool in detecting biomarkers for psychiatric comorbidities in epilepsy is positron emission tomography (PET).

Methods: Behavioral and biochemical variables were cross-correlated with the results from two μPET scans using the tracers [ F]fluoro-2-deoxy-D-glucose ([ F]FDG) and 2'-methoxyphenyl-(N-2'-pyridinyl)-p- F-fluoro-benzamidoethylpiperazine ([ F]MPPF) to explore potential biomarkers for neurobehavioral comorbidities in an electrically induced post-status epilepticus rat model of epilepsy.

Results: In rats with epilepsy, μPET analysis revealed a local reduction in hippocampal [ F]FDG uptake, and a local increase in [ F]MPPF binding. These changes exhibited a correlation with burrowing as a "luxury" behavior, social interaction, and anxiety-associated behavioral patterns. Interestingly, hippocampal [ F]FDG uptake did not correlate with spontaneous recurrent seizure activity.

Significance: In the electrically induced post-status epilepticus rat model, we demonstrated hippocampal hypometabolism and its correlation with a range of neurobehavioral alterations. These findings require further confirmation in other preclinical models and patients with epilepsy and psychiatric disorders to address the value of [ F]FDG uptake as an imaging biomarker candidate for psychiatric comorbidities in patients as well as for severity assessment in rodent epilepsy models.
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http://dx.doi.org/10.1111/epi.14586DOI Listing
December 2018

Tianeptine antagonizes the reduction of PV+ and GAD67 cells number in dorsal hippocampus of socially isolated rats.

Prog Neuropsychopharmacol Biol Psychiatry 2019 03 25;89:386-399. Epub 2018 Oct 25.

Vinča Institute of Nuclear Sciences, Laboratory for molecular biology and endocrinology, University of Belgrade, Serbia. Electronic address:

Adult male rats exposed to chronic social isolation (CSIS) show depressive- and anxiety-like behaviors and reduce the numbers of parvalbumin-positive (PV+) interneurons in the dorsal hippocampus. We aimed to determine whether tianeptine (Tian), administered during the last three weeks of a six-week-social isolation (10 mg/kg/day), may reverse CSIS-induced behavioral changes and antagonize the CSIS-induced reduction in the number of PV+ interneurons. We also studied whether Tian affects the GABA-producing enzyme GAD67+ cells, in Stratum Oriens (SO), Stratum Pyramidale (SP), Stratum Radiatum (SR) and Stratum Lacunosum Moleculare (LM) of CA1-3, as well as in molecular layer-granule cell layer (ML-GCL) and Hilus (H) of the dentate gyrus (DG). CSIS-induced reduction in the number of PV+ cells was layer/subregion-specific with the greatest decrease in SO of CA2. Reduction in the number of PV+ cells was significantly higher than GAD67+ cells, indicating that PV+ cells are the main target following CSIS. Tian reversed CSIS-induced behavior phenotype and antagonized the reduction in the number of PV+ and GAD67+ cells in all subregions. In controls, Tian led to an increase in the number of PV+ and GAD67+ cells in SP of all subregions and PV+ interneurons in ML-GCL of DG, while treatment during CSIS, compared to CSIS alone, resulted with an increase of PV+ interneurons in SO and SP CA1, SP CA2/CA3 and ML-GCL DG with simultaneous increase in GAD67+ cells in all CA1, LM CA2, SO/SR/LM CA3. Data show that Tian offers protection from CSIS via modulation of the dorsal hippocampal GABAergic system.
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http://dx.doi.org/10.1016/j.pnpbp.2018.10.013DOI Listing
March 2019

Brain serotonin critically contributes to the biological effects of electroconvulsive seizures.

Eur Arch Psychiatry Clin Neurosci 2018 Dec 17;268(8):861-864. Epub 2018 Jul 17.

Department of Psychiatry and Psychotherapy, Charité-University Medicine Berlin, Charitéplatz 1, 10117, Berlin, Germany.

Compounds targeting serotonin (5-HT) are widely used as antidepressants. However, the role of 5-HT in mediating the effects of electroconvulsive seizure (ECS) therapy remains undefined. Using Tph2 mice depleted of brain 5-HT, we studied the effects of ECS on behavior and neurobiology. ECS significantly prolonged the start latency in the elevated O-Maze test, an effect that was abolished in Tph2 mice. Furthermore, in the absence of 5-HT, the ECS-induced increase in adult neurogenesis and in brain-derived neurotrophic factor signaling in the hippocampus were significantly reduced. Our results indicate that brain 5-HT critically contributes to the neurobiological responses to ECS.
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http://dx.doi.org/10.1007/s00406-018-0924-0DOI Listing
December 2018