Publications by authors named "Miriam Schneider"

58 Publications

Persistence of humoral response upon SARS-CoV-2 infection.

Rev Med Virol 2021 Jun 30:e2272. Epub 2021 Jun 30.

Department of Scientific Coordination and Management, Danube Private University, Krems/Donau, Austria.

SARS-CoV-2 continues to leave its toll on global health and the economy. Management of the pandemic will rely heavily on the degree of adaptive immunity persistence following natural SARS-CoV-2 infection. Along with the progression of the pandemic, more literature on the persistence of the SARS-CoV-2-specific antibody response is becoming available. Here, we summarize findings on the persistence of the humoral, including neutralizing antibody, response at three to eight months post SARS-CoV-2 infection in non-pregnant adults. While the comparability of the literature is limited, findings on the detectability of immunoglobulin G class of antibodies (IgG) were most consistent and were reported in most studies to last for six to eight months. Studies investigating the response of immunoglobins M and A (IgM, IgA) were limited and reported mixed results, in particular, for IgM. The majority of studies observed neutralizing antibodies at all time points tested, which in some studies lasted up to eight months. The presence of neutralizing antibodies has been linked to protection from re-infection, suggesting long-term immunity to SARS-CoV-2. These neutralizing capacities may be challenged by emerging virus variants, but mucosal antibodies as well as memory B and T cells may optimize future immune responses. Thus, further longitudinal investigation of PCR-confirmed seropositive individuals using sensitive assays is warranted to elucidate the nature and duration of a more long-term humoral response.
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http://dx.doi.org/10.1002/rmv.2272DOI Listing
June 2021

Cannabis Use and Car Crashes: A Review.

Front Psychiatry 2021 28;12:643315. Epub 2021 May 28.

Clinic and Polyclinic for Psychiatry and Psychotherapy, Clinic of the Ludwig-Maximilian-University Munich, Munich, Germany.

In this review, state-of-the-art evidence on the relationship between cannabis use, traffic crash risks, and driving safety were analyzed. Systematic reviews, meta-analyses, and other relevant papers published within the last decade were systematically searched and synthesized. Findings show that meta-analyses and culpability studies consistently indicate a slightly but significantly increased risk of crashes after acute cannabis use. These risks vary across included study type, crash severity, and method of substance application and measurement. Some studies show a significant correlation between high THC blood concentrations and car crash risk. Most studies do not support this relationship at lower THC concentrations. However, no scientifically supported clear cut-off concentration can be derived from these results. Further research is needed to determine dose-response effects on driving skills combined with measures of neuropsychological functioning related to driving skills and crash risk.
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http://dx.doi.org/10.3389/fpsyt.2021.643315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8195290PMC
May 2021

Context and trade-offs characterize real-world threat detection systems: A review and comprehensive framework to improve research practice and resolve the translational crisis.

Neurosci Biobehav Rev 2020 08 19;115:25-33. Epub 2020 May 19.

University of California Los Angeles, Department of Ecology and Evolutionary Biology, Los Angeles, CA, USA. Electronic address:

A better understanding of context in decision-making-that is, the internal and external conditions that modulate decisions-is required to help bridge the gap between natural behaviors that evolved by natural selection and more arbitrary laboratory models of anxiety and fear. Because anxiety and fear are mechanisms evolved to manage threats from predators and other exigencies, the large behavioral, ecological and evolutionary literature on predation risk is useful for re-framing experimental research on human anxiety-related disorders. We review the trade-offs that are commonly made during antipredator decision-making in wild animals along with the context under which the behavior is performed and measured, and highlight their relevance for focused laboratory models of fear and anxiety. We then develop an integrative mechanistic model of decision-making under risk which, when applied to laboratory and field settings, should improve studies of the biological basis of normal and pathological anxiety and may therefore improve translational outcomes.
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http://dx.doi.org/10.1016/j.neubiorev.2020.05.002DOI Listing
August 2020

Cannabis use and psychosis: a review of reviews.

Eur Arch Psychiatry Clin Neurosci 2020 Jun 28;270(4):403-412. Epub 2019 Sep 28.

Department of Psychiatry and Psychotherapy, Klinikum der Universität München, Nussbaumstrasse 7, 80336, Munich, Germany.

We conducted a systematic review of meta-analyses and systematic reviews to evaluate the impact of cannabis use on the onset and course of psychoses. Following a systematic literature search of five data bases (2005-2016) and consecutive structured evaluation, we were able to include 26 systematic reviews and meta-analyses. The methodological quality of the included publications were in the range of high and poor. The scientific literature indicates that psychotic illness arises more frequently in cannabis users compared to non-users, cannabis use is associated with a dose-dependent risk of developing psychotic illness, and cannabis users have an earlier onset of psychotic illness compared to non-users. Cannabis use was also associated with increased relapse rates, more hospitalizations and pronounced positive symptoms in psychotic patients. We make recommendations about the type of research that is required to better characterize the relationship between cannabis use and the development and outcomes of psychosis.
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http://dx.doi.org/10.1007/s00406-019-01068-zDOI Listing
June 2020

[Efficacy and safety of medicinal cannabis: results of the CaPRis study].

Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2019 Jul;62(7):825-829

Vitos Klinik Psychiatrie und Psychotherapie, Herborn, Deutschland.

In the 1990s, the endocannabinoid system was discovered as part of the human physiology. Since then, the effects of cannabis as a medicine have been researched more systematically. To summarize the scientific knowledge, the German Federal Ministry of Health commissioned an expertise.The project "Cannabis: Potential and Risks: a Scientific Analysis" (CaPRis), which started in 2016, aimed at analyzing the potential of medicinal cannabis and the risks of recreational cannabis use. A search of systematic reviews (SRs) and randomized-controlled trials (RCTs) were conducted in five international databases (publication date: 2006-2017). For the medical use of cannabis 16 SRs (of 186 RCTs) were included from a global search and nine further RCTs were comprised from a de novo search. All studies were methodologically assessed.Evidence for the efficacy of cannabis medicine (given as an adjunct to other medication) was found in patients with chronic pain and spasticity due to multiple sclerosis. Benefits were also found for appetite stimulation, improvement of nausea, and weight gain in patients with cancer, HIV/AIDS or in palliative care. Effects were often small. For other physical or mental disorders, only few or no controlled human studies are available. Adverse effects of cannabis medicine are often reported; severe adverse effects were mentioned in single cases only.To provide reliable treatment recommendations for clinicians and patients, more large-sized RCTs with follow-up assessments, consistent outcome measures, and active comparisons are needed.
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http://dx.doi.org/10.1007/s00103-019-02965-3DOI Listing
July 2019

Correction to: How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

Eur Arch Psychiatry Clin Neurosci 2019 12;269(8):995

Cannabinoid Research and Treatment Group, Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nußbaumstr. 7, 80336, Munich, Germany.

The article "How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review", written by Eva Hoch, was originally published Online First without open access. After publication in volume 269, issue 1, page 87-105 the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2019 and the article is forthwith distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.
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http://dx.doi.org/10.1007/s00406-019-00999-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6841644PMC
December 2019

How effective and safe is medical cannabis as a treatment of mental disorders? A systematic review.

Eur Arch Psychiatry Clin Neurosci 2019 Feb 31;269(1):87-105. Epub 2019 Jan 31.

Cannabinoid Research and Treatment Group, Department of Psychiatry and Psychotherapy, University Hospital, LMU Munich, Nußbaumstr. 7, 80336, Munich, Germany.

We conducted a review of systematic reviews (SRs) and randomized-controlled trials (RCTs) to analyze efficacy and safety of cannabis-based medication in patients with mental disorders. Five data bases were systematically searched (2006-August 2018); 4 SRs (of 11 RCTs) and 14 RCTs (1629 participants) were included. Diagnoses were: dementia, cannabis and opioid dependence, psychoses/schizophrenia, general social anxiety, posttraumatic stress disorder, anorexia nervosa, attention-deficit hyperactivity disorder, and Tourette`s disorder. Outcome variables were too heterogeneous to conduct a  meta-analysis. A narrative synthesis method was applied. The study quality was assessed using the risk-of-bias tool and SIGN-checklists. THC- and CBD-based medicines, given as adjunct to pharmaco- and psychotherapy, were associated with improvements of several symptoms of mental disorders, but not with remission. Side effects occurred, but severe adverse effects were mentioned in single cases only. In order to provide reliable treatment recommendations, more and larger RCTs with follow-up assessments, consistent outcome measures and active comparisons are needed.
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http://dx.doi.org/10.1007/s00406-019-00984-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595000PMC
February 2019

The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts.

Front Mol Neurosci 2018 5;11:230. Epub 2018 Jul 5.

Institute of Physiological Chemistry, University Medical Center of the Johannes Gutenberg University, Mainz, Germany.

Defining functional domains and amino acid residues in G protein coupled receptors (GPCRs) represent an important way to improve rational drug design for this major class of drug targets. The cannabinoid type 1 (CB1) receptor is one of the most abundant GPCRs in the central nervous system and is involved in many physiological and pathophysiological processes. Interestingly, cannabinoid type 1 receptor with a phenylalanine 238 to leucine mutation (CB1F238L) has been already linked to a number of both and alterations. While CB1F238L causes significantly reduced presynaptic neurotransmitter release at the cellular level, behaviorally this mutation induces increased risk taking, social play behavior and reward sensitivity in rats. However, the molecular mechanisms underlying these changes are not fully understood. In this study, we tested whether the F238L mutation affects trafficking and axonal/presynaptic polarization of the CB1 receptor . Steady state or ligand modulated surface expression and lipid raft association was analyzed in human embryonic kidney 293 (HEK293) cells stably expressing either wild-type cannabinoid type 1 receptor (CB1wt) or CB1F238L receptor. Axonal/presynaptic polarization of the CB1F238L receptor was assessed in transfected primary hippocampal neurons. We show that the CB1F238L receptor displays increased association with lipid rafts, which coincides with increased lipid raft mediated constitutive endocytosis, leading to a reduction in steady state surface expression of the CB1F238L receptor. Furthermore, the CB1F238L receptor showed increased axonal polarization in primary hippocampal neurons. These data demonstrate that endocytosis of the CB1 receptor is an important mediator of axonal/presynaptic polarization and that phenylalanine 238 plays a key role in CB1 receptor trafficking and axonal polarization.
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http://dx.doi.org/10.3389/fnmol.2018.00230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6041392PMC
July 2018

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy.

Acta Neuropathol 2018 01 7;135(1):95-113. Epub 2017 Nov 7.

Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, UNSW Sydney, Sydney, NSW, 2052, Australia.

N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease-a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CNS pathology and lasting neurological benefits. This finding signifies the first successful post-symptomatic treatment of a white matter disorder using an adeno-associated virus vector tailored towards oligodendroglial-restricted transgene expression.
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http://dx.doi.org/10.1007/s00401-017-1784-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5756261PMC
January 2018

Intra-accumbal blockade of endocannabinoid CB1 receptors impairs learning but not retention of conditioned relief.

Neurobiol Learn Mem 2017 Oct 15;144:48-52. Epub 2017 Jun 15.

Institute for Pharmacology and Toxicology, Otto-von-Guericke University Magdeburg, Germany; Center of Behavioral Brain Sciences, Otto-von-Guericke University Magdeburg, Germany. Electronic address:

Humans and animals are able to associate an environmental cue with the feeling of relief from an aversive event, a phenomenon called relief learning. Relief from an aversive event is rewarding and a relief-associated cue later induces an attenuation of the startle magnitude or approach behavior. Previous studies demonstrated that the nucleus accumbens is essential for relief learning. Here, we asked whether accumbal cannabinoid type 1 (CB1) receptors are involved in relief learning. In rats, we injected the CB1 receptor antagonist/inverse agonist SR141716A (rimonabant) directly into the nucleus accumbens at different time points during a relief learning experiment. SR141716A injections immediately before the conditioning inhibited relief learning. However, SR141716A injected immediately before the retention test was not effective when conditioning was without treatment. These findings indicate that accumbal CB1 receptors play an important role in the plasticity processes underlying relief learning.
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http://dx.doi.org/10.1016/j.nlm.2017.06.001DOI Listing
October 2017

Towards trans-diagnostic mechanisms in psychiatry: neurobehavioral profile of rats with a loss-of-function point mutation in the dopamine transporter gene.

Dis Model Mech 2017 04 6;10(4):451-461. Epub 2017 Feb 6.

Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany

The research domain criteria (RDoC) matrix has been developed to reorient psychiatric research towards measurable behavioral dimensions and underlying mechanisms. Here, we used a new genetic rat model with a loss-of-function point mutation in the dopamine transporter (DAT) gene (_N157K) to systematically study the RDoC matrix. First, we examined the impact of the _N157K mutation on monoaminergic signaling. We then performed behavioral tests representing each of the five RDoC domains: negative and positive valence systems, cognitive, social and arousal/regulatory systems. The use of RDoC may be particularly helpful for drug development. We studied the effects of a novel pharmacological approach metabotropic glutamate receptor mGluR2/3 antagonism, in DAT mutants in a comparative way with standard medications. Loss of DAT functionality in mutant rats not only elevated subcortical extracellular dopamine concentration but also altered the balance of monoaminergic transmission. DAT mutant rats showed deficits in all five RDoC domains. Thus, mutant rats failed to show conditioned fear responses, were anhedonic, were unable to learn stimulus-reward associations, showed impaired cognition and social behavior, and were hyperactive. Hyperactivity in mutant rats was reduced by amphetamine and atomoxetine, which are well-established medications to reduce hyperactivity in humans. The mGluR2/3 antagonist LY341495 also normalized hyperactivity in DAT mutant rats without affecting extracellular dopamine levels. We systematically characterized an altered dopamine system within the context of the RDoC matrix and studied mGluR2/3 antagonism as a new pharmacological strategy to treat mental disorders with underlying subcortical dopaminergic hyperactivity.
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http://dx.doi.org/10.1242/dmm.027623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5399565PMC
April 2017

Ontogeny of sensorimotor gating and short-term memory processing throughout the adolescent period in rats.

Dev Cogn Neurosci 2017 06 19;25:167-175. Epub 2016 Nov 19.

Department of Psychology, University of Heidelberg, Germany. Electronic address:

Adolescence and puberty are highly susceptible developmental periods during which the neuronal organization and maturation of the brain is completed. The endocannabinoid (eCB) system, which is well known to modulate cognitive processing, undergoes profound and transient developmental changes during adolescence. With the present study we were aiming to examine the ontogeny of cognitive skills throughout adolescence in male rats and clarify the potential modulatory role of CB1 receptor signalling. Cognitive skills were assessed repeatedly every 10th day in rats throughout adolescence. All animals were tested for object recognition memory and prepulse inhibition of the acoustic startle reflex. Although cognitive performance in short-term memory as well as sensorimotor gating abilities were decreased during puberty compared to adulthood, both tasks were found to show different developmental trajectories throughout adolescence. A low dose of the CB1 receptor antagonist/inverse agonist SR141716 was found to improve recognition memory specifically in pubertal animals while not affecting behavioral performance at other ages tested. The present findings demonstrate that the developmental trajectory of cognitive abilities does not occur linearly for all cognitive processes and is strongly influenced by pubertal maturation. Developmental alterations within the eCB system at puberty onset may be involved in these changes in cognitive processing.
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http://dx.doi.org/10.1016/j.dcn.2016.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987840PMC
June 2017

Adverse Social Experiences in Adolescent Rats Result in Enduring Effects on Social Competence, Pain Sensitivity and Endocannabinoid Signaling.

Front Behav Neurosci 2016 20;10:203. Epub 2016 Oct 20.

Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of HeidelbergMannheim, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of HeidelbergMannheim, Germany.

Social affiliation is essential for many species and gains significant importance during adolescence. Disturbances in social affiliation, in particular social rejection experiences during adolescence, affect an individual's well-being and are involved in the emergence of psychiatric disorders. The underlying mechanisms are still unknown, partly because of a lack of valid animal models. By using a novel animal model for social peer-rejection, which compromises adolescent rats in their ability to appropriately engage in playful activities, here we report on persistent impairments in social behavior and dysregulations in the endocannabinoid (eCB) system. From postnatal day (pd) 21 to pd 50 adolescent female Wistar rats were either reared with same-strain partners (control) or within a group of Fischer 344 rats (inadequate social rearing, ISR), previously shown to serve as inadequate play partners for the Wistar strain. Adult ISR animals showed pronounced deficits in social interaction, social memory, processing of socially transmitted information, and decreased pain sensitivity. Molecular analysis revealed increased CB1 receptor (CB1R) protein levels and CP55, 940 stimulated [S]GTPγS binding activity specifically in the amygdala and thalamus in previously peer-rejected rats. Along with these changes, increased levels of the eCB anandamide (AEA) and a corresponding decrease of its degrading enzyme fatty acid amide hydrolase (FAAH) were seen in the amygdala. Our data indicate lasting consequences in social behavior and pain sensitivity following peer-rejection in adolescent female rats. These behavioral impairments are accompanied by persistent alterations in CB1R signaling. Finally, we provide a novel translational approach to characterize neurobiological processes underlying social peer-rejection in adolescence.
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http://dx.doi.org/10.3389/fnbeh.2016.00203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5071316PMC
October 2016

Lipids in psychiatric disorders and preventive medicine.

Neurosci Biobehav Rev 2017 05 16;76(Pt B):336-362. Epub 2016 Jun 16.

Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. Electronic address:

Psychiatric disorders like mood disorders, schizophrenia, or drug addiction affect a sizeable proportion of the human population and severely compromise quality of life. Therefore, measures to prevent the manifestation, and treatments to ameliorate the symptoms, of these disorders are in high demand. Brain lipids determine the localization and function of proteins in the cell membrane of neurons. Lipids may also act as neurotransmitters or other signalling molecules. The lipid composition of the brain can be influenced by nutrition, environmental factors, and by behavioural activity. Thus, lipids represent a target for preventive medicine of psychiatric disorders. Here we review how brain lipids contribute to normal behaviour and to major psychiatric disorders with the focus on phospholipids/fatty acids, sphingolipids, and endocannabinoids. Accumulating evidence suggests a crucial role for membrane forming and signalling lipids in the brain in the etiopathologies of depression, bipolar disorders, schizophrenia, and drug addiction. Lipids also represent potential preventive interventions for these psychiatric disorders by either targeted dietary supplementation or pharmacological manipulation of lipid regulating enzymes.
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http://dx.doi.org/10.1016/j.neubiorev.2016.06.002DOI Listing
May 2017

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus.

Eur Arch Psychiatry Clin Neurosci 2017 Aug 4;267(5):455-463. Epub 2016 Jun 4.

Department of Child and Adolescent Psychiatry, University Hospital Carl Gustav Carus, Faculty of Medicine, Technical University of Dresden, Dresden, Germany.

Epilepsy is a major risk factor for autism spectrum disorder (ASD) and complicates clinical manifestations and management of ASD significantly. Tuberous sclerosis complex (TSC), caused by TSC1 or TSC2 mutations, is one of the medical conditions most commonly associated with ASD and has become an important model to examine molecular pathways associated with ASD. Previous research showed reversal of autism-like social deficits in Tsc1 and Tsc2 mouse models by mammalian target of rapamycin (mTOR) inhibitors. However, at least 70 % of individuals with TSC also have epilepsy, known to complicate the severity and treatment responsiveness of the behavioural phenotype. No previous study has examined the impact of seizures on neurocognitive reversal by mTOR inhibitors. Adult Tsc2 (Eker)-rats express social deficits similar to Tsc2 mice, with additive social deficits from developmental status epilepticus (DSE). DSE was induced by intraperitoneal injection with kainic acid at post-natal days P7 and P14 (n = 12). The experimental group that modelled TSC pathology carried the Tsc2 (Eker)-mutation and was challenged with DSE. The wild-type controls had not received DSE (n = 10). Four-month-old animals were analysed for social behaviour (T1), then treated three times during 1 week with 1 mg/kg everolimus and finally retested in the post-treatment behavioural analysis (T2). In the experimental group, both social interaction and social cognition were impaired at T1. After treatment at T2, behaviour in the experimental group was indistinguishable from controls. The mTOR inhibitor, everolimus, reversed social deficit behaviours in the Tsc2 haploinsufficiency plus DSE animal model to control levels.
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http://dx.doi.org/10.1007/s00406-016-0703-8DOI Listing
August 2017

Adolescent social rejection alters pain processing in a CB1 receptor dependent manner.

Eur Neuropsychopharmacol 2016 07 2;26(7):1201-12. Epub 2016 May 2.

Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address:

Experiences of social rejection represent a major source of distress and in particular peer rejection during adolescence has been implicated in various psychiatric disorders. Moreover, experimentally induced acute social rejection alters pain perception in humans, implicating overlapping neurocircuits for social and physical pains. We recently demonstrated that rearing of adolescent Wistar rats with inadequate, less playful play partners (Fischer 344) persistently decreases pain sensitivity, although the detailed mechanisms mediating the aversiveness during the social encounter remained unsettled. With the present study we examined the behavioral performance during acute interaction of female adolescent Wistar rats with either age-matched same-strain partners or rats from the Fischer 344 strain. We here identify the low responsiveness upon playful attacks, which appears to be characteristic for social play in the Fischer 344 strain, as one of the main aversive components for adolescent Wistar animals during cross-strain encounters, which subsequently diminishes thermal pain reactivity. A detailed behavioral analysis further revealed increased ultrasonic vocalization at 50kHz and an increased frequency of playful attacks for adolescent Wistar animals paired with a Fischer 344 rat compared to same-strain control pairs. Finally, an acute injection of a subthreshold dose of the cannabinoid type 1 receptor inverse agonist/antagonist SR141716 before the social encounter abolished enhanced play-soliciting behavior in Wistar/Fischer 344 pairs as well as the behavioral consequences of the rejection experience in adolescent Wistar rats, further emphasizing an important modulatory role of the endocannabinoid system in mediating the effects of social behavior and social pain.
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http://dx.doi.org/10.1016/j.euroneuro.2016.04.007DOI Listing
July 2016

Oxytocin Enhances Social Recognition by Modulating Cortical Control of Early Olfactory Processing.

Neuron 2016 05 21;90(3):609-21. Epub 2016 Apr 21.

Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany. Electronic address:

Oxytocin promotes social interactions and recognition of conspecifics that rely on olfaction in most species. The circuit mechanisms through which oxytocin modifies olfactory processing are incompletely understood. Here, we observed that optogenetically induced oxytocin release enhanced olfactory exploration and same-sex recognition of adult rats. Consistent with oxytocin's function in the anterior olfactory cortex, particularly in social cue processing, region-selective receptor deletion impaired social recognition but left odor discrimination and recognition intact outside a social context. Oxytocin transiently increased the drive of the anterior olfactory cortex projecting to olfactory bulb interneurons. Cortical top-down recruitment of interneurons dynamically enhanced the inhibitory input to olfactory bulb projection neurons and increased the signal-to-noise of their output. In summary, oxytocin generates states for optimized information extraction in an early cortical top-down network that is required for social interactions with potential implications for sensory processing deficits in autism spectrum disorders.
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http://dx.doi.org/10.1016/j.neuron.2016.03.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860033PMC
May 2016

Enhanced Functional Activity of the Cannabinoid Type-1 Receptor Mediates Adolescent Behavior.

J Neurosci 2015 Oct;35(41):13975-88

Institute of Psychopharmacology and.

Unlabelled: Adolescence is characterized by drastic behavioral adaptations and comprises a particularly vulnerable period for the emergence of various psychiatric disorders. Growing evidence reveals that the pathophysiology of these disorders might derive from aberrations of normal neurodevelopmental changes in the adolescent brain. Understanding the molecular underpinnings of adolescent behavior is therefore critical for understanding the origin of psychopathology, but the molecular mechanisms that trigger adolescent behavior are unknown. Here, we hypothesize that the cannabinoid type-1 receptor (CB1R) may play a critical role in mediating adolescent behavior because enhanced endocannabinoid (eCB) signaling has been suggested to occur transiently during adolescence. To study enhanced CB1R signaling, we introduced a missense mutation (F238L) into the rat Cnr1 gene that encodes for the CB1R. According to our hypothesis, rats with the F238L mutation (Cnr1(F238L)) should sustain features of adolescent behavior into adulthood. Gain of function of the mutated receptor was demonstrated by in silico modeling and was verified functionally in a series of biochemical and electrophysiological experiments. Mutant rats exhibit an adolescent-like phenotype during adulthood compared with wild-type littermates, with typical high risk/novelty seeking, increased peer interaction, enhanced impulsivity, and augmented reward sensitivity for drug and nondrug reward. Partial inhibition of CB1R activity in Cnr1(F238L) mutant rats normalized behavior and led to a wild-type phenotype. We conclude that the activity state and functionality of the CB1R is critical for mediating adolescent behavior. These findings implicate the eCB system as an important research target for the neuropathology of adolescent-onset mental health disorders.

Significance Statement: We present the first rodent model with a gain-of-function mutation in the cannabinoid type-1 receptor (CB1R). Adult mutant rats exhibit an adolescent-like phenotype with typical high risk seeking, impulsivity, and augmented drug and nondrug reward sensitivity. Adolescence is a critical period for suboptimal behavioral choices and the emergence of neuropsychiatric disorders. Understanding the basis of these disorders therefore requires a comprehensive knowledge of how adolescent neurodevelopment triggers behavioral reactions. Our behavioral observations in adult mutant rats, together with reports on enhanced adolescent CB1R signaling, suggest a pivotal role for the CB1R in an adolescent brain as an important molecular mediator of adolescent behavior. These findings implicate the endocannabinoid system as a notable research target for adolescent-onset mental health disorders.
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http://dx.doi.org/10.1523/JNEUROSCI.1937-15.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604232PMC
October 2015

No evidence for differential dose effects of hydrocortisone on intrusive memories in female patients with complex post-traumatic stress disorder--a randomized, double-blind, placebo-controlled, crossover study.

J Psychopharmacol 2015 Oct 6;29(10):1077-84. Epub 2015 Jul 6.

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

Background: Post-traumatic stress disorder is characterized by intrusive traumatic memories. Presently, a controversial debate is ongoing regarding whether reduced cortisol secretion in post-traumatic stress disorder promotes an automatic retrieval of trauma-associated memories. Hence, a pharmacological elevation of cortisol was proposed to decrease post-traumatic stress disorder symptoms, particularly intrusions. The present study investigated the impact of two different doses of hydrocortisone on automatic memory retrieval using a randomized, double-blind, placebo-controlled, crossover study in 30 inpatients with post-traumatic stress disorder.

Methods: All participants were female and received various psychotropic medications. They were randomly assigned to one of two groups within a crossover design: they received either 1 week placebo followed by 1 week hydrocortisone 10/d, followed by 1 week placebo, followed by hydrocortisone 30 mg/d (15 participants) or 1 week hydrocortisone 30 mg/d, followed by 1 week placebo, followed by 1 week hydrocortisone 10 mg/d, followed by 1 week placebo (15 participants). The outcome measures were the frequency and the intensity of intrusions, the overall symptomatology of post-traumatic stress disorder and the general psychopathology.

Results: We did not find any differences in the frequency and the intensity of post-traumatic stress disorder-related intrusions between the 10 mg hydrocortisone, the 30 mg hydrocortisone and the placebo condition. All effect sizes for the hydrocortisone condition vs. placebo were very small. Additionally, the overall symptomatology of post-traumatic stress disorder and the general psychopathology did not differ between the hydrocortisone therapies and placebo.

Conclusions: Our results do not show any effect of the hydrocortisone administration on intrusions in complex post-traumatic stress disorder.
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http://dx.doi.org/10.1177/0269881115592339DOI Listing
October 2015

Septal Glucagon-Like Peptide 1 Receptor Expression Determines Suppression of Cocaine-Induced Behavior.

Neuropsychopharmacology 2015 Jul 11;40(8):1969-78. Epub 2015 Feb 11.

Translational Neuroscience Facility and Department of Physiology, School of Medical Sciences, UNSW Australia, Sydney, NSW, Australia.

Glucagon-like peptide 1 (GLP-1) and its receptor GLP-1R are a key component of the satiety signaling system, and long-acting GLP-1 analogs have been approved for the treatment of type-2 diabetes mellitus. Previous reports demonstrate that GLP-1 regulates glucose homeostasis alongside the rewarding effects of food. Both palatable food and illicit drugs activate brain reward circuitries, and pharmacological studies suggest that central nervous system GLP-1 signaling holds potential for the treatment of addiction. However, the role of endogenous GLP-1 in the attenuation of reward-oriented behavior, and the essential domains of the mesolimbic system mediating these beneficial effects, are largely unknown. We hypothesized that the central regions of highest Glp-1r gene activity are essential in mediating responses to drugs of abuse. Here, we show that Glp-1r-deficient (Glp-1r(-/-)) mice have greatly augmented cocaine-induced locomotor responses and enhanced conditional place preference compared with wild-type (Glp-1r(+/+)) controls. Employing mRNA in situ hybridization we located peak Glp-1r mRNA expression in GABAergic neurons of the dorsal lateral septum, an anatomical site with a crucial function in reward perception. Whole-cell patch-clamp recordings of dorsal lateral septum neurons revealed that genetic Glp-1r ablation leads to increased excitability of these cells. Viral vector-mediated Glp-1r gene delivery to the dorsal lateral septum of Glp-1r(-/-) animals reduced cocaine-induced locomotion and conditional place preference to wild-type levels. This site-specific genetic complementation did not affect the anxiogenic phenotype observed in Glp-1r(-/-) controls. These data reveal a novel role of GLP-1R in dorsal lateral septum function driving behavioral responses to cocaine.
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http://dx.doi.org/10.1038/npp.2015.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839521PMC
July 2015

Lack of protracted behavioral abnormalities following intermittent or continuous chronic mild hypoxia in perinatal C57BL/6 mice.

Neurosci Lett 2014 Aug 14;577:77-82. Epub 2014 Jun 14.

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

Several prospective studies indicated perinatal hypoxia as risk factor for psychiatric disorders like schizophrenia. It is thought that hypoxia prior to or during birth may contribute to alterations leading to the protracted clinical manifestation during young adulthood. However, only a small fraction of children with a history of perinatal hypoxia develop later psychotic symptoms, therefore it is not known if hypoxia alone is sufficient to trigger long-term behavioral changes. Here we exposed C57BL/6 mice from postnatal day 3-7 (P3-P7) to two established paradigms of chronic mild hypoxia (10% ambient O2), intermittent and continuous. Subsequently, mice were analysed during young adult stages using several basic behavioral tests. Previous studies demonstrated severe, but only transient, cortical damage in these paradigms; it is not clear, if these reversible morphological changes are accompanied by long-term behavioral effects. We found that neither intermittent nor continuous perinatal hypoxia induced long-term behavioral alterations. This may be due to the high regenerative capacity of the perinatal brain. Other possibilities include a potential resistance to perinatal hypoxia of the mouse strain used here or a level of hypoxia that was insufficient to trigger significant behavioral changes. Therefore, our data do not exclude a role of perinatal hypoxia as risk factor for psychiatric disorders. They rather suggest that either other, more severe hypoxic conditions like anoxia, or the presence of additional factors (as genetic risk factors) are necessary for generating long-term behavioral abnormalities.
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http://dx.doi.org/10.1016/j.neulet.2014.06.022DOI Listing
August 2014

The CB1 receptor as an important mediator of hedonic reward processing.

Neuropsychopharmacology 2014 Sep 10;39(10):2387-96. Epub 2014 Apr 10.

Reseach Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

The endocannabinoid (ECB) system has emerged recently as a key mediator for reward processing. It is well known that cannabinoids affect appetitive learning processes and can induce reinforcing and rewarding effects. However, the involvement of the ECB system in hedonic aspects of reward-related behavior is not completely understood. With the present study, we investigated the modulatory role of the ECB system on hedonic perception, measured by the pleasure attenuated startle (PAS) paradigm for a palatable food reward. Here, a conditioned odor is thought to induce a pleasant affective state that attenuates an aversive reflex-the acoustic startle response. Modulatory effects of the CB1 receptor antagonist/inverse agonist SR1411716 and the cannabinoid agonist WIN 55 212-2 on PAS were examined in rats. PAS was also measured in CB1 receptor knockout (KO) and wild-type (WT) mice. Pharmacological inhibition as well as the absence of CB1 receptors was found to reduce PAS, whereas WIN 55 212-2 administration increased PAS. Finally, presentation of a conditioned reward cue was found to induce striatal FosB/ΔFosB expression in WT mice, but not in KO mice, indicating a reduced stimulation of reward-related brain regions in conditioned KO mice by odor presentation. We here show that in addition to our previous studies in rats, PAS may also serve as a valuable and suitable measure to assess hedonic processing in mice. Our data further indicate that the ECB system, and in particular CB1 receptor signaling, appears to be highly important for the mediation of hedonic aspects of reward processing.
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http://dx.doi.org/10.1038/npp.2014.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138748PMC
September 2014

Mechanisms of disturbed emotion processing and social interaction in borderline personality disorder: state of knowledge and research agenda of the German Clinical Research Unit.

Borderline Personal Disord Emot Dysregul 2014 9;1:12. Epub 2014 Sep 9.

Department of Psychosomatic Medicine and Psychotherapy, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim / Heidelberg University, J 5, 68159 Mannheim, Germany.

The last two decades have seen a strong rise in empirical research in the mechanisms of emotion dysregulation in borderline personality disorder. Major findings comprise structural as well as functional alterations of brain regions involved in emotion processing, such as amygdala, insula, and prefrontal regions. In addition, more specific mechanisms of disturbed emotion regulation, e.g. related to pain and dissociation, have been identified. Most recently, social interaction problems and their underlying neurobiological mechanisms, e.g. disturbed trust or hypersensitivity to social rejection, have become a major focus of BPD research. This article covers the current state of knowledge and related relevant research goals. The first part presents a review of the literature. The second part delineates important open questions to be addressed in future studies. The third part describes the research agenda for a large German center grant focusing on mechanisms of emotion dysregulation in BPD.
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http://dx.doi.org/10.1186/2051-6673-1-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4579501PMC
September 2015

Phenotype of mice with inducible ablation of GluA1 AMPA receptors during late adolescence: relevance for mental disorders.

Hippocampus 2014 Apr 23;24(4):424-35. Epub 2013 Dec 23.

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

Adolescence is characterized by important molecular and anatomical changes with relevance for the maturation of brain circuitry and cognitive function. This time period is of critical importance in the emergence of several neuropsychiatric disorders accompanied by cognitive impairment, such as affective disorders and schizophrenia. The molecular mechanisms underlying these changes at neuronal level during this specific developmental stage remains however poorly understood. GluA1-containing AMPA receptors, which are located predominantly on hippocampal neurons, are the primary molecular determinants of synaptic plasticity. We investigated here the consequences of the inducible deletion of GluA1 AMPA receptors in glutamatergic neurons during late adolescence. We generated mutant mice with a tamoxifen-inducible deletion of GluA1 under the control of the CamKII promoter for temporally and spatially restricted gene manipulation. GluA1 ablation during late adolescence induced cognitive impairments, but also marked hyperlocomotion and sensorimotor gating deficits. Unlike the global genetic deletion of GluA1, inducible GluA1 ablation during late adolescence resulted in normal sociability. Deletion of GluA1 induced redistribution of GluA2 subunits, suggesting AMPA receptor trafficking deficits. Mutant animals showed increased hippocampal NMDA receptor expression and no change in striatal dopamine concentration. Our data provide new insight into the role of deficient AMPA receptors specifically during late adolescence in inducing several cognitive and behavioral alterations with possible relevance for neuropsychiatric disorders.
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http://dx.doi.org/10.1002/hipo.22236DOI Listing
April 2014

Impact of pubertal stage at first drink on adult drinking behavior.

Alcohol Clin Exp Res 2013 Oct 17;37(10):1804-11. Epub 2013 May 17.

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

Background: Early alcohol use is one of the strongest predictors of later alcohol use disorders, with early use usually taking place during puberty. Many researchers have suggested drinking during puberty as a potential biological basis of the age at first drink (AFD) effect. However, the influence of the pubertal phase at alcohol use initiation on subsequent drinking in later life has not been examined so far.

Methods: Pubertal stage at first drink (PSFD) was determined in N = 283 young adults (131 males, 152 females) from an epidemiological cohort study. At ages 19, 22, and 23 years, drinking behavior (number of drinking days, amount of alcohol consumed, hazardous drinking) was assessed using interview and questionnaire methods. Additionally, an animal study examined the effects of pubertal or adult ethanol (EtOH) exposure on voluntary EtOH consumption in later life in 20 male Wistar rats.

Results: PSFD predicted drinking behavior in humans in early adulthood, indicating that individuals who had their first drink during puberty displayed elevated drinking levels compared to those with postpubertal drinking onset. These findings were corroborated by the animal study, in which rats that received free access to alcohol during the pubertal period were found to consume more alcohol as adults, compared to the control animals that first came into contact with alcohol during adulthood.

Conclusions: The results point to a significant role of stage of pubertal development at first contact with alcohol for the development of later drinking habits. Possible biological mechanisms and implications for prevention are discussed.
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http://dx.doi.org/10.1111/acer.12154DOI Listing
October 2013

Adolescent peer-rejection persistently alters pain perception and CB1 receptor expression in female rats.

Eur Neuropsychopharmacol 2014 Feb 10;24(2):290-301. Epub 2013 May 10.

Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address:

Peer-interactions are particularly important during adolescence and teenagers display enhanced sensitivity toward rejection by peers. Social rejection has been shown to induce alterations in pain perception in humans. However, the neurobiological consequences of adolescent social rejection have yet to be extensively characterized, and no appropriate animal model is available. Here, we propose inadequate playful interactions in adolescent rats as a novel animal model for social peer-rejection and examine potential long-term consequences into adulthood. Acute social pairing of female adolescent Wistar rats with an age-matched rat from the less playful Fischer344 strain was found to alter social play and decrease pain reactivity, indicating Fischer rats as inadequate social partners for Wistar animals. Therefore, in a second experiment, adolescent female Wistar rats were either reared with another Wistar rat (adequate social rearing; control) or with a Fischer rat (inadequate social rearing; play-deprived). Beginning on day 50, all Wistar rats were group housed with same-strain partners and tested for behavioral, neurobiological and endocrine differences in adulthood. Playful peer-interactions were decreased during adolescence in play-deprived animals, without affecting social contact behavior. Consequently, adult play-deprived rats showed decreased pain sensitivity and increased startle reactivity compared to controls, but did not differ in activity, anxiety-related behavior or social interaction. Both groups also differed in their endocrine stress-response, and expression levels of the cannabinoid CB1 receptor were increased in the thalamus, whereas FAAH levels were decreased in the amygdala. The present animal model therefore represents a novel approach to assess the long-term consequences of peer-rejection during adolescence.
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http://dx.doi.org/10.1016/j.euroneuro.2013.04.004DOI Listing
February 2014

Synthetic microRNA-mediated downregulation of Nogo-A in transgenic rats reveals its role as regulator of synaptic plasticity and cognitive function.

Proc Natl Acad Sci U S A 2013 Apr 1;110(16):6583-8. Epub 2013 Apr 1.

Brain Research Institute, University of Zürich and Department of Health Sciences and Technology, Eidgenössiche Technische Hochschule, Switzerland, 8057 Zürich, Switzerland.

We have generated a transgenic rat model using RNAi and used it to study the role of the membrane protein Nogo-A in synaptic plasticity and cognition. The membrane protein Nogo-A is expressed in CNS oligodendrocytes and subpopulations of neurons, and it is known to suppress neurite growth and regeneration. The constitutively expressed polymerase II-driven transgene was composed of a microRNA-targeting Nogo-A placed into an intron preceding the coding sequence for EGFP, thus quantitatively labeling cells according to intracellular microRNA expression. The transgenic microRNA in vivo efficiently reduced the concentration of Nogo-A mRNA and protein preferentially in neurons. The resulting significant increase in long-term potentiation in both hippocampus and motor cortex indicates a repressor function of Nogo-A in synaptic plasticity. The transgenic rats exhibited prominent schizophrenia-like behavioral phenotypes, such as perseveration, disrupted prepulse inhibition, and strong withdrawal from social interactions. This fast and efficient microRNA-mediated knockdown provides a way to silence gene expression in vivo in transgenic rats and shows a role of Nogo-A in regulating higher cognitive brain functions.
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http://dx.doi.org/10.1073/pnas.1217665110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3631667PMC
April 2013

Adolescence as a vulnerable period to alter rodent behavior.

Authors:
Miriam Schneider

Cell Tissue Res 2013 Oct 22;354(1):99-106. Epub 2013 Feb 22.

Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health Mannheim, Medical Faculty Mannheim, J5, University of Heidelberg, 68159, Mannheim, Germany,

Adolescence and puberty are highly important periods for postnatal brain maturation. During adolescence, drastic changes of neuronal architecture and function occur that concomitantly lead to distinct behavioral alterations. Unsurprisingly in view of the multitude of ongoing neurodevelopmental processes in the adolescent brain, most adult neuropsychiatric disorders have their roots exactly during this time span. Adolescence and puberty are therefore crucial developmental periods in terms of understanding the causes and mechanisms of adult mental illness. Valid animal models for adolescent behavior and neurodevelopment might offer better insights into the underlying mechanisms and help to identify specific time windows with heightened susceptibility during development. In order to increase the translational value of such models, we urgently need to define the detailed timing of adolescence and puberty in laboratory rodents. The aim of the present review is to provide a more precise delineation of the time course of these developmental periods during postnatal life in rats and mice and to discuss the impact of adolescence and related neurodevelopmental processes on the heightened susceptibility for mental disorders.
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http://dx.doi.org/10.1007/s00441-013-1581-2DOI Listing
October 2013

Behavioral differences in three Wistar Han rat lines for emotional reactivity, cognitive processing and ethanol intake.

Physiol Behav 2013 Feb 7;110-111:102-8. Epub 2013 Jan 7.

Research Group Developmental Neuropsychopharmacology, Institute of Psychopharmacology, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

Many laboratories obtain their experimental animals from commercial suppliers and are therefore dependent on their conditions and breeding schedules. A breeding stop or the substitution of a particular rat line by the supplier forces the customers to abandon their conventional test animals and to re-establish all behavioral paradigms with a new rat line. Therefore, it is vital to know whether behavioral differences emerge in various breeding lines of the same rat strain. In a recent case, the commercial supplier Harlan Laboratories GmbH is substituting the previous HsdHan:WIST line of Wistar rats with the RccHan:WIST line descending from a different breeding stock. We therefore tested animals of both lines (RccHan:WIST and HsdHan:WIST from Harlan Laboratories GmbH) as well as Wistar rats of the same line but obtained from a different supplier (Janvier) in a broad range of behavioral paradigms. We observed differences in locomotor activity, in classical anxiety-related paradigms (elevated plus maze and light/dark emergence test), as well as in object recognition memory and prepulse inhibition (PPI) of the acoustic startle reflex (ASR). We also found differences in ethanol intake and preference, but not regarding the intake of a palatable food reward and a bitter solution (quinine). These results demonstrate considerable variations in the behavioral phenotype between different breeding lines of the same Wistar rat strain and aim to increase the awareness of behavioral scientists for line and supplier differences affecting animal behavior.
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http://dx.doi.org/10.1016/j.physbeh.2012.12.019DOI Listing
February 2013

Mapping brain regions in which deep brain stimulation affects schizophrenia-like behavior in two rat models of schizophrenia.

Brain Stimul 2013 Jul 8;6(4):490-9. Epub 2012 Oct 8.

Department of Psychiatry and Psychotherapy, Charité Campus Mitte, Germany.

Background And Objectives: The development of more efficient treatment remains a major unmet need in the realm of schizophrenia disease. Using the maternal immune stimulation and the pubertal cannabinoid administration rat model of schizophrenia, the present study aimed at testing the hypothesis that deep brain stimulation (DBS) serves as a novel therapeutic technique for this disorder.

Methods: Adult offspring of dams, treated with the immune activating agent poly I:C (4 mg/kg, n = 50) or saline (n = 50), underwent bilateral stereotactic electrode implantation into one of the following brain regions: subthalamic nucleus (STN, n = 12/10), entopeduncularis nucleus (EP, n = 10/11), globus pallidus (GP, n = 10/10), medial prefrontal cortex (mPFC, n = 8/8), or dorsomedial thalamus (DM, n = 10/11). Adult rats treated with the CB1 receptor agonist WIN 55,212-2 (WIN, n = 16) or saline (n = 12) during puberty were bilaterally implanted with electrodes into either the mPFC (n = 8/6) or the DM (n = 8/6). After a post-operative recovery period of one week, all rats were tested on a well-established cross-species phenomenon that is disrupted in schizophrenia, the pre-pulse inhibition (PPI) of the acoustic startle reflex (ASR) under different DBS conditions.

Results: Poly I:C induced deficits in PPI of the ASR were normalized upon DBS. DBS effects depended on both stimulation target and stimulation parameters. Most prominent effects were found under DBS at high frequencies in the mPFC and DM. These effects were replicated in the pubertal WIN administration rat model of schizophrenia.

Conclusions: Brain regions, in which DBS normalized PPI deficits, might be of therapeutic relevance to the treatment of schizophrenia. Results imply that DBS could be considered a plausible therapeutic technique in the realm of schizophrenia disease.
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http://dx.doi.org/10.1016/j.brs.2012.09.004DOI Listing
July 2013