Refine
Has Fulltext
- yes (57)
Is part of the Bibliography
- yes (57)
Year of publication
Document Type
- Journal article (57)
Language
- English (57)
Keywords
- ADHD (7)
- mice (7)
- anxiety (5)
- depression (5)
- serotonin (5)
- hippocampus (4)
- animal behavior (3)
- chronic stress (3)
- emotion (3)
- knockout mice (3)
- neurodevelopment (3)
- prefrontal cortex (3)
- psychiatric disorders (3)
- DNA methylation (2)
- FAAH (2)
- SLC2A3 (2)
- Serotonin (2)
- aggression (2)
- aging (2)
- anxiety-like behavior (2)
- attention-deficit/hyperactivity disorder (ADHD) (2)
- behavior (2)
- chronic heart failure (2)
- endocannabinoid (2)
- genetics (2)
- glucose transporter (2)
- inflammation (2)
- insulin receptor (2)
- knockout (2)
- mouse (2)
- myelination (2)
- myocardial infarction (2)
- oxidative stress (2)
- pro-inflammatory cytokines (2)
- serotonin transporter (2)
- serotonin transporter gene (2)
- startle reflex (2)
- 3-dimensional MRI (1)
- 5-HT receptors (1)
- 5-HT transporter (1)
- 5-HT1A receptor (1)
- 5-HTT (1)
- 5-HTT knockout mice (1)
- 5-HTTLPR (1)
- 5-HTTLPR polymorphism (1)
- Abelson helper integration-1 (AHI1) (1)
- Activation (1)
- Acute tryptophan depletion (1)
- Adult (1)
- Aggression (1)
- Aggressive behaviour (1)
- Antisocial behavior (1)
- Anxiety-like behavior (1)
- Association (1)
- Attention Deficit Hyperactivity Disorder (ADHD) (1)
- BDNF (1)
- BDNF Val66Met (1)
- Big Five (1)
- Bipolar disorder (1)
- C57BL/6 mice (1)
- CB1 receptor antagonists (1)
- CDH13 (1)
- CDH13 Expression (1)
- CDH13 mRNA (1)
- COMT (1)
- CRISPR-Cas Systems (1)
- Cadherin (CDH13) (1)
- Cadherin-13 (CDH13) (1)
- Central nervous system (1)
- Chronic stress (1)
- Conduct disorder (1)
- Cytokines (1)
- DRD4 (1)
- Deficit/hyperactivity disorder (1)
- Depression (1)
- Diagnostic approach (1)
- Dopamine (1)
- Fgf-signalling (1)
- GABA (1)
- GAD1 (1)
- GLUT3 (1)
- GWAS (1)
- Gene (1)
- Human CDH13 (1)
- Hypothalamus (1)
- Induced Pluripotent Stem Cells (1)
- Insensitivity (1)
- Interferon-alpha (1)
- Knock-out mice (1)
- LPS (1)
- Large multicenter ADHD (1)
- Long-term depression (1)
- Major depression (1)
- Medizin (1)
- Messenger-RNA (1)
- Mice (1)
- Mood disorders (1)
- Mouse-brain (1)
- NMDA receptor subunits NR2A and NR2B (1)
- Neuronal plasticity (1)
- OXTR (1)
- Physiological functions (1)
- RNA expression (1)
- Rat-brain (1)
- Rating scale (1)
- Restraint stress (1)
- S-HT (1)
- SARS-CoV-2 (1)
- SERT (1)
- SSRI (1)
- Schizophrenie (1)
- Serotonin transporter (1)
- Serotonin transporter polymorphism (1)
- Sert-deficient mice (1)
- Susceptibility loci (1)
- T-cadherin (1)
- Toll-like receptor 4 (TLR4) (1)
- Tryptophan hydroxylase-2 (Tph2) (1)
- Western diet (1)
- Xenopus laevis oocytes (1)
- adolescence (1)
- adulthood (1)
- adversity (1)
- affective disorders (1)
- affective state (1)
- aggressiveness (1)
- agreeableness (1)
- allostatic load (1)
- amino acid analysis (1)
- anhedonia (1)
- animal behaviour (1)
- animal performance (1)
- antidepressant (1)
- antidepressants (1)
- antioxidant nutrients (1)
- anxiety disorders (1)
- anxiety like (1)
- association (1)
- astrocytes (1)
- attention (1)
- attentional bias (1)
- attention‐deficit (1)
- autism-like behavior (1)
- autoinhibition (1)
- blood flow (1)
- brain asymmetry (1)
- brain development (1)
- brain disorders (1)
- brain laterality (1)
- cadherin-13 (CDH13) (1)
- cadherins (1)
- celecoxib (1)
- cell membranes (1)
- childhood maltreatment (1)
- chronic social stress (1)
- citalopram (1)
- collagens (1)
- comparative genomics (1)
- congenital heart-deffects (1)
- coping with challenge (1)
- copy number variation (1)
- copy-number variation (1)
- corticotropin releasing factor (1)
- crystal structure (1)
- dangerous world (1)
- deficient mice (1)
- developmental plasticity (1)
- dicholine succinate (1)
- diet (1)
- dorsal raphe (1)
- dorsal raphe nucleus (1)
- electroencephalogram (EEG) (1)
- elevated plus-maze (1)
- emotional behavior (1)
- emotional information (1)
- energy expenditure (1)
- energy metabolism (1)
- environment interaction (1)
- environmental enrichment (1)
- events (1)
- evolutionary biology (1)
- executive function training (1)
- executive functions (1)
- expression (1)
- extinction (1)
- false belief (1)
- fear (1)
- fear conditioning (1)
- fear learning (1)
- female (1)
- female aggression (1)
- forced swimming (1)
- gene-by-environment interaction (1)
- geneexpression (1)
- genetic variants (1)
- genetics of the nervous system (1)
- genomic analysis (1)
- genomics (1)
- glia (1)
- glucose (1)
- glucose tolerance (1)
- glycogen synthase kinase-3 β (GSK-3β) (1)
- heterosis (1)
- heterozygote (1)
- hiPSC (1)
- hippocampal neurogenesis (1)
- hippocampal plasticity (1)
- human induced pluripotent stem cell (hiPSC) (1)
- humans (1)
- hyperactivity (1)
- hyperactivity disorder (1)
- iPSC (1)
- immediate early genes (1)
- immediate-early gene (1)
- impulsivity (1)
- in vivo (1)
- induced pluripotent stem cells (1)
- inducible cyclooxygenase-2 (COX-2) (1)
- inflammatory diseases (1)
- insulin receptor (IR) (1)
- integrins (1)
- ischemic stroke (1)
- judgement bias (1)
- knock-out mice (1)
- laboratory environment (1)
- lacking (1)
- lactosylceramide alpha-2,3-sialyltransferase (ST3GAL5) (1)
- large‐scale data (1)
- learning (1)
- learning curves (1)
- lerned helplessness (1)
- life history (1)
- life stress (1)
- linked polymorphic region (1)
- locomotor activity (1)
- long-term potentiation (1)
- major depression (1)
- major depressive disorder (MDD) (1)
- match-mismatch (1)
- maternal care (1)
- maternal separation (1)
- mechanismofaction (1)
- median and dorsal raphe (1)
- membrane potential (1)
- membrane proteins (1)
- mental disorders (1)
- metaanalysis (1)
- middle aged (1)
- moderation (1)
- molecular neuroscience (1)
- monoamine transporters (1)
- mouse model (1)
- mouse-brain (1)
- nervous system (1)
- neurodegeneration (1)
- neurodevelopmental disorders / genetics (1)
- neuroinflammation (1)
- neuronal plasticity (1)
- neuropsychiatric disorders (1)
- nitricoxidesynthase (1)
- nucleus (1)
- obesity (1)
- panic disorder (1)
- phosphorylated glycogen synthase kinase-3beta (pGSK-3beta) (1)
- plasticity (1)
- platelet activation (1)
- platelet aggregation (1)
- platelets (1)
- polygenic risk score (1)
- polymorphism (1)
- post-traumatic stress disorder (1)
- predation stress (1)
- predictive adaptive response hypothesis (1)
- primary response genes (1)
- promoter region (1)
- radial glia (1)
- rare mendelian disorders (1)
- rat brain (1)
- receptors (1)
- regulatory T cells (1)
- response inhibition (1)
- rhesus macaques (1)
- s allele (1)
- serotonin deficiency (1)
- serotonin receptors (1)
- serotonin transporter deficient mice (1)
- serotonin-specific neurons (1)
- sex differences (1)
- sialic acid (1)
- sialyltransferase (1)
- sleep EEG (1)
- social behaviour (1)
- social experience (1)
- spatial memory (1)
- stem cells (1)
- stress resilience (1)
- structural MRI (1)
- substance abuse disorder (1)
- swim test (1)
- synapse formation (1)
- telomere length (1)
- theory of mind (1)
- toll-like receptors (1)
- transporter gene SLC2A3 (1)
- treatment guidelines (1)
- tryptophan (1)
- tryptophan hydroxylase 2 (1)
- tryptophan hydroxylase-2 (1)
- tryptophan hydroxylase-2 (Tph2) (1)
- venturesomeness (1)
- white-matter integrity (1)
- working memory (1)
Institute
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (35)
- Lehrstuhl für Molekulare Psychiatrie (23)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (6)
- Institut für Humangenetik (5)
- Theodor-Boveri-Institut für Biowissenschaften (5)
- Institut für Psychologie (3)
- Physiologisches Institut (3)
- Institut für Anatomie und Zellbiologie (2)
- Medizinische Klinik und Poliklinik I (2)
- Neurologische Klinik und Poliklinik (2)
Several studies reported training-induced improvements in executive function tasks and also observed transfer to untrained tasks. However, the results are mixed and there is a large interindividual variability within and across studies. Given that training-related performance changes would require modification, growth or differentiation at the cellular and synaptic level in the brain, research on critical moderators of brain plasticity potentially explaining such changes is needed. In the present study, a pre-post-follow-up design (N = 122) and a 3-weeks training of two response inhibition tasks (Go/NoGo and Stop-Signal) was employed and genetic variation (Val66Met) in the brain-derived neurotrophic factor (BDNF) promoting differentiation and activity-dependent synaptic plasticity was examined. Because Serotonin (5-HT) signaling and the interplay of BDNF and 5-HT are known to critically mediate brain plasticity, genetic variation in the 5-HTT gene-linked polymorphic region (5-HTTLPR) was also addressed. The overall results show that the kind of training (i.e., adaptive vs. non-adaptive) did not evoke genotype-dependent differences. However, in the Go/NoGo task, better inhibition performance (lower commission errors) were observed for BDNF Val/Val genotype carriers compared to Met-allele ones supporting similar findings from other cognitive tasks. Additionally, a gene-gene interaction suggests a more impulsive response pattern (faster responses accompanied by higher commission error rates) in homozygous l-allele carriers relative to those with the s-allele of 5-HTTLPR. This, however, is true only in the presence of the Met-allele of BDNF, while the Val/Val genotype seems to compensate for such non-adaptive responding. Intriguingly, similar results were obtained for the Stop-Signal task. Here, differences emerged at post-testing, while no differences were observed at T1. In sum, although no genotype-dependent differences between the relevant training groups emerged suggesting no changes in the trained inhibition function, the observed genotype-dependent performance changes from pre- to post measurement may reflect rapid learning or memory effects linked to BDNF and 5-HTTLPR. In line with ample evidence on BDNF and BDNF-5-HT system interactions to induce (rapid) plasticity especially in hippocampal regions and in response to environmental demands, the findings may reflect genotype-dependent differences in the acquisition and consolidation of task-relevant information, thereby facilitating a more adaptive responding to task-specific requirements.
Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior.
While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome.
Background
Serotonin (5-hydroxytryptamin, 5-HT) is an indolamine platelet agonist, biochemically derived from tryptophan. 5-HT is secreted from the enterochromaffin cells into the gastrointestinal tract and blood. Blood 5-HT has been proposed to regulate hemostasis by acting as a vasoconstrictor and by triggering platelet signaling through 5-HT receptor 2A (5HTR2A). Although platelets do not synthetize 5-HT, they take 5-HT up from the blood and store it in their dense granules which are secreted upon platelet activation.
Objective
To identify the molecular composite of the 5-HT uptake system in platelets and elucidate the role of platelet released 5-HT in thrombosis and ischemic stroke. Methods: 5-HT transporter knockout mice (5Htt\(^{-/-}\)) were analyzed in different in vitro and in vivo assays and in a model of ischemic stroke.
Results
In 5Htt\(^{-/-}\) platelets, 5-HT uptake from the blood was completely abolished and agonist-induced Ca2+ influx through store operated Ca\(^{2+}\) entry (SOCE), integrin activation, degranulation and aggregation responses to glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) were reduced. These observed in vitro defects in 5Htt\(^{-/-}\) platelets could be normalized by the addition of exogenous 5-HT. Moreover, reduced 5-HT levels in the plasma, an increased bleeding time and the formation of unstable thrombi were observed ex vivo under flow and in vivo in the abdominal aorta and carotid artery of 5Htt\(^{-/-}\) mice. Surprisingly, in the transient middle cerebral artery occlusion (tMCAO) model of ischemic stroke 5Htt\(^{-/-}\) mice showed nearly normal infarct volume and the neurological outcome was comparable to control mice.
Conclusion
Although secreted platelet 5-HT does not appear to play a crucial role in the development of reperfusion injury after stroke, it is essential to amplify the second phase of platelet activation through SOCE and plays an important role in thrombus stabilization.
Background
Aggression, hyperactivity, impulsivity, helplessness and anhedonia are all signs of depressive-like disorders in humans and are often reported to be present in animal models of depression induced by stress or by inflammatory challenges. However, chronic mild stress (CMS) and clinically silent inflammation, during the recovery period after an infection, for example, are often coincident, but comparison of the behavioural and molecular changes that underpin CMS vs a mild inflammatory challenge and impact of the combined challenge is largely unexplored. Here, we examined whether stress-induced behavioural and molecular responses are analogous to lipopolysaccharide (LPS)-induced behavioural and molecular effects and whether their combination is adaptive or maladaptive.
Methods
Changes in measures of hedonic sensitivity, helplessness, aggression, impulsivity and CNS and systemic cytokine and 5-HT-system-related gene expression were investigated in C57BL/6J male mice exposed to chronic stress alone, low-dose LPS alone or a combination of LPS and stress.
Results
When combined with a low dose of LPS, chronic stress resulted in an enhanced depressive-like phenotype but significantly reduced manifestations of aggression and hyperactivity. At the molecular level, LPS was a strong inducer of TNFα, IL-1β and region-specific 5-HT2A mRNA expression in the brain. There was also increased serum corticosterone as well as increased TNFα expression in the liver. Stress did not induce comparable levels of cytokine expression to an LPS challenge, but the combination of stress with LPS reduced the stress-induced changes in 5-HT genes and the LPS-induced elevated IL-1β levels.
Conclusions
It is evident that when administered independently, both stress and LPS challenges induced distinct molecular and behavioural changes. However, at a time when LPS alone does not induce any overt behavioural changes per se, the combination with stress exacerbates depressive and inhibits aggressive behaviours.
Chronic administration of selective serotonin reuptake inhibitors (SSRIs), which up-regulates central serotonin (5-HT) system function, enhances adult hippocampal neurogenesis. However, the relationship between central 5-HT system and adult neurogenesis has not fully been understood. Here, we report that lowering 5-HT level in adulthood is also able to enhance adult hippocampal neurogenesis. We used tamoxifen (TM)-induced Cre in Pet1-CreER\(^{T2}\) mice to either deplete central serotonergic (5-HTergic) neurons or inactivate 5-HT synthesis in adulthood and explore the role of central 5-HT in adult hippocampal neurogenesis. A dramatic increase in hippocampal neurogenesis is present in these two central 5-HT-deficient mice and it is largely prevented by administration of agonist for 5-HTR2c receptor. In addition, the survival of new-born neurons in the hippocampus is enhanced. Furthermore, the adult 5-HT-deficient mice showed reduced depression-like behaviors but enhanced contextual fear memory. These findings demonstrate that lowering central 5-HT function in adulthood can also enhance adult hippocampal neurogenesis, thus revealing a new aspect of central 5-HT in regulating adult neurogenesis.
Immunological abnormalities associated with pathological conditions, such as higher infection rates, inflammatory diseases, cancer or cardiovascular events are common in patients with panic disorder. In the present study, T cell receptor excision circles (TRECs), Forkhead-Box-Protein P3 gene (FOXP3) methylation of regulatory T cells (Tregs) and relative telomere lengths (RTLs) were investigated in a total and subsamples of 131 patients with panic disorder as compared to 131 age- and sex-matched healthy controls in order to test for a potential dysfunction and premature aging of the immune system in anxiety disorders. Significantly lower TRECs (p = 0.004) as well as significant hypermethylation of the FOXP3 promoter region (p = 0.005) were observed in female (but not in male) patients with panic disorder as compared to healthy controls. No difference in relative telomere length was discerned between patients and controls, but significantly shorter telomeres in females, smokers and older persons within the patient group. The presently observed reduced TRECs in panic disorder patients and FOXP3 hypermethylation in female patients with panic disorder potentially reflect impaired thymus and immunosuppressive Treg function, which might partly account for the known increased morbidity and mortality of anxiety disorders conferred by e.g. cancer and cardiovascular disorders.
Aggressiveness is a behavioral trait that has the potential to be harmful to individuals and society. With an estimated heritability of about 40%, genetics is important in its development. We performed an exploratory genome-wide association (GWA) analysis of childhood aggressiveness in attention deficit hyperactivity disorder (ADHD) to gain insight into the underlying biological processes associated with this trait. Our primary sample consisted of 1,060 adult ADHD patients (aADHD). To further explore the genetic architecture of childhood aggressiveness, we performed enrichment analyses of suggestive genome-wide associations observed in aADHD among GWA signals of dimensions of oppositionality (defiant/vindictive and irritable dimensions) in childhood ADHD (cADHD). No single polymorphism reached genome-wide significance (P<5.00E-08). The strongest signal in aADHD was observed at rs10826548, within a long noncoding RNA gene (beta = -1.66, standard error (SE) = 0.34, P = 1.07E-06), closely followed by rs35974940 in the neurotrimin gene (beta = 3.23, SE = 0.67, P = 1.26E-06). The top GWA SNPs observed in aADHD showed significant enrichment of signals from both the defiant/vindictive dimension (Fisher's P-value = 2.28E-06) and the irritable dimension in cADHD (Fisher's P-value = 0.0061). In sum, our results identify a number of biologically interesting markers possibly underlying childhood aggressiveness and provide targets for further genetic exploration of aggressiveness across psychiatric disorders.
Rationale
While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation.
Objective
Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene.
Results
Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2\(^{−/−}\)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2\(^{−/−}\) males displayed increased impulsivity and high aggressiveness. Tph2\(^{−/−}\) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2\(^{−/−}\) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner.
Conclusions
Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
Central insulin receptor-mediated signaling is attracting the growing attention of researchers because of rapidly accumulating evidence implicating it in the mechanisms of plasticity, stress response, and neuropsychiatric disorders including depression. Dicholine succinate (DS), a mitochondrial complex II substrate, was shown to enhance insulin-receptor mediated signaling in neurons and is regarded as a sensitizer of the neuronal insulin receptor. Compounds enhancing neuronal insulin receptor-mediated transmission exert an antidepressant-like effect in several pre-clinical paradigms of depression; similarly, such properties for DS were found with a stress-induced anhedonia model. Here, we additionally studied the effects of DS on several variables which were ameliorated by other insulin receptor sensitizers in mice. Pre-treatment with DS of chronically stressed C57BL6 mice rescued normal contextual fear conditioning, hippocampal gene expression of NMDA receptor subunit NR2A, the NR2A/NR2B ratio and increased REM sleep rebound after acute predation. In 18-month-old C57BL6 mice, a model of elderly depression, DS restored normal sucrose preference and activated the expression of neural plasticity factors in the hippocampus as shown by Illumina microarray. Finally, young naive DS-treated C57BL6 mice had reduced depressive- and anxiety-like behaviors and, similarly to imipramine-treated mice, preserved hippocampal levels of the phosphorylated (inactive) form of GSK3 beta that was lowered by forced swimming in pharmacologically naive animals. Thus, DS can ameliorate behavioral and molecular outcomes under a variety of stress- and depression-related conditions. This further highlights neuronal insulin signaling as a new factor of pathogenesis and a potential pharmacotherapy of affective pathologies.