Refine
Has Fulltext
- yes (25)
Is part of the Bibliography
- yes (25)
Year of publication
Document Type
- Journal article (25) (remove)
Language
- English (25)
Keywords
- ADHD (4)
- mice (4)
- psychiatric disorders (3)
- serotonin (3)
- SLC2A3 (2)
- T-cadherin (2)
- aging (2)
- anxiety (2)
- anxiety-like behavior (2)
- chronic stress (2)
- glucose transporter (2)
- long-term potentiation (2)
- neurodevelopment (2)
- 5-HT receptors (1)
- 5-HTT (1)
- 5-HTT knockout mice (1)
- Adult (1)
- Aggression (1)
- Aggressive behaviour (1)
- Antisocial behavior (1)
- Association (1)
- Cadherin-13 (CDH13) (1)
- Chronic stress (1)
- Clinical Genetics (1)
- Conduct disorder (1)
- Cytokines (1)
- DNA (1)
- DNA methylation (1)
- DYT1 (1)
- Deficit/hyperactivity disorder (1)
- Diagnostic approach (1)
- Dystonia (1)
- GABA (1)
- GAD1 (1)
- GLUT3 (1)
- GWAS (1)
- Gene (1)
- Illumina Human Exome Bead Chip (1)
- LPS (1)
- Large multicenter ADHD (1)
- NMDA receptor subunits NR2A and NR2B (1)
- RNA expression (1)
- Rating scale (1)
- S-HT (1)
- SERT (1)
- Serotonin (1)
- Sert-deficient mice (1)
- Susceptibility loci (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)
- aggression (1)
- aggressiveness (1)
- allostatic load (1)
- amino acid analysis (1)
- animal behavior (1)
- attention deficit/hyperactivity disorder (1)
- autism-like behavior (1)
- brain development (1)
- brain disorders (1)
- cadherin-13 (CDH13) (1)
- cell membranes (1)
- chip analyses (1)
- chronic social stress (1)
- coping with challenge (1)
- copy number variation (1)
- crystal structure (1)
- dangerous world (1)
- deficit hyperactivity disorder (1)
- depression (1)
- developmental plasticity (1)
- dicholine succinate (1)
- diet (1)
- dopamine (1)
- dorsal raphe (1)
- elevated plus-maze (1)
- emotion (1)
- emotional behavior (1)
- energy metabolism (1)
- environmental enrichment (1)
- extinction (1)
- fear (1)
- fear learning (1)
- female aggression (1)
- gene-by-environment interaction (1)
- genetics (1)
- genome-wide association (1)
- glucose (1)
- glucose tolerance (1)
- glycogen synthase kinase-3 β (GSK-3β) (1)
- heterosis (1)
- hippocampal plasticity (1)
- hippocampus (1)
- human induced pluripotent stem cell (hiPSC) (1)
- immediate-early gene (1)
- induced pluripotent stem cells (1)
- insulin receptor (1)
- knockout (1)
- knockout mice (1)
- life history (1)
- match-mismatch (1)
- maternal care (1)
- maternal separation (1)
- median and dorsal raphe (1)
- membrane potential (1)
- membrane proteins (1)
- molecular medicine (1)
- mouse (1)
- myelination (1)
- nervous system (1)
- neurodegeneration (1)
- neurodevelopmental disorders (1)
- neuropsychiatric disorders (1)
- neuroscience (1)
- obesity (1)
- peripheral injury (1)
- phosphorylated glycogen synthase kinase-3beta (pGSK-3beta) (1)
- positive interneurons (1)
- predation stress (1)
- predictive adaptive response hypothesis (1)
- prefrontal cortex (1)
- radial glia (1)
- response inhibition (1)
- second hit (1)
- serotonin deficiency (1)
- serotonin receptors (1)
- serotonin transporter (1)
- serotonin-specific neurons (1)
- sleep EEG (1)
- social experience (1)
- stress (1)
- swim test (1)
- synapse formation (1)
- synaptic plasticity (1)
- tryptophan hydroxylase 2 (1)
- tryptophan hydroxylase-2 (Tph2) (1)
Institute
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (16)
- Lehrstuhl für Molekulare Psychiatrie (12)
- Theodor-Boveri-Institut für Biowissenschaften (3)
- Institut für Anatomie und Zellbiologie (2)
- Institut für Humangenetik (2)
- Klinik und Poliklinik für Kinder- und Jugendpsychiatrie, Psychosomatik und Psychotherapie (2)
- Neurologische Klinik und Poliklinik (2)
- Physiologisches Institut (2)
- Institut für Klinische Neurobiologie (1)
- Institut für Molekulare Infektionsbiologie (1)
EU-Project number / Contract (GA) number
- 602805 (25) (remove)
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.
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.
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.
Behavioral profiles are influenced by both positive and negative experiences as well as the genetic disposition. Traditionally, accumulating adversity over lifetime is considered to predict increased anxiety like behavior ("allostatic load"). The alternative "mismatch hypothesis" suggests increased levels of anxiety if the early environment differs from the later-life environment. Thus, there is a need for a whole-life history approach to gain a deeper understanding of how behavioral profiles are shaped. The aim of this study was to elucidate the effects of life history on the behavioral profile of mice varying in serotonin transporter (5-HIT) genotype, an established mouse model of increased anxiety-like behavior. For this purpose, mice grew up under either adverse or beneficial conditions during early phases of life. In adulthood, they were further subdivided so as to face a situation that either matched or mismatched the condition experienced so far, resulting in four different life histories. Subsequently, mice were tested for their anxiety-like and exploratory behavior. The main results were: (1) Life history profoundly modulated the behavioral profile. Surprisingly, mice that experienced early beneficial and later escapable adverse conditions showed less anxiety-like and more exploratory behavior compared to mice of other life histories. (2) Genotype significantly influenced the behavioral profile, with homozygous 5-HTT knockout mice displaying highest levels of anxiety-like and lowest levels of exploratory behavior. Our findings concerning life history indicate that the absence of adversity does not necessarily cause lower levels of anxiety than accumulating adversity. Rather, some adversity may be beneficial, particularly when following positive events. Altogether, we conclude that for an understanding of behavioral profiles, it is not sufficient to look at experiences during single phases of life, but the whole life history has to be considered.
Serotonin deficiency induced after brain maturation rescues consequences of early life adversity
(2021)
Brain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKOxMS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.