Refine
Has Fulltext
- yes (33)
Is part of the Bibliography
- yes (33)
Year of publication
Document Type
- Journal article (33)
Language
- English (33)
Keywords
- anxiety (4)
- depression (4)
- mice (4)
- ADHD (3)
- emotion (3)
- hippocampus (3)
- DNA methylation (2)
- FAAH (2)
- aggression (2)
- animal behavior (2)
- behavior (2)
- chronic heart failure (2)
- endocannabinoid (2)
- genetics (2)
- knockout (2)
- knockout mice (2)
- myocardial infarction (2)
- psychiatric disorders (2)
- serotonin (2)
- serotonin transporter (2)
- startle reflex (2)
- 5-HT transporter (1)
- 5-HT1A receptor (1)
- 5-HTT knockout mice (1)
- 5-HTTLPR (1)
- Abelson helper integration-1 (AHI1) (1)
- Activation (1)
- Acute tryptophan depletion (1)
- Aggressive behaviour (1)
- Anxiety-like behavior (1)
- Attention Deficit Hyperactivity Disorder (ADHD) (1)
- BDNF (1)
- BDNF Val66Met (1)
- Big Five (1)
- Bipolar disorder (1)
- CDH13 (1)
- CDH13 Expression (1)
- CDH13 mRNA (1)
- CRISPR-Cas Systems (1)
- Cadherin (CDH13) (1)
- Cadherin-13 (CDH13) (1)
- Chronic stress (1)
- Cytokines (1)
- Depression (1)
- GABA (1)
- GAD1 (1)
- Human CDH13 (1)
- Induced Pluripotent Stem Cells (1)
- Insensitivity (1)
- Interferon-alpha (1)
- Knock-out mice (1)
- LPS (1)
- Long-term depression (1)
- Major depression (1)
- Messenger-RNA (1)
- Mice (1)
- Mood disorders (1)
- Mouse-brain (1)
- Neuronal plasticity (1)
- Physiological functions (1)
- RNA expression (1)
- Rat-brain (1)
- Restraint stress (1)
- S-HT (1)
- SERT (1)
- Schizophrenie (1)
- Serotonin (1)
- Serotonin transporter (1)
- Serotonin transporter polymorphism (1)
- Sert-deficient mice (1)
- Toll-like receptor 4 (TLR4) (1)
- Tryptophan hydroxylase-2 (Tph2) (1)
- Western diet (1)
- Xenopus laevis oocytes (1)
- adolescence (1)
- adversity (1)
- affective state (1)
- aggressiveness (1)
- aging (1)
- agreeableness (1)
- amino acid analysis (1)
- animal performance (1)
- antidepressant (1)
- antidepressants (1)
- anxiety disorders (1)
- anxiety like (1)
- anxiety-like behavior (1)
- astrocytes (1)
- attention-deficit/hyperactivity disorder (ADHD) (1)
- attentional bias (1)
- autism-like behavior (1)
- autoinhibition (1)
- brain development (1)
- brain disorders (1)
- cadherins (1)
- cell membranes (1)
- chronic stress (1)
- congenital heart-deffects (1)
- coping with challenge (1)
- copy-number variation (1)
- corticotropin releasing factor (1)
- crystal structure (1)
- deficient mice (1)
- diet (1)
- dorsal raphe nucleus (1)
- emotional behavior (1)
- emotional information (1)
- energy expenditure (1)
- executive function training (1)
- executive functions (1)
- expression (1)
- extinction (1)
- fear (1)
- fear learning (1)
- female (1)
- gene-by-environment interaction (1)
- geneexpression (1)
- genetic variants (1)
- glia (1)
- glucose (1)
- glucose tolerance (1)
- glucose transporter (1)
- heterosis (1)
- heterozygote (1)
- human induced pluripotent stem cell (hiPSC) (1)
- humans (1)
- immediate early genes (1)
- immediate-early gene (1)
- in vivo (1)
- inflammation (1)
- inflammatory diseases (1)
- insulin receptor (1)
- judgement bias (1)
- knock-out mice (1)
- laboratory environment (1)
- lacking (1)
- learning (1)
- learning curves (1)
- locomotor activity (1)
- long-term potentiation (1)
- major depressive disorder (MDD) (1)
- maternal separation (1)
- mechanismofaction (1)
- median and dorsal raphe (1)
- membrane potential (1)
- membrane proteins (1)
- middle aged (1)
- monoamine transporters (1)
- mouse (1)
- mouse model (1)
- myelination (1)
- nervous system (1)
- neurodevelopment (1)
- neurodevelopmental disorders / genetics (1)
- neuroinflammation (1)
- neuronal plasticity (1)
- neuropsychiatric disorders (1)
- nitricoxidesynthase (1)
- nucleus (1)
- obesity (1)
- oxidative stress (1)
- panic disorder (1)
- plasticity (1)
- prefrontal cortex (1)
- primary response genes (1)
- promoter region (1)
- rare mendelian disorders (1)
- rat brain (1)
- receptors (1)
- regulatory T cells (1)
- response inhibition (1)
- serotonin deficiency (1)
- serotonin receptors (1)
- serotonin transporter deficient mice (1)
- serotonin transporter gene (1)
- serotonin-specific neurons (1)
- sialic acid (1)
- sialyltransferase (1)
- social experience (1)
- spatial memory (1)
- swim test (1)
- synapse formation (1)
- telomere length (1)
- transporter gene SLC2A3 (1)
- treatment guidelines (1)
- tryptophan (1)
- tryptophan hydroxylase 2 (1)
- tryptophan hydroxylase-2 (1)
- working memory (1)
Institute
- Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie (33) (remove)
Reduced function of the serotonin transporter (SERT) is associated with increased susceptibility to anxiety and depression and with type-2 diabetes, which is especially true in older women. Preference for a “Western diet” (WD), enriched with saturated fat, cholesterol, and sugars, may aggravate these conditions. In previous studies, decreased glucose tolerance, central and peripheral inflammation, dyslipidemia, emotional, cognitive, and social abnormalities were reported in WD-fed young female mice. We investigated the metabolic, molecular, and behavioral changes associated with a 3-week-long dietary regime of either the WD or control diet in 12-month-old female mice with three different Sert genotypes: homozygous (Slc6a4) gene knockout (Sert\(^{−/−}\): KO), heterozygous (Sert\(^{+/−}\): HET), or wild-type mice (Sert\(^{+/+}\): WT). In the WT-WD and KO-WD groups, but not in HET-WD-fed mice, most of changes induced by the WD paralleled those found in the younger mice, including brain overexpression of inflammatory marker Toll-like receptor 4 (Tlr4) and impaired hippocampus-dependent performance in the marble test. However, the 12-month-old female mice became obese. Control diet KO mice exhibited impaired hippocampal-dependent behaviors, increased brain expression of the serotonin receptors Htr2c and Htr1b, as well as increased Tlr4 and mitochondrial regulator, peroxisome proliferator-activated receptor gamma-coactivator-1a (Ppargc1a). Paradoxically, these, and other changes, were reversed in KO-WD mutants, suggesting a complex interplay between Sert deficiency and metabolic factors as well as potential compensatory molecular mechanisms that might be disrupted by the WD exposure. Most, but not all, of the changes in gene expression in the brain and liver of KO mice were not exhibited by the HET mice fed with either diet. Some of the WD-induced changes were similar in the KO-WD and HET-WD-fed mice, but the latter displayed a “rescued” phenotype in terms of diet-induced abnormalities in glucose tolerance, neuroinflammation, and hippocampus-dependent performance. Thus, complete versus partial Sert inactivation in aged mice results in distinct metabolic, molecular, and behavioral consequences in response to the WD. Our findings show that Sert\(^{+/−}\) mice are resilient to certain environmental challenges and support the concept of heterosis as evolutionary adaptive mechanism.
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.
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.
The transport of glucose across the cell plasma membrane is vital to most mammalian cells. The glucose transporter (GLUT; also called SLC2A) family of transmembrane solute carriers is responsible for this function in vivo. GLUT proteins encompass 14 different isoforms in humans with different cell type-specific expression patterns and activities. Central to glucose utilization and delivery in the brain is the neuronally expressed GLUT3. Recent research has shown an involvement of GLUT3 genetic variation or altered expression in several different brain disorders, including Huntington’s and Alzheimer’s diseases. Furthermore, GLUT3 was identified as a potential risk gene for multiple psychiatric disorders. To study the role of GLUT3 in brain function and disease a more detailed knowledge of its expression in model organisms is needed. Zebrafish (Danio rerio) has in recent years gained popularity as a model organism for brain research and is now well-established for modeling psychiatric disorders. Here, we have analyzed the sequence of GLUT3 orthologs and identified two paralogous genes in the zebrafish, slc2a3a and slc2a3b. Interestingly, the Glut3b protein sequence contains a unique stretch of amino acids, which may be important for functional regulation. The slc2a3a transcript is detectable in the central nervous system including distinct cellular populations in telencephalon, diencephalon, mesencephalon and rhombencephalon at embryonic and larval stages. Conversely, the slc2a3b transcript shows a rather diffuse expression pattern at different embryonic stages and brain regions. Expression of slc2a3a is maintained in the adult brain and is found in the telencephalon, diencephalon, mesencephalon, cerebellum and medulla oblongata. The slc2a3b transcripts are present in overlapping as well as distinct regions compared to slc2a3a. Double in situ hybridizations were used to demonstrate that slc2a3a is expressed by some GABAergic neurons at embryonic stages. This detailed description of zebrafish slc2a3a and slc2a3b expression at developmental and adult stages paves the way for further investigations of normal GLUT3 function and its role in brain disorders.
Converging evidence suggests a role of serotonin (5-hydroxytryptamine, 5-HT) and tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of 5-HT synthesis in the brain, in modulating long-term, neurobiological effects of early-life adversity. Here, we aimed at further elucidating the molecular mechanisms underlying this interaction, and its consequences for socio-emotional behaviors, with a focus on anxiety and social interaction. In this study, adult, male Tph2 null mutant (Tph2\(^{-/-}\)) and heterozygous (Tph2\(^{+/-}\)) mice, and their wildtype littermates (Tph2\(^{+/+}\)) were exposed to neonatal, maternal separation (MS) and screened for behavioral changes, followed by genome-wide RNA expression and DNA methylation profiling. In Tph2\(^{-/-}\) mice, brain 5-HT deficiency profoundly affected socio-emotional behaviors, i.e., decreased avoidance of the aversive open arms in the elevated plus-maze (EPM) as well as decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Tph2\(^{+/-}\) mice showed an ambiguous profile with context-dependent, behavioral responses. In the EPM they showed similar avoidance of the open arm but decreased prosocial and increased rule breaking behavior in the resident-intruder test when compared to their wildtype littermates. Notably, MS effects on behavior were subtle and depended on the Tph2 genotype, in particular increasing the observed avoidance of EPM open arms in wildtype and Tph2\(^{+/-}\) mice when compared to their Tph2\(^{-/-}\) littermates. On the genomic level, the interaction of Tph2 genotype with MS differentially affected the expression of numerous genes, of which a subset showed an overlap with DNA methylation profiles at corresponding loci. Remarkably, changes in methylation nearby and expression of the gene encoding cholecystokinin, which were inversely correlated to each other, were associated with variations in anxiety-related phenotypes. In conclusion, next to various behavioral alterations, we identified gene expression and DNA methylation profiles to be associated with TPH2 inactivation and its interaction with MS, suggesting a gene-by-environment interaction-dependent, modulatory function of brain 5-HT availability.
Brain serotonin (5-hydroxytryptamine, 5-HT) system dysfunction is implicated in exaggerated fear responses triggering various anxiety-, stress-, and trauma-related disorders. However, the underlying mechanisms are not well understood. Here, we investigated the impact of constitutively inactivated 5-HT synthesis on context-dependent fear learning and extinction using tryptophan hydroxylase 2 (Tph2) knockout mice. Fear conditioning and context-dependent fear memory extinction paradigms were combined with c-Fos imaging and electrophysiological recordings in the dorsal hippocampus (dHip). Tph2 mutant mice, completely devoid of 5-HT synthesis in brain, displayed accelerated fear memory formation and increased locomotor responses to foot shock. Furthermore, recall of context-dependent fear memory was increased. The behavioral responses were associated with increased c-Fos expression in the dHip and resistance to foot shock-induced impairment of hippocampal long-term potentiation (LTP). In conclusion, increased context-dependent fear memory resulting from brain 5-HT deficiency involves dysfunction of the hippocampal circuitry controlling contextual representation of fear-related behavioral responses.
Prenatal stress (PS) has been shown to influence the development of the fetal brain and to increase the risk for the development of psychiatric disorders in later life. Furthermore, the variation of human serotonin transporter (5-HTT, SLC6A4) gene was suggested to exert a modulating effect on the association between early life stress and the risk for depression. In the present study, we used a 5-HttxPS paradigm to investigate whether the effects of PS are dependent on the 5-Htt genotype. For this purpose, the effects of PS on cognition, anxiety-and depression-related behavior were examined using a maternal restraint stress paradigm of PS in C57BL6 wild-type (WT) and heterozygous 5-Htt deficient (5-Htt +/-) mice. Additionally, in female offspring, a genome-wide hippocampal gene expression profiling was performed using the Affymetrix GeneChip (R) Mouse Genome 430 2.0 Array. 5-Htt +/- offspring showed enhanced memory performance and signs of reduced anxiety as compared to WT offspring. In contrast, exposure of 5-Htt +/- mice to PS was associated with increased depressive-like behavior, an effect that tended to be more pronounced in female offspring. Further, 5-Htt genotype, PS and their interaction differentially affected the expression of numerous genes and related pathways within the female hippocampus. Specifically, MAPK and neurotrophin signaling were regulated by both the 5-Htt +/- genotype and PS exposure, whereas cytokine and Wnt signaling were affected in a 5-Htt genotypexPS manner, indicating a genexenvironment interaction at the molecular level. In conclusion, our data suggest that although the 5-Htt +/- genotype shows clear adaptive capacity, 5-Htt +/- mice -particularly females-at the same time appear to be more vulnerable to developmental stress exposure when compared to WT offspring. Moreover, hippocampal gene expression profiles suggest that distinct molecular mechanisms mediate the behavioral effects of the 5-Htt genotype, PS exposure, and their interaction.
Background:
Antidepressant drugs (ADs) have been shown to activate BDNF (brain-derived neurotrophic factor) receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands.
Methodology:
In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines.
Principal Findings:
Using a chemical-genetic TrkB(F616A) mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf(-/-) knock-out mice (132.4+/-8.5% of control; P = 0.01), indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT) deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB.
Conclusions:
The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the ability of ADs to induce TrkB activity in brain.
Sodium-glucose transporters (SGLT) belong to the solute carrier 5 family, which is characterized by sodium dependent transport of sugars and other solutes. In contrast, the human SGLT3 (hSGLT3) isoform, encoded by SLC5A4, acts as a glucose sensor that does not transport sugar but induces membrane depolarization by Na\(^{+}\) currents upon ligand binding. Whole-exome sequencing (WES) of several extended pedigrees with high density of attention-deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (ΔM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. Since mutations in homologous domains of hSGLT1 and hSGLT2 were found to affect intestinal and renal function, respectively, we analyzed the functional properties of hSGLT3[wt] and [ΔM500] by voltage clamp and current clamp recordings from cRNA-injected Xenopus laevis oocytes.
The cation conductance of hSGLT3[wt] was activated by application of glucose or the specific agonist 1-desoxynojirimycin (DNJ) as revealed by inward currents in the voltage clamp configuration and cell depolarization in the current clamp mode. Almost no currents and changes in membrane potential were observed when glucose or DNJ were applied to hSGLT3[ΔM500]-injected oocytes, demonstrating a loss of function by this amino acid deletion in hSGLT3. To monitor membrane targeting of wt and mutant hSGLT3, fusion constructs with YFP were generated, heterologously expressed in Xenopus laevis oocytes and analyzed for membrane fluorescence by confocal microscopy. In comparison to hSGLT3[wt] the fluorescent signal of mutant [ΔM500] was reduced by 43% indicating that the mutant phenotype might mainly result from inaccurate membrane targeting. As revealed by homology modeling, residue M500 is located in TM11 suggesting that in addition to the core structure (TM1-TM10) of the transporter, the surrounding TMs are equally crucial for transport/sensor function.
In conclusion, our findings indicate that the deletion [ΔM500] in hSGLT3 inhibits membrane targeting and thus largely disrupts glucose-induced sodium conductance, which may, in interaction with other ADHD risk-related gene variants, influence the risk for ADHD in deletion carriers.