Refine
Has Fulltext
- yes (57)
Is part of the Bibliography
- yes (57)
Year of publication
Document Type
- Journal article (57)
Language
- English (57) (remove)
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)
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.
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.
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.
Genetic and molecular mechanisms that play a causal role in mental illnesses are challenging to elucidate, particularly as there is a lack of relevant in vitro and in vivo models. However, the advent of induced pluripotent stem cell (iPSC) technology has provided researchers with a novel toolbox. We conducted a systematic review using the PRISMA statement. A PubMed and Web of Science online search was performed (studies published between 2006–2020) using the following search strategy: hiPSC OR iPSC OR iPS OR stem cells AND schizophrenia disorder OR personality disorder OR antisocial personality disorder OR psychopathy OR bipolar disorder OR major depressive disorder OR obsessive compulsive disorder OR anxiety disorder OR substance use disorder OR alcohol use disorder OR nicotine use disorder OR opioid use disorder OR eating disorder OR anorexia nervosa OR attention-deficit/hyperactivity disorder OR gaming disorder. Using the above search criteria, a total of 3515 studies were found. After screening, a final total of 56 studies were deemed eligible for inclusion in our study. Using iPSC technology, psychiatric disease can be studied in the context of a patient’s own unique genetic background. This has allowed great strides to be made into uncovering the etiology of psychiatric disease, as well as providing a unique paradigm for drug testing. However, there is a lack of data for certain psychiatric disorders and several limitations to present iPSC-based studies, leading us to discuss how this field may progress in the next years to increase its utility in the battle to understand psychiatric disease.
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.
Genetic variability is being discussed as a source of inter‐individual differences in Theory of Mind development. Previous studies documented an association between variations in DRD4 VNTR 48 bp, OXTR rs53576, COMT rs4680, and Theory of Mind task performance. As empirical evidence on these associations is sparse, we conducted a preregistered replication attempt of a study reporting a link between DRD4 VNTR 48 bp and false belief understanding in 50‐month‐old children [Lackner, C., Sabbagh, M. A., Hallinan, E., Liu, X., & Holden, J. J. (2012). Developmental Science, 15(2), 272–280.]. Additionally, we attempted a replication of studies on the role of OXTR rs53576 and COMT rs4680 in Theory of Mind. In both replication attempts, we did not find any evidence for associations between the sampled genetic markers and Theory of Mind ability in a series of analyses. Extending the replication attempt of Lackner et al., we employed longitudinal data from several tasks and measurement points, which allowed us to run follow‐up robustness checks with more reliable scores. These extensive analyses corroborated our null finding. This comprehensive non‐replication is important to balance current research on genetic markers of Theory of Mind. In a combined evaluation of our own and previous studies, we point to substantial methodological issues that research on the genetic basis of Theory of Mind development faces. We conclude that these limitations currently prevent firm conclusions on genetic influences on Theory of Mind development.
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.
The interaction between brain serotonin (5-HT) deficiency and environmental adversity may predispose females to excessive aggression. Specifically, complete inactivation of the gene encoding tryptophan hydroxylase-2 (Tph2) results in the absence of neuronal 5-HT synthesis and excessive aggressiveness in both male and female null mutant (Tph2\(^{−/−}\)) mice. In heterozygous male mice (Tph2\(^{+/−}\)), there is a moderate reduction in brain 5-HT levels, and when they are exposed to stress, they exhibit increased aggression. Here, we exposed female Tph2\(^{+/−}\) mice to a five-day rat predation stress paradigm and assessed their emotionality and social interaction/aggression-like behaviors. Tph2\(^{+/−}\) females exhibited excessive aggression and increased dominant behavior. Stressed mutants displayed altered gene expression of the 5-HT receptors Htr1a and Htr2a, glycogen synthase kinase-3 β (GSK-3β), and c-fos as well as myelination-related transcripts in the prefrontal cortex: myelin basic protein (Mbp), proteolipid protein 1 (Plp1), myelin-associated glycoprotein (Mag), and myelin oligodendrocyte glycoprotein (Mog). The expression of the plasticity markers synaptophysin (Syp) and cAMP response element binding protein (Creb), but not AMPA receptor subunit A2 (GluA2), were affected by genotype. Moreover, in a separate experiment, naïve female Tph2\(^{+/−}\) mice showed signs of enhanced stress resilience in the modified swim test with repeated swimming sessions. Taken together, the combination of a moderate reduction in brain 5-HT with environmental challenges results in behavioral changes in female mice that resemble the aggression-related behavior and resilience seen in stressed male mutants; additionally, the combination is comparable to the phenotype of null mutants lacking neuronal 5-HT. Changes in myelination-associated processes are suspected to underpin the molecular mechanisms leading to aggressive behavior.
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.
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.
Human induced pluripotent stem cells (hiPSCs) have revolutionized the generation of experimental disease models, but the development of protocols for the differentiation of functionally active neuronal subtypes with defined specification is still in its infancy. While dysfunction of the brain serotonin (5-HT) system has been implicated in the etiology of various neuropsychiatric disorders, investigation of functional human 5-HT specific neurons in vitro has been restricted by technical limitations. We describe an efficient generation of functionally active neurons from hiPSCs displaying 5-HT specification by modification of a previously reported protocol. Furthermore, 5-HT specific neurons were characterized using high-end fluorescence imaging including super-resolution microscopy in combination with electrophysiological techniques. Differentiated hiPSCs synthesize 5-HT, express specific markers, such as tryptophan hydroxylase 2 and 5-HT transporter, and exhibit an electrophysiological signature characteristic of serotonergic neurons, with spontaneous rhythmic activities, broad action potentials and large afterhyperpolarization potentials. 5-HT specific neurons form synapses reflected by the expression of pre- and postsynaptic proteins, such as Bassoon and Homer. The distribution pattern of Bassoon, a marker of the active zone along the soma and extensions of neurons, indicates functionality via volume transmission. Among the high percentage of 5-HT specific neurons (~ 42%), a subpopulation of CDH13 + cells presumably designates dorsal raphe neurons. hiPSC-derived 5-HT specific neuronal cell cultures reflect the heterogeneous nature of dorsal and median raphe nuclei and may facilitate examining the association of serotonergic neuron subpopulations with neuropsychiatric disorders.
A deficiency in GM3-derived gangliosides, resulting from a lack of lactosylceramide-alpha-2,3-sialyltransferase (ST3GAL5), leads to severe neuropathology, including epilepsy and metabolic abnormalities. Disruption of ganglioside production by this enzyme may also have a role in the development of neuropsychiatric disorders. ST3Gal5 knock-out (St3gal5\(^{−/−}\)) mice lack a-, b-, and c-series gangliosides, but exhibit no overt neuropathology, possibly owing to the production of compensatory 0-series glycosphingolipids. Here, we sought to investigate the possibility that St3gal5\(^{−/−}\) mice might exhibit attention-deficit/hyperactivity disorder (ADHD)-like behaviours. In addition, we evaluated potential metabolic and electroencephalogram (EEG) abnormalities. St3gal5\(^{−/−}\) mice were subjected to behavioural testing, glucose tolerance tests, and the levels of expression of brain and peripheral A and B isoforms of the insulin receptor (IR) were measured. We found that St3gal5\(^{−/−}\) mice exhibit locomotor hyperactivity, impulsivity, neophobia, and anxiety-like behavior. The genotype also altered blood glucose levels and glucose tolerance. A sex bias was consistently found in relation to body mass and peripheral IR expression. Analysis of the EEG revealed an increase in amplitude in St3gal5\(^{−/−}\) mice. Together, St3gal5\(^{−/−}\) mice exhibit ADHD-like behaviours, altered metabolic and EEG measures providing a useful platform for better understanding of the contribution of brain gangliosides to ADHD and associated comorbidities.
Several attributes intuitively considered to be typical mammalian features, such as complex behavior, live birth and malignant disease such as cancer, also appeared several times independently in lower vertebrates. The genetic mechanisms underlying the evolution of these elaborate traits are poorly understood. The platyfish, X. maculatus, offers a unique model to better understand the molecular biology of such traits. We report here the sequencing of the platyfish genome. Integrating genome assembly with extensive genetic maps identified an unexpected evolutionary stability of chromosomes in fish, in contrast to in mammals. Genes associated with viviparity show signatures of positive selection, identifying new putative functional domains and rare cases of parallel evolution. We also find that genes implicated in cognition show an unexpectedly high rate of duplicate gene retention after the teleost genome duplication event, suggesting a hypothesis for the evolution of the behavioral complexity in fish, which exceeds that found in amphibians and reptiles.
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.
Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.
Background
Although 5-HTTLPR has been shown to influence the risk of life stress-induced depression in the majority of studies, others have produced contradictory results, possibly due to weak effects and/or sample heterogeneity.
Methods
In the present study we investigated how age, type and intensity of life-stressors modulate the effect of 5-HTTLPR on depression and anxiety in a European population cohort of over 2300 subjects. Recent negative life events (RLE), childhood adversity (CHA), lifetime depression, Brief Symptoms Inventory (BSI) depression and anxiety scores were determined in each subject. Besides traditional statistical analysis we calculated Bayesian effect strength and relevance of 5-HTTLPR genotypes in specified models.
Results
The short (s) low expressing allele showed association with increased risk of depression related phenotypes, but all nominally significant effects would turn to non-significant after correction for multiple testing in the traditional analysis. Bayesian effect strength and relevance analysis, however, confirmed the role of 5-HTTLPR. Regarding current (BSI) and lifetime depression 5-HTTLPR-by-RLE interactions were confirmed. Main effect, with other words direct association, was supported with BSI anxiety. With more frequent RLE the prevalence or symptoms of depression increased in ss carriers. Although CHA failed to show an interaction with 5-HTTLPR, in young subjects CHA sensitized towards the depression promoting effect of even mild RLE. Furthermore, the direct association of anxiety with the s allele was driven by young (\(\leq\)30) individuals.
Limitations
Our study is cross-sectional and applies self-report questionnaires.
Conclusions
Albeit 5-HTTLPR has only weak/moderate effects, the s allele is directly associated with anxiety and modulates development of depression in homogeneous subgroups.