Posttranslational modifications of histone tails in chromatin template can result from environmental experiences such as stress and substance abuse. However, the role of epigenetic modifications as ...potential predisposing factors in affective behavior is less well established. To address this question, we used our selectively bred lines of high responder (bHR) and low responder (bLR) rats that show profound and stable differences in affective responses, with bLRs being prone to anxiety-and depression-like behavior and bHRs prone to addictive behavior. We first asked whether these phenotypes are associated with basal differences in epigenetic profiles. Our results reveal broad between-group differences in basal levels of trimethylated histone protein H3 at lysine 9 (H3K9me3) in hippocampus (HC), amygdala, and nucleus accumbens. Moreover, levels of association of H3K9me3 at Glucocorticoid Receptor (GR) and Fibroblast growth Factor 2 (FGF2) promoters differ reciprocally between bHRs and bLRs in these regions, consistent with these genes' opposing levels of expression and roles in modulating anxiety behavior. Importantly, this basal epigenetic pattern is modifiable by FGF2, a factor that modulates anxiety behavior. Thus, early-life FGF2, which decreases anxiety, altered the levels of H3K9me3 and its binding at FGF2 and GR promoters of bLRs rendering them more similar to bHRs. Conversely, knockdown of HC FGF2 altered both anxiety behavior and levels of H3K9me3 in bHRs, rendering them more bLR-like. These findings implicate FGF2 as a modifier of epigenetic mechanisms associated with emotional responsiveness, and point to H3K9me3 as a key player in the regulation of affective vulnerability.
Emotions are characterized not only by their valence but also by whether they are stable or labile. Yet, we do not understand the molecular or circuit mechanisms that control the dynamic nature of ...emotional responses. We have shown that glucocorticoid receptor overexpression in the forebrain (GRov) leads to a highly reactive mouse with increased anxiety behavior coupled with greater swings in emotional responses. This phenotype is established early in development and persists into adulthood. However, the neural circuitry mediating this lifelong emotional lability remains unknown. In the present study, optogenetic stimulation in ventral dentate gyrus (vDG) of GRov mice led to a greater range and a prolonged duration of anxiety behavior. cFos expression analysis showed that the amplified behavioral response to vDG activation in GRov mice is coupled to increased neuronal activity in specific brain regions. Relative to wild type mice, GRov mice displayed glutamatergic/GABAergic activation imbalance in ventral CA1 (vCA1) and selectively increased glutamatergic activation in the basal posterior amygdaloid complex. Moreover, forebrain GR overexpression led to increased activation of molecularly distinct subpopulations of neurons within the hippocampus and the posterior basolateral amygdala (pBLA) as evident from the increased cFos co-labeling in the calbindin1+ glutamatergic neurons in vCA1 and in the DARPP-32/Ppp1r1b+ glutamatergic neurons in pBLA. We propose that a molecularly distinct hippocampal-amygdala circuit is shaped by stress early in life and tunes the dynamics of emotional responses.
Individuals with mood disorders exhibit alterations in the fibroblast growth factor system, including reduced hippocampal fibroblast growth factor-2 (FGF2). It is difficult, however, to pinpoint ...whether these alterations are a cause or consequence of the disorder. The present study asks whether FGF2 administered the day after birth has long-lasting effects on hippocampal development and emotionality. We show that early-life FGF2 shifts the pace of neurogenesis, with an early acceleration around weaning followed by a deceleration in adulthood. This, in turn, results in a denser dentate gyrus with more neurons. To assess the impact of early-life FGF2 on emotionality, we use rats selectively bred for differences in locomotor response to novelty. Selectively bred low-responder (bLR) rats show low levels of novelty-induced locomotion and exhibit high levels of anxiety- and depression-like behavior compared with their selectively bred high-responder counterparts. Early-life FGF2 decreased anxiety-like behavior in highly anxious bLRs without altering other behaviors and without affecting high-responder rats. Laser capture microscopy of the dentate gyrus followed by microarray analysis revealed genes that were differentially expressed in bLRs exposed to early-life FGF2 vs. vehicle-treated bLRs. Some of the differentially expressed genes that have been positively associated with anxiety were down-regulated, whereas genes that promote cell survival were up-regulated. Overall, these results show a key role for FGF2 in the developmental trajectory of the hippocampus as well as the modulation of anxiety-like behavior in adulthood, and they point to potential downstream targets for the treatment of anxiety disorders.
Background Inhibitory control or regulatory difficulties have been explored in major depressive disorder (MDD) but typically in the context of affectively salient information. Inhibitory control is ...addressed specifically by using a task devoid of affectively-laden stimuli, to disentangle the effects of altered affect and altered inhibitory processes in MDD. Methods Twenty MDD and 22 control volunteer participants matched by age and gender completed a contextual inhibitory control task, the Parametric Go/No-go (PGNG) task during functional magnetic resonance imaging. The PGNG includes three levels of difficulty, a typical continuous performance task and two progressively more difficult versions including Go/No-go hit and rejection trials. After this test, 15 of 20 MDD patients completed a full 10-week treatment with s-citalopram. Results There was a significant interaction among response time (control subjects better), hits (control subjects better), and rejections (patients better). The MDD participants had greater activation compared with the control group in frontal and anterior temporal areas during correct rejections (inhibition). Activation during successful inhibitory events in bilateral inferior frontal and left amygdala, insula, and nucleus accumbens and during unsuccessful inhibition (commission errors) in rostral anterior cingulate predicted post-treatment improvement in depression symptoms. Conclusions The imaging findings suggest that in MDD subjects, greater neural activation in frontal, limbic, and temporal regions during correct rejection of lures is necessary to achieve behavioral performance equivalent to control subjects. Greater activation in similar regions was further predictive of better treatment response in MDD.
Mitochondria provide most of the energy for brain cells by the process of oxidative phosphorylation. Mitochondrial abnormalities and deficiencies in oxidative phosphorylation have been reported in ...individuals with schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD) in transcriptomic, proteomic, and metabolomic studies. Several mutations in mitochondrial DNA (mtDNA) sequence have been reported in SZ and BD patients.
Dorsolateral prefrontal cortex (DLPFC) from a cohort of 77 SZ, BD, and MDD subjects and age-matched controls (C) was studied for mtDNA sequence variations and heteroplasmy levels using Affymetrix mtDNA resequencing arrays. Heteroplasmy levels by microarray were compared to levels obtained with SNaPshot and allele specific real-time PCR. This study examined the association between brain pH and mtDNA alleles. The microarray resequencing of mtDNA was 100% concordant with conventional sequencing results for 103 mtDNA variants. The rate of synonymous base pair substitutions in the coding regions of the mtDNA genome was 22% higher (p = 0.0017) in DLPFC of individuals with SZ compared to controls. The association of brain pH and super haplogroup (U, K, UK) was significant (p = 0.004) and independent of postmortem interval time.
Focusing on haplogroup and individual susceptibility factors in psychiatric disorders by considering mtDNA variants may lead to innovative treatments to improve mitochondrial health and brain function.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in ...the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.
Adolescent drug use reliably predicts increased addiction liability in adulthood, but not all individuals are equally impacted. To explore the biological bases of this differential reactivity to ...early life drug experience, we used a genetic rat model of temperament and evaluated the impact of adolescent cocaine exposure on adult psychomotor sensitization. Relative to adult bred low-responder (bLR) rats, bred high-responders (bHR) are more sensitive to the psychomotor-activating effects of cocaine and reinstate drug-seeking behavior more readily following prolonged cocaine exposure and/or abstinence. We found that a 7-day sensitizing cocaine regimen (15 mg/kg/day) during either adolescence or adulthood produced psychomotor sensitization in bHRs only, while a dual cocaine exposure prevented further sensitization, suggesting limits on neuroplasticity. By contrast, adolescent cocaine in bLRs shifted their resilient phenotype, rendering them more responsive to cocaine in adulthood following adolescent cocaine. To begin to explore the neural correlates of these behavioral phenotypes, we assessed two functionally opposite epigenetic chromatin modifications implicated in addiction liability, permissive acetylation (ac) and repressive tri-methylation (me3) on Histone 3 Lysine 9 (H3K9), in four striatal sub-regions. In bHRs, decreased H3K9me3 and increased acH3K9 in the nucleus accumbens (NAc) core associated with cocaine sensitization. In bLRs, the combination of cocaine exposure in adolescence and adulthood, which lead to an increased response to a cocaine challenge, also increased acH3K9 in the core. Thus, adolescent cocaine experience interacts with genetic background to elicit different behavioral profiles relevant to addiction in adulthood, with concurrent modifications in the epigenetic histone profiles in the NAc that associate with cocaine sensitization and with metaplasticity.
Transcriptional profiling has become a common tool for investigating the nervous system. During analysis, differential expression results are often compared to functional ontology databases, which ...contain curated gene sets representing well-studied pathways. This dependence can cause neuroscience studies to be interpreted in terms of functional pathways documented in better studied tissues (e.g., liver) and topics (e.g., cancer), and systematically emphasizes well-studied genes, leaving other findings in the obscurity of the brain “ignorome”. To address this issue, we compiled a curated database of 918 gene sets related to nervous system function, tissue, and cell types (“Brain.GMT”) that can be used within common analysis pipelines (GSEA, limma, edgeR) to interpret results from three species (rat, mouse, human). Brain.GMT includes brain-related gene sets curated from the Molecular Signatures Database (MSigDB) and extracted from public databases (GeneWeaver, Gemma, DropViz, BrainInABlender, HippoSeq) and published studies containing differential expression results. Although Brain.GMT is still undergoing development and currently only represents a fraction of available brain gene sets, “brain ignorome” genes are already better represented than in traditional Gene Ontology databases. Moreover, Brain.GMT substantially improves the quantity and quality of gene sets identified as enriched with differential expression in neuroscience studies, enhancing interpretation.
•We compiled a curated database of 918 gene sets related to nervous system function, tissue, and cell types (“Brain.GMT”).•Brain.GMT can be used within common analysis pipelines (GSEA, limma, edgeR) to interpret neuroscience transcriptional profiling results from three species (rat, mouse, human).•Although Brain.GMT is still undergoing development, it substantially improved the interpretation of differential expression results within our initial use cases.
Display omitted
A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, ...neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
