To better understand the molecular mechanisms of depression and antidepressant action, we administered chronic social defeat stress followed by chronic imipramine (a tricyclic antidepressant) to mice ...and studied adaptations at the levels of gene expression and chromatin remodeling of five brain-derived neurotrophic factor (Bdnf) splice variant mRNAs (I-V) and their unique promoters in the hippocampus. Defeat stress induced lasting downregulation of Bdnf transcripts III and IV and robustly increased repressive histone methylation at their corresponding promoters. Chronic imipramine reversed this downregulation and increased histone acetylation at these promoters. This hyperacetylation by chronic imipramine was associated with a selective downregulation of histone deacetylase (Hdac) 5. Furthermore, viral-mediated HDAC5 overexpression in the hippocampus blocked imipramine's ability to reverse depression-like behavior. These experiments underscore an important role for histone remodeling in the pathophysiology and treatment of depression and highlight the therapeutic potential for histone methylation and deacetylation inhibitors in depression.
The mechanism of action of electroconvulsive seizures (ECS), one of the most effective treatments of major depression, may involve the regulation of gene expression. Chromatin remodeling at gene ...promoter regions is increasingly recognized as a key control point of gene expression and may, therefore, partly mediate acute and chronic effects of ECS on gene activity. Here, we assayed how posttranslational modifications of histones, a major form of chromatin remodeling, are altered at several gene promoters in rat hippocampus at 30 min, 2 hr, and 24 hr after acute or repeated ECS. We performed chromatin immunoprecipitation assays to measure levels of histone H3 and H4 acetylation and phosphoacetylation at the promoters of the c-fos, BDNF, and CREB (cAMP response element-binding protein) genes, the expression of which is altered by ECS. We found that, with few exceptions, levels of H4 acetylation correlated with mRNA levels for c-fos, BDNF, and CREB throughout the acute and chronic time course study, whereas acetylation and phosphoacetylation of H3 were detected more selectively. Our findings suggest that the chronic downregulation of c-fos transcription, observed in this study, may be achieved at the level of H4 acetylation, whereas chronic upregulation of BDNF transcription may be sustained via control of H3 acetylation, selectively at the BDNF P3 and P4 promoters. These data provide the first in vivo demonstration of the involvement of chromatin remodeling in ECS-induced regulation of gene expression in the brain and will help in understanding the mechanisms underlying the efficacy of ECS in the treatment of depression.
Mice experiencing repeated aggression develop a long-lasting aversion to social contact, which can be normalized by chronic, but not acute, administration of antidepressant. Using viral-mediated, ...mesolimbic dopamine pathway-specific knockdown of brain-derived neurotrophic factor (BDNF), we showed that BDNF is required for the development of this experience-dependent social aversion. Gene profiling in the nucleus accumbens indicates that local knockdown of BDNF obliterates most of the effects of repeated aggression on gene expression within this circuit, with similar effects being produced by chronic treatment with antidepressant. These results establish an essential role for BDNF in mediating long-term neural and behavioral plasticity in response to aversive social experiences.
Given that cocaine induces neuroadaptations through regulation of gene expression, we investigated whether chromatin remodeling at specific gene promoters may be a key mechanism. We show that cocaine ...induces specific histone modifications at different gene promoters in striatum, a major neural substrate for cocaine's behavioral effects. At the
cFos promoter, H4 hyperacetylation is seen within 30 min of a single cocaine injection, whereas no histone modifications were seen with chronic cocaine, consistent with cocaine's ability to induce cFos acutely, but not chronically. In contrast, at the
BDNF and
Cdk5 promoters, genes that are induced by chronic, but not acute, cocaine, H3 hyperacetylation was observed with chronic cocaine only. ΔFosB, a cocaine-induced transcription factor, appears to mediate this regulation of the
Cdk5 gene. Furthermore, modulating histone deacetylase activity alters locomotor and rewarding responses to cocaine. Thus, chromatin remodeling is an important regulatory mechanism underlying cocaine-induced neural and behavioral plasticity.
We analyzed the influence of the transcription factor ΔFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a ...deficit in escape behavior. Repeated IS induces ΔFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit—with the strongest ΔFosB induction observed in the most resilient animals. Induction of ΔFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for ΔFosB, is downregulated upon ΔFosB induction. Local overexpression of ΔFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of ΔFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.
Mary E. Fowkes, MD, PhD Hefti, Marco M; Crary, John F; Miller, Douglas C
Journal of neuropathology and experimental neurology,
05/2021, Letnik:
80, Številka:
5
Journal Article
We analyzed the influence of the transcription factor DeltaFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a ...deficit in escape behavior. Repeated IS induces DeltaFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit-with the strongest DeltaFosB induction observed in the most resilient animals. Induction of DeltaFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for DeltaFosB, is downregulated upon DeltaFosB induction. Local overexpression of DeltaFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of DeltaFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.
We analyzed the influence of the transcription factor ΔFosB on learned helplessness, an animal model of affective disorder wherein a subset of mice exposed to inescapable stress (IS) develop a ...deficit in escape behavior. Repeated IS induces ΔFosB in the ventrolateral periaqueductal gray (vlPAG), and levels of the protein are highly predictive of an individual's subsequent behavorial deficit--with the strongest ΔFosB induction observed in the most resilient animals. Induction of ΔFosB by IS predominates in substance P-positive neurons in the vlPAG, and the substance P gene, a direct target for ΔFosB, is downregulated upon ΔFosB induction. Local overexpression of ΔFosB in the vlPAG using viral-mediated gene transfer dramatically reduces depression-like behaviors and inhibits stress-induced release of substance P. These results indicate that IS-induced accumulation of ΔFosB in the vlPAG desensitizes substance P neurons enriched in this area and opposes behavioral despair by promoting active defense responses.
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