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Aberrant H3.3 dynamics in NAc promote vulnerability to depressive-like behavior.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Nov 01; Vol. 113 (44), pp. 12562-12567. Date of Electronic Publication: 2016 Oct 18. - Publication Year :
- 2016
-
Abstract
- Human major depressive disorder (MDD), along with related mood disorders, is among the world's greatest public health concerns; however, its pathophysiology remains poorly understood. Persistent changes in gene expression are known to promote physiological aberrations implicated in MDD. More recently, histone mechanisms affecting cell type- and regional-specific chromatin structures have also been shown to contribute to transcriptional programs related to depressive behaviors, as well as responses to antidepressants. Although much emphasis has been placed in recent years on roles for histone posttranslational modifications and chromatin-remodeling events in the etiology of MDD, it has become increasingly clear that replication-independent histone variants (e.g., H3.3), which differ in primary amino acid sequence from their canonical counterparts, similarly play critical roles in the regulation of activity-dependent neuronal transcription, synaptic connectivity, and behavioral plasticity. Here, we demonstrate a role for increased H3.3 dynamics in the nucleus accumbens (NAc)-a key limbic brain reward region-in the regulation of aberrant social stress-mediated gene expression and the precipitation of depressive-like behaviors in mice. We find that molecular blockade of these dynamics promotes resilience to chronic social stress and results in a partial renormalization of stress-associated transcriptional patterns in the NAc. In sum, our findings establish H3.3 dynamics as a critical, and previously undocumented, regulator of mood and suggest that future therapies aimed at modulating striatal histone dynamics may potentiate beneficial behavioral adaptations to negative emotional stimuli.<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Adult
Aged
Animals
Depressive Disorder genetics
Depressive Disorder metabolism
Female
Gene Expression Regulation
Gene Knockdown Techniques
Histones genetics
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
Nucleus Accumbens metabolism
Protein Isoforms genetics
Protein Isoforms metabolism
Stress, Psychological genetics
Depressive Disorder physiopathology
Histones metabolism
Nucleus Accumbens physiopathology
Stress, Psychological physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 113
- Issue :
- 44
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 27791098
- Full Text :
- https://doi.org/10.1073/pnas.1608270113