Epigenetic regulation of RAC1 induces synaptic remodeling in stress disorders and depression
Sam A. Golden,Daniel J. Christoffel,Mitra Heshmati,Georgia E. Hodes,Jane Magida,Keithara Davis,Michael E. Cahill,Caroline Dias,Efrain Ribeiro,Jessica L. Ables,Pamela J. Kennedy,Alfred J. Robison,Javier González-Maeso,Rachael L. Neve,Gustavo Turecki,Subroto Ghose,Carol A. Tamminga,Scott J. Russo +17 more
TLDR
The data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.Abstract:
Depression induces structural and functional synaptic plasticity in brain reward circuits, although the mechanisms promoting these changes and their relevance to behavioral outcomes are unknown. Transcriptional profiling of the nucleus accumbens (NAc) for Rho GTPase-related genes, which are known regulators of synaptic structure, revealed a sustained reduction in RAS-related C3 botulinum toxin substrate 1 (Rac1) expression after chronic social defeat stress. This was associated with a repressive chromatin state surrounding the proximal promoter of Rac1. Inhibition of class 1 histone deacetylases (HDACs) with MS-275 rescued both the decrease in Rac1 transcription after social defeat stress and depression-related behavior, such as social avoidance. We found a similar repressive chromatin state surrounding the RAC1 promoter in the NAc of subjects with depression, which corresponded with reduced RAC1 transcription. Viral-mediated reduction of Rac1 expression or inhibition of Rac1 activity in the NAc increases social defeat-induced social avoidance and anhedonia in mice. Chronic social defeat stress induces the formation of stubby excitatory spines through a Rac1-dependent mechanism involving the redistribution of synaptic cofilin, an actin-severing protein downstream of Rac1. Overexpression of constitutively active Rac1 in the NAc of mice after chronic social defeat stress reverses depression-related behaviors and prunes stubby spines. Taken together, our data identify epigenetic regulation of RAC1 in the NAc as a disease mechanism in depression and reveal a functional role for Rac1 in rodents in regulating stress-related behaviors.read more
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The brain reward circuitry in mood disorders
Scott J. Russo,Eric J. Nestler +1 more
TL;DR: This Review synthesizes recent data from human and rodent studies from which emerges a circuit-level framework for understanding reward deficits in depression, and discusses some of the molecular and cellular underpinnings of this framework, ranging from adaptations in glutamatergic synapses and neurotrophic factors to transcriptional and epigenetic mechanisms.
Journal ArticleDOI
Social stress induces neurovascular pathology promoting depression.
Caroline Menard,Caroline Menard,Madeline L. Pfau,Georgia E. Hodes,Veronika Kana,Victoria X. Wang,Sylvain Bouchard,Aki Takahashi,Aki Takahashi,Meghan E. Flanigan,Hossein Aleyasin,Katherine B. LeClair,William G.M. Janssen,Benoit Labonté,Eric M. Parise,Zachary S. Lorsch,Sam A. Golden,Mitra Heshmati,Carol A. Tamminga,Gustavo Turecki,Matthew Campbell,Zahi A. Fayad,Cheuk Y. Tang,Miriam Merad,Scott J. Russo +24 more
TL;DR: Chronic social defeat stress induces loss of protein claudin-5, leading to abnormalities in blood vessel morphology, increased blood brain barrier permeability, infiltration of immune signals and depression-like behaviors.
Journal ArticleDOI
Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress.
Georgia E. Hodes,Madeline L. Pfau,Marylene Leboeuf,Sam A. Golden,Daniel J. Christoffel,Dana Bregman,Nicole Rebusi,Mitra Heshmati,Hossein Aleyasin,Brandon L. Warren,Benoit Lebonté,Sarah R. Horn,Kyle A.B. Lapidus,Viktoria Stelzhammer,Erik H. F. Wong,Sabine Bahn,Vaishnav Krishnan,Carlos A. Bolaños-Guzmán,James W. Murrough,Miriam Merad,Scott J. Russo +20 more
TL;DR: It is established that preexisting differences in stress-responsive IL-6 release from BM-derived leukocytes functionally contribute to social stress-induced behavioral abnormalities, and a potential new form of treatment for stress disorders.
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Stress and the social brain: behavioural effects and neurobiological mechanisms
Carmen Sandi,József Haller +1 more
TL;DR: Research in animals and humans has revealed some of the structural, functional and molecular changes in the brain that underlie the effects of stress on social behaviour and will have implications both for the clinic and for society.
Journal ArticleDOI
Pathogenesis of depression: Insights from human and rodent studies
TL;DR: This review summarizes the most recent discoveries and insights for which parallel findings have been obtained in human depressed subjects and rodent models of mood disorders in order to examine the potential etiology of depression.
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