SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens

Abstract

Depression is a recurring and life-threatening illness that affects up to 120 million people worldwide. In the present study, we show that chronic social defeat stress, an ethologically validated model of depression in mice, increases SIRT1 levels in the nucleus accumbens (NAc), a key brain reward region. Increases in SIRT1, a well characterized class III histone deacetylase, after chronic social defeat suggest a role for this enzyme in mediating depression-like behaviors. When resveratrol, a pharmacological activator of SIRT1, was directly infused bilaterally into the NAc, we observed an increase in depression-and anxiety-like behaviors. Conversely, intra-NAc infusions of EX-527, a SIRT1 antagonist, reduced these behaviors; EX-527 also reduced acute stress responses in stress-naive mice. Next, we increased SIRT1 levels directly in NAc by use of viral-mediated gene transfer and observed an increase in depressive-and anxiety-like behaviors when mice were assessed in the open-field, elevated-plus-maze, and forced swim tests. Using a Cre-inducible viral vector system to overexpress SIRT1 selectively in dopamine D1 or D2 subpopulations of medium spiny neurons (MSNs) in the NAc, we found that SIRT1 promotes depressive-like behaviors only when overexpressed in D1 MSNs, with no effect seen in D2 MSNs. Conversely, selective ablation of SIRT1 in the NAc using viral-Cre in floxed Sirt1 mice resulted in decreased depression-and anxiety-like behaviors. Together, these results demonstrate that SIRT1 plays an essential role in the NAc in regulating mood-related behavioral abnormalities and identifies a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders.

The Genetic Architecture of Major Depressive Disorder in Han Chinese Women

“…31 The identification of mitochondrial genes as risk factors for MDD might also explain some clinical features of the illness. For example, SIRT1 (OMIM 604479) influences processes that feature among the vegetative symptoms 32 of MDD: alterations in food intake, 33 wake fulness, 34 and circadian rhythms. 35 The involvement of mitochondrial genes might also explain why MDD increases the risk of cardiovascular disease.…”

SIRT1 in forebrain excitatory neurons produces sexually dimorphic effects on depression-related behaviors and modulates neuronal excitability and synaptic transmission in the medial prefrontal cortex

“…Given the opposing effects of SIRT1 in different brain regions [16,17], additional studies examined the effects of ICV injection of SRT2104 on CUS-induced depressionrelated behaviors. ICV cannulated mice were subjected to 10 days of CUS and received two ICV injections of SRT2104 (0.03 μg) or vehicle at 23 and 3 h prior to behavioral testing (Fig.…”

“…Several studies in animal models support an important role of SIRT1 in emotional regulation [16][17][18][19][20]. However, the exact neural network that mediates SIRT1 actions on depression remains unclear.…”

Abundant collateralization of temporal lobe projections to the accumbens, bed nucleus of stria terminalis, central amygdala and lateral septum

“…The expression of cyclic AMP response element binding protein (CREB) in Acb medium spiny neurons is regulated bidirectionally in relation to anxiety and reward (Carlezon et al, 1998; Barrot et al, 2002; 2005; Carlezon et al, 2005; Nestler and Carlezon, 2006; Dong et al, 2006; Wallace et al, 2009). EA and ventral striatum both respond vigorously to novelty (Garris et al, 1997; Rebec et al, 1997; Lee et al, 2006; 2008; Horvitz, 2000) and both also modulate reactions to stress, pain and depression (Altier and Stewart, 1998; 1999; Neugebauer et al, 2004; Leknes and Tracey, 2008; Rouwette et al, 2012; Chen et al, 2012; Kim et al, 2016). An integrated response to reward, threat and novelty thus reflects considerable overlap among the functions of the EA and ventral striatum, and it shouldn't be neglected that the LS also contributes to numerous and diverse associative and affective functions shared by the EA and ventral striatum (Jakab and Leranth, 1995; Risold and Swanson, 1997a; b; Sheehan et al., 2003).…”