A Novel Cell and Circuit-Specific Role for SIRT1 in Depression
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Material below summarizes the article SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens, published on August 10, 2016, in JNeurosci and authored by Hee-Dae Kim, Jennifer Hesterman, Tanessa Call, Samantha Magazu, Elizabeth Keeley, Kristyna Armenta, Hope Kronman, Rachael L. Neve, Eric J. Nestler, and Deveroux Ferguson.
Major depressive disorder (MDD) is a significant cause of disability with few effective treatments. More than 350 million individuals worldwide suffer from depression. In the United States, approximately 30 million individuals suffer from depression, which accounts for approximately $60 billion dollars lost in annual productivity. Current treatment approaches for depression are largely ineffective and leave more than 50 percent of patients symptomatic.
The development of novel antidepressant medications has been stagnant over the past several decades, with a majority of antidepressants derived from classic monoaminergic mechanisms serendipitously discovered more than half a century ago. Therefore, there is an urgent need to design and develop novel therapeutics to treat depression.
A recent groundbreaking human genetics study revealed SIRT1 as one of the first two genes successfully linked to MDD in a genome-wide investigation. SIRT1, a member of the sirtuin family, is characterized as a Class III histone deacetylase (HDAC), which regulates the acetylation state of histones, the packaging substrate of DNA and other proteins and thereby influences gene expression and cellular physiology.
Additional genetic association studies identified single nucleotide polymorphisms (SNPs) in the SIRT1 gene associated with risk of anxiety (panic disorders and social phobias) in humans. Also, an independent study of Japanese subjects found a significant association between another SIRT1 SNP and major depressive disorders. These findings introduce a novel signaling pathway for the development of innovative antidepressants to treat major depressive disorders.
Using both pharmacological and viral-vector transgenic approaches, we demonstrated that chronic social defeat stress, an ethologically validated model of depression, induces SIRT1 expression in the nucleus accumbens (NAc), a brain region associated with reward and that SIRT1 induction in this region promotes depression- and anxiety-like behaviors.
These findings suggest an important role for SIRT1 acting in the NAc in regulating mood disorders and present a novel path forward for the development of a new class of antidepressants targeting the sirtuin-signaling pathway.
We specifically showed the following:
- SIRT1 levels are increased in the nucleus accumbens (NAc), a key brain reward region.
- Resveratrol (a pharmacological activator of SIRT1) infused bilaterally in the NAc increases anxiety- and depression-like behaviors.
- Intra-NAc infusions of EX-527 (an antagonist of SIRT1) reduces anxiety- and depression-like behaviors.
- Directly increasing SIRT1 levels by viral-mediated overexpression of SIRT1 in the NAc increases depressive- and anxiety-like behaviors.
- Selective ablation of SIRT1 in the NAc using adeno-associated viruses in floxed SIRT1 transgenic mice decreases anxiety-like behaviors.
Our results strongly support the recent CONVERGE Consortium finding that identified a robust reproducible association of the SIRT1 gene loci with major depression in humans.
Critically, we wanted to determine if SIRT1 influences depression- and anxiety-like behaviors in a cell- and circuit-specific manner. It is currently believed that activation of Dopamine D1 receptor medium spiny neurons (D1-MSNs) produces positive rewarding behavior, whereas activation of Dopamine D2 receptor medium spiny neurons (D2-MSNs) leads to aversive behaviors.
We demonstrated a cell-type specific role of SIRT1 in the regulation of these behavioral abnormalities in the NAc. We showed that the overexpressing SIRT1 selectively in D1-MSNs, but not in D2-MSNs promotes depressive- and anxiety-like behaviors and hypothesize that SIRT1 acts as a transcriptional repressor in the D1 pathway, thereby decreasing the ability to experience reward.
We thus hypothesize that increases in SIRT1-mediated transcriptional repression leads to decreases in activity of the D1 pathway. This is of particular importance due to the opposing role of D1-MSN and D2-MSN in reward, action-value, reinforcement, and responses to drugs of abuse.
Taken together, these results suggest that SIRT1 plays an essential role in regulating depression- and anxiety-related behaviors and introduces a novel-signaling pathway for the development of innovative antidepressants to treat MDD.
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SIRT1 Mediates Depression-Like Behaviors in the Nucleus Accumbens. Hee-Dae Kim, Jennifer Hesterman, Tanessa Call, Samantha Magazu, Elizabeth Keeley, Kristyna Armenta, Hope Kronman, Rachael L. Neve, Eric J. Nestler, Deveroux Ferguson. The Journal of Neuroscience Aug 2016, 36 (32) 8441-8452; DOI: http://dx.doi.org/10.1523/JNEUROSCI.0212-16.2016