Study on the Mechanism for SIRT1 during the Process of Exercise Improving Depression

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Abstract

The mechanism behind the onset of depression has been the focus of current research in the neuroscience field. Silent information regulator 1 (SIRT1) is a key player in regulating energy metabolism, and it can regulate depression by mediating the inflammatory response (e.g., nuclear factor-kappa B (NF-κB), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β)), gene expression in the nucleus accumben (NAc) and CA1 region of the hippocampus (e.g., nescient helix-loop-helix2 (NHLH2), monoamine oxidase (MAO-A), and 5-Hydroxyindole-3-acetic acid (5-HIAA)), and neuronal regeneration in the CA3 region of the hippocampus. Exercise is an important means to improve energy metabolism and depression, but it remains to be established how SIRT1 acts during exercise and improves depression. By induction and analysis, SIRT1 can be activated by exercise and then improve the function of the hypothalamic–pituitary–adrenal (HPA) axis by upregulating brain-derived neurotrophic factors (BDNF), inhibit the inflammatory response (suppression of the NF-κB and TNF-α/indoleamine 2,3-dioxygenase (IDO)/5-Hydroxytryptamine (5-HT) pathways), and promote neurogenesis (activation of the insulin-like growth factor1 (IGF-1) and growth-associated protein-43 (GAP-43) pathways, etc.), thereby improving depression. The present review gives a summary and an outlook based on this finding and makes an analysis, which will provide a new rationale and insight for the mechanism by which exercise improves depression.

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A novel pathway regulates memory and plasticity via SIRT1 and miR-134

Li Gao, Wen-Yuan Wang, Ying-Wei Mao … (2010)

The NAD-dependent deacetylase Sir2 was initially identified as a mediator of replicative lifespan in budding yeast and was subsequently shown to modulate longevity in worms and flies1,2. Its mammalian homologue, SIRT1, appears to have evolved complex systemic roles in cardiac function, DNA repair, and genomic stability. Recent studies suggest a functional relevance of SIRT1 in normal brain physiology and neurological disorders. However, it is unknown if SIRT1 plays a role in higher-order brain functions. We report that SIRT1 modulates synaptic plasticity and memory formation via a microRNA-mediated mechanism. Activation of SIRT1 enhances, while its loss-of-function impairs, synaptic plasticity. Surprisingly, these effects were mediated via post-transcriptional regulation of CREB expression by a brain-specific microRNA, miR-134. SIRT1 normally functions to limit expression of miR-134 via a repressor complex containing the transcription factor YY1, and unchecked miR-134 expression following SIRT1 deficiency results in the down-regulated expression of CREB and BDNF, thereby impairing synaptic plasticity. These findings demonstrate a novel role for SIRT1 in cognition and a previously unknown microRNA-based mechanism by which SIRT1 regulates these processes. Furthermore, these results describe a separate branch of SIRT1 signaling, in which SIRT1 has a direct role in regulating normal brain function in a manner that is disparate from its cell survival functions, demonstrating its value as a potential therapeutic target for the treatment of CNS disorders.

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Pathogenesis of depression: Insights from human and rodent studies.

Caroline Ménard, Georgia Hodes, Scott J Russo (2016)

Major depressive disorder (MDD) will affect one out of every five people in their lifetime and is the leading cause of disability worldwide. Nevertheless, mechanisms associated with the pathogenesis of MDD have yet to be completely understood and current treatments remain ineffective in a large subset of patients. In this review, we summarize 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. These mechanisms range from synaptic plasticity mechanisms to epigenetics and the immune system where there is strong evidence to support a functional role in the development of specific depression symptomology. Ultimately we conclude by discussing how novel therapeutic strategies targeting central and peripheral processes might ultimately aid in the development of effective new treatments for MDD and related stress disorders.

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Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal brain-derived neurotrophic factor (BDNF)

Lauretta El Hayek, Mohamad Khalifeh, Victor Zibara … (2019)

Exercise promotes learning and memory formation. These effects depend on increases in hippocampal BDNF, a growth factor associated with cognitive improvement and the alleviation of depression symptoms. Identifying molecules that are produced during exercise and that mediate hippocampal Bdnf expression will allow us to harness the therapeutic potential of exercise. Here, we report that an endogenous molecule produced during exercise in male mice induces the Mus musculus Bdnf gene and promotes learning and memory formation. The metabolite lactate, which is released during exercise by the muscles, crosses the blood-brain barrier and induces Bdnf expression and TRKB signaling in the hippocampus. Indeed, we find that lactate-dependent increases in BDNF are associated with improved spatial learning and memory retention. The action of lactate is dependent on the activation of the Sirtuin1 deacetylase. SIRT1 increases the levels of the transcriptional coactivator PGC1a and the secreted molecule FNDC5, known to mediate Bdnf expression. These results reveal an endogenous mechanism to explain how physical exercise leads to the induction of BDNF, and identify lactate as a potential endogenous molecule that may have therapeutic value for CNS diseases in which BDNF signaling is disrupted.SIGNIFICANCE STATEMENT It is established that exercise promotes learning and memory formation and alleviates the symptoms of depression. These effects are mediated through inducing Bdnf expression and signaling in the hippocampus. Understanding how exercise induces Bdnf and identifying the molecules that mediate this induction will allow us to design therapeutic strategies that can mimic the effects of exercise on the brain, especially for patients with CNS disorders characterized by a decrease in Bdnf expression and who cannot exercise because of their conditions. We identify lactate as an endogenous metabolite that is produced during exercise, crosses the blood-brain barrier and promotes hippocampal dependent learning and memory in a BDNF-dependent manner. Our work identifies lactate as a component of the "exercise pill."