Major depression and anxiety disorders are significant causes of disability and socioeconomic burden. Despite the prevalence and considerable impact of these affective disorders, their pathophysiology remains elusive. Thus, there is an urgent need to develop novel therapeutics for these conditions. We evaluated the role of SIRT1 in regulating dysfunctional processes of reward by using chronic social defeat stress to induce depression- and anxiety-like behaviors. Chronic social defeat stress induces physiological and behavioral changes that recapitulate depression-like symptomatology and alters gene expression programs in the nucleus accumbens, but cell type–specific changes in this critical structure remain largely unknown. We examined transcriptional profiles of D1-expressing medium spiny neurons (MSNs) lacking deacetylase activity of SIRT1 by RNA sequencing in a cell type–specific manner using the RiboTag line of mice. We analyzed differentially expressed genes using gene ontology tools including SynGO and EnrichR and further demonstrated functional changes in D1-MSN–specific SIRT1 knockout (KO) mice using electrophysiological and behavioral measurements. RNA sequencing revealed altered transcriptional profiles of D1-MSNs lacking functional SIRT1 and showed specific changes in synaptic genes including glutamatergic and GABAergic (gamma-aminobutyric acidergic) receptors in D1-MSNs. These molecular changes may be associated with decreased excitatory and increased inhibitory neural activity in Sirt1 KO D1-MSNs, accompanied by morphological changes. Moreover, the D1-MSN–specific Sirt1 KO mice exhibited proresilient changes in anxiety- and depression-like behaviors. SIRT1 coordinates excitatory and inhibitory synaptic genes to regulate the GABAergic output tone of D1-MSNs. These findings reveal a novel signaling pathway that has potential for the development of innovative treatments for affective disorders.

中文翻译：

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SIRT1 协调神经活动的转录调控并调节伏隔核中的抑郁样行为


重度抑郁症和焦虑症是导致残疾和社会经济负担的重要原因。尽管这些情感障碍普遍存在并产生相当大的影响，但它们的病理生理学仍然难以捉摸。因此，迫切需要为这些疾病开发新的治疗方法。我们通过使用慢性社交失败压力诱导抑郁和焦虑样行为，评估了 SIRT1 在调节功能失调的奖励过程中的作用。慢性社交失败压力会引起生理和行为变化，这些变化概括了类似抑郁症的症状，并改变了伏隔核中的基因表达程序，但这一关键结构中的细胞类型特异性变化在很大程度上仍然是未知的。我们使用小鼠的 RiboTag 系以细胞类型特异性方式进行 RNA 测序，检查了缺乏 SIRT1 脱乙酰酶活性的表达 D1 的中等棘神经元 （MSN） 的转录谱。我们使用包括 SynGO 和 EnrichR 在内的基因本体工具分析了差异表达基因，并使用电生理学和行为测量进一步证明了 D1-MSN 特异性 SIRT1 敲除 （KO） 小鼠的功能变化。RNA 测序显示缺乏功能性 SIRT1 的 D1-MSN 的转录谱发生改变，并显示 D1-MSN 中突触基因的特异性变化，包括谷氨酸能和 GABA 能 （γ-氨基丁酸能） 受体。这些分子变化可能与 Sirt1 KO D1-MSN 中兴奋性神经活性降低和抑制性神经活性增加有关，并伴有形态学变化。此外，D1-MSN 特异性 Sirt1 KO 小鼠在焦虑和抑郁样行为中表现出促弹性变化。SIRT1 协调兴奋性和抑制性突触基因，以调节 D1-MSN 的 GABA 能输出音调。 这些发现揭示了一种新的信号通路，具有开发情感障碍创新疗法的潜力。