A novel cell and circuit-specific role for SIRT1 in depression

SIRT1 在抑郁症中的新细胞和电路特异性作用

• 批准号: 10162330
• 负责人: Deveroux Ferguson
• 金额: $ 45.35万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10162330
• 关键词: Ablation; Acetylation; Antidepressive Agents; Anxiety; Bacterial Artificial Chromosomes; Behavior; Bilateral; Brain region; Cell physiology; Cells; Chronic; Chronic stress; Data; Dependovirus; Depressed mood; Development; Diagnostic tests; Dopamine D1 Receptor; Dopamine D2 Receptor; Electrophysiology (science); Family; Functional disorder; Gene Expression; Genes; Genetic Markers; Genetic study; HDAC4 gene; Histone Deacetylase; Histones; Human; Human Genetics; Individual; Infusion procedures; Knowledge; Link; LoxP-flanked allele; Major Depressive Disorder; Measures; Mediating; Mental Depression; Messenger RNA; Morphology; Mus; Neurons; Nucleus Accumbens; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Predisposition; Prevalence; Preventive measure; Property; Publications; Reporting; Reproducibility; Resveratrol; Rewards; RiboTag; Role; SIRT1 gene; Signal Pathway; Signal Transduction; Simplexvirus; Sirtuins; Stress; Syndrome; Testing; Therapeutic; Transgenic Mice; Viral; anxiety-like behavior; brain reward regions; cell type; depression model; depressive symptoms; disability; experience; genetic linkage; genome-wide; genome-wide analysis; genomic locus; man; member; neural circuit; non-histone protein; novel; novel therapeutics; overexpression; social defeat; stress related disorder; targeted treatment; therapeutic development; therapeutic target

Project Summary/Abstract Major depressive disorder (MDD) is a leading cause of disability, with ~20% of individuals suffering from clinical depression during their lifetime. Depression is a heterogeneous syndrome consisting of several subtypes and abnormalities in multiple brain regions. Despite the prevalence of depression and its considerable impact, knowledge about its pathophysiology is limited. Thus, there is an urgent need to discover novel signaling pathways contributing to the development of depression so that better diagnostic tests, treatments, and preventive measures can be attained. A recent ground breaking report revealed SIRT1 as one of the first two genes successfully linked to MDD in a genome-wide study. SIRT1, a member of the sirtuin family, is characterized as a Class III histone deacetylase (HDAC), which regulates the acetylation state of histones and non-histone proteins and thereby influences gene expression and cellular physiology. Preliminary data from our lab show that chronic social defeat stress (CSDS), an ethologically validated model of depression and other stress-related disorders, regulates SIRT1 levels in the NAc, a key brain reward region. Additionally we demonstrate that SIRT1 overexpression in the NAc increases anxiety and despair-like behaviors. What is not understood is how SIRT1 influences anxiety and despair-like behaviors in a cell and circuit-specific manner. This is of particular importance due to the opposing role of D1 medium spiny neurons (MSNs) and D2 MSNs in reward- and depression-related behaviors. A central hypothesis of this project is that SIRT1 signaling acts through the D1 pathway to mediate anxiety- and despair-like behaviors. To test this hypothesis, first we will use Cre-inducible RiboTag (RT) mice, which have been crossed with D1-Cre and D2- Cre bacterial artificial chromosome (BAC) transgenic mice, allowing for the cell-type specific isolation of mRNA from D1 or D2 MSNs. Following CSDS we will measure SIRT1 mRNA from D1 and D2 MSN isolated from RiboTag-D1 Cre and RiboTag-D2 Cre mice. Second, to determine through which MSN subtype SIRT1 acts to mediate anxiety- and depressive- like behaviors we will selectively overexpress SIRT1 in D1 or D2 MSNs in the NAc and third we will utilize electrophysiology and morphological approaches, to uncover cell-type specific SIRT1 dependent neural circuits that mediate depression-like behaviors. If successful this study will have several positive impacts: 1) it would have identified the SIRT1-signaling pathway as a potential target in the development of urgently needed novel antidepressants; 2) it will provide additional support for the development of non-monoaminergic medications to treat depression; and 3) it will identify the neural circuit and cell-type specific mechanisms through which SIRT1 mediates depression-like behaviors.

项目总结/摘要 重度抑郁症（MDD）是残疾的主要原因，约20%的人患有抑郁症。 临床抑郁症患者的一生抑郁症是一种异质性综合征， 多个脑区的亚型和异常。尽管抑郁症的流行及其 虽然其影响相当大，但对其病理生理学的了解有限。因此，迫切需要发现 新的信号通路有助于抑郁症的发展，以便更好的诊断测试， 可以采取治疗和预防措施。最近的一份突破性报告显示，SIRT 1是一种 在一项全基因组研究中，前两个基因成功地与MDD联系在一起。SIRT 1，sirtuin的成员 组蛋白去乙酰化酶（HDAC）是一种III类组蛋白去乙酰化酶，它调节组蛋白的乙酰化状态。 组蛋白和非组蛋白，从而影响基因表达和细胞生理学。初步 来自我们实验室的数据表明，慢性社会失败压力（CSDS），一种行为学验证的模型， 抑郁症和其他与压力有关的疾病，调节NAc中的SIRT 1水平，NAc是一个关键的大脑奖励区域。 此外，我们证明SIRT 1在NAc中的过表达增加了焦虑和绝望样焦虑。 行为。目前尚不清楚SIRT 1如何影响细胞中的焦虑和绝望样行为， 具体的电路方式。这是特别重要的，因为D1中型多刺神经元的相反作用 （MSN）和D2 MSN在奖励和抑郁相关的行为。这个项目的一个核心假设是， SIRT 1信号传导通过D1通路介导焦虑和绝望样行为。为了验证这一 假设，首先，我们将使用Cre诱导的RiboTag（RT）小鼠，其已经与D1-Cre和D2-Cre杂交。 Cre细菌人工染色体（BAC）转基因小鼠，允许细胞类型特异性分离 来自D1或D2 MSN的mRNA。在CSDS之后，我们将测量来自分离的D1和D2 MSN的SIRT 1 mRNA 来自RiboTag-D1 Cre和RiboTag-D2 Cre小鼠。第二，确定通过哪个MSN亚型SIRT 1 作为调解焦虑和抑郁样行为，我们将选择性地在D1或D2中过表达SIRT 1 第三，我们将利用电生理学和形态学方法来揭示细胞类型。 特定的SIRT 1依赖神经回路，介导抑郁样行为。如果这项研究成功， 有几个积极的影响：1）它将确定SIRT 1信号通路作为一个潜在的目标， 开发急需的新型抗抑郁药; 2）它将为 开发非单胺能药物治疗抑郁症; 3）它将识别神经回路， SIRT 1介导抑郁样行为的细胞类型特异性机制。

项目成果

Early impairment of cortical circuit plasticity and connectivity in the 5XFAD Alzheimer's disease mouse model.

• DOI: 10.1038/s41398-022-02132-4
• 发表时间: 2022-09-08
• 期刊: TRANSLATIONAL PSYCHIATRY
• 影响因子: 6.8
• 作者: Chen, Chang;Ma, Xiaokuang;Wei, Jing;Shakir, Neha;Zhang, Jessica K.;Zhang, Le;Nehme, Antoine;Cui, Yuehua;Ferguson, Deveroux;Bai, Feng;Qiu, Shenfeng
• 通讯作者: Qiu, Shenfeng

Shisa6 mediates cell-type specific regulation of depression in the nucleus accumbens.

• DOI: 10.1038/s41380-021-01217-8
• 发表时间: 2021-12
• 期刊: Molecular psychiatry
• 影响因子: 11
• 作者: Kim HD;Wei J;Call T;Quintus NT;Summers AJ;Carotenuto S;Johnson R;Ma X;Xu C;Park JG;Qiu S;Ferguson D
• 通讯作者: Ferguson D