Astrocyte-derived signals for neuronal and behavioral modulation and its implications in mental illness.

星形胶质细胞衍生的神经元和行为调节信号及其对精神疾病的影响。

基本信息

批准号：
10183448
负责人：
Weikang Cai
金额：
$ 32.76万
依托单位：
NEW YORK INST OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-16 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10183448
关键词：
Address Astrocytes Autopsy Behavior Behavioral Biological Assay Brain Chronic Chronic stress Cognition Complex Control Groups Data Depressive disorder Development Diabetes Mellitus Dopamine Eating Electrophysiology (science)Emotions Epidemiology Etiology Exocytosis Exposure to Gene Silencing Genetic Glutamates Homeostasis Hormones House mice Housing Image Impairment In Vitro Individual Injections Insulin Light Link Luciferases Lysosomes Major Depressive Disorder Measures Medial Mediating Mental Depression Mental disorders Metabolic Microdialysis Molecular Moods Morphology Motivation Mus Mutation Neurons Neurotransmitters Noise Norepinephrine Nucleotides Nucleus Accumbens Nutrient Palate Pathogenesis Pathway interactions Pharmacology Physical activity Play Prefrontal Cortex Regulation Research Resolution Rewards Role Route Serine Serotonin Signal Transduction Signaling Molecule Site Sleep Stress Sucrose Synaptic plasticity Testing Tyrosine Phosphorylation Viral Virus base behavioral outcome density depressive symptoms dopamine system experience gamma-Aminobutyric Acid in vivo inhibitor/antagonist insight insulin signaling monoamine mortality mouse model negative affect neural circuit neural network neurotransmission neurotransmitter release novel novel therapeutic intervention overexpression presynaptic putamen reward processing risk variant selective expression severe mental illness signal processing social defeat stressor trafficking

项目摘要

Project Summary/Abstract: Major depressive disorder (MDD) is a common but serious mental illness that negatively affects emotion, cognition, physical activity, and increases mortality. In general, the manifestation of depression is thought to be due to the imbalance of neurotransmitters in the brain. These neurotransmitters include glutamate, GABA, and especially a class of monoamines, such as serotonin, dopamine, and norepinephrine. Many recent studies have demonstrated the importance of dopamine homeostasis and dynamics on reward and motivation especially after exposure to chronic stress. Our previous studies have identified a novel astrocyte-dependent modulatory mechanism for the dopamine system, in which the hormone insulin regulates ATP release in astrocytes, which in turn contributes to the modulation of dopamine release and depressive-like behavior in mice. These exciting findings provide a novel and potentially important molecular basis for the etiology of depressive disorders, given the epidemiological link between diabetes and major depression. How insulin mediates astrocytic ATP release has yet to be elucidated, although exocytosis from secretory lysosomes has been suggested as a major route of ATP release by astrocytes. Therefore, in the proposed research, we aim to further investigate the molecular mechanism and functional relevance of the astrocytic insulin action and ATP release on dopaminergic signaling under chronic stress. We hypothesize that insulin regulates the exocytosis of ATP from secretory lysosomes in astrocytes to contribute to dopamine release, and impairment of this astrocyte-initiated pathway will negatively impact dopamine release and exacerbate deficits in reward in mice exposed to chronic stress. To test this central hypothesis, we have developed a new genetic mouse model, in which we can specifically delete astrocytic vesicular nucleotide transporters (VNUTs) that are required for loading ATP into secretory lysosomes. Consistent with our original findings, preliminary analyses show that astrocyte-specific VNUTKO mice display increased depressive-like behavior and decreased activation of medium spiny neurons in the nucleus accumbens, indicating decreased dopamine signaling. Moving forward, in Aim 1, we will continue to use astrocyte-specific VNUTKO mice to determine the role of ATP exocytosis by astrocyte on dopamine signaling and reward in these mice after exposure to both unpredictable chronic mild stress (CMS) and chronic social defeat stress (CSDS). In Aim 2, taking advantage of the highly sensitive luciferase-based ATP quantification and the super-resolution living imaging by Nanoimager S, we will quantify the insulin-induced lysosomal trafficking and exocytosis of ATP in cultured astrocytes. Further in vitro and in vivo applications of pharmacological inhibitors and viral expression of mutations of key signaling molecules will dissect the molecular mechanisms of insulin-stimulated ATP release by astrocytes. Together, the proposed research will expand our understanding of the etiology of depressive disorders from a novel perspective of insulin action in astrocytes and may reveal new therapeutic approaches for depression.

项目摘要/摘要：重度抑郁症（MDD）是一种常见但严重的精神疾病，会对情绪产生负面影响，认知、身体活动并增加死亡率。一般来说，抑郁症的表现被认为是由于大脑中神经递质的不平衡。这些神经递质包括谷氨酸、GABA 和特别是一类单胺，例如血清素、多巴胺和去甲肾上腺素。最近的许多研究证明了多巴胺稳态和动态对奖励和动机的重要性尤其是在长期承受压力之后。我们之前的研究已经发现了一种新型的星形胶质细胞依赖性多巴胺系统的调节机制，其中胰岛素激素调节 ATP 释放星形胶质细胞，反过来又有助于调节多巴胺释放和抑郁样行为老鼠。这些令人兴奋的发现为该病的病因学提供了新颖且潜在重要的分子基础。鉴于糖尿病和重度抑郁症之间的流行病学联系，抑郁症。胰岛素如何尽管分泌性溶酶体的胞吐作用已被证实，但介导星形细胞 ATP 释放的机制尚未阐明。被认为是星形胶质细胞释放 ATP 的主要途径。因此，在拟议的研究中，我们的目标是进一步研究星形细胞胰岛素作用和ATP的分子机制和功能相关性慢性应激下多巴胺能信号的释放。我们假设胰岛素调节胞吐作用星形胶质细胞中分泌性溶酶体的 ATP 有助于多巴胺的释放，以及这种作用的损害星形胶质细胞启动的途径将对多巴胺释放产生负面影响并加剧小鼠的奖励缺陷长期承受压力。为了检验这一中心假设，我们开发了一种新的遗传小鼠模型，我们可以专门删除星形细胞囊泡核苷酸转运蛋白（VNUT），这是将 ATP 装载到分泌性溶酶体中。初步分析表明，与我们最初的发现一致星形胶质细胞特异性 VNUTKO 小鼠表现出抑郁样行为增加和伏隔核中的中等棘神经元，表明多巴胺信号传导减少。移动接下来，在目标 1 中，我们将继续使用星形胶质细胞特异性 VNUTKO 小鼠来确定 ATP 的作用在暴露于不可预测的环境后，星形胶质细胞对多巴胺信号传导和奖励的胞吐作用慢性轻度压力（CMS）和慢性社交失败压力（CSDS）。在目标 2 中，利用高度基于灵敏的荧光素酶的 ATP 定量和 Nanoimager S 的超分辨率活体成像，我们将量化培养的星形胶质细胞中胰岛素诱导的溶酶体运输和 ATP 胞吐作用。进一步在体外药理抑制剂的体内应用和关键信号突变的病毒表达分子将剖析星形胶质细胞胰岛素刺激 ATP 释放的分子机制。一起，拟议的研究将扩大我们对小说中抑郁症病因的理解星形胶质细胞中胰岛素作用的视角，可能揭示抑郁症的新治疗方法。