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Cell Subtype Mechanisms Underlying Stress Susceptibility and Resilence

压力敏感性和弹性的细胞亚型机制

基本信息

批准号：
10553727
负责人：
Mary Kay Lobo
金额：
$ 51.37万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10553727
关键词：
Affect Atrophic Autopsy Behavior Biological Process Bipolar Disorder Brain CSF1 gene Cells Chronic Data Dopamine Receptor Dorsal Female Foundations Future Globus Pallidus Hypothalamic structure Individual Inflammatory Response Label Lateral Ligands Link Macrophage Colony-Stimulating Factor Receptor Major Depressive Disorder Mediating Mental Depression Mental disorders Messenger RNA Microglia Molecular Morphology Motivation Mus Neuroglia Neurons Nucleus Accumbens Outcome Phenotype Play Population Positive Valence Post-Traumatic Stress Disorders Predisposition Process Rewards RiboTag Ribosomes Risk Factors Rodent Role Schizophrenia Shapes Signal Transduction Stress Structure Symptoms Testing Therapeutic Ventral Tegmental Area Virus Work behavioral construct behavioral outcome brain reward regions cell type efficacious treatment improved inducible Cre knock-down male molecular subtypes motivated behavior neuronal circuitry prevent promote resilience research and development resilience resilient behavior response reward circuitry sex social defeat social stress stress resilience tool transcriptome transcriptome sequencing translatome

项目摘要

Project Summary: Stress alters the structure and function of brain reward circuitry leading to disruption of reward and motivation. Stress can be a major risk factor or trigger episodes of psychiatric disorders, which encompass altered motivational behavior; including major depressive disorder, bipolar disorder, schizophrenia, and post traumatic stress disorder. Current studies emphasize a need to approach psychiatric diseases from a combined circuit and molecular perspective to link candidate molecules to dysfunctional cell subtypes. Our previous work provided an initial foundation for understanding nucleus accumbens, a major brain reward region, medium spiny neuron (MSN) subtypes in response to stress. However, there is a critical need for a comprehensive understanding that encompasses intrinsic molecular regulators of these MSN subtype adaptations and the extrinsic regulators (such as microglia) that help to shape these structural adaptations in mice susceptible to stress, as well as those displaying resilient response to stress. In this proposal we will completely characterize structural adaptations in D1-MSN subpopulations, microglia, and the interaction between the two in stress susceptible and resilient conditions of both sexes using chronic social defeat stress (CSDS) and chronic witness defeat stress (CWDS) paradigms. We will manipulate microglia and D1-MSN subpopulations to determine how these alterations affect the other cell type, D1-MSN circuit activity, and ultimately stress vulnerable or resilient behavior including reward value behaviors. Finally, using cell subtype RNA-seq we will determine how microglia impact stress mediated molecular adaptations in D1-MSN subtype populations and how D1-MSNs impact stress mediated microglia adaptations. Collectively our studies can provide improved understanding of NAc cell subtype mechanisms in susceptible and resilient subjects. Our studies could uncover future therapeutic avenues aimed at mimicking stress resilient mechanisms or combating stress susceptible mechanisms in psychiatric motivational symptoms

项目总结：应激改变大脑奖赏回路的结构和功能，导致奖赏和动力。压力可能是一个主要的风险因素或触发精神障碍的发作，包括动机行为改变；包括严重抑郁障碍、双相情感障碍、精神分裂症和POST 创伤性应激障碍。目前的研究强调有必要从合并的将候选分子与功能失调的细胞亚型联系起来的电路和分子观点。我们之前的工作为理解伏隔核，一个主要的大脑奖赏区域，中棘提供了初步的基础应激反应的神经元(MSN)亚型。然而，迫切需要一种全面的理解包括这些MSN亚型适应的内在分子调节和外源性调节因子(如小胶质细胞)有助于形成易感小鼠的这些结构性适应压力，以及那些对压力表现出弹性反应的人。在这份提案中，我们将完全描述 D_1-MSN亚群、小胶质细胞的结构适应及其在应激中的相互作用慢性社会失败应激(CSDS)和慢性目击证人对两性易感和弹性状况的影响战胜压力(CWDS)范式。我们将操纵小胶质细胞和D1-MSN亚群来确定这些改变影响了另一种细胞类型，D1-MSN电路活动，并最终应激脆弱或有弹性行为包括奖励价值行为。最后，使用细胞亚型rna-seq，我们将确定小胶质细胞是如何冲击应激介导的D_1-MSN亚型群体的分子适应及D_1-MSN如何影响应激介导的小胶质细胞适应。总的来说，我们的研究可以提供对NAC细胞亚型的更好理解易感受试者和弹性受试者的机制。我们的研究可能会发现未来的治疗途径在精神病患者中模仿应激恢复机制或对抗应激敏感机制动机症状