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：
10770060
负责人：
Mary Kay Lobo
金额：
$ 6.12万
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 2023-09-19
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10770060
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

项目摘要：压力改变了大脑奖励电路的结构和功能，从而破坏了奖励和动机。压力可能是主要的危险因素或触发精神疾病的发作，其中包括改变动机行为；包括重大抑郁症，躁郁症，精神分裂症和后创伤性应激障碍。当前的研究强调需要从共同的合并中解决精神病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透视。我们以前的工作为理解伏隔核，一个主要的大脑奖励区域，中刺提供了初步的基础神经元（MSN）亚型响应压力。但是，迫切需要全面了解这些MSN亚型适应的内在分子调节剂和外在调节剂（例如小胶质细胞）有助于塑造小鼠的这些结构适应压力以及表现出对压力的弹性反应的压力。在此提案中，我们将完全描述 D1-MSN亚群，小胶质细胞和两者之间的相互作用的结构适应使用慢性社会失败压力（CSD）和慢性证人击败压力（CWDS）范式。我们将操纵小胶质细胞和D1-MSN亚群来确定如何这些改变会影响其他细胞类型，D1-MSN电路活动，并最终压力易受伤害或弹性包括奖励价值行为的行为。最后，使用细胞亚型RNA-seq，我们将确定小胶质细胞 D1-MSN亚型种群中应力介导的分子适应以及D1-MSN如何影响应力介导的小胶质细胞适应。我们的研究总共可以提高对NAC细胞亚型的了解易感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模仿应力弹性机制或打击精神病中的压力易感机制动机症状