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Roles of Stress and Glucocorticoids in Dopaminergic Projections and Behaviors

压力和糖皮质激素在多巴胺能投射和行为中的作用

基本信息

批准号：
8467749
负责人：
Minae Niwa
金额：
$ 7.46万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-10 至 2014-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467749
关键词：
Address Adolescence Adrenal Cortex Adrenal Glands Affect Age Age-Months Behavior Behavioral Breeding Cells Communication Corticosterone Disease Dominant-Negative Mutation Dopamine Early Intervention Endocrine Endocrine system Environmental Risk Factor Epigenetic Process Functional disorder Future Gene Combinations Genetic Genetic Risk Genetically Engineered Mouse Glucocorticoid Receptor Glucocorticoids Knockout Mice Lead Link Mental disorders Methamphetamine Modeling Molecular Mus Neurons Nucleus Accumbens Pathology Patients Phenotype PrP Prions Production Publishing RU-486 Receptor Signaling Regulation Reporting Research Research Personnel Research Proposals Risk Factors Role Signal Transduction Stress Swimming System Technology Testing Training Transgenic Mice Transgenic Model Tyrosine 3-Monooxygenase base behavior measurement dopamine transporter dopaminergic neuron environmental stressor frontal lobe hypothalamic-pituitary-adrenal axis mutant new therapeutic target prepulse inhibition promoter response stressor translational approach

项目摘要

DESCRIPTION (provided by applicant): In response to stressors, the hypothalamic-pituitary-adrenal (HPA) axis is activated, resulting in the release of glucocorticoids from adrenal cortex. Functional and circuitry disturbances of dopaminergic neurons underlie many psychiatric disorders. Nevertheless, mechanistic links of this endocrine system to dopaminergic neurons in the disease contexts remain elusive. This applicant has previously reported that four different Disc1 genetically-engineered mice (DISC1 mice) manifest various behavioral deficits relevant to psychiatric disorders and show dopaminergic disturbance, suggesting that dopaminergic disturbance may be a central and common deficit in these models. Psychiatric conditions are usually elicited not merely by genetic factor(s), however, but by a combination of gene-environmental factors. Thus, we hypothesized that DISC1 mice might be useful models with which to examine how stressors modify the dopamine-associated pathologies, and further hypothesized that the HPA axis might participate in the mechanism. To address these questions, we have used a transgenic model expressing a dominant-negative mutant DISC1 under the expression control of the prion protein promoter (DISC1-DN-Tg-PrP) in combination with isolation stress during adolescence. We will examine whether blocking overactivation of the HPA axis normalizes dopaminergic disturbance and behavioral deficits in this model. We hypothesize that cell-autonomous epigenetic mechanisms in response to glucocorticoids may underlie, at least in part, the distinct regulation of mesocortical and mesolimbic dopaminergic projections in the mice. To address this question, we will use several technologies that allow us to examine molecular assessment of circuitry in a projection-dependent manner. Using mice with glucocorticoid receptor (GR) deletion based on dopamine transporter expression, we will also address the role of GR in disturbance of dopaminergic neurons in DISC1-DN-Tg-PrP mice with isolation. Here we plan to examine overall interactions of endocrine-epigenetic-neuron systems in the pathophysiology of psychiatric disorders that occur under synergistic influence of genetic-environmental factors. This training and research proposal will enable this applicant to develop into an independent investigator in psychiatric research. The mechanism(s) of endocrine-epigenetic-neuron systems can be extended towards translational approaches in the near future.

描述（由申请人提供）：对压力源的反应，下丘脑-垂体-肾上腺（HPA）轴被激活，导致肾上腺皮质释放糖皮质激素。多巴胺能神经元的功能和电路紊乱是许多精神疾病的基础。然而，在疾病背景下，这种内分泌系统与多巴胺能神经元的机制联系仍然难以捉摸。该申请人之前曾报道过四种不同的Disc1基因工程小鼠（Disc1小鼠）表现出与精神疾病相关的各种行为缺陷，并表现出多巴胺能障碍，这表明多巴胺能障碍可能是这些模型中中心和常见的缺陷。然而，精神疾病通常不仅仅是由遗传因素引起的，而是由基因-环境因素的结合引起的。因此，我们假设DISC1小鼠可能是研究应激源如何改变多巴胺相关病理的有用模型，并进一步假设下丘脑轴可能参与该机制。为了解决这些问题，我们使用了一种转基因模型，在朊蛋白启动子（DISC1- dn - tg - prp）的表达控制下，结合青春期隔离应激，表达显性阴性突变体DISC1。我们将研究阻断下丘脑轴的过度激活是否会使该模型中的多巴胺能障碍和行为缺陷正常化。我们假设细胞对糖皮质激素反应的自主表观遗传机制可能是小鼠中皮层和中边缘多巴胺能投射的独特调节的基础，至少在一定程度上是如此。为了解决这个问题，我们将使用几种技术，使我们能够以依赖投影的方式检查电路的分子评估。以多巴胺转运体表达为基础的糖皮质激素受体（GR）缺失小鼠为研究对象，我们还将探讨GR在分离的DISC1-DN-Tg-PrP小鼠多巴胺能神经元紊乱中的作用。在这里，我们计划检查内分泌-表观遗传-神经元系统在遗传-环境因素协同影响下发生的精神疾病病理生理学中的整体相互作用。这项培训和研究计划将使申请人发展成为精神病学研究的独立研究者。在不久的将来，内分泌-表观遗传-神经元系统的机制可以扩展到翻译方法。