Roles of Stress and Glucocorticoids in Dopaminergic Projections and Behaviors

描述(申请人提供)：应激源时，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回路障碍是许多精神障碍的基础。然而，这种内分泌系统与疾病背景下的多巴胺能神经元之间的机械联系仍然难以捉摸。这位申请人此前曾报道，四种不同的DISC1基因工程小鼠(DISC1小鼠)表现出与精神障碍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的中心和常见缺陷。然而，精神疾病通常不仅是由遗传因素引起的(S)，而且是基因-环境因素的组合。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HPA轴可能参与了这一机制。为了解决这些问题，我们使用了在Pron蛋白启动子(DISC1-dN-TG-PrP)的表达控制下表达显性负突变DISC1的转基因模型，并结合青春期的隔离应激。在这个模型中，我们将研究阻断HPA轴的过度激活是否使多巴胺能障碍和行为缺陷正常化。我们推测，细胞自主的表观遗传机制对糖皮质激素的反应可能至少部分地是小鼠中皮质和中边缘多巴胺能投射的不同调节的基础。为了解决这个问题，我们将使用几种技术，允许我们以投影相关的方式检查电路的分子评估。利用基于多巴胺转运蛋白表达的糖皮质激素受体(GR)缺失的小鼠，我们还将通过分离的方法研究GR在DISC1-DN-TG-PrP小鼠多巴胺能神经元紊乱中的作用。在这里，我们计划研究在遗传-环境因素协同影响下发生的精神障碍的病理生理学中，内分泌-表观遗传-神经元系统的整体相互作用。这项培训和研究建议将使这名申请者发展成为精神病学研究的独立调查员。内分泌-表观遗传-神经元系统的机制(S)在不久的将来可以扩展到翻译方法。

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.