Stress-Induced Compulsive Behaviors: CRF Regulation (#3 of 14)

IRCSSA将调查压力、自我控制和成瘾行为的潜在机制。的 成瘾或强迫行为的发展，被假设为涉及丧失 抑制（自我）控制行为和增强奖励的动机。大量数据显示， 压力对成瘾行为的几乎所有方面都有深远的影响，我们的数据表明， 压力可以促进习惯性或强迫性反应的发展。我们假设压力 促进从目标导向的行为模式转变为习惯性的行为模式，通过两者所支配的效果 纹状体和前额叶皮质（RFC）的大脑结构。成瘾行为的表现也是 与奖励相关线索的激励影响增加相关，被认为是 介导的核神经元（NAc）<$一个关键网站的动机方面的自然和 毒品奖励RFC和NAc都接受来自腹侧被盖的多巴胺能传入 RFC接收来自蓝斑（LC）的去甲肾上腺素能输入，这些输入信号是来自VTA区（VTA）的。 压力和成瘾药物都会激活神经投射。压力也会增加促肾上腺皮质激素释放的水平- 因子（CRF），一种在整合应激反应中具有重要作用的神经肽。由于两 VTA和LC表达CRF受体，应激诱导这些区域CRF的增加可能提供了一种 压力可以影响成瘾行为背后的认知动机过程。要求1 将测试慢性压力产生认知缺陷和相关动机改变的假设。 通过同时减少抑制控制和增强抑制控制， 奖励相关线索的动机影响，从而促进工具性 习惯目的2将使用基于选择性RNAi的方法来确定VTA和LC CRF受体的作用 压力对这些食物行为的影响。目的3将探索应激诱导的基因变化 在LC和VTA中的表达。总之，这些研究将补充对应激诱导的脑损伤的成像研究。 皮质-边缘-纹状体功能的改变和内源性大麻素的行为/细胞研究， RFC锥体神经元和PFC-纹状体回路中的儿茶酚胺能信号，以及线索诱导的项目 在人类和动物模型中的渴望和自我控制/决策。这些研究的结果 将阐明压力诱导强迫行为的大脑机制，然后导致新的 用于预防和减少强迫行为如成瘾的药物开发和治疗。

The IRCSSA will investigate mechanisms underlying stress, self-control and addictive behaviors. The development of addictive, or compulsive behaviors, is hypothesized to involve a combination of loss of inhibitory (self) control over behavior and enhanced motivation for rewards. A wealth of data has shown profound effects of stress on virtually all aspects of addictive behavior and our data suggest that chronic stress can facilitate the development of habitual or compulsive responses. We hypothesize that stress promotes the transition from goal-directed to habitual behavioral patterns through effects governed by both striatal and prefrontal cortical (RFC) brain structures. The expression of addictive behavior is also associated with increases in the motivational impact of reward-associated cues, effects thought to be mediated by the nucleus accumbens (NAc) ¿ a critical site for the motivational aspects of both natural and drug rewards. Both the RFC and the NAc receive afferent dopaminergic input from the ventral tegmental area (VTA), and the RFC receives and noradrenergic inputs from the locus coeruleus (LC), and these projections are activated both by stress and addictive drugs. Stress also increases levels of corticotrophinreleasing- factor (CRF), a neuropeptide with an important role in integrating responses to stress. Since both the VTA and LC express CRF receptors, stress-induced increases in CRF in these regions may provide a link by which stress can influence the cognitive-motivational processes underlying addictive behavior. Aim 1 will test the hypothesis that chronic stress produces cognitive deficits and motivational alterations associated with compulsive behavior in experimental animals by concurrently reducing inhibitory control and enhancing the motivational impact of reward-associated cues, thereby promoting the development of instrumental habits. Aim 2 will use selective RNAi-based approaches to determine the role of VTA and LC CRF receptors in the effects of stress on these food-motivated behaviors. Aim 3 will explore stress-induced changes in gene expression in the LC and VTA. Together, these studies will complement the imaging studies on stressinduced alterations in cortico-limbic-striatal function and behavioral/cellular studies on endocannabinoids and catecholaminergic signaling in RFC pyramidal neurons and PFC-striatal circuits, as well as projects on cueinduced craving and self-control/decision making in human and animal models. Findings from these studies will elucidate brain mechanisms underlying stress induced compulsive behaviors that can then lead to new drug development and therapies for preventing and decreasing compulsive behaviors such as addictions.