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。这个 成瘾性或强迫性行为的发展被假设为涉及到 对行为进行抑制性(自我)控制，增强奖励动机。大量数据表明 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，慢性 压力可以促进习惯性或强迫性反应的发展。我们假设压力 通过两者控制的效果，促进从目标导向型到习惯性行为模式的转变 纹状体和前额叶皮质(RFC)脑结构。成瘾行为的表现也是 与奖励相关线索的动机影响的增加有关，影响被认为是 伏隔核(NAC)的调节作用？这是天然的和非自然的 毒品奖励。RFC和NAC都接受来自腹侧被盖的传入多巴胺能传入。 区(VTA)，RFC接受来自蓝斑(LC)的去甲肾上腺素能传入，这些 压力和上瘾药物都会激活投射。压力还会增加促肾上腺皮质激素的释放水平- 因子(CRF)，一种在整合应激反应中起重要作用的神经肽。因为这两个 VTA和LC表达CRF受体，应激诱导这些区域CRF的增加可能提供 压力可以影响成瘾行为潜在的认知-动机过程的联系。目标1 将检验慢性压力会导致认知缺陷和相关的动机改变这一假设 通过同时减少抑制控制和加强对实验动物的强迫行为 奖赏相关线索的动机效应，从而促进工具性线索的发展 习惯。AIM 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 压力对这些食物驱动的行为的影响。目标3将探索压力诱导的基因变化 在LC和VTA中的表达。总之，这些研究将补充压力诱导的成像研究。 皮质-边缘-纹状体功能的改变及内源性大麻素和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对CUE诱导的投射 人类和动物模型中的渴望和自我控制/决策。这些研究的发现 将阐明压力诱导的强迫行为背后的大脑机制，这些行为随后可能导致新的 预防和减少上瘾等强迫行为的药物开发和治疗。

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.