Corticotropin-Releasing Factor/Serotonergic Interactions

描述（由申请人提供）：压力与多种精神疾病有关，包括创伤后应激障碍、抑郁、焦虑和药物滥用。压力和这些精神疾病之间的一个联系是促肾上腺皮质激素释放因子（CRF），一种协调压力反应的神经肽。在应激反应中，CRF调节中缝背核（DR）-5-羟色胺（5-HT）系统的活性，该系统与应激相关的精神障碍有关。CRF分别通过CRF 1和CRF 2受体对DR-5-HT神经元具有相反的抑制和兴奋作用。低水平的CRF，如在急性应激过程中释放的CRF启动CRF 1介导的5-HT神经元活性的抑制，这与促进逃避休克和积极应对游泳应激有关。应激史导致DR中CRF受体的细胞再分布，使得CRF 2被募集到质膜。这将DR-5-HT系统的调节从CRF 1介导的抑制切换到CRF 2介导的兴奋，并促进习得性无助和不动。这项研究的一个工作假设是，压力诱导的DR神经元中CRF受体的重新分布是一种细胞机制，是压力诱导的认知和社会行为障碍的基础，这是由性别和应对方式决定的。压力相关的精神疾病在女性中更普遍，但我们对CRF调节DR-5-HT功能的认识仅基于使用雄性大鼠的研究。因此，这些研究将使用雄性和雌性动物。目的1将描述CRF对女性DR-5-HT神经元活性的影响，并确定在男性DR中发生的应激诱导的CRF受体再分布是否也发生在女性中。目的2将使用居民入侵者的压力作为一个社会压力模型，具有有限的持续时间，并导致CRF受体的再分布在一个亚群的脆弱大鼠。使用这种应激源，CRF受体的作用 将在雄性和雌性大鼠中评估应激诱导的认知和社会损伤中DR神经元的再分布。目的3将使用雄性和雌性CRF过表达小鼠作为慢性应激的遗传模型，并确定这种情况是否会导致DR神经元中CRF受体的重新分布，从而转化为前脑5-HT的变化以及对行为和认知功能的影响。我们过去的工作特点的调节雄性大鼠DR-5-HT系统的CRF 1和CRF 2受体，并确定应激诱导的CRF 1/CRF 2重新分配的细胞机制，压力可以影响这个系统产生适应不良的精神病理学。在这里，我们解决性别差异在这种细胞机制中的作用，其对认知过程的影响，是功能失调的情绪障碍和潜在的遗传升高的CRF，已被提出发生在压力相关的精神疾病，产生相同的细胞和行为的后果。

DESCRIPTION (provided by applicant): Stress has been implicated in diverse psychiatric diseases including post-traumatic stress disorder, depression, anxiety and substance abuse. One link between stress and these psychiatric disorders is corticotropin-releasing factor (CRF), the neuropeptide that orchestrates the stress response. In response to stress CRF regulates activity of the dorsal raphe (DR)-serotonin (5-HT) system, a system that has been implicated in stress-related psychiatric disorders. CRF has opposing inhibitory and excitatory effects on DR-5-HT neurons through CRF1 and CRF2 receptors, respectively. Low levels of CRF such as those released during acute stress initiate CRF1-mediated inhibition of 5-HT neuronal activity and this is associated with the promotion of escape from shock and active coping in response to swim stress. A history of stress causes a cellular redistribution of CRF receptors in the DR such that CRF2 is recruited to the plasma membrane. This switches regulation of the DR-5-HT system from CRF1-mediated inhibition to CRF2-mediated excitation and promotes learned helplessness and immobility. A working hypothesis of this research is that stress-induced redistribution of CRF receptors in DR neurons is a cellular mechanism that underlies stress-induced impairments in cognition and social behavior and that this is determined by sex and coping style. Stress-related psychiatric disorders are more prevalent in females, but our knowledge of CRF regulation of DR-5-HT function is based solely on studies using male rats. Therefore, both males and females will be used in these studies. AIM 1 will characterize CRF effects on female DR-5-HT neuronal activity and determine whether the stress-induced CRF receptor redistribution that occurs in male DR also occurs in females. Aim 2 will use resident-intruder stress as a social stress model that has a limited duration and causes CRF receptor redistribution in a subpopulation of vulnerable rats. Using this stressor, the role of CRF receptor redistribution in DR neurons in stress-induced cognitive and social impairments will be assessed in male and female rats. Aim 3 will use male and female CRF-overexpressing mice as a genetic model of chronic stress and determine whether this condition causes CRF receptor redistribution in DR neurons that translates to changes in forebrain 5-HT and effects on behavior and cognitive function. Our past work characterized regulation of the male rat DR-5-HT system by CRF1 and CRF2 receptors and identified stress-induced CRF1/CRF2 redistribution as a cellular mechanism by which stress can impact this system to produce maladaptive psychopathology. Here we address the role of sex differences in this cellular mechanism, its impact on cognitive processes that are dysfunctional in mood disorders and the potential for genetic elevations of CRF, as have been proposed to occur in stress-related psychiatric disorders, to produce the same cellular and behavioral consequences.