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(DR)- 5-羟色胺（5-HT）系统的活动，该系统与应激相关的精神疾病有关。CRF分别通过CRF1和CRF2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（如急性应激期间释放的CRF）启动crf1介导的5-HT神经元活性抑制，这与促进休克逃避和游泳应激反应中的主动应对有关。应激史导致DR中CRF受体的细胞再分配，使CRF2被招募到质膜上。这将DR-5-HT系统的调节从crf1介导的抑制转变为crf2介导的兴奋，并促进习得性无助和不动。本研究的一个有效假设是，应激诱导的DR神经元中CRF受体的再分配是一种细胞机制，它是应激诱导的认知和社会行为损伤的基础，这是由性别和应对方式决定的。与压力相关的精神疾病在女性中更为普遍，但我们对CRF调节DR-5-HT功能的了解仅基于对雄性大鼠的研究。因此，在这些研究中，男性和女性都会被使用。AIM 1将表征CRF对雌性DR-5- ht神经元活动的影响，并确定应激诱导的CRF受体再分配是否发生在雄性DR中，也发生在雌性DR中。目的2将使用居民-入侵者压力作为一种社会压力模型，该模型具有有限的持续时间，并在易感大鼠亚群中引起CRF受体重新分配。利用这种应激源，CRF受体的作用

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.