Behavioral significance of neuroendocrine peptides

本项目资助的前期工作对我们理解中枢神经系统促肾上腺皮质激素释放因子（CRF）和尿皮质素（UCN）家族神经肽和受体在应激行为反应中的作用做出了重大贡献。在上一个资助期，CRF2敲除和尿皮质素的行为效应被确定，导致脑CRF2受体具有潜在的抗应激和抑制食欲作用的假设。上一个资助期的初步结果确定了对CRF诱导的应激行为反应和UCN诱导的食欲抑制重要的特定大脑部位。目前的建议将测试的假设，CRF相关的神经肽在中枢神经系统中的功能作用，介导的行为反应的压力。一个子假设是 CRF通过中央延伸杏仁核中的CRF1受体产生焦虑样反应，尿皮质素通过下丘脑中的CRF2受体抑制食欲。具体目标1将探讨延长杏仁核（杏仁核的内侧和中央核，终纹的内侧和外侧床核，以及内侧核中的过渡区）在CRF1受体阻断和CRF2受体激活的抗应激样作用中的作用。具体目标2将探索下丘脑中特定核团在抑制CRF1和CRF2激动剂产生的摄食中的作用， 微结构膳食模式分析方法。具体目标3将探索CRF1和CRF2受体系统在应激反应中的功能相互作用，这些应激反应与大鼠中CRF1和CRF2受体的激活或失活有关，使用药理学和慢病毒RNA干扰方法。具体目标4将使用组成性Ucn缺陷或条件性转基因CRF2激动剂过表达的分子小鼠模型来研究尿皮质素和CRF2受体活化在活化、应激和摄食行为反应中的作用。这些研究将提供有关CRF相关神经肽和受体在应激源行为反应和食欲调节中的作用的关键信息，因此可能会提供CRF系统信号传导在各种应激相关病理学中的作用的见解。

Previous work in the present project grant has contributed significantly to our understanding of the role of central nervous system corticotropin-releasing factor (CRF) and urocortin (Ucn) family neuropeptides and receptors in behavioral responses to stressors. In the previous funding period, the behavioral effects of CRF2 knockouts and urocortins were identified, leading to the hypothesis that brain CRF2 receptors have potential anti-stress and appetite-suppressing roles. Preliminary results in the previous funding period identified specific brain sites important for CRF-induced behavioral responses to stressors and Ucn-induced appetite suppression. The present proposal will test the hypothesis that CRF-related neuropeptides have a functional role in the central nervous system to mediate behavioral responses to stress. A subhypothesis is that CRF produces anxiogenic-like responses via CRF1 receptors in the central extended amygdala and that urocortins suppress appetite via CRF2 receptors in the hypothalamus. Specific Aim 1 will explore the role of the extended amygdala (medial and central nuclei of the amygdala, medial and lateral bed nucleus of the stria terminalis, and a transition zone in the medial nucleus accumbens) in the anti-stress-like effects of blockade of CRF1 receptors and of activation of CRF2 receptors. Specific Aim 2 will explore the role of specific nuclei in the hypothalamus in the suppression of feeding produced by CRF1 and CRF2 agonists using a microstructural meal pattern analysis approach in rats. Specific Aim 3 will explore the functional interaction of CRF1 and CRF2 receptor systems in the stress responses associated with activation or inactivation of CRF1 and CRF2 receptors in rats using pharmacological and lentiviral RNA interference approaches. Specific Aim 4 will use molecular murine models of constitutive Ucn deficiency or conditional transgenic CRF2 agonist overexpression to study the role of urocortins and CRF2 receptor activation in activation, stress and feeding behavioral responses. These studies will provide key information regarding the role of CRF-related neuropeptides and receptors in behavioral responses to stressors and regulation of appetite, and as a result may provide insights into the role of CRF system signaling in a variety of stress-related pathologies.