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)和尿皮质激素(UCN)家族神经肽和受体在应激源行为反应中的作用做出了重要贡献。在之前的资金支持期间，已经确定了CRF2基因敲除和尿皮质激素的行为效应，导致了大脑CRF2受体具有潜在的抗应激和抑制食欲作用的假设。在之前的资助期中的初步结果确定了特定的大脑部位，这些部位对CRF诱导的应激源的行为反应和UCN诱导的食欲抑制非常重要。目前的建议将检验这一假设，即CRF相关神经肽在中枢神经系统中具有调节应激行为反应的功能作用。一个假设是 CRF通过中央杏仁核的CRF1受体产生类似焦虑的反应，而尿皮质激素通过下丘脑的CRF2受体抑制食欲。具体目标1将探讨延伸的杏仁核(杏仁核的内侧核和中央核、终纹的内侧和外侧床核以及伏隔内侧核的过渡区)在阻断CRF1受体和激活CRF2受体的抗应激样效应中的作用。特指目标2将探讨下丘脑特定核团在抑制CRF1和CRF2激动剂产生的摄食中的作用。 大鼠微结构进食模式分析方法。具体目的3将利用药理学和慢病毒RNA干扰方法，探索CRF1和CRF2受体系统在与CRF1和CRF2受体激活或失活相关的应激反应中的功能相互作用。特指目标4将使用结构性UCN缺乏或条件性转基因CRF2激动剂过表达的分子模型来研究urocortins和CRF2受体激活在激活、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，从而可能为CRF系统信号在各种应激相关病理中的作用提供见解。

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.