CRF and urocortin systems

埃默里大学Silvio O. Conte Center for the Neuroscience of Mental Disease（CCNMD）汇集了一批基础和临床研究专家，研究与抑郁症病理生理学相关的几种动物模型和临床模型。大量的研究已经建立了一个可能的联系，抑郁症和中央促肾上腺皮质激素释放因子（CRF）的神经回路。CRF是..丘脑-垂体-肾上腺（HPA）轴的主要生理调节器。一个新兴的数据库已经积累，这清楚地表明，CRF和尿皮质素生产的神经元系统整合不仅有机体的内分泌应激反应，但也自主，免疫和行为应激反应以及。此外，下丘脑和下丘脑外CRF神经元的过度活跃似乎参与了情绪和焦虑障碍的病理生理学。我们建议在大鼠和灵长类动物的早期生活应激相关抑郁样综合征模型中比较中央CRF/尿皮质素系统的功能。新生儿母亲分离的大鼠模型和可变觅食需求的灵长类动物模型都被证明可以改变中枢CRF神经回路活动。我们假设，在某些关键时期的脆弱性的早期生活压力修改下丘脑和下丘脑外CRF神经元，以及改变输入这些CRF神经回路的方式，以产生神经化学，内分泌和行为的高反应性的压力在成年人。这些动物的初步数据显示，去甲肾上腺素能、肾上腺素能和多巴胺能系统的改变可能改变CRF神经元功能，或可能由于CRF神经元功能的改变而改变。我们将测试这些模型的“环境规划”是否有类似的神经生物学基础的朗埃文斯大鼠品系和恒河猴。在所有这些研究中，我们还将评估早期生活压力的后果是否存在与性别相关的差异。在本年度，我们将：（1）表征这些大鼠和灵长类动物模型中不同年龄的CRF和尿皮质素神经系统的状态，（2）评估这些系统对成年动物中急性和慢性应激源的反应性，（3）评估当给予成年动物或在早期生活应激暴露期间时，机械上不同的抗抑郁药改变这些系统的能力，和（4）确定选择性靶向CRF 1与CRF 2 α受体亚型是否改变早期生活压力的生物学和行为作用。总的来说，通过利用和指导本中心其他项目的研究结果，这些研究将寻求阐明早期生活环境影响如何导致成人精神病发病率的脆弱性的神经生物学基础，这已经得到临床和流行病学数据的支持。

The Emory University Silvio O. Conte Center for the Neuroscience of Mental Disease (CCNMD) brings together a group of expert basic and clinical investigators to study several animal models and clinical models relevant to the pathophysiology of depression. Considerable research has established a possible link between major depression and central corticotropin-releasing factor (CRF) containing neural circuits. CRF is the..major physiological regulator of the ~yp0thalamic~pituitary~adrenal (HPA) axis. A burgeoning database has accumulated which clearly suggests that CRF- and urocortin-producing neuronal systems integrate not only the Organism's endocrine response to stress, but also their autonomic, immunologic, and behavioral responses to stress as well. Moreover, hyperactivity of both hypothalamic and extrahypothalamic CRF neurons appears to be involved in the pathophysiology of both mood and anxiety disorders. We propose to compare the function of central CRF/urocortin systems in rat and primate models of early life stress-related depressive- like syndrome. The rat model of neonatal maternal separation and the primate model of variable foraging demand have both been shown to alter central CRF neurocircuit activity. We postulate that early life stress during some critical period of vulnerability modifies hypothalamic and extrahypothalamic CRF neurons as well as altering inputs to these CRF neurocircuits in-such a way as to produce ne\1rochemical, endocrine, and behavioral hyper-responsivity to stressors in adults. Preliminary data in these animals sh6ws alterations in noradrenergic, serotonergic and dopaminergic systems that may modify CRF neuronal function or may be modified as a result of altered CRF neuronal function. We will test whether these models of "environmental programming" have similar neurobiological underpinnings in the Long Evans rat strain and the rhesus macaque monkey. In all of these studies, we will also evaluate whether there are gender-related differences to the consequences of early life stress. In the current pr6posal we will: (1) characterize the state of CRF and urocortin neural systems in these rat and primate models at different ages, (2) assess the responsivity of these systems to acute and chronic stressors in adult animals, (3) evaluate the ability of mechanistically distinct antidepressants to modify these systems when administered to adult animals or during the period of early life stress exposure, and (4) determine whether selective targeting of the CRF1 versus CRF2alpha receptor subtype modifies the biological and behavioral actions of early life stress,. Overall, by utilizing and being guided by findings from the other projects in this Center, these studies will seek to elucidate the neurobiological basis of how early life environmental influences lead to a vulnerability to psychiatric morbidity in adults that is already supported by clinical and epidemiological data.