CRF and urocortin systems

埃默里大学Silvio O. Conte精神疾病神经科学中心（CCNMD）汇集了一组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。大量研究已经确立了重度抑郁症与中枢促肾上腺皮质激素释放因子（CRF）包含的神经回路之间的可能联系。CRF是丘脑-垂体-肾上腺（HPA）轴的主要生理调节因子。一个迅速发展的数据库清楚地表明，产生CRF和尿皮质素的神经系统不仅整合了生物体对压力的内分泌反应，而且还整合了它们对压力的自主、免疫和行为反应。此外，下丘脑和下丘脑外CRF神经元的过度活跃似乎与情绪和焦虑障碍的病理生理有关。我们建议比较大鼠和灵长类动物早期生活压力相关抑郁样综合征模型中中枢CRF/尿皮质素系统的功能。大鼠的新生儿母亲分离模型和灵长类动物的可变觅食需求模型都被证明可以改变中央CRF神经回路的活动。我们假设，早期生活压力在某些脆弱的关键时期会改变下丘脑和下丘脑外的CRF神经元，并改变这些CRF神经回路的输入，从而在成人中产生新的化学、内分泌和对压力源的行为超反应。这些动物的初步数据显示，去甲肾上腺素能、血清素能和多巴胺能系统的改变可能会改变CRF神经元功能，也可能由于CRF神经元功能的改变而改变。我们将在朗埃文斯大鼠品系和恒河猴身上测试这些“环境编程”模型是否具有相似的神经生物学基础。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。在目前的建议中，我们将：(1)表征这些大鼠和灵长类动物模型在不同年龄时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急性和慢性应激源的反应；(3)评估不同机制的抗抑郁药在成年动物或生命早期应激暴露期间改变这些系统的能力。(4)确定CRF1和crf2 α受体亚型的选择性靶向是否会改变早期生活应激的生物学和行为行为。总的来说，通过利用和指导本中心其他项目的发现，这些研究将寻求阐明早期生活环境影响如何导致成人易患精神疾病的神经生物学基础，这已经得到了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.