CRF and urocortin systems

埃默里大学西尔维奥·孔特精神疾病神经科学中心(CCNMD)汇集了一批专业的基础和临床研究人员，研究与抑郁症病理生理学相关的几个动物模型和临床模型。大量研究已经确定了抑郁症与中枢促肾上腺皮质激素释放因子(CRF)之间可能的联系，CRF含有神经回路。CRF是丘脑-垂体-肾上腺(HPA)轴的主要生理调节因子。一个新兴的数据库已经积累起来，它清楚地表明，产生CRF和urocortin的神经系统不仅整合了有机体对应激的内分泌反应，而且还整合了它们对应激的自主神经、免疫和行为反应。此外，下丘脑和下丘脑外CRF神经元的过度活动似乎都与情绪和焦虑障碍的病理生理学有关。我们建议比较中枢CRF/urocortin系统在早期生活应激相关抑郁样综合征的大鼠和灵长类动物模型中的功能。新生儿母体分离的大鼠模型和不同觅食需求的灵长类动物模型都被证明改变了中枢CRF神经回路活动。我们推测，在某些脆弱的关键时期，早期生活应激改变了下丘脑和下丘脑外CRF神经元，并改变了这些CRF神经回路的输入，从而在成人中产生了对应激源的神经化学、内分泌和行为高反应性。这些动物的初步数据显示，去甲肾上腺素、5-羟色胺和多巴胺能系统的变化可能会改变CRF的神经元功能，也可能会因CRF神经元功能的改变而改变。我们将测试这些“环境编程”模型在Long Evans鼠品系和恒河猴身上是否有类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性别相关的差异。在目前的研究中，我们将：(1)描述不同年龄大鼠和灵长类动物模型中CRF和Urocortin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响应性，(3)评估在成年动物应用时或在早期生活应激期间，机械上不同的抗抑郁药改变这些系统的能力，以及(4)确定选择性靶向CRF1和CRF2pha受体亚型是否改变早期生活应激的生物和行为行为，。总体而言，通过利用该中心其他项目的研究结果并以其为指导，这些研究将试图阐明早期生活环境影响如何导致成年人易患精神疾病的神经生物学基础，这一点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.