CRF and urocortin systems

CRF 和尿皮质素系统

• 批准号: 6259199
• 负责人: PAUL M PLOTSKY
• 金额: $ 23.19万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6259199
• 关键词: Macaca mulatta; age difference; behavioral /social science research tag; corticotropin releasing factor; disease /disorder proneness /risk; early experience; environmental stressor; gender difference; hormone receptor; hypothalamic pituitary adrenal axis; laboratory rat; major depression; mother deprivation; neural plasticity; stress

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.

埃默里大学Silvio O. Conte精神疾病神经科学中心（CCNMD）汇集了一组专家基础和临床研究者，研究了与抑郁症的病理生理学有关的几种动物模型和临床模型。大量研究已经建立了重度抑郁症与含有神经回路的中央皮质激素释放因子（CRF）之间的可能联系。 CRF是〜yp0thalamic〜垂体〜肾上腺（HPA）轴的Major生理调节剂。一个迅速发展的数据库积累了，这清楚地表明，产生CRF和泌尿诺素的神经元系统不仅整合了生物体对压力的内分泌反应，还整合了它们的自主，免疫，免疫和行为对压力的反应。此外，下丘脑和偏椎骨外CRF神经元的多动症似乎都参与情绪和焦虑症的病理生理学。我们建议比较中央CRF/尿道素系统在大鼠和早期应激相关抑郁症综合征的灵长类动物模型中的功能。新生儿母体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会改变中央CRF神经信仰活性。我们假设，在某些关键时期的早期生活压力会改变下丘脑和偏丘脑外CRF神经元，并改变对这些CRF神经信号的输入，从而产生NE \ 1ro化学，内分泌，内分泌和行为上分泌，以及对成人压力的行为超反应性。这些动物的初步数据SH6WS改变了甲肾上腺素能，血清素能和多巴胺能系统，这些系统可能会改变CRF神经元功能或可能因CRF神经元功能的改变而被修饰。我们将测试这些“环境编程”模型是否在长埃文斯大鼠菌株和恒河猴猕猴中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。在当前的PR6POLAS中，我们将：（1）在不同年龄的这些大鼠和灵长类动物模型中表征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压力源的响应性，（3）评估机械上不同的抗抑郁物在对成年动物进行启动时（以及在该系统中的启动）的能力，并确定（在成年动物的启动过程中）是否确定（以及（4与CRF2Alpha受体亚型相对于早期生活压力的生物学和行为作用。总体而言，通过利用并受到该中心其他项目的发现的指导，这些研究将寻求阐明神经生物学的基础，即早期生活环境的影响如何导致成年人在成年人中对精神病发病率的脆弱性，而临床和流行病学数据已经支持了。