Neuroendocrine Effects of Repeated Social Defeat

长期或反复暴露在压力下会产生许多神经系统的可塑性，包括那些调节下丘脑-垂体-肾上腺（HPA）轴的神经系统。下丘脑轴对生理和行为有广泛的影响，包括代谢和心血管功能的调节。在暴露于反复应激（如寒冷或约束）的动物中，基础活性的变化以及随后应激引起的HPA活性的变化可见一斑。这个项目使用了一种更自然的啮齿动物压力模型，即反复暴露于社会失败。在社会环境背景下的失败，包括个体是当地的居民还是入侵者，是许多社会性啮齿动物（如老鼠）在自然生活中所熟悉的情况。虽然一次失败会产生持续几周的神经内分泌和行为影响，但在野外，一只动物经常遭受失败的情况更为常见。因此，大鼠的反复失败为研究与慢性反复应激相关的神经可塑性提供了一个潜在的强大模型。利用分子生物学和行为学的新结合，本项目的目标是：1)描述在反复失败的大鼠中基础和应激诱导的HPA活性如何变化；2)研究室旁丘脑在反复失败范式中的具体作用，室旁丘脑是抑制其他应激情境下HPA反应的脑区；3)发现新的大脑区域，这些区域的活动因反复失败而增加，因为这些区域是调节HPA活动的潜在位点。研究结果对于识别参与行为调节的新型脑回路非常重要，并对我们更多地了解社会压力与身体压力的作用以及社会性的进化产生影响。这个项目也培养了一个新的研究者的职业生涯，他结合了分子生物学和行为的不同寻常的背景。

Chronic or repeated exposure to stress produces plasticity in a number of neural systems, including those that regulate the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis has widespread effects on physiology and behavior, including modulation of metabolism and cardiovascular function. Changes in basal activity as well as subsequent stress-induced HPA activity are seen in animals exposed to repeated stress such as cold or restraint. This project uses a more naturalistic model of stress in rodents, that of repeated exposure to social defeat. Defeat in the context of social environment, including which individual is a resident or an intruder in the local area, is a familiar situation in the natural life of many social rodents such as rats. Although a single defeat produces neuroendocrine and behavioral effects that last a few weeks, it is more common in the wild to have an individual animal regularly subjected to defeat. Therefore, repeated defeat in rats represents a potentially powerful model for the study of neural plasticity associated with chronic, repeated stress. Using a novel combination of molecular biology and behavior, the goals of this project are to 1) characterize how basal and stress-induced HPA activity change in rats subject to repeated defeat; 2) study the specific role of the paraventricular thalamus, a brain region that inhibits HPA responses in other stress situations, in the repeated defeat paradigm; and 3) identify novel brain regions in which activity is increased by repeated defeat, since these are potential sites of regulation of HPA activity. Results will be important for identifying novel brain circuitry involved in the modulation of behavior, and with an impact on our understanding more about the role of social versus physical stress, and about the evolution of sociality. This project also fosters the career of a new investigator who combines an unusual background in molecular biology and behavior.