Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Biol Psychiatry. 2012 Feb 15;71(4):317-26. doi: 10.1016/j.biopsych.2011.05.036. Epub 2011 Jul 23.
Faulty regulation of the central extrahypothalamic corticotropin-releasing factor (CRF) expression is associated with stress-related psychopathologies including anxiety disorders and depression. Extensive pharmacological literature describes the effects of CRF agonists or antagonists' administration on anxiety-like behavior. However, the relevance of the endogenous agonist, presumed to be CRF, has never been explicitly demonstrated. Several genetic models have been used to study the role of CRF in the physiological response to stress and in stress-related disorders. Nevertheless, developmental compensatory mechanisms and lack of spatial and temporal specificity limited the interpretations of these studies.
Two lentiviral-based systems were designed, generated, and used to knockdown (KD) or conditionally overexpress (OE) CRF in the central amygdala (CeA) of adult mice. Behavioral responses associated with the CeA, such as anxiety, depression and fear memory, and the plasma corticosterone levels were evaluated under both basal and stressful conditions.
Changing the CeA-CRF levels mildly affected anxiety-like behaviors under basal conditions. However, following exposure to an acute stressor, CeA-CRF-KD strongly attenuated stress-induced anxiety-like behaviors, whereas a short-term CeA-CRF-overexpression enhanced the stress-induced effects on these behaviors. Interestingly, a significant increase in basal corticosterone levels in the CeA-CRF-KD mice was observed, demonstrating the importance of endogenous CeA-CRF levels for basal, but not stress-induced, corticosterone levels.
These results highlight the pivotal role of CeA CRF expression regulation in mediating adequate behavioral responses to stress and introduce these novel viral tools as a useful approach for dissecting the role of central CRF in mediating behavioral and neuroendocrine responses to stress.
中央下丘脑外促肾上腺皮质激素释放因子（CRF）表达的调节失常与应激相关的精神病理有关，包括焦虑障碍和抑郁症。大量药理学文献描述了 CRF 激动剂或拮抗剂给药对类焦虑行为的影响。然而，内源性激动剂（推测为 CRF）的相关性从未被明确证明。已经使用了几种遗传模型来研究 CRF 在应激生理反应和应激相关疾病中的作用。然而，发育代偿机制和缺乏时空特异性限制了这些研究的解释。
设计、生成了两种基于慢病毒的系统，并用于在成年小鼠的中央杏仁核（CeA）中敲低（KD）或条件性过表达（OE）CRF。在基础和应激条件下，评估与 CeA 相关的行为反应，如焦虑、抑郁和恐惧记忆，以及血浆皮质酮水平。
改变 CeA-CRF 水平在基础条件下轻度影响类焦虑行为。然而，在暴露于急性应激源后，CeA-CRF-KD 强烈减弱了应激诱导的类焦虑行为，而短期 CeA-CRF 过表达增强了应激对这些行为的影响。有趣的是，在 CeA-CRF-KD 小鼠中观察到基础皮质酮水平显著升高，这表明内源性 CeA-CRF 水平对基础而非应激诱导的皮质酮水平的重要性。
这些结果强调了 CeA CRF 表达调节在介导对压力的适当行为反应中的关键作用，并介绍了这些新型病毒工具作为一种有用的方法，用于剖析中枢 CRF 在介导行为和神经内分泌对压力的反应中的作用。
