Deletion of CRH From GABAergic Forebrain Neurons Promotes Stress Resilience and Dampens Stress-Induced Changes in Neuronal Activity
Deletion of CRH From GABAergic Forebrain Neurons Promotes Stress Resilience and Dampens Stress-Induced Changes in Neuronal Activity
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DOI：
10.3389/fnins.2019.00986
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发表时间：
2019-09-20
影响因子：
4.3
通讯作者：
Deussing, Jan M.
中科院分区：
文献类型：
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作者：
Dedic, Nina;Kuhne, Claudia;Deussing, Jan M.
促肾上腺皮质激素释放激素(CRH)系统的失调与应激相关的心理病理有关，如抑郁和焦虑。虽然大多数研究都将CRH/CRH受体1信号与厌恶、应激样行为联系起来，但最近的研究发现，在基线条件下，不同的CRH回路在维持积极的情绪价值和食欲反应方面发挥着至关重要的作用。在这里，我们讨论了CRH的缺失，特别是GABA能前脑神经元(CRH(CKO-GABA)小鼠)在基线和慢性应激条件下是否会对一般行为产生不同的影响。在CRH(CKO-GAB)A小鼠中的表达图谱显示，在皮质和边缘区域(包括海马体、杏仁中央核和终纹床核)的GABA能神经元中没有CRH，但在下丘脑室旁核中没有。因此，与对照组相比，条件性CRH基因敲除动物在昼夜节律和应激诱导的皮质酮释放方面没有变化。在基线条件下，前脑GABA能神经元缺乏CRH可导致社会交往障碍，但对其他行为指标包括运动、焦虑、强迫游泳试验中的不动、声惊吓反应和恐惧条件反射没有影响。有趣的是，在暴露于慢性社会失败压力后，CRH(CKO-GABA)小鼠表现出弹性表型，伴随着压力诱导的即刻早期基因c-fos和Zif268在几个脑区的表达受抑。总之，我们的数据揭示了GABA能CRH回路在维持幼稚动物适当的社会行为中的需求，并进一步支持了CRH在基线和严重应激条件下促进不同行为状态的能力。
Dysregulation of the corticotropin-releasing hormone (CRH) system has been implicated in stress-related psychopathologies such as depression and anxiety. Although most studies have linked CRH/CRH receptor 1 signaling to aversive, stress-like behavior, recent work has revealed a crucial role for distinct CRH circuits in maintaining positive emotional valence and appetitive responses under baseline conditions. Here we addressed whether deletion of CRH, specifically from GABAergic forebrain neurons (Crh(CKO-GABA) mice) differentially affects general behavior under baseline and chronic stress conditions. Expression mapping in Crh(CKO-GAB)A mice revealed absence of Crh in GABAergic neurons of the cortex and limbic regions including the hippocampus, central nucleus of the amygdala and the bed nucleus of the stria terminals, but not in the paraventricular nucleus of hypothalamus. Consequently, conditional CRH knockout animals exhibited no alterations in circadian and stress-induced corticosterone release compared to controls. Under baseline conditions, absence of Crh from forebrain GABAergic neurons resulted in social interaction deficits but had no effect on other behavioral measures including locomotion, anxiety, immobility in the forced swim test, acoustic startle response and fear conditioning. Interestingly, following exposure to chronic social defeat stress, Crh(CKO-GABA) mice displayed a resilient phenotype, which was accompanied by a dampened, stress-induced expression of immediate early genes c-fos and zif268 in several brain regions. Collectively our data reveals the requirement of GABAergic CRH circuits in maintaining appropriate social behavior in naive animals and further supports the ability of CRH to promote divergent behavioral states under baseline and severe stress conditions.