Stressor controllability, resilience and prefrontal endocannabinoids

摘要 控制压力源的开始、抵消或强度的能力是影响压力的最重要因素之一。 确定压力源的生理和心理后果。跨越物种，控制 压力导致恢复力，而无法控制的压力使人容易患上精神疾病。控制 压力通过包括腹内侧前额叶皮层（vmPFC）的神经回路起作用。在出版和 初步研究表明，对压力的控制增加了vmPFC的内在兴奋性， 我建议在这里测试内源性大麻素（eCB）在这种现象中的作用。已知eCB 通过调节局部抑制性中间神经元改变vmPFC兴奋性。我们的假设是 控制压力的经历触发eCB释放，这减弱了体内GABA能中间神经元的活性。 vmPFC导致压力恢复。这个项目包含了一项关于压力应对的性别差异的研究 这将有助于填补我们对女性压力和弹性的理解方面的巨大空白。中 一组发现实验，我们试图量化可控或不可控后vmPFC中的eCB水平 应激使用LC-MS/MS和使用急性切片定量前额GABA能抑制活性 电生理学和免疫组织化学。预测是可控的压力会提高eCB， 减少GABA能突触传递和GABA能神经元活化。在机械研究中，我们将 通过使用病毒的组合靶向eCB降解酶来敲低或升高vmPFC eCB 过表达和药理学。通过将这些操作与暴露于可控或 我们可以确定eCB是否是必要的和足够的压力弹性在以后的 社交焦虑和恐惧的行为测试

ABSTRACT The ability to control the onset, offset or intensity of a stressor is one of the most important factors in determining the physiological and psychological consequences of the stressor. Across species, control over stress leads to resilience while uncontrollable stressors predispose one to psychiatric disease. Control over stress operates via a neural circuit that includes the ventromedial prefrontal cortex (vmPFC). In published and pilot studies we have established that control over stress increases the intrinsic excitability of the vmPFC and propose to test here the role of endogenous cannabinoids (eCBs) in this phenomenon. eCBs are known to alter vmPFC excitability by modulation of local inhibitory interneurons. Our working hypothesis that the experience of control over stress triggers eCB release which blunts activity of GABAergic interneurons within the vmPFC leading to stress resilience. This project incorporates a study of sex differences in stress coping mechanisms, which will help fill the massive gap in our understanding of stress and resilience in women. In a set of discovery experiments we seek to quantify eCB levels in the vmPFC after controllable or uncontrollable stress using LC-MS/MS and quantify prefrontal GABAergic inhibitory activity using acute slice electrophysiology and immunuohistochemistry. The prediction is that controllable stress elevates eCBs, reduces GABAergic synaptic transmission and GABAergic neuronal activation. In mechanistic studies we will knock down or elevate vmPFC eCBs by targeting the eCB degredation enzymes using a combination of viral overexpression and pharmacology. By combining these manipulations with exposure to controllable or uncontrollable stress we can determine whether eCBs are necessary and sufficient for stress resilience in later behavioral tests of social anxiety and fear.