Stressor controllability, resilience and prefrontal endocannabinoids

摘要 控制应激源的开始、抵消或强度的能力是 确定应激源的生理和心理后果。跨物种，控制 压力导致韧性，而无法控制的压力源使人容易患上精神疾病。控制 压力通过包括腹内侧额叶皮质(VmPFC)在内的神经回路起作用。在已出版的和 初步研究证实，对压力的控制增加了vmPFC的内在兴奋性，并 建议在这里测试内源性大麻素(ECB)在这一现象中的作用。众所周知，欧洲央行 通过调节局部抑制性中间神经元改变vmPFC的兴奋性。我们的工作假设是 控制压力的经验触发ECB释放，从而钝化体内GABA能中间神经元的活动 VmPFC导致压力恢复能力。该项目结合了一项关于应对压力的性别差异的研究。 这将有助于填补我们在了解妇女的压力和复原力方面的巨大差距。在一个 一组发现实验，我们寻求在可控或不可控之后量化vmPFC中的ECB水平 LC-MS/MS分析应激反应及急性切片定量前额叶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能神经元激活。在力学研究中，我们将 通过使用病毒组合靶向ECB脱氢酶来击倒或提升vmPFC ECB 过度表达和药理学。通过将这些操作与暴露在可控或可控的 无法控制的压力我们可以在以后确定ECB对于压力恢复是否是必要的和充分的 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.