Neural activity within the ventromedial prefrontal cortex (vmPFC) is a critical determinant of stressor-induced anxiety. Pharmacological activation of the vmPFC during stress protects against stress-induced social anxiety suggesting that altering the excitatory/inhibitory (E/I) tone in the vmPFC may promote stress resilience. E/I balance is maintained, in part, by endogenous cannabinoid (eCB) signaling with the calcium dependent retrograde release of 2-arachidonoylglycerol (2-AG) suppressing presynaptic neurotransmitter release. We hypothesized that raising 2-AG levels, via inhibition of its degradation enzyme monoacylglycerol lipase (MAGL) with KML29, would shift vmPFC E/I balance and promote resilience. In acute slice experiments, bath application of KML29 (100 nM) augmented evoked excitatory neurotransmission as evidenced by a left-shift in fEPSP I/O curve, and decreased sIPSC amplitude. In whole-cell recordings, KML29 increased resting membrane potential but reduced the after depolarization, bursting rate, membrane time constant and slow after hyperpolarization. Intra-vmPFC administration of KML29 (200ng/0.5μL/hemisphere) prior to inescapable stress (IS) exposure (25, 5s tail shocks) prevented stress induced anxiety as measured by juvenile social exploration 24 h after stressor exposure. Conversely, systemic administration of KML29 (40 mg/kg, i.p.) 2 h before IS exacerbated stress induced anxiety. MAGL inhibition in the vmPFC may promote resilience by augmenting the output of neurons that project to brainstem and limbic structures that mediate stress responses.

中文翻译：

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单酰基甘油脂肪酶α抑制作用改变前额叶皮层兴奋性，并钝化大鼠创伤性应激的后果。

腹侧前额叶皮层（vmPFC）内的神经活动是应激源性焦虑的关键决定因素。应激期间vmPFC的药理激活可以防止应激引起的社交焦虑，这表明，改变vmPFC中的兴奋性/抑制性（E / I）调性可以促进应激弹性。E / I平衡部分通过内源性大麻素（eCB）信号与2花生四烯酰甘油（2-AG）的钙依赖性逆行释放来抑制突触前神经递质释放来维持。我们假设通过用KML29抑制2-AG降解酶单酰基甘油脂肪酶（MAGL）来提高2-AG的水平，将改变vmPFC E / I平衡并增强弹性。在急性切片实验中 洗澡应用KML29（100 nM）会增加诱发的兴奋性神经传递，这可以通过fEPSP I / O曲线的左移和sIPSC振幅的降低来证明。在全细胞记录中，KML29增加了静息膜电位，但降低了去极化后的细胞数量，爆发率，膜时间常数以及超极化后的速度。暴露于无法避免的压力（IS）（25，5s尾巴电击）之前，对KML29（200ng /0.5μL/半球）进行vmPFC内给药可预防应激诱发的焦虑，这是通过在应激源暴露24小时后进行的青少年社会探索而得出的。相反，在IS发作前2小时全身性给予KML29（40 mg / kg，ip）可以加剧压力引起的焦虑。vmPFC中的MAGL抑制可能通过增加投射到介导应激反应的脑干和边缘结构的神经元的输出来促进弹性。