Department of Pharmacology, University of North Carolina at Chapel Hill, Thurston Bowles Building 104 Manning Drive, Chapel Hill, NC, 27599, USA.
Laboratory of Behavioral and Genomic Neuroscience, National Institute on Alcohol Abuse and Alcoholism, 5625 Fishers Lane Rockville, MD, 20852-9411, USA.
Neuropharmacology. 2018 Sep 1;139:68-75. doi: 10.1016/j.neuropharm.2018.06.032. Epub 2018 Jun 28.
Chronic stress contributes to the neuropathology of mental health disorders, including those associated with anxiety. The basolateral amygdala (BLA) coordinates emotional behavioral responses through glutamatergic outputs to downstream regions such as the prefrontal cortex (PFC), nucleus accumbens core (NAcc) and bed nucleus of the stria terminalis (BNST). We explored the effects of chronic stress on BLA outputs to the PFC, NAcc and BNST using slice electrophysiology combined with optogenetics in two inbred mouse strains with distinct stress-induced anxiety responses. We found that ten consecutive days of chronic restraint stress enhanced pre-synaptic glutamate release at BLA-to-PFC synapses in C57BL/6J mice, but reduced pre-synaptic glutamate release at these synapses in DBA/2J mice. To assess the behavioral relevance of enhanced glutamate output at BLA-to-PFC synapses, we approximated the effects of chronic stress on the BLA-PFC circuit using optogenetics. We found that photostimulation of the BLA-PFC circuit in unstressed C57BL/6J mice produced persistent (i.e., post-stimulation) increased anxiety-like behavior and hyperactivity in the elevated plus-maze - a profile consistent with prototypical behavioral responses of stressed C57BL/6J mice. These data demonstrate that chronic stress dysregulates the BLA-PFC circuit by altering pre-synaptic glutamate release from BLA outputs, and provide a mechanism by which chronic stress can lead to increased anxiety.
慢性应激会导致心理健康障碍的神经病理学，包括与焦虑相关的障碍。基底外侧杏仁核（BLA）通过谷氨酸能输出与下游区域（如前额叶皮层（PFC）、伏隔核核心（NAcc）和终纹床核（BNST））协调情绪行为反应。我们使用切片电生理学结合光遗传学，在两种具有不同应激诱导焦虑反应的近交系小鼠中，研究了慢性应激对 BLA 输出到 PFC、NAcc 和 BNST 的影响。我们发现，连续 10 天的慢性束缚应激增强了 C57BL/6J 小鼠 BLA 到 PFC 突触的前突触谷氨酸释放，但减少了 DBA/2J 小鼠这些突触的前突触谷氨酸释放。为了评估 BLA 到 PFC 突触谷氨酸输出增强的行为相关性，我们使用光遗传学来近似慢性应激对 BLA-PFC 回路的影响。我们发现，在未受应激的 C57BL/6J 小鼠中，光刺激 BLA-PFC 回路会产生持久的（即刺激后）焦虑样行为和高架十字迷宫中的过度活跃——这一特征与应激 C57BL/6J 小鼠的典型行为反应一致。这些数据表明，慢性应激通过改变 BLA 输出的前突触谷氨酸释放来调节 BLA-PFC 回路，并提供了慢性应激导致焦虑增加的一种机制。
