Exposure to prolonged stress is a major risk-factor for psychiatric disorders such as generalized anxiety and major depressive disorder. Human imaging studies have identified structural and functional abnormalities in the prefrontal cortex of subjects with depression and anxiety disorders, particularly Brodmann's area 25 (BA25). Further, deep brain stimulation of BA25 reduces symptoms of treatment-resistant depression. The rat homolog of BA25 is the infralimbic cortex (IL), which is critical for cognitive appraisal, executive function, and physiological stress reactivity. Previous studies indicate that the IL undergoes stress-induced changes in excitatory/inhibitory balance culminating in reduced activity of glutamate output neurons. However, the regulatory role of IL glutamate output in mood-related behaviors after chronic variable stress (CVS) is unknown. Here, we utilized a lentiviral-packaged small-interfering RNA to reduce translation of vesicular glutamate transporter 1 (vGluT1 siRNA), thereby constraining IL glutamate output. This viral-mediated gene transfer was used in conjunction with a quantitative anatomical analysis of cells expressing the stable immediate-early gene product FosB/ΔFosB, which accumulates in response to repeated neural activation. Through assessment of FosB/ΔFosB-expressing neurons across the frontal lobe in adult male rats, we mapped regions altered by chronic stress and determined the coordinating role of the IL in frontal cortical plasticity. Specifically, CVS-exposed rats had increased density of FosB/ΔFosB-expressing cells in the IL and decreased density in the insula. The latter effect was dependent on IL glutamate output. Next, we examined the interaction of CVS and reduced IL glutamate output in behavioral assays examining coping, anxiety-like behavior, associative learning, and nociception. IL glutamate knockdown decreased immobility during the forced swim test compared to GFP controls, both in rats exposed to CVS as well as rats without previous stress exposure. Further, vGluT1 siRNA prevented CVS-induced avoidance behaviors, while also reducing risk aversion and passive coping. Ultimately, this study identifies the necessity of IL glutamatergic output for regulating frontal cortical neural activity and behavior following chronic stress. These findings also highlight how disruption of excitatory/inhibitory balance within specific frontal cortical cell populations may impact neurobehavioral adaptation and lead to stress-related disorders.

长时间承受压力是精神疾病（如广泛性焦虑症和严重抑郁症）的主要危险因素。人体成像研究已经确定了患有抑郁症和焦虑症的受试者的前额叶皮层的结构和功能异常，尤其是布罗德曼氏区25（BA25）。此外，深层脑刺激BA25可以减轻难治性抑郁症的症状。BA25的大鼠同源物是下肢皮质（IL），这对于认知评估，执行功能和生理应激反应性至关重要。先前的研究表明，IL经历应激诱导的兴奋性/抑制性平衡变化，最终导致谷氨酸输出神经元活性降低。然而，IL谷氨酸输出在慢性可变压力（CVS）后情绪相关行为中的调节作用尚不清楚。在这里，我们利用慢病毒包装的小干扰RNA来减少水泡谷氨酸转运蛋白1（vGluT1 siRNA）的翻译，从而限制IL谷氨酸的输出。此病毒介导的基因转移与表达稳定的早期早期基因产物FosB /ΔFosB的细胞的定量解剖分析结合使用，该产物可响应反复的神经激活而积累。通过评估成年雄性大鼠额叶中表达FosB /ΔFosB的神经元，我们绘制了慢性应激改变的区域，并确定了IL在额叶皮层可塑性中的协调作用。特别，暴露于CVS的大鼠的IL中表达FosB /ΔFosB的细胞密度增加，而岛中的密度降低。后一种效应取决于IL谷氨酸输出。接下来，我们在行为测试中检查了应对，焦虑样行为，联想学习和伤害感受的行为分析，从而研究了CVS与IL谷氨酸输出减少的相互作用。与GFP对照相比，无论是在暴露于CVS的大鼠中还是未经历过应激暴露的大鼠中，IL谷氨酸敲低都降低了其与GFP对照相比的固定性。此外，vGluT1 siRNA阻止了CVS诱导的回避行为，同时还减少了风险规避和被动应对。最终，该研究确定了IL谷氨酸能输出在慢性应激后调节额叶皮质神经活动和行为的必要性。