Luscher Bernhard, Jiang Tong, Feng Mengyang, Hutsell Alexander
Pennsylvania State University.
Res Sq. 2024 Jul 11:rs.3.rs-4408723. doi: 10.21203/rs.3.rs-4408723/v1.
Clinical and preclinical studies have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, disinhibition of SST neurons in mice results in resilience to the behavioral effects of chronic stress. Here we established a low-dose chronic chemogenetic protocol to map these changes in positively and negatively motivated behaviors to specific brain regions. AAV-hM3Dq mediated chronic activation of SST neurons in the prelimbic cortex (PLC) had antidepressant drug-like effects on anxiety- and anhedonia-related motivated behaviors in male but not female mice. Analogous manipulation of the ventral hippocampus (vHPC) had such effects in female but not male mice. Moreover, activation of SST neurons in the PLC of male and the vHPC of female mice resulted in stress resilience. Activation of SST neurons in the PLC reversed prior chronic stress-induced defects in motivated behavior in males but was ineffective in females. Conversely, activation of SST neurons in the vHPC reversed chronic stress-induced behavioral alterations in females but not males. Quantitation of c-Fos and FosB neurons in chronic stress-exposed mice revealed that chronic activation of SST neurons leads to a paradoxical increase in pyramidal cell activity. Collectively, these data demonstrate that GABAergic microcircuits driven by dendrite targeting interneurons enable sex- and brain-region-specific neural plasticity that promotes stress resilience and reverses stress-induced anxiety- and anhedonia-like motivated behavior. Our studies provide a mechanistic rationale for antidepressant efficacy of dendrite-targeting, low-potency GABA receptor agonists, independent of sex and despite striking sex differences in the relevant brain substrates.
临床和临床前研究已确定生长抑素（SST）阳性中间神经元是调节对与应激相关的精神疾病易感性的关键因素。相反，小鼠中SST神经元的去抑制会导致对慢性应激行为影响的恢复力。在这里，我们建立了一种低剂量慢性化学遗传学方案，以将这些正向和负向动机行为的变化映射到特定脑区。腺相关病毒-hM3Dq介导的前边缘皮质（PLC）中SST神经元的慢性激活对雄性而非雌性小鼠的焦虑和快感缺失相关动机行为具有类抗抑郁药物作用。对腹侧海马（vHPC）的类似操作在雌性而非雄性小鼠中产生了此类作用。此外，雄性小鼠PLC和雌性小鼠vHPC中SST神经元的激活导致应激恢复力。PLC中SST神经元的激活逆转了雄性先前慢性应激诱导的动机行为缺陷，但对雌性无效。相反，vHPC中SST神经元的激活逆转了雌性而非雄性慢性应激诱导的行为改变。对慢性应激暴露小鼠中c-Fos和FosB神经元的定量分析表明，SST神经元的慢性激活导致锥体细胞活性出现反常增加。总体而言，这些数据表明，由树突靶向中间神经元驱动的GABA能微电路实现了性别和脑区特异性神经可塑性，从而促进应激恢复力并逆转应激诱导的焦虑和快感缺失样动机行为。我们的研究为树突靶向、低效GABA受体激动剂的抗抑郁疗效提供了机制依据，该疗效与性别无关，尽管相关脑基质存在显著的性别差异。
