Corticolimbic Somatostatin-Related Inhibitory Dysfunction in Major Depression

描述（由申请人提供）：重度抑郁症（MDD）中的情绪调节改变和情绪低落状态被认为反映了受影响个体中皮质边缘结构和功能的改变，并涉及背外侧前额叶皮层（DLPFC）、膝下前扣带皮层（sgACC）和杏仁核。具体地说，低GABA相关抑制可能是杏仁核对情绪突出刺激的感知和中继不足以及sgACC对这种中继信息的整合不足的基础，而sgACC具有更高的DLPFC处理。然而，这些建议的主要细胞和分子证据很少。我们现在已经确定了生长抑素（SST）的选择性下调，抑制性神经肽表达的GABA神经元的一个子集，在DLPFC，sgACC和杏仁核的MDD受试者。在各队列中证实了低SST，对女性受试者的影响更大，并且与疾病的严重程度中度相关。在微电路水平，SST GABA神经元靶向锥体神经元的远端树突，但SST神经元的不同子集显示不同的解剖定位和生理特性，可能介导不同的信息处理。总之，这导致我们假设特定皮质层和杏仁核中的低SST水平是MDD的关键风险因素，并且其他因素决定了疾病的严重程度。因此，我们进一步假设，在具有挑战性的条件下，次优SST功能可能引发细胞和分子适应不良的变化，导致情绪调节改变和情绪低落状态，这些变化将为未来开发新的治疗方法提供线索。因此，为了研究SST在情绪调节中的贡献，我们将首先表征MDD受试者的人类死后大脑（皮层和杏仁核）中变化的解剖学和微电路特异性（目的1）。然后，我们将在啮齿动物模型中测试“低SST风险因子”假设，并预测具有低SST（杂合突变体）的小鼠在不可预测的慢性轻度应激后将表现出发展高度焦虑样/抑郁样行为（定义为“情绪性”）的增加的脆弱性（目的2）。最后，我们将使用在SST中间神经元亚型中表达绿色荧光蛋白的小鼠，其最接近于MDD中受影响的亚型，以研究低SST和应激相关的细胞特异性适应不良分子变化（目的3）。总之，MDD中的低SST为研究疾病机制提供了细胞和分子线索，以及MDD生物学紊乱（神经网络功能障碍和GABA相关功能降低）的最重要假设之间的潜在分子联系。然而，SST还承担了几个中枢和外周功能，药理学操作具有多种（副）作用，因此必须确定SST GABA神经元中的适应不良分子变化，作为表型的潜在介质，以及作为未来研究和开发旨在减轻MDD负担的新疗法的新的和潜在的选择性靶点。

DESCRIPTION (provided by applicant): Altered emotion regulation and low mood states in major depressive disorder (MDD) are thought to reflect altered corticolimbic structure and function in affected individuals, and involve the dorsolateral prefrontal cortex (DLPFC), the subgenual anterior cingulate cortex (sgACC) and the amygdala. Specifically, low GABA-related inhibition may underlie inadequate sensing and relaying of emotionally-salient stimuli by the amygdala and deficient integration of this relayed information by the sgACC with higher DLPFC processing. However, primary cellular and molecular evidence for these proposals are sparse. We have now identified a selective downregulation of somatostatin (SST), an inhibitory neuropeptide expressed in a subset of GABA neurons, in the DLPFC, sgACC and amygdala of subjects with MDD. Low SST was confirmed across cohorts, affected female subjects more robustly, and moderately correlated with the severity of the illness. At the microcircuitry level, SST GABA neurons target the distal dendrites of pyramidal neurons, but different subsets of SST neurons display different anatomical localizations and physiological properties, potentially mediating different information processing. Together, this lead us to hypothesize that low SST levels in specific cortical layers and amygdala nuclei are critical risk factors for MDD, and that additional factors determine the severity of the illness. Accordingly, we further hypothesize that, under challenging conditions, suboptimal SST function may trigger cellular and molecular maladaptive changes that lead to altered emotion regulation and low mood states, changes that will provide leads for the future development of novel therapeutics. Hence, to investigate the contribution of SST in mood regulation, we will first characterize the anatomical and microcircuitry specificity of changes in the human postmortem brains of MDD subjects (cortical layer & amygdala nuclei) (Aim 1). We will then test the "low SST - risk factor" hypothesis in a rodent model, and predict that mice with low SST (heterozygous mutant) will display increased vulnerability to develop high anxiety-like/depressive-like behaviors (defined as "emotionality") after unpredictable chronic mild stress (Aim 2). Finally, we will use mice expressing green fluorescent protein in the SST interneuron subtype(s), which most closely corresponds to the subtype affected in MDD, to investigate low SST- and stress-associated cell-specific maladaptive molecular changes (Aim 3). In summary, low SST in MDD provide a cellular and molecular lead to investigate mechanisms of the illness, and a potential molecular link between foremost hypotheses for biological disturbances in MDD (neural network dysfunction and reduced GABA-related function). However, SST also assumes several central and peripheral functions, and pharmacological manipulation has multiple (side-)effects, so it is essential to identify maladaptive molecular changes in SST GABA neurons, as potential mediators of the phenotype and as novel and potentially selective targets for the future investigation and development of novel therapeutics aimed at relieving the burden of MDD.