Corticolimbic Somatostatin-Related Inhibitory Dysfunction in Major Depression

描述(申请人提供)：严重抑郁障碍(MDD)患者情绪调节改变和情绪低落状态被认为反映了受影响个体皮质边缘结构和功能的改变，涉及背外侧前额叶皮质(DLPFC)、亚膝前扣带回皮质(SgACC)和杏仁核。具体地说，低GABA相关抑制可能是杏仁核对情绪显著刺激的感知和传递不足的基础，以及sgACC对这种传递的信息与较高的DLPFC处理的整合不足的基础。然而，这些提议的主要细胞和分子证据很少。我们现在已经发现，在MDD受试者的DLPFC、sgACC和杏仁核中，生长抑素(SST)选择性下调，生长抑素是一种在GABA神经元亚群中表达的抑制性神经肽。在队列中证实了低SST，受影响的女性受试者更强烈，并且与疾病的严重程度中等相关。在微电路水平上，SST GABA神经元靶向于锥体神经元的远侧树突，但不同的SST神经元亚群表现出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，次优的SST功能可能会引发细胞和分子的适应不良变化，导致情绪调节改变和情绪低落状态，这些变化将为未来新疗法的发展提供指导。因此，为了研究SST在情绪调节中的作用，我们将首先表征MDD受试者死后大脑(皮质层和杏仁核)变化的解剖学和微回路特异性(目标1)。然后，我们将在啮齿动物模型中测试“低SST风险因素”假说，并预测低SST(杂合突变)的小鼠在不可预测的慢性温和应激(目标2)后，将显示出更容易出现高度焦虑/抑郁样行为(定义为“情绪性”)。最后，我们将使用在SST中间神经元亚型(S)中表达绿色荧光蛋白的小鼠，该亚型与MDD中受影响的亚型最接近，以研究低SST和压力相关的细胞特异性适应不良分子变化(目标3)。综上所述，MDD的低SST为研究疾病的机制提供了细胞和分子线索，并为MDD的生物学障碍(神经网络功能障碍和GABA相关功能降低)的最重要假说之间提供了潜在的分子联系。然而，SST还承担着几种中枢和外周功能，而药物操作具有多种副作用，因此有必要确定SST GABA神经元中不适应的分子变化，作为潜在的表型介体，并作为未来旨在减轻MDD负担的新疗法的研究和开发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.