The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.
Department of Neurology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Nat Commun. 2023 Apr 5;14(1):1880. doi: 10.1038/s41467-023-37601-x.
Major depressive disorder ranks as a major burden of disease worldwide, yet the current antidepressant medications are limited by frequent non-responsiveness and significant side effects. The lateral septum (LS) is thought to control of depression, however, the cellular and circuit substrates are largely unknown. Here, we identified a subpopulation of LS GABAergic adenosine A receptors (AR)-positive neurons mediating depressive symptoms via direct projects to the lateral habenula (LHb) and the dorsomedial hypothalamus (DMH). Activation of AR in the LS augmented the spiking frequency of AR-positive neurons leading to a decreased activation of surrounding neurons and the bi-directional manipulation of LS-AR activity demonstrated that LS-ARs are necessary and sufficient to trigger depressive phenotypes. Thus, the optogenetic modulation (stimulation or inhibition) of LS-AR-positive neuronal activity or LS-AR-positive neurons projection terminals to the LHb or DMH, phenocopied depressive behaviors. Moreover, AR are upregulated in the LS in two male mouse models of repeated stress-induced depression. This identification that aberrantly increased AR signaling in the LS is a critical upstream regulator of repeated stress-induced depressive-like behaviors provides a neurophysiological and circuit-based justification of the antidepressant potential of AR antagonists, prompting their clinical translation.
重度抑郁症是全球范围内的主要疾病负担之一，但目前的抗抑郁药物存在频繁的无反应和明显的副作用等局限性。外侧隔核（LS）被认为可以控制抑郁，但细胞和回路的基质在很大程度上还不清楚。在这里，我们通过直接投射到外侧缰核（LHb）和背内侧下丘脑（DMH），鉴定了 LS 中 GABA 能腺苷 A 受体（AR）阳性神经元亚群来介导抑郁症状。LS 中的 AR 激活增加了 AR 阳性神经元的放电频率，导致周围神经元的激活减少，LS-AR 活性的双向操纵表明 LS-AR 是触发抑郁表型所必需且充分的。因此，LS-AR 阳性神经元活性或 LS-AR 阳性神经元投射末梢至 LHb 或 DMH 的光遗传学调节（刺激或抑制）可模拟抑郁行为。此外，在两种雄性小鼠的重复应激诱导抑郁模型中，LS 中的 AR 上调。这一发现表明 LS 中异常增加的 AR 信号是重复应激诱导的类似抑郁样行为的关键上游调节剂，为 AR 拮抗剂的抗抑郁潜力提供了神经生理和基于回路的依据，促使它们进行临床转化。
