Department of Pharmacology, College of Pharmacy, China Pharmaceutical University, 639 Longmian Road, Jiangning District, Nanjing 211198, China.
Cereb Cortex. 2024 Oct 3;34(10). doi: 10.1093/cercor/bhae399.
Behavioral despair is one of the clinical manifestations of major depressive disorder and an important cause of disability and death. However, the neural circuit mechanisms underlying behavioral despair are poorly understood. In a well-established chronic behavioral despair (CBD) mouse model, using a combination of viral tracing, in vivo fiber photometry, chemogenetic and optogenetic manipulations, in vitro electrophysiology, pharmacological profiling techniques, and behavioral tests, we investigated the neural circuit mechanisms in regulating behavioral despair. Here, we found that CBD enhanced CaMKIIα neuronal excitability in the dorsal dentate gyrus (dDG) and dDGCaMKIIα neurons involved in regulating behavioral despair in CBD mice. Besides, dDGCaMKIIα neurons received 5-HT inputs from median raphe nucleus (MRN) and were mediated by 5-HT1A receptors, whereas MRN5-HT neurons received CaMKIIα inputs from lateral hypothalamic (LH) and were mediated by AMPA receptors to regulate behavioral despair. Furthermore, fluvoxamine exerted its role in resisting behavioral despair through the LH-MRN-dDG circuit. These findings suggest that a previously unidentified circuit of LHCaMKIIα-MRN5-HT-dDGCaMKIIα mediates behavioral despair induced by CBD. Furthermore, these support the important role of AMPA receptors in MRN and 5-HT1A receptors in dDG that might be the potential targets for treatment of behavioral despair, and explain the neural circuit mechanism of fluvoxamine-resistant behavioral despair.
行为绝望是重性抑郁障碍的临床表现之一，也是导致残疾和死亡的重要原因。然而，行为绝望的神经回路机制仍不清楚。在一个成熟的慢性行为绝望（CBD）小鼠模型中，我们结合病毒追踪、活体光纤光度测定、化学遗传学和光遗传学操作、体外电生理学、药理学分析技术和行为测试，研究了调节行为绝望的神经回路机制。在这里，我们发现 CBD 增强了背齿状回（dDG）中 CaMKIIα 神经元的兴奋性，dDGCaMKIIα 神经元参与调节 CBD 小鼠的行为绝望。此外，dDGCaMKIIα 神经元接收来自中缝核（MRN）的 5-HT 输入，并由 5-HT1A 受体介导，而 MRN5-HT 神经元接收来自下丘脑外侧区（LH）的 CaMKIIα 输入，并由 AMPA 受体介导，以调节行为绝望。此外，氟伏沙明通过 LH-MRN-dDG 回路发挥其抵抗行为绝望的作用。这些发现表明，一个以前未被识别的 LHCaMKIIα-MRN5-HT-dDGCaMKIIα 回路介导了 CBD 诱导的行为绝望。此外，这些研究支持了 AMPA 受体在 MRN 中的重要作用和 5-HT1A 受体在 dDG 中的作用，这可能是治疗行为绝望的潜在靶点，并解释了氟伏沙明抵抗行为绝望的神经回路机制。
