Division of Systems Neuroscience, Department of Psychiatry, Columbia University and Research Foundation for Mental Hygiene, Inc., New York State Psychiatric Institute, New York, New York.
Alzheimer's Center at Temple, Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Biol Psychiatry. 2024 Apr 15;95(8):800-809. doi: 10.1016/j.biopsych.2023.10.007. Epub 2023 Oct 18.
Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HTR) is a G protein-coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HTRs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined.
We exposed male and female mice expressing 5-HTRs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HTR agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HTRs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior.
We found that activating 5-HTRs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HTR activation rescued stress-induced vDG hyperactivity. Moreover, 5-HTR activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test.
Our findings show that activating 5-HTRs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.
腹侧齿状回（vDG）颗粒细胞的过度活跃会增加对慢性应激的易感性。然而，vDG 中哪些受体可以被靶向以抑制这种过度活跃并赋予应激弹性尚不清楚。5-羟色胺 1A 受体（5-HTR）是一种 G 蛋白偶联抑制受体，与应激适应、焦虑、抑郁和抗抑郁反应有关。5-HTRs 在 DG 中高度表达，但它们通过调节颗粒细胞活性促进应激弹性的潜力尚未被研究过。
我们使仅在 DG 颗粒细胞中表达 5-HTR 的雄性和雌性小鼠暴露于 10 天的慢性社交挫败应激（CSDS）中，并在整个 CSDS 范式中，每天在每次挫败前 30 分钟用 5-HTR 激动剂 8-OH-DPAT 治疗。然后，我们使用全细胞电流钳记录、即时早期基因 cFos 的免疫组织化学、皮质酮免疫测定和行为测试来确定激活颗粒细胞上的 5-HTRs 如何影响 DG 活动、神经内分泌应激反应和回避行为。
我们发现，激活 5-HTRs 使 DG 颗粒细胞超极化，并减少 CSDS 后 vDG 中的 cFos+颗粒细胞，表明 5-HTR 激活挽救了应激诱导的 vDG 过度活跃。此外，5-HTR 激活抑制了 CSDS 对皮质酮的反应，并防止了社交互动测试和开阔场测试中应激诱导的回避的发展。
我们的发现表明，激活 DG 颗粒细胞上的 5-HTRs 可以防止应激诱导的 vDG 神经元过度活跃，并赋予对慢性应激的弹性。
