Université Côte d'Azur, Nice, 06560, France.
Institut de Pharmacologie Moléculaire & Cellulaire, CNRS, UMR7275, Valbonne, France.
Nat Commun. 2018 Oct 25;9(1):4449. doi: 10.1038/s41467-018-06809-7.
Stressful life events are primary environmental factors that markedly contribute to depression by triggering brain cellular maladaptations. Dysregulation of ventral tegmental area (VTA) dopamine neurons has been causally linked to the appearance of social withdrawal and anhedonia, two classical manifestations of depression. However, the relevant inputs that shape these dopamine signals remain largely unknown. We demonstrate that chronic social defeat (CSD) stress, a preclinical paradigm of depression, causes marked hyperactivity of laterodorsal tegmentum (LDTg) excitatory neurons that project to the VTA. Selective chemogenetic-mediated inhibition of cholinergic LDTg neurons prevent CSD-induced VTA DA neurons dysregulation and depressive-like behaviors. Pro-depressant outcomes are replicated by pairing activation of LDTg cholinergic terminals in the VTA with a moderate stress. Prevention of CSD outcomes are recapitulated by blocking corticotropin-releasing factor receptor 1 within the LDTg. These data uncover a neuro-circuitry of depressive-like disorders and demonstrate that stress, via a neuroendocrine signal, profoundly dysregulates the LDTg.
生活压力事件是主要的环境因素，通过触发大脑细胞适应不良，显著导致抑郁。腹侧被盖区（VTA）多巴胺神经元的失调与社会退缩和快感缺失的出现有关，这是两种典型的抑郁表现。然而，塑造这些多巴胺信号的相关输入在很大程度上仍是未知的。我们证明，慢性社会挫败（CSD）应激，一种抑郁的临床前范例，导致投射到 VTA 的外侧脑桥背核（LDTg）兴奋性神经元的显著过度活跃。选择性化学遗传介导的 LDTg 胆碱能神经元抑制可防止 CSD 诱导的 VTA DA 神经元失调和抑郁样行为。将 VTA 中的 LDTg 胆碱能末梢的激活与适度应激相结合，可复制促抑郁的结果。在 LDTg 内阻断促肾上腺皮质激素释放因子受体 1 可重现预防 CSD 的结果。这些数据揭示了一种抑郁障碍的神经回路，并表明应激通过神经内分泌信号，严重扰乱了 LDTg。
