Neural mechanism of acute stress regulation by trace aminergic signalling in the lateral habenula in male mice

Stress management is necessary for vertebrate survival. Chronic stress drives depression by excitation of the lateral habenula (LHb), which silences dopaminergic neurons in the ventral tegmental area (VTA) via GABAergic neuronal projection from the rostromedial tegmental nucleus (RMTg). However, the effect of acute stress on this LHb-RMTg-VTA pathway is not clearly understood. Here, we used fluorescent in situ hybridisation and in vivo electrophysiology in mice to show that LHb aromatic L-amino acid decarboxylase-expressing neurons (D-neurons) are activated by acute stressors and suppress RMTg GABAergic neurons via trace aminergic signalling, thus activating VTA dopaminergic neurons. We show that the LHb regulates RMTg GABAergic neurons biphasically under acute stress. This study, carried out on male mice, has elucidated a molecular mechanism in the efferent LHb-RMTg-VTA pathway whereby trace aminergic signalling enables the brain to manage acute stress by preventing the hypoactivity of VTA dopaminergic neurons.

应激管理对于脊椎动物的生存不可或缺。慢性应激通过激活外侧缰核（lateral habenula, LHb）诱发抑郁，后者经由被盖吻内侧核（rostromedial tegmental nucleus, RMTg）发出的γ-氨基丁酸能（GABAergic）神经元投射，抑制腹侧被盖区（ventral tegmental area, VTA）内的多巴胺能神经元。然而，急性应激对该LHb-RMTg-VTA通路的影响尚未明确。
本研究以小鼠为实验对象，采用荧光原位杂交与在体电生理技术，证实外侧缰核内表达芳香族L-氨基酸脱羧酶的神经元（简称D神经元）可被急性应激激活，并通过痕量胺能信号通路抑制被盖吻内侧核的γ-氨基丁酸能神经元，进而激活腹侧被盖区的多巴胺能神经元。研究发现，外侧缰核在急性应激状态下对被盖吻内侧核的γ-氨基丁酸能神经元呈现双相调控作用。
本项基于雄性小鼠的研究阐明了传出性LHb-RMTg-VTA通路的分子机制：痕量胺能信号可通过阻止腹侧被盖区多巴胺能神经元的活动低下，帮助大脑实现急性应激的应对管理。