Department of Physiology, College of Basic Medical Sciences, Jilin University, Xinmin Street No. 126, Changchun, 130021, People's Republic of China.
Department of Rehabilitation Medicine, First Hospital of Jilin University, Changchun, 130021, People's Republic of China.
Eur Arch Psychiatry Clin Neurosci. 2024 Jun;274(4):867-878. doi: 10.1007/s00406-023-01743-2. Epub 2024 Jan 18.
A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHb-VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHb-VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHb-VTA axons. Conversely, optogenetic inhibition of the LHb-VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.
许多不同的受体分布在外侧缰核（LHb）的谷氨酸能神经元中。这些谷氨酸能神经元参与不同的神经通路，这可能确定 LHb 如何调节各种生理功能。然而，向腹侧被盖区（VTA）投射的表达多巴胺 D1 受体（D1R）的缰核神经元（LHb-VTA）的作用仍不清楚。在目前的研究中，为了确定 LHb 中表达 D1R 的神经元的活动，使用 D1R-Cre 小鼠建立了慢性束缚应激（CRS）抑郁模型。腺相关病毒被注射到 D1R-Cre 小鼠的双侧 LHb 中，以检查光遗传学激活 LHb 中的 D1R 表达神经元及其投射是否会诱导抑郁样行为。光纤分别植入 LHb 和 VTA。为了研究光遗传学抑制 LHb-VTA 回路是否能产生抗抑郁样效果，在 D1R-Cre CRS 模型中，将腺相关病毒注射到双侧 LHb 中，并将光纤植入双侧 VTA。CRS 抑郁模型中 LHb 中的 D1R 表达神经元活动增加。LHb 中 D1R 表达神经元的光遗传学激活诱导了行为绝望和快感缺失，这也可以通过激活 LHb-VTA 轴突来诱导。相反，LHb-VTA 回路的光遗传学抑制改善了 CRS 抑郁模型中的行为绝望和快感缺失。LHb 中的 D1R 表达谷氨酸能神经元及其投射到 VTA 的神经元参与了抑郁样行为的发生和调节。
