Neuromodulation Laboratory, School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Department of Biological Sciences, Sunway University, Bandar Sunway, Petaling Jaya 47500, Malaysia.
Cells. 2023 May 23;12(11):1449. doi: 10.3390/cells12111449.
High-frequency stimulation (HFS) is a promising therapy for patients with depression. However, the mechanisms underlying the HFS-induced antidepressant-like effects on susceptibility and resilience to depressive-like behaviors remain obscure. Given that dopaminergic neurotransmission has been found to be disrupted in depression, we investigated the dopamine(DA)-dependent mechanism of the antidepressant-like effects of HFS of the prelimbic cortex (HFS PrL). We performed HFS PrL in a rat model of mild chronic unpredictable stress (CUS) together with 6-hydroxydopamine lesioning in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA). Animals were assessed for anxiety, anhedonia, and behavioral despair. We also examined levels of corticosterone, hippocampal neurotransmitters, neuroplasticity-related proteins, and morphological changes in dopaminergic neurons. We found 54.3% of CUS animals exhibited decreased sucrose consumption and were designated as CUS-susceptible, while the others were designated CUS-resilient. HFS PrL in both the CUS-susceptible and CUS-resilient animals significantly increased hedonia, reduced anxiety, decreased forced swim immobility, enhanced hippocampal DA and serotonin levels, and reduced corticosterone levels when compared with the respective sham groups. The hedonic-like effects were abolished in both DRN- and VTA-lesioned groups, suggesting the effects of HFS PrL are DA-dependent. Interestingly, VTA-lesioned sham animals had increased anxiety and forced swim immobility, which was reversed by HFS PrL. The VTA-lesioned HFS PrL animals also had elevated DA levels, and reduced p-p38 MAPK and NF-κB levels when compared to VTA-lesioned sham animals. These findings suggest that HFS PrL in stressed animals leads to profound antidepressant-like responses possibly through both DA-dependent and -independent mechanisms.
高频刺激（HFS）是一种有前途的治疗抑郁症患者的方法。然而，高频刺激诱导抗抑郁样效应的机制尚不清楚。鉴于多巴胺能神经传递在抑郁症中被发现受到干扰，我们研究了高频刺激前额皮质（HFS PrL）的抗抑郁样效应的多巴胺（DA）依赖性机制。我们在轻度慢性不可预测应激（CUS）大鼠模型中进行了 HFS PrL，同时进行了中缝背核（DRN）和腹侧被盖区（VTA）的 6-羟多巴胺损伤。对动物进行焦虑、快感缺失和行为绝望评估。我们还检查了皮质酮、海马神经递质、神经可塑性相关蛋白和多巴胺能神经元的形态变化。我们发现 54.3%的 CUS 动物表现出蔗糖消耗减少，被指定为 CUS 易感动物，而其余动物被指定为 CUS 抗性动物。HFS PrL 可显著增加 CUS 易感和 CUS 抗性动物的快感，减少焦虑，减少强迫游泳不动，增强海马 DA 和 5-羟色胺水平，并降低皮质酮水平，与各自的假手术组相比。DRN 和 VTA 损伤组的快感样效应被消除，表明 HFS PrL 的作用是依赖于 DA 的。有趣的是，VTA 损伤的假手术动物表现出焦虑和强迫游泳不动增加，而 HFS PrL 则逆转了这种情况。与 VTA 损伤的假手术动物相比，VTA 损伤的 HFS PrL 动物的 DA 水平升高，p-p38 MAPK 和 NF-κB 水平降低。这些发现表明，应激动物的 HFS PrL 可能通过依赖和不依赖 DA 的机制导致深刻的抗抑郁样反应。
