Cavalleri Laura, Dassieni Irene, Marcotto Giulia Sofia, Zoli Michele, Merlo Pich Emilio, Collo Ginetta
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
Department of Biomedical, Metabolic and Neural Sciences, Center for Neuroscience and Neurotechnology, University of Modena and Reggio Emilia, Modena, Italy.
Neurosci Appl. 2024 Feb 14;3:104049. doi: 10.1016/j.nsa.2024.104049. eCollection 2024.
Impaired neuroplasticity in neurons endowed in limbic circuits is considered a hallmark of chronic stress and depression. The reasons for this impairment are still partially unclear, but converging findings suggest that it can be reverted by exposure to rapid-acting antidepressants. In this study we revamped the hypothesis that the abnormal high circulating levels of cortisol observed in Major Depressive Disorders with anhedonia may contribute to drive the limbic circuit neuroplasticity impairment. Here we used an established in-vitro translational model based on human iPSC-derived dopaminergic neurons to extend the evidence obtained in rodents of glucocorticoid-induced hypotrophy of cortical dendrites. The predictive value of this model was tested by assessing the reversal potential of rapid-acting antidepressants on cortisol-induced hypotrophy. Human mesencephalic dopaminergic neurons were differentiated in-vitro from healthy donor iPSCs for 60-70 days. Cortisol effects were assessed by measuring maximal dendrite length, primary dendrite number and soma area 3 days after last exposure. Concentration- and time-response curves were initially established. Cortisol produced a concentration- and time-dependent reduction of dendritic arborization of human dopaminergic neurons, with maximal effects at 50 μM for 4-day dosing. These effects were reverted when followed by 1-hr exposure to ketamine or (2R,6R)-hydroxynorketamine at concentrations of 0.01 μM and 0.05 μM, respectively, resulting approximately 10- or 100-fold lower than those effective in neurons not exposed to cortisol. Overall, in this study high cortisol impaired dendritic arborization in human dopaminergic neurons and sensitized their neuroplasticity response to very low doses of rapid-acting antidepressants known to upregulate AMPA-mediated glutamatergic neurotransmission.
边缘回路中的神经元神经可塑性受损被认为是慢性应激和抑郁症的一个标志。这种损伤的原因仍部分不明，但越来越多的研究结果表明，暴露于速效抗抑郁药可以使其恢复。在本研究中，我们重新提出了一个假设，即在伴有快感缺失的重度抑郁症中观察到的异常高循环皮质醇水平可能导致边缘回路神经可塑性损伤。在这里，我们使用了一个基于人诱导多能干细胞衍生的多巴胺能神经元建立的体外转化模型，以扩展在啮齿动物中获得的糖皮质激素诱导皮质树突萎缩的证据。通过评估速效抗抑郁药对皮质醇诱导的萎缩的逆转潜力来测试该模型的预测价值。人脑中脑多巴胺能神经元从健康供体诱导多能干细胞体外分化60 - 70天。在最后一次暴露3天后，通过测量最大树突长度、初级树突数量和胞体面积来评估皮质醇的作用。最初建立浓度和时间反应曲线。皮质醇导致人多巴胺能神经元树突分支的浓度和时间依赖性减少，在50 μM剂量4天时效果最大。当分别在0.01 μM和0.05 μM浓度下暴露于氯胺酮或(2R,6R)-羟基去甲氯胺酮1小时后，这些作用得到逆转，其有效浓度分别比未暴露于皮质醇的神经元低约10倍或100倍。总体而言，在本研究中，高皮质醇损害了人多巴胺能神经元的树突分支，并使其神经可塑性反应对已知可上调AMPA介导的谷氨酸能神经传递的极低剂量速效抗抑郁药敏感。
