UMR 1253, iBrain, Université de Tours, Inserm, Tours, France; Department of Cell Biology, Medical Research Institute, Alexandria University, Egypt.
UMR 1253, iBrain, Université de Tours, Inserm, Tours, France.
Psychoneuroendocrinology. 2021 Feb;124:105097. doi: 10.1016/j.psyneuen.2020.105097. Epub 2020 Dec 1.
Major depressive disorder is a common debilitating mental health problem that represents one of the leading causes of disability. Up to date, the therapeutic targets and approaches are still limited. Adult hippocampal neurogenesis (AHN) has been proposed as a critical contributor to the pathophysiology and treatment of depression, altering the hippocampal control over stress response at network, neuroendocrine and behavioral levels. These findings together have suggested that manipulating AHN may be a promising therapeutic strategy for depression. To investigate this question, we assessed whether increasing adult neurogenesis would be sufficient to produce antidepressant-like effects at behavioral and neuroendocrine levels in a mouse model of depression; the unpredictable chronic mild stress (UCMS). For this purpose, we used a bi-transgenic mouse line (iBax) in which AHN increase was induced by deletion of the pro-apoptotic gene Bax from the neural progenitors following the tamoxifen-dependent action of CreERT2 recombinases. UCMS induced a syndrome that is reminiscent of depression-like states, including anhedonia (cookie test), physical changes (coat deterioration, reduced weight gain), anxiety-like behaviors (higher latency in the novelty-supressed feeding -NSF- test), passive stress-coping behaviors (immobility in the forced swim test -FST-) and a blunted hypothalamo-pituitary-adrenal (HPA) axis reactivity to acute stress in addition to AHN decrease. Tamoxifen injection reversed the AHN decrease as well as partly counteracted UCMS effects on the cookie test and HPA axis but not for the coat state, weight gain, NSF test and FST. Taken together, our results suggest that a strategy directing at increasing AHN may be able to alleviate some depression-related behavioral and neuroendocrine dimensions of UCMS, such as anhedonia and HPA axis reactivity deficits, but may be hardly sufficient to produce a complete recovery.
重度抑郁症是一种常见的使人衰弱的心理健康问题，也是导致残疾的主要原因之一。迄今为止，治疗靶点和方法仍然有限。成人海马神经发生 (AHN) 被认为是抑郁症病理生理学和治疗的关键因素，改变了海马对网络、神经内分泌和行为水平应激反应的控制。这些发现共同表明，操纵 AHN 可能是治疗抑郁症的一种有前途的策略。为了研究这个问题，我们评估了在慢性不可预测性轻度应激 (UCMS) 抑郁模型中，增加成年神经发生是否足以在行为和神经内分泌水平上产生抗抑郁样效应。为此，我们使用了一种双转基因小鼠系 (iBax)，其中神经祖细胞中的促凋亡基因 Bax 可通过 CreERT2 重组酶的他莫昔芬依赖性作用缺失，从而诱导 AHN 增加。UCMS 诱导的综合征类似于抑郁症状态，包括快感缺失 (饼干测试)、身体变化 (毛发恶化、体重增加减少)、焦虑样行为 (新奇抑制进食 -NSF- 测试中的潜伏期更高)、被动应激应对行为 (强迫游泳测试 -FST- 中的不动) 以及下丘脑-垂体-肾上腺 (HPA) 轴对急性应激的反应性降低，此外 AHN 也减少了。他莫昔芬注射逆转了 AHN 的减少，部分抵消了 UCMS 对饼干测试和 HPA 轴的影响，但对毛发状态、体重增加、NSF 测试和 FST 没有影响。综上所述，我们的结果表明，增加 AHN 的策略可能能够缓解 UCMS 与抑郁相关的一些行为和神经内分泌方面，例如快感缺失和 HPA 轴反应缺陷，但可能难以完全恢复。
