压力应激韧性的神经机制

The neural mechanisms of resilience

抑郁症是最常见的精神疾病之一,其患病人群在不断增长.并且,抑郁症的终生患病率为15%~18%,即大约每5人中就有一个人在其一生中经历过抑郁发作.压力应激作为一种环境因素是抑郁症的主要成因之一.经历了压力应激却没有发展至抑郁症的人群具有压力应激韧性(resilience).探索压力应激韧性的神经机制,对抑郁症在临床上预防和治疗将发挥至关重要的作用.本文主要关注压力应激韧性的神经机制的研究进展,首先简要介绍了压力应激韧性研究中常用的慢性社交挫败应激模型(chronic social defeat stress,CSDS),其次重点对压力应激韧性相关的大脑区域在分子、细胞和神经环路水平上的研究进展进行总结,接下来介绍压力应激韧性的临床前机制研究所带来的临床转化,最后讨论和展望压力应激韧性在未来的研究方向.

Major depressive disorder(MDD)is one of the most common neuropsychiatric disorders,affecting approximately 280 million people worldwide.Furthermore,the lifetime prevalence of MDD is approximately 20%.Individuals suffering from MDD are unable to experience a normal life and often have suicide ideation,which becomes a major threat to themselves and significant burden to their families and society.Moreover,the development of new therapeutic drugs is lagging behind.Roughly 50%of patients with depression fail to respond to first-line antidepressant therapy.Thus,it is essential to identify innovative therapeutic targets based on research into the etiology and pathology of depression.Stress,as an environmental risk factor,is a major cause of depression.Compared to the individuals who are sensitive to stress and prone to develop depression(susceptible),most individuals are capable of adapting well and being resilient to avoid depression(resilient).As a result,studying the mechanism of resilience provides a new avenue for finding new treatment strategies.Indeed,resilience to depression has attracted an increasing number of researchers,leading to significant advances in understanding resilience mechanisms.The main purpose of this review article is to summarize the development of resilience investigations in four parts.The first is an introduction to the chronic social defeat stress(CSDS)model,which has been widely used in research on stress resilience in rodents.Depressive-like behaviors such as social avoidance and anhedonia can be induced by CSDS.And chronic treatment of typical antidepressants and acute treatment of ketamine normalize these aberrant behaviors seen in CSDS model.The model is also used to segregate the socially defeated animals into susceptible and resilient subgroups.Second,we show how the brain nuclei involved in stress resilience influence resilient phenotype at the molecular,cellular and circuit levels.These brain regions are mainly the ventral tegmental area(VTA),nucleus accumbens(NAc),locus coeruleus(LC),medial prefrontal cortex(mPFC),amygdala,hippocampus,lateral septum(LS)and primary auditory cortex(A1).Third,we present the clinical translation based on promising preclinical results concerning the KCNQ subtype of K+channels and HCN channels(mediating Ih current).KCNQ plays a critical role in stress resilience by maintaining the balanced excitability of dopaminergic neurons in the VTA.Ezogabine is a KCNQ opener approved by the FDA for the treatment of epilepsy.In clinical trials,ezogabine has shown significant efficacy in the treatment of depression.And HCN is another promising candidate target for new depression therapy.HCN inhibitor cilobradine(also called DK-AH 269)decreases the firing activity of VTA dopaminergic neurons and rescues depressionlike behaviors in susceptible animals.Finally,we discuss the general animal models used in stress research,neural circuit mechanism of resilience and future research directions in the light of the information stated above.