Delineating neural circuitry of STress REsilience and Stress Susceptibility using DREADD combined with fMRI technique (STRESS-DREADD)

抑郁症已成为导致疾病致残的第二大原因，有3亿人受到影响。抑郁症导致的自杀是15-29岁青少年的第二大死因。长期的压力暴露极大地增加了抑郁的风险。然而，人们应对严重压力的方式存在一定程度的个体差异，从脆弱到韧性不等。由于目前没有一种抗抑郁药物对50%以上的患者有效，精神病学的一个新前沿可能是诱导自然的弹性机制来治疗抑郁症。我们的目的是从目前尚未被探索的纵向角度来理解应激恢复现象，即研究应激前后的大脑，以便将恢复能力和易感性的特征和状态依赖的标志分离出来，并将适应不良反应与适应前反应分开。了解是什么使个体对压力的有害影响更具抵抗力，可能会为治疗方法的发展提供新的途径。一旦我们知道了识别弹性和敏感性的关键区域和投影，我们的目标是通过化学遗传学刺激/抑制这些大脑投影，以找出它是否在应激敏感大鼠中诱导应激弹性，反之亦然。我们将使用慢性轻度应激模型进行纵向研究，慢性轻度应激模型是最真实和广泛验证的抑郁症动物模型之一，并将使用高场功能磁共振成像(FMRI)来识别：(1)大脑成像的弹性和易感性易感性的内表型，即特征标记(无应激环境)，(2)状态依赖的弹性和易感性的内表型(应激后)。接下来，我们将使用高场fMRI和最近开发的由设计者药物独家激活的设计者受体(DREADD)技术的尖端组合，通过实验探讨关键区域和投射的焦点调制对识别应激和敏感性的影响，以找出这种操作是否会导致应激敏感大鼠应激弹性的成像内表型和行为特征，反之亦然。

Depression has become the second leading cause of illness-induced disability with 300 million people affected. Suicide due to depression is the second leading cause of death in 15-29-year-olds. Chronic stress exposure greatly raises depression risk. However, there is a degree of inter-individual variation in the way people respond to severe stress, with a spectrum ranging from vulnerability to resilience. Since no current antidepressant is effective for more than 50% of patients, a new frontier in psychiatry could be an induction of natural mechanisms of resilience to treat depression. Our aim is to understand the phenomenon of stress resilience in currently non-explored longitudinal perspective, i.e. to study brain before and after stress in order to separate trait and state-dependent markers of resilience and susceptibility, and also to separate maladaptive from pro-adaptive stress response. The understanding of what makes individuals more resistant to the deleterious effects of stress could suggest new path for the development of treatments. Once we know the key regions and projections discerning resilience and susceptibility, we aim to chemogenetically excite/inhibit these brain projections to find out whether it induces stress resilience in stress-susceptible rats, and vice versa.We will perform a longitudinal study using chronic mild stress model, one of the most realistic and extensively validated animal models of depression, and will use high-field functional magnetic resonance imaging (fMRI) to identify: (1) brain imaging endophenotypes of predisposition to resilience and susceptibility, i.e. trait markers (stress-free environment), (2) state-dependent endophenotypes of resilience and susceptibility (post-stress). Next, we will use a cutting-edge combination of high-field fMRI and a recently developed Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technique, to experimentally probe the effects of focal modulation of key regions and projections discerning resilience and susceptibility, in order to find out whether this manipulation would result in imaging endophenotype and behavior characteristic for stress resilience in stress-susceptible rats, and vice versa.