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

抑郁症已成为疾病导致残疾的第二大原因，有3亿人受到影响。抑郁症导致的自杀是15-29岁人群死亡的第二大原因。长期的压力暴露会大大增加患抑郁症的风险。然而，人们应对严重压力的方式存在一定程度的个体差异，其范围从脆弱到恢复。由于目前没有一种抗抑郁药对50%以上的患者有效，精神病学的一个新前沿可能是诱导抗抑郁的自然机制来治疗抑郁症。我们的目标是从目前尚未探索的纵向视角来理解应激恢复现象，即研究应激前后的大脑，以分离应激恢复和易感性的特征和状态依赖标记，并区分适应不良和适应不良的应激反应。了解是什么使个体对压力的有害影响更有抵抗力，可能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易感性的关键区域和预测，我们的目标是化学上激发/抑制这些大脑预测，以找出它是否诱导应激易感大鼠的应激恢复，反之亦然。我们将使用最现实和最广泛验证的抑郁症动物模型之一慢性轻度应激模型进行纵向研究，并将使用高场功能磁共振成像（fMRI）来确定：(1)大脑成像对恢复力和易感性的易感性，即特征标记（无压力环境）；(2)状态依赖的恢复力和易感性的内表型（应激后）。接下来，我们将采用尖端的高场功能磁共振成像技术和最新开发的设计药物特异性激活设计受体（DREADD）技术，实验探索识别弹性和易感性的关键区域和投影的焦点调节的影响，以了解这种操作是否会导致应激易感大鼠的成像内表型和应激恢复的行为特征，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.