Stress Mechanisms Increasing Risk of Mood-Disorders

 描述(申请人提供)：华盛顿大学的Silvio O.Conte中心的设计有一个特定的目标，即了解压力暴露如何加剧抑郁症状，并增加脆弱个体抑郁发作的风险。临床经验已经在无节制的压力暴露史和情绪障碍风险之间建立了强烈的相互作用，但压力介质如何在大脑功能中产生持久的变化，从而导致抑郁症状尚不清楚。基于对这些机制的新见解的新疗法有可能增强这一脆弱群体的压力弹性。该中心的研究目的旨在了解1)反复应激后释放的强啡肽如何在小鼠引起与应激性焦虑症有关的厌恶效应；2)中缝背核(DRN)调节腹侧被盖区(VTA)多巴胺能系统的5-羟色胺能输入如何影响神经元的兴奋性，并因反复的社会挫败应激暴露而改变；3)应激暴露如何改变DRN 5-羟色胺能神经元的基因表达；4)重复应激如何改变CRF对投射到伏核(NAC)的VTA神经元释放多巴胺的调节。这些在小鼠身上的研究将结合使用转基因Cre驱动系、条件性基因失活、光遗传学和DREADD技术来选择性地调节已知在情绪调节中重要的DRN-&VTA-&NAC神经元回路的特定成分。这些研究将使用行为、电生理和快速扫描伏安法技术来测量由电路的不同组件介导的反应。将对雄性和雌性小鼠进行研究，以确定特定性别的反应。该中心将包括翻译研究，试图将老鼠研究与患有难治性抑郁症的女性的压力反应联系起来。支持这项临床研究的一个看似合理的假设是，影响外周血淋巴细胞基因表达的炎性介质也可能在大脑中扮演应激介质的角色。例如，细胞因子和强啡肽都调节5-羟色胺转运体的功能，而它们对神经元回路的影响之间的联系可能会提出新的治疗方法。UW-CONTE中心将以协调和协同的模式支持基础科学和临床研究，以及社区外联和培训任务。

 DESCRIPTION (provided by applicant): The Silvio O. Conte Center at the University of Washington is designed with a specific goal of understanding how stress-exposure can exacerbate depressive symptoms and increase the risk of a depressive episode in vulnerable individuals. Clinical experience has established a strong interaction between a history of unregulated stress exposure and the risk of mood disorders, but how the stress- mediators produce enduring changes in brain function that result in depressive symptoms is not clear. Novel therapeutics based on new insights to these mechanisms have the potential to enhance stress-resilience in this vulnerable population. The research aims of this Center are designed to understand 1) how the dynorphins, which are released in response to repeated stress, cause aversive effects in mice that have been suggested to be responsible for a component of stress-induced dysphoria in humans; 2) how the serotonergic inputs from the dorsal raphe nucleus (DRN) that regulate the dopaminergic system in the ventral tegmental area (VTA) affect neuronal excitability and are changed by repeated social defeat stress exposure; 3) how stress exposure alters gene expression in the serotonergic neurons of the DRN; and 4) how repeated stress exposure alters the regulation by CRF of the dopamine release by VTA neurons projecting to the nucleus accumbens (NAc). These studies in mice will combined the use of transgenic Cre driver lines, conditional gene inactivation, optogenetics, and DREADD techniques to selectively regulate specific components of the DRN-> VTA -> NAc neuronal circuit known to be important in mood regulation. The studies will use behavioral, electrophysiological and fast-scan voltammetry techniques to measure the responses mediated by the different components of the circuit. Both male and female mice will be studied to identify sex-specific responses. The Center will include translational studies that attempt to link the mouse studies to stress responses in Women with treatment-resistant depression. A plausible hypothesis underlying this clinical study component is that the inflammatory mediators affecting gene expression in peripheral blood lymphocytes may also be acting as stress-mediators in brain. For example, both cytokines and dynorphins regulate the serotonin transporter function, and a link between their effects on neuronal circuits may suggest novel therapeutic approaches. The UW-Conte Center will support basic science and clinical research, as well as community Outreach and Training missions in a coordinated and synergistic mode.