Novel Prophylactic and Therapeutic Interventions for Stress-Induced Depression

 描述（由申请人提供）： 这项MERIT审查拨款申请的总体目标是将多酚作为潜在的预防剂和治疗剂用于退伍军人抑郁症。拟议的研究对退伍军人群体具有重要意义，因为大约30%的退伍军人，特别是来自持久自由行动/伊拉克自由行动的退伍军人，受到情绪焦虑症，特别是抑郁症的影响。我们最近确定了一种安全且耐受性良好的生物活性多酚制剂，可有效地将多种（我们确定的16种）生物可利用的多酚代谢物输送到大脑。此外，我们发现，口服补充这种制剂显着促进抑郁症/焦虑表型的反复社交失败压力（RSDS）抑郁症小鼠模型的恢复力。中脑核（NAc）中棘神经元（MSN）的突触可塑性异常在应激相关抑郁/焦虑的发生发展中起着关键作用。我们提出的研究旨在确定选择多酚代谢物，可以保持突触可塑性在体外的原代NAc MSN富集的文化和在体内的RSDS模型。我们的证据表明，在NAc MSN中Rac 1（一种控制肌动蛋白重塑的GTP酶相关蛋白）的下调是抑郁症/焦虑症中异常突触重塑的核心，并且对抑郁症/焦虑症的恢复力也可能通过兴奋性VGLUT 2的衰减和/或抑制性VGAT MSN突触机制的促进而增强。基于这一证据，在拟议的研究中，我们将首先筛选单个多酚代谢物在MSN富集培养物中调节Rac 1、VGLUT 2和VGAT的体外剂量反应生物活性。基于体外筛选的结果，我们将优先考虑三种最具生物活性的候选物，并使用多酚前体作为能够将鉴定的代谢物递送至大脑的潜在“前药”进行体内剂量探索研究。根据这一结果， 通过一系列研究，我们将确定多酚前体的最低安全有效剂量，其浓度足以与NAc中的分子靶标（例如Rac 1）结合。在疗效研究中，我们将测试这些脑生物可利用的生物活性代谢物通过前体传递是否可以通过使NAc中的应激诱导的病理性神经可塑性重塑和功能性电生理变化正常化来促进对应激诱导的抑郁/焦虑表型的恢复。总的来说，我们提出的研究结果将确定新的预防和治疗药物，可以预防和逆转慢性压力导致的适应不良行为反应。拟议的研究还将提供多酚对应激介导的抑郁症的有益作用的新机制。拟议的研究将为安全多酚“前药”的转化应用提供动力，以促进对压力相关疾病的心理恢复力，包括退伍军人的抑郁症和焦虑症。

 DESCRIPTION (provided by applicant): The overall goal of this MERIT review grant application is to characterize polyphenols as potential prophylactic as well as therapeutic agents in veterans with depression. The proposed studies have important implications for the veteran population since approximately 30% of veterans, in particular those from Operation Enduring Freedom/Operation Iraqi Freedom, are affected by mood anxiety disorders, especially depression. We recently identified a safe and well-tolerated bioactive polyphenol preparation effective in delivering multiple (16 that we identified) bioavailable polyphenol metabolites to the brain. Moreover, we found that oral supplementation with this preparation significantly promotes resilience to depression/anxiety phenotypes in the repeated social defeat stress (RSDS) mouse model of depression. Synaptic plasticity abnormalities in nucleus accumbens (NAc) medium spiny neurons (MSN) play a key role in the development of stress-related depression/anxiety. Our proposed studies are designed to identify select polyphenol metabolites that can preserve synaptic plasticity in vitro i primary NAc MSN-enriched cultures and in vivo in the RSDS model. Our evidence indicates that down-regulation of Rac1 (a GTPase-related protein that controls actin remodeling) in NAc MSNs is central to aberrant synaptic remodeling in depression/anxiety, and that resilience to depression/anxiety may also be augmented by attenuation of excitatory VGLUT2 and/or promotion of inhibitory VGAT MSN synaptic mechanisms. Based on this evidence, in the proposed studies, we will first screen individual polyphenol metabolites for their in vitro dose-response bioactivities in modulating Rac1, VGLUT2, and VGAT in MSN- enriched cultures. Based on the outcomes of the in vitro screening, we will then prioritize the three most bioactive candidates and conduct dose-finding studies in vivo using polyphenol precursors as potential "pro- drugs" able to deliver the identified metabolites to the brain. Based on the outcomes of this set of studies, we will identify the lowest safe and efficacious doses of polyphenol precursors with sufficient concentration to engage the molecular targets (e.g. Rac1) in the NAc. In efficacy studies, we will then test whether these brain bioavailable bioactive metabolites delivered through precursors may promote resilience to stress-induced depression/anxiety phenotypes by normalizing stress-induced pathological neuroplasticity remodeling and functional electrophysiological changes in the NAc. Collectively, the outcomes from our proposed studies will identify novel prophylactic as well as therapeutic agents that can prevent and reverse the maladaptive behavioral responses that result from chronic stress. The proposed studies will also provide novel mechanisms underlying the beneficial role of polyphenols on stress-mediated depression. The proposed studies will provide the impetus for translational application of safe polyphenol "pro-drugs" to promote psychological resilience to stress-related conditions, including depression and anxiety disorders in veterans.