Decreased CNS leptin activity in co-morbid depression and obesity

这项提案的首要目标是证明肥胖引起的神经炎症 中缝核减少了5-羟色胺的合成，从而降低了海马5-羟色胺水平， 从而为肥胖中的共病抑郁疾病提供了神经化学机制。 与普通成年人相比，退伍军人中肥胖的发生率更高 美国人口，目前的估计表明，超过80%的退伍军人可能被归类为肥胖 或者超重。肥胖的并发症会延伸到中枢神经系统(CNS)，包括 患抑郁症等神经精神疾病共病的风险增加。不幸的是，这些 流行病学研究无法确定这种共病的神经化学机制。临床 研究为这个悬而未决的问题提供了一些见解，因为肥胖的人更有可能 与非5-羟色胺选择性摄取抑制剂(SSRI)相比，表现出治疗耐药性 肥胖的人。肥胖的特征是慢性轻度炎症，而神经性炎症 被认为是共病肥胖和肥胖患者5-羟色胺能活动减少的原因 抑郁症。尽管取得了这些进展，但仍有几个关键问题有待解决：1)是 肥胖患者中缝核区神经炎症增加？2)中缝核区神经炎症 减少中缝核内5-羟色胺的合成，从而降低海马5-羟色胺 级别？以及3)我们能否确定逆转这些变化和/或易于获得的治疗策略 导致这种共病的生物标记物？ 脑内5-羟色胺水平的降低被认为是高血压发病的关键因素。 抑郁症。有趣的是，我们正在进行的研究表明，海马5-羟色胺水平 在肥胖大鼠中显著减少，从而提供了一种潜在的神经化学机制 肥胖会增加患神经精神疾病的风险。因为中缝核是主要的位置 脑内5-羟色胺的合成，中缝核内的神经炎症可能是脑内5-羟色胺合成的关键部位 导致肥胖症患者抑郁的神经化学缺陷。鉴于这些观察结果， 这一建议的假设是，中缝核内的瘦素抵抗会降低海马区 5-羟色胺外流，从而为抑郁症的共病提供了一种神经化学机制 肥胖。这一假设将在以下目标中得到检验。 目标1将确定中缝核的神经炎症是否会减少5-羟色胺的合成和 肥胖雄性和雌性啮齿动物海马区的SSRI反应。 Aim 2将决定与退伍军人管理局一致的生活方式干预措施是否会发生变化！重量 管理计划可以逆转肥胖引发的神经炎症、5-羟色胺缺乏和抑郁- 肥胖大鼠的类似行为。 总而言之，这些研究将确定中缝核神经炎症为神经化学物质和神经化学物质。 肥胖者伴发抑郁疾病的机制。最重要的是，我们的学习将 为这一举措的重要性提供进一步的证据！计划，特别是当它与 改善肥胖退伍军人的神经精神健康。

The overarching goal of this proposal is to demonstrate obesity-induced neuroinflammation in the raphe nucleus decreases serotonin synthesis which decreases hippocampal serotonin levels, thereby providing a neurochemical mechanism for co-morbid depressive illness in obesity. The incidence of obesity is greater in the VA population when compared with the general adult US population, with current estimates suggesting that over 80% of Veterans may be classified as obese or overweight. The complications of obesity extend to the central nervous system (CNS) and include an increased risk of developing neuropsychiatric co-morbidities like depressive illness. Unfortunately, these epidemiological studies cannot determine the neurochemical mechanism for this comorbidity. Clinical studies provide some insight into this unanswered question in that obese individuals are more likely to exhibit treatment resistance to serotonin selective uptake inhibitors (SSRIs) when compared to non- obese individuals. Obesity is characterized by chronic mild inflammation and neuroinflammation has been proposed to be responsible for decreases in serotonergic activity in co-morbid obesity and depression. In spite of these advances, several critical questions remain to be addressed: 1) is neuroinflammation increased in the raphe nucleus in obesity?; 2) does raphe nucleus neuroinflammation decrease serotonin (5-HT) synthesis in the raphe nucleus and thereby decrease hippocampal 5-HT levels? and 3) can we identify treatment strategies to reverse these changes and/or readily accessible biomarkers that drive this comorbidity? Decreases in brain 5-HT levels are proposed to be a critical factor in the pathogenesis of depressive illness. Interestingly, our ongoing studies suggest that hippocampal 5-HT levels are significantly reduced in obese rats, thereby providing a potential neurochemical mechanism through which obesity increases the risk of neuropsychiatric disorders. As the raphe nucleus is the primary site of synthesis of 5-HT in the brain, neuroinflammation in the raphe nucleus may be a critical site for the neurochemical deficits that drive depressive illness in obesity. In view of these observations, the hypothesis of this proposal is that leptin resistance in the raphe nucleus decreases hippocampal 5-HT efflux, thereby providing a neurochemical mechanism for comorbid depressive illness in obesity. This hypothesis will be tested in the following Aims.  Aim 1 will determine whether neuroinflammation in the raphe nucleus decreases 5-HT synthesis and SSRI responses in the hippocampus of obese male and female rodents.  Aim 2 will determine whether lifestyle interventions that are consistent with the VA MOVE! weight management program can reverse obesity-induced neuroinflammation, 5-HT deficits and depressive- like behaviors in obese rats. Collectively, these studies will identify raphe nucleus neuroinflammation as the locus and neurochemical mechanism for comorbid depressive illness in obese individuals. Most importantly, our studies will provide further evidence for the importance of the MOVE! Program, particularly as it relates to the improvement of neuropsychiatric health of obese Veterans.