Decreased CNS leptin activity in co-morbid depression and obesity

这项提案的首要目标是证明肥胖诱导的神经炎症， 中缝核减少5-羟色胺合成从而降低海马5-羟色胺水平， 从而为肥胖症中的共病抑郁症提供神经化学机制。 与一般成年人相比，VA人群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。肥胖症的并发症扩展到中枢神经系统（CNS），包括 神经精神共病如抑郁症的风险增加。可惜这些 流行病学研究不能确定这种合并症的神经化学机制。临床 研究提供了一些关于这个未回答的问题的见解，因为肥胖的人更有可能 与非5-羟色胺选择性摄取抑制剂（SSRIs）相比， 肥胖的人肥胖的特征是慢性轻度炎症和神经炎症， 被认为是导致共病肥胖症中β-肾上腺素能活性降低的原因， 萧条尽管取得了这些进展，但仍有几个关键问题有待解决：1） 肥胖者中缝核神经炎症增加？2)中缝核神经炎症 减少中缝核中5-羟色胺（5-HT）的合成，从而减少海马5-HT 水平？和3）我们是否可以确定治疗策略来逆转这些变化和/或容易获得 生物标志物驱动这种并发症？ 脑内5-HT水平的降低被认为是脑缺血的发病机制中的一个关键因素。 抑郁症有趣的是，我们正在进行的研究表明，海马5-HT水平是 在肥胖大鼠中显著降低，从而通过以下途径提供潜在的神经化学机制： 肥胖会增加神经精神疾病的风险。因为中缝核是 中缝核的神经炎症可能是脑内5-HT合成的关键部位， 神经化学缺陷导致肥胖者患抑郁症。鉴于这些意见， 该建议的假设是中缝核中的瘦素抵抗降低了海马 5-羟色胺外排，从而提供了一个神经化学机制，共病抑郁症， 肥胖这一假设将在以下目标中得到检验。 目的1将确定中缝核中的神经炎症是否减少5-HT合成， 肥胖雄性和雌性啮齿动物海马中的SSRI反应。 目标2将确定是否生活方式的干预是一致的VA移动！重量 管理计划可以逆转肥胖引起的神经炎症，5-HT缺陷和抑郁症， 就像肥胖大鼠的行为一样。 总的来说，这些研究将确定中缝核神经炎症的场所和神经化学 肥胖者共病抑郁症的发病机制最重要的是，我们的研究将 为MOVE的重要性提供了进一步的证据！特别是当它涉及到 肥胖退伍军人神经精神健康改善。

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.