Hippocampal Dysfunction Prolongs Stress Responses in Leptin Receptor Mutant Mice

描述(由申请人提供)：2型(胰岛素抵抗)糖尿病患者的抑郁和焦虑率更高。糖尿病与临床抑郁症患病率的增加有关。糖尿病患者大脑结构的变化发生在对压力相关的情绪障碍也很敏感的颞叶回路中。糖尿病患者表现出海马区萎缩，特别是在齿状回亚区，海马区萎缩与这一人群的记忆和情绪调节变化有关。鉴于海马区活动在适当终止下丘脑-垂体-肾上腺轴(HPA轴)对应激反应中的作用已被证实，在胰岛素抵抗个体中，海马区功能受损与HPA轴调节失调之间可能存在某种机制联系。该方案中的研究旨在确定，在肥胖和胰岛素抵抗的遗传性小鼠模型中，海马体萎缩是否会抑制HPA轴，启动糖皮质激素介导的突触损伤循环。我们将使用瘦素受体突变小鼠(db/db小鼠)来测试这个模型，这些小鼠患有肥胖和糖尿病，表现出高水平的皮质酮，这是啮齿动物的主要糖皮质激素。海马脑源性神经营养因子(BDNF)的表达显著减少，我们有初步数据表明，db/db小鼠肾上腺皮质对应激反应的负反馈受到损害。我们计划使用慢病毒来操纵BDNF的表达，以确定海马神经营养因子表达变化对HPA轴负反馈的网络影响。我们将在化学鉴定的神经元群体中测量神经激活的标记物，以评估在束缚应激后，沿着介导HPA轴关闭的回路的招募。这些针对瘦素受体缺陷小鼠的研究可以阐明人类人群中糖尿病和抑郁症并存的相关机制。

DESCRIPTION (provided by applicant): Rates of depression and anxiety are greater among individuals with type 2 (insulin resistant) diabetes. Diabetes is associated with an increased prevalence of clinical depression. Changes in brain structure in diabetes occur within temporal lobe circuits that are also sensitive to stress-related mood disorders. Diabetics exhibit hippocampal atrophy, particularly in the dentate gyrus subfield, and hippocampal atrophy is associated with changes in memory and mood regulation in this population. Given the established role of hippocampal activity in appropriate termination of the hypothalamic-pituitary-adrenal axis (HPA axis) response to stress, it is likely that there is some mechanistic relationship between impairment of hippocampal function and HPA axis dysregulation in insulin resistant individuals. The studies in this proposal are designed to determine whether hippocampal atrophy disinhibits the HPA axis, initiating a cycle of glucocorticoid- mediated synaptic impairment in a genetic mouse model of obesity and insulin resistance. We will test this model using leptin receptor mutant mice (db/db mice), which are obese and diabetic and exhibit elevated levels of corticosterone, the primary glucocorticoid in rodents. Hippocampal brain-derived neurotrophic factor (BDNF) expression is significantly reduced and we have preliminary data demonstrating that negative feedback on the adrenocortical response to stress is impaired in db/db mice. We plan to manipulate BDNF expression using a lentivirus to determine the network consequences of alterations in hippocampal neurotrophic factor expression for HPA axis negative feedback. We will measure markers of neural activation in chemically identified neuronal populations to evaluate recruitment along the circuitry mediating HPA axis shutoff after restraint stress. These studies in leptin receptor deficient mice could elucidate mechanisms related to the comorbidity between diabetes and depression in human populations.