Hippocampal Dysfunction Prolongs Stress Responses in Leptin Receptor Mutant Mice

描述（由申请人提供）：抑郁和焦虑的比例在2型（胰岛素抵抗）糖尿病患者中更高。糖尿病与临床抑郁症的患病率增加有关。糖尿病患者大脑结构的变化发生在颞叶回路内，而颞叶回路对压力相关的情绪障碍也很敏感。糖尿病患者表现为海马萎缩，特别是在齿状回亚区，海马萎缩与该人群的记忆和情绪调节变化有关。鉴于海马活动在适当终止下丘脑-垂体-肾上腺轴（HPA轴）对应激的反应中所起的作用，在胰岛素抵抗个体中，海马功能损伤与HPA轴失调之间可能存在某种机制关系。本研究旨在确定在肥胖和胰岛素抵抗的遗传小鼠模型中，海马萎缩是否解除了HPA轴的抑制，从而启动了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）来测试该模型，这些小鼠患有肥胖和糖尿病，并且表现出高水平的皮质酮（啮齿动物的主要糖皮质激素）。海马脑源性神经营养因子（BDNF）表达显著降低，我们有初步数据表明，在db/db小鼠中，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操纵BDNF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标记物，以评估约束应激后沿通路介导HPA轴关闭的招募。在瘦素受体缺陷小鼠中进行的这些研究可以阐明人类糖尿病和抑郁症合并症的相关机制。

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.