DEPRESSION, ALZHEIMERS DISEASE AND SYNAPTIC CONNECTIVITY IN A TRANSGENIC MOUSE MO

大量阿尔茨海默病（AD）患者表现出抑郁症状。这种合并症对这些人的生活质量特别有害。这些疾病的病因和中枢通路是一个深入研究的课题。虽然抑郁症的动物模型已经有一段时间了，但直到最近才开发出AD的双转基因小鼠（dtg）模型。初步结果表明，这些小鼠的蓝斑（LC）中的去甲肾上腺素能细胞的显着损失。去甲肾上腺素途径也与抑郁行为有关。此外，LC投射到下丘脑室旁核（PVN）可能在调节下丘脑-垂体-肾上腺轴中起重要作用。这个轴由促肾上腺皮质激素释放激素驱动 (CRH)在AD和抑郁症中，PVN中含有血管加压素（VP）的细胞受损。这项提议的一个主要目标是研究这些小鼠的抑郁特征。此外，去甲肾上腺素能神经末梢和PVN细胞之间的突触连接含有CRH和VP将在光镜和电镜（EM）水平进行研究。假设：1）双转基因小鼠将表现出抑郁行为; 2）在老年dtg小鼠中抑郁症状将加重; 3）在dtg小鼠的PVN中将观察到含有CRH和VP的神经元的数量减少; 4）在dtg小鼠中将获得去甲肾上腺素能末梢与PVN的含有CRH和VP的神经元之间的突触接触的数量减少。将使用年轻、成年和老年dtg小鼠及其野生型对照。Porsolt强迫游泳试验和悬尾试验将用于评估抑郁症 特色将应用免疫细胞化学结合体视学在光和EM水平上定量特定细胞数量和突触。这些研究的结果将增强我们对可能参与抑郁症和AD伴随表达的电路的理解。这样的知识可以导致更好的干预，在这种毁灭性的共病条件。

A significant number of patients with Alzheimer's disease (AD) manifest depressive symptoms. This comorbid condition is exceptionally detrimental to quality of life in these individuals. The etiology and central pathways affected in these disorders is a subject of intense investigation. Although animal models of depression have been available for some time, only recently has a double transgenic mouse (dtg) model of AD been developed. Preliminary results indicate a significant loss of noradrenergic cells in the locus coeruleus (LC) of these mice. Noradrenergic pathways are also implicated in depressive behavior. Moreover, LC projection to the paraventricular nucleus (PVN) of the hypothalamus may play an important role in regulation of the hypothalamic-pituitary adrenal axis. This axis, driven by corticotropin-releasing hormone (CRH) and vasopressin (VP) containing cells in the PVN is impaired in both AD and depression. A major goal of this proposal is to investigate depressive characteristics in these mice. Moreover, synaptic connectivity between noradrenergic nerve terminals and PVN cells containing CRH and VP will be investigated at both light and electron microscopic (EM) level. It is hypothesized that: 1) the double transgenic mice will manifest depressive behavior; 2) the depressive symptoms will be exaggerated in the aged dtg mice; 3) a reduced number of CRH and VP containing neurons will be observed in the PVN of dtg mice; 4) a reduced number of synaptic contacts between noradrenergic terminals and CRH and VP containing neurons of PVN will be obtained in dtg mice. Young, adult and old dtg mice and their wild type control will be used. Porsolt forced swim test and tail suspension tests will be used to evaluate depressive characteristics. Immunocytochemistry combined with stereology will be applied to quantify specific cell number and synapses at both light and EM levels. Results from these studies will enhance our understanding of circuits that might be involved in concomitant expression of depression and AD. Such knowledge can lead to better interventions in this devastating comorbid condition.