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

转基因小鼠模型中的抑郁症、阿尔茨海默病和突触连接

• 批准号: 7062411
• 负责人: KEBRETEN F MANAYE
• 金额: $ 7.54万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7062411
• 关键词: Alzheimer' s disease; aging; behavior test; behavioral /social science research tag; comorbidity; corticotropin releasing factor; depression; electron microscopy; genetically modified animals; immunocytochemistry; laboratory mouse; light microscopy; minority institution research support; neuroanatomy; neurobiology; neuropsychology; neuroregulation; norepinephrine; paraventricular nucleus; sign /symptom; synapses; vasopressins

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.

相当数量的阿尔茨海默病(AD)患者表现出抑郁症状。这种并存的情况对这些人的生活质量特别有害。这些疾病的病因学和中枢通路是一个深入研究的主题。虽然抑郁症的动物模型已经存在一段时间了，但直到最近才发展出双转基因小鼠(Dtg)的AD模型。初步结果表明，这些小鼠的蓝斑(LC)内去甲肾上腺素能细胞显著减少。去甲肾上腺素能通路也与抑郁行为有关。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。这个轴是由促肾上腺皮质激素释放激素驱动的 阿尔茨海默病和抑郁症患者室旁核内含有促肾上腺皮质激素释放激素和加压素的细胞均受损。这项建议的一个主要目标是研究这些小鼠的抑郁特征。此外，还将在光镜和电子显微镜水平上研究去甲肾上腺素能神经末梢与含CRH和VP的PVN细胞之间的突触连接。假设：1)双转基因小鼠将表现出抑郁行为；2)抑郁症状在老龄dtg小鼠中会被夸大；3)在dtg小鼠的PVN中，含有CRH和VP的神经元将减少；4)去甲肾上腺素能终末与PVN中的CRH和VP神经元的突触接触将减少。将使用幼年、成年和老年dtg小鼠及其野生型对照。将使用Porsolt强迫游泳试验和尾部悬挂试验来评估抑郁 特点。免疫细胞化学结合体视学将被应用于在光和EM水平上对特定细胞数量和突触进行量化。这些研究的结果将加强我们对可能涉及抑郁症和AD伴随表达的回路的理解。这些知识可以导致在这种毁灭性的并存状况下进行更好的干预。