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: 6992638
• 负责人: KEBRETEN F MANAYE
• 金额: $ 7.42万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6992638
• 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.

大量阿尔茨海默病 (AD) 患者表现出抑郁症状。这种共病对这些人的生活质量特别不利。这些疾病的病因和影响的中枢通路是深入研究的主题。尽管抑郁症的动物模型已经出现了一段时间，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）去甲肾上腺素能细胞显着损失。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）可能在下丘脑-垂体肾上腺轴的调节中发挥重要作用。该轴由促肾上腺皮质激素释放激素驱动 在 AD 和抑郁症中，PVN 中含有 CRH（CRH）和加压素（VP）的细胞均受到损害。该提案的一个主要目标是研究这些小鼠的抑郁特征。此外，将在光和电子显微镜（EM）水平上研究去甲肾上腺素能神经末梢和含有CRH和VP的PVN细胞之间的突触连接。推测：1）双转基因小鼠会表现出抑郁行为； 2）老年dtg小鼠的抑郁症状会加重； 3) 在dtg小鼠的PVN中将观察到含有CRH和VP的神经元数量减少； 4)在dtg小鼠中，去甲肾上腺素能末端与含有PVN神经元的CRH和VP之间的突触接触数量减少。将使用年轻、成年和老年dtg小鼠及其野生型对照。 Porsolt强迫游泳测试和悬尾测试将用于评估抑郁症 特征。免疫细胞化学与体视学相结合将用于在光和电磁水平上量化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 伴随表达的回路的理解。这些知识可以更好地干预这种毁灭性的共病。