Wyoming Sensory Biology COBRE

怀俄明州感官生物学 COBRE

• 批准号: 10395258
• 负责人: Qian-Quan Sun
• 金额: $ 28.74万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10395258
• 关键词: Age; Aggressive behavior; Aging; Agitation; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Amyloid beta-Protein; Anatomy; Area; Behavior; Behavioral; Biology; Caregivers; Centers of Research Excellence; Circadian Dysregulation; Circadian Rhythms; Clinical; Delirium; Disease; Exhibits; Female; Gene Expression Profile; Genes; Hour; Hypothalamic structure; Immune; Inflammatory; Institutionalization; Lead; Light; Midbrain structure; Motor Activity; Mus; Neurobiology; Neurons; Pathology; Pathway interactions; Patients; Periodicity; Phase; Proteins; Quality of life; Rest; Resting Phase; Sensory; Sex Differences; Sleep; Sleep Disorders; Structure; Symptoms; Syndrome; System; Tissues; Transcript; Woman; Work; Wyoming; base; circadian; circadian pacemaker; circadian regulation; cytokine; experience; experimental study; inflammatory marker; male; men; mouse model; neuroinflammation; neuropathology; novel; parabrachial nucleus; postsynaptic; protein biomarkers; suprachiasmatic nucleus; tau aggregation; tau-1; tetra-4-amidinophenoxypropane; transcriptome sequencing; white matter

Abstract Women are much more likely than men to develop Alzheimer’s disease (AD) and related dementias, which are associated with progressive disruption of circadian rhythms. Additionally, women are more likely than men to develop circadian disorders, such as sleep disorders, and one particular feature of circadian dysfunction in patients with AD and related dementias is “sundowning syndrome”, a poorly understood clinical phenomenon characterized by agitation, aggression, and delirium during the early evening hours. Sundowing symptoms have a major impact on the quality of life for both the patient and their caregivers, who are also more likely to be women, and often lead to the decision to seek institutionalization. The neurobiology of sundowning remains unknown, however the temporal periodicity of sundowning symptoms suggests a possible disturbance in the master circadian clock, the suprachiasmatic nucleus (SCN) of the hypothalamus, or in the pathways by which the SCN modulates particular rhythms. Rhythms of sleep-wake and locomotor activity (LMA) are regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). Additionally, we recently demonstrated that the propensity for behavioral aggression also follows a daily rhythm that is regulated by the SCN, via an additional pathway through the SPZ, to the ventromedial hypothalamus (VMH). Importantly, disrupting this SCNSPZVMH pathway led to increased aggression during the early resting phase (the light period for nocturnal mice), which is temporally analogous to when AD and dementia patients who experience sundowning display increased agitation and aggression. This suggests that the function of certain structures within this circuit may be compromised in AD and dementia. Interesting, women have also been shown to have a particular profile of inflammatory markers in AD, however these differences have never been examined directly in areas associated with circadian regulation. We have begun examining circadian rhythms in the TAPP mouse model, which develops amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology), and our preliminary results suggest that these mice exhibit increased early resting period aggression and disrupted LMA at very early ages of AD pathology. In this proposal, we will examine whether sex-differences in specific inflammatory markers are associated with sex differences in increased aggression during the early resting phase and disrupted LMA rhythms in female and male TAPP mice, and in their female and male wild-type controls. We will focus our analysis in a circuit-based and region-specific manner, by specifically examining lysates from dissected hypothalamic tissue containing the SCN and SPZ, and dissected midbrain tissue containing areas which we know project to the circadian system and which display heavy phosphorylated tau pathology at later ages.

抽象的 女性比男性更容易患阿尔茨海默病 (AD) 和相关痴呆症， 此外，女性比男性更有可能出现这种情况。 出现昼夜节律紊乱，例如睡眠障碍，以及昼夜节律功能障碍的一个特殊特征 患有 AD 和相关痴呆症的患者被称为“日落综合症”，这是一种人们知之甚少的临床现象 傍晚时分的特征是烦躁、攻击性和谵妄。 对患者及其护理人员的生活质量产生重大影响，他们也更有可能 女性，并经常导致寻求收容的决定仍然是日落的神经生物学。 未知，但是日落症状的时间周期性表明可能存在干扰 主生物钟、下丘脑的视交叉上核 (SCN) 或在其通路中 SCN 调节特定的睡眠-觉醒节律和运动活动 (LMA)。 SCN 通过其主要突触后靶标室旁区 (SPZ) 的通路到达 此外，我们最近证明了行为倾向。 攻击行为也遵循由 SCN 通过 SPZ 的额外途径调节的日常节律， 重要的是，破坏该 SCNSPZVMH 通路会导致 在早期休息阶段（夜间活动的小鼠的光照期）攻击性增加，这在时间上是短暂的 类似于 AD 和痴呆症患者在经历日落时表现出更加激动和 这表明该回路中某些结构的功能可能会在 AD 中受到损害。 有趣的是，女性也被证明具有特殊的炎症标志物。 然而，这些差异从未在与昼夜节律调节相关的领域得到直接研究。 我们已经开始检查 TAPP 小鼠模型的昼夜节律，该模型会产生β-淀粉样蛋白 (a-beta) 斑块和 tau 神经原纤维缠结（AD 神经病理学的两个标志），以及我们的初步结果 表明这些小鼠在很小的时候就表现出早期休息期攻击性的增加和 LMA 的破坏 在这项提案中，我们将检查特定炎症标志物的性别差异是否存在。 与早期休息阶段攻击性增加和 LMA 中断的性别差异有关 我们将重点关注雌性和雄性 TAPP 小鼠及其雌性和雄性野生型对照的节律。 通过专门检查解剖的裂解物，以基于电路和特定区域的方式进行分析 包含 SCN 和 SPZ 的下丘脑组织，以及包含我们所研究的区域的解剖中脑组织 了解昼夜节律系统的项目，并在晚年表现出严重磷酸化的 tau 蛋白病理学。