Wyoming Sensory Biology COBRE

摘要 女性比男性更容易患阿尔茨海默病（AD）和相关痴呆症， 与昼夜节律的渐进性破坏有关。此外，女性比男性更有可能 发生昼夜节律紊乱，如睡眠障碍，昼夜节律功能障碍的一个特殊特征是， 患有AD和相关痴呆的患者是“日落综合征”，这是一种知之甚少的临床现象 以在傍晚时分的激动、攻击和精神错乱为特征。日落症状有 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 妇女，并往往导致决定寻求机构。日落的神经生物学 未知，然而，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 SCN调节特定的节奏。睡眠-觉醒和运动活动（LMA）的节律由以下因素调节： SCN通过其主要的突触后靶点室旁下区（SPZ）， 下丘脑背内侧核（DMH）。此外，我们最近证明，行为倾向 攻击性也遵循由SCN调节的每日节律，经由通过SPZ的附加途径， 下丘脑腹内侧（VMH）。重要的是，破坏这种SCN + SPZ + VMH途径导致了 在早期休息阶段（夜间小鼠的光照期）增加攻击性， 类似于当经历日落的AD和痴呆患者显示出增加的激动， 侵略这表明，在AD中，该回路中某些结构的功能可能受到损害 和痴呆症。有趣的是，女性也被证明有一个特定的炎症标志物， 然而，这些差异从未在与昼夜节律调节相关的领域直接进行过研究。 我们已经开始研究TAPP小鼠模型的昼夜节律，该模型产生淀粉样蛋白β（a-β） 斑块和tau神经元缠结（AD神经病理学的标志），以及我们的初步结果 表明这些小鼠在很小的年龄就表现出早期休息期攻击性增加和LMA破坏 AD病理学在这个建议中，我们将研究是否性别差异在特定的炎症标志物， 与性别差异有关，在早期休息阶段增加攻击性和中断LMA 雌性和雄性TAPP小鼠以及它们的雌性和雄性野生型对照中的节律。呢我们一起来 以基于电路和区域特异性的方式进行分析，通过特异性检查来自解剖的裂解物， 含有SCN和SPZ的下丘脑组织，以及含有我们 已知对昼夜节律系统的影响，并且在较晚的年龄显示重磷酸化tau病理。

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.