Wyoming Sensory Biology COBRE

摘要 女性比男性更容易患上阿尔茨海默病(AD)和相关的痴呆症，这是 与昼夜节律的进行性打乱有关。此外，女性比男性更有可能 发生昼夜节律紊乱，如睡眠紊乱，而昼夜节律紊乱的一个特殊特征是 阿尔茨海默病和相关痴呆症患者被称为“日落综合征”，这是一种鲜为人知的临床现象 烦躁的以傍晚时分的激动、攻击性和精神错乱为特征的阳光明媚的症状有 对患者和他们的照顾者的生活质量产生重大影响，他们也更有可能 而且往往会导致寻求体制化的决定。日落遗迹的神经生物学 未知，然而日落症状的时间周期性表明可能是 主生物钟，下丘脑的视交叉上核(SCN)，或通过其通路 SCN调节特定的节奏。睡眠-觉醒和运动活动(LMA)的节律由 SCN通过其主要突触后靶点--室旁区(SPZ)到达 背内侧下丘脑(DMH)。此外，我们最近证明了行为倾向 攻击性也遵循由SCN调节的每日节律，通过SPZ的另一条途径， 至下丘脑腹内侧(VMH)。重要的是，破坏SCNSPZVMH途径导致 在早期休眠阶段(夜间小鼠的光照阶段)，攻击性增加，这是暂时的 类似于当经历日落的AD和痴呆症患者表现出更多的焦虑和 攻击性。这表明在AD中，该回路内的某些结构的功能可能受到损害 和痴呆症。有趣的是，女性也被证明具有特定的炎性标志物 然而，这些差异从未在与昼夜节律相关的区域被直接研究过。 我们已经开始研究TAPP小鼠模型的昼夜节律，这种模型会产生淀粉样β蛋白(a-beta)。 斑块和tau神经原纤维缠结(这两个都是AD神经病理的标志)，以及我们的初步结果 提示这些小鼠在安静早期表现出更强的攻击性，并在很小的时候就破坏了LMA AD病理学的研究。在这项提案中，我们将检查特定炎症标志物中的性别差异是否 与静息早期攻击性增加和LMA中断的性别差异有关 雌性和雄性TAPP小鼠以及它们的雌性和雄性野生型对照小鼠的节律。我们将专注于我们的 通过专门检查解剖的裂解液，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 知道投射到昼夜节律系统，并在以后的年龄表现出严重的磷酸化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.