Circadian behavior circuits, Alzheimer’s pathology, chemogenetic output and input

阿尔茨海默病（AD）和相关痴呆与昼夜节律的进行性破坏有关。AD和相关痴呆患者的昼夜节律功能障碍的一个特殊特征是“日落综合征”，这是一种知之甚少的临床现象，其特征在于傍晚时分的激动、攻击和谵妄。日落的神经生物学仍然未知，但是其症状的时间周期性表明主生物钟，下丘脑的视交叉上核（SCN）或SCN调节特定节律的途径可能存在干扰。视网膜内的光敏视网膜神经节细胞（RGC）表达黑视素，通过视网膜下丘脑束（RHT）投射到SCN，并在每日的光暗周期中携带其活性。Clifford Saper博士的实验室已经表明，睡眠-觉醒和运动活动（LMA）节律是由SCN通过其主要的突触后靶点，脑室旁下区（SPZ）到下丘脑背内侧（DMH）的通路调节的。最近，我在Saper博士实验室的博士后工作揭示了雄性小鼠的攻击倾向也遵循由GABA能SPZ神经元调节的每日节律。这项工作进一步表明，这些SPZGABA神经元从SCN接收功能输入，以相位依赖的方式活跃，并投射到腹内侧下丘脑（VMH）内的神经元，驱动攻击行为，这表明中央生物钟在24小时内门控攻击倾向的新途径。重要的是，我发现，破坏SCN- SPZ- VMH通路会导致早期休息期（夜间小鼠的光照期）的攻击性增加，这在时间上类似于经历日落的患者表现出增加的激动和攻击性。这表明该回路中某些结构的功能可能在AD和相关痴呆中受到损害，并且该通路可能是治疗显示日落的患者的昼夜节律功能障碍和攻击性的有希望的治疗靶点。我开始通过检查TAPP小鼠（也称为APPSwe-Tau）的昼夜节律来测试这一假设，TAPP小鼠会出现淀粉样蛋白β（α-β）斑块和tau神经元缠结（两者都是AD神经病理学的标志）。我发现，这些小鼠表现出增加的早期休息期侵略和钝化活跃期LMA后不久，他们被称为发展AD相关的神经病理学。在这个提议中，我试图通过检查这些小鼠的脑组织中SCN，SPZ中的α-β和tau以及它们的输出靶点VMH和DMH来扩展这项工作。有人假设，与日落相关的昼夜节律功能障碍可能是由于AD相关的干扰，提供输入的昼夜节律系统，如胆碱能和胆碱能途径，我也将检查AD相关的神经病理学在这些领域。我还将评估所有这些途径中的细胞损失，以及视网膜中的细胞损失（特别是投射到SCN并夹带SCN的RGC）。最后，我试图确定操纵SPZ和RGC活性（使用化学遗传激活）对TAPP小鼠的攻击性增加和昼夜睡眠-觉醒节律减弱的影响，以及对AD神经病理学模式的影响。虽然日落是一个重要的临床问题，但很少有工作集中在昼夜节律系统如何影响激动和攻击性，几乎没有关于AD如何影响这些电路的研究。询问这样的电路，并确定其神经元活动的操纵是否可以改善小鼠中AD相关的行为障碍，可能指向一种最终的治疗方法，可以大大提高AD患者及其护理人员的生活质量。

Alzheimer’s disease (AD) and related dementias are associated with progressive disruption of circadian rhythms. 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. The neurobiology of sundowning remains unknown, however the temporal periodicity of it 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. Intrinsically photosensitive retinal ganglion cells (RGCs), that express the photopigment melanopsin, project to the SCN via the retinohypothalamic tract (RHT) and entrain its activity the daily lightdark cycle. Dr. Clifford Saper’s lab has shown that sleep-wake and locomotor activity (LMA) rhythms are regulated by the SCN via a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), to the dorsomedial hypothalamus (DMH). More recently, my work postdoctoral work in Dr. Saper’s lab revealed that aggression propensity in male mice also follows a daily rhythm that is regulated by GABAergic SPZ neurons. This work further demonstrated that these SPZGABA neurons receive functional input from the SCN, are active in a phase-dependent manner, and project to neurons within the ventromedial hypothalamus (VMH) that drive attack behavior, altogether suggesting a novel pathway by which the central circadian clock gates aggression propensity across the 24h day. Importantly, I found that disrupting the 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 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 related dementias, and that this pathway may be a promising therapeutic target for treating circadian dysfunction and aggression in patients who display sundowning. I began testing this hypothesis by examining circadian rhythms in TAPP mice (also known as APPSwe-Tau), which develop amyloid-beta (a-beta) plaques and tau neurofibrillary tangles (both hallmarks of AD neuropathology). I found that these mice exhibit increased early resting period aggression and blunted active period LMA at ages shortly after they are known to develop AD-related neuropathology. In this proposal, I seek to expand on this work by examining brain tissue from these mice for a-beta and tau in the SCN, the SPZ, and their output targets the VMH and the DMH. It has been hypothesized that circadian dysfunction associated with sundowning may instead result from AD-related disturbances to areas that provide input to the circadian system, such as serotoninergic and cholinergic pathways, and I will also examine AD-related neuropathology in such areas. I will also assess cell loss in all of these pathways, as well as in the retina (specifically RGCs that project to and entrain the SCN). Finally, I seek to determine the effects of manipulating SPZ and RGC activity (using chemogenetic activation) on increased aggression and blunted circadian sleep-wake rhythms in TAPP mice, and on the patterns of AD neuropathology. While sundowning is an important clinical problem, there has been little work focused on how the circadian system effects agitation and aggression, and almost none on how such circuits are affected by AD. Interrogating such circuits, and determining whether manipulation of their neuronal activity can ameliorate AD-related behavioral disturbances in mice, may point to an eventual therapy that could greatly improve quality of life for AD patients and their caregivers.