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

阿尔茨海默病(AD)和相关的痴呆与进行性的昼夜节律紊乱有关。阿尔茨海默病和相关痴呆患者的昼夜节律紊乱的一个特殊特征是“日落综合征”，这是一种鲜为人知的临床现象，其特征是在傍晚时分出现躁动、攻击性和精神错乱。日落的神经生物学尚不清楚，但其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)--受到了干扰，或SCN调节特定节奏的途径。固有的光敏性视网膜神经节细胞(RGC)表达光色素黑素，通过视网膜下丘脑束(RHT)投射到SCN，并在每日的光暗循环中进行活动。Clifford Saper博士的实验室已经证明，睡眠-觉醒和运动活动(LMA)的节律由SCN通过其主要突触后目标--室旁区(SPZ)--到下丘脑背内侧(DMH)的一条通路来调节。最近，我在萨珀博士的实验室进行的博士后研究发现，雄性小鼠的攻击性倾向也遵循由GABA能SPZ神经元调节的每日节律。这项工作进一步证明，这些SPZGABA神经元接受来自SCN的功能输入，以一种阶段依赖的方式活跃，并投射到下丘脑腹内侧(VMH)内驱动攻击行为的神经元，总之，这表明了一种新的途径，中央昼夜节律时钟通过它来控制24小时内的攻击倾向。重要的是，我发现扰乱scn􀀂spz􀀂vmh通路会导致早期休息阶段(夜间活动的小鼠的光照阶段)攻击性增加，这在时间上类似于经历日落的患者表现出更多的焦虑和攻击性。这表明在AD和相关痴呆中，这个回路中的某些结构的功能可能受到损害，这一通路可能是治疗日落患者的昼夜节律障碍和攻击性的一个有前途的治疗靶点。我通过研究TAPP小鼠(也称为APPswe-Tau)的昼夜节律开始验证这一假设，这种小鼠会形成淀粉样β蛋白(a-beta)斑块和tau神经原纤维缠结(这两个都是AD神经病理的特征)。我发现，这些小鼠在患上与AD相关的神经病理后不久，表现出更多的早期休眠期攻击性和钝化的活动期LMA。在这项提议中，我试图通过检查这些小鼠的脑组织中SCN、SPZ中的a-beta和tau来扩展这项工作，并以VMH和DMH为目标输出。有人假设，与日落相关的昼夜节律障碍可能是由于AD相关区域对昼夜节律系统的输入造成的，例如5-羟色胺和胆碱能通路，我也将在这些区域检查与AD相关的神经病理学。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(特别是投射和缠绕SCN的RGC)。最后，我试图确定操纵SPZ和RGC活动(使用化学激活)对TAPP小鼠增加的攻击性和钝化的昼夜睡眠-觉醒节律的影响，以及对AD神经病理模式的影响。虽然日落是一个重要的临床问题，但关于昼夜节律系统如何影响躁动和攻击性的研究很少，几乎没有关于AD如何影响这些回路的研究。询问这些回路，并确定操纵它们的神经元活动是否可以改善小鼠与AD相关的行为障碍，可能会指出一种最终的治疗方法，可以极大地提高AD患者及其照顾者的生活质量。

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.