The circuit basis of sundowning-related circadian dysfunction in Alzheimer's disease and Alzheimer's disease-related dementias

这个项目的长期目标是了解昼夜节律背后的回路机制。 阿尔茨海默病(AD)和阿尔茨海默病的功能障碍和相关行为障碍 相关痴呆(ADRD)。AD/ADRD与昼夜节律的进行性扰乱有关， 包括体温、运动活动和其他节律，与健康的老年人匹配 控制。这表明AD相关的病理改变了主昼夜节律起搏器( 下丘脑视交叉上核(SCN)，使这种节律与每日的明暗周期同步。 在大约20%的AD/ADRD患者中，一种特殊的昼夜节律紊乱形式是“日落”，其特征是 在下午晚些时候和傍晚早些时候通过激动、攻击性和游荡。人类的神经生物学 日落仍然是未知的，但我们的实验室已经开发了一个工作模型来解释如何扰乱昼夜节律 老鼠体内的路径可能会导致与日落相关的时间紊乱。众所周知，SCN负责监管 体温和运动活动节律通过其主要突触后靶点 室旁区(SPZ)。我们最近发现，老鼠的攻击性倾向也遵循每天的 节律由SCN和SPZ通过单独的下游途径调节。重要的是，扰乱了这一切 通路增加了从活动到休息阶段的转换前后的攻击性，这在时间上类似于 当夕阳西下的病人表现出焦虑和攻击性时。与广告相关的对SCN、SPZ或其 因此，输入路径可能会导致体温、运动活动(以 漫游)，以及与日落有关的攻击性。解决潜在的机械连接问题 与AD相关的病理和昼夜节律功能，我们在 Tapp小鼠AD模型。我们发现脑干的臂旁外侧核(LPB)是一种主要的 Ptau网站，发现LPB项目对SCN和SPZ都有作用，并揭示了强有力的证据 LPB ptau在AD相关昼夜节律障碍和攻击性中的作用在这里，我们将检验我们的假设 LPBàSCN/SPZ通路是正常昼夜节律功能所必需的，而该通路中的ptau是AD的基础。 相关的昼夜节律紊乱和日落相关的行为障碍。我们将使用逆行递送 来自SCN和SPZ的Cre重组酶，以及LPB中依赖Cre的载体来特异性地操纵 LPBàSCN/SPZ神经元。我们将确定LPBàSCN/SPZ神经元的化学发生操作是否尖锐 改善或加重TAPP小鼠的昼夜节律紊乱和攻击性增加。我们也会表示 P301L突变(以及随后的ptau)仅在野生型小鼠和Wistar小鼠LPBàSCN/SPZ神经元中发生 高水平的α-β，以检查ptau和a-β在这一途径中的相互作用。最后，我们将使用 Cre-小鼠品系，靶向特定的LPB亚群，这些亚群差异地投射到昼夜节律系统 确定它们在正常的昼夜节律功能和ptau相关的昼夜节律功能障碍中的各自作用。

The long-term goal of this project is to gain an understanding of the circuit mechanisms underlying circadian dysfunction and associated behavioral disturbances in Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). AD/ADRD are associated with progressive disruption of circadian rhythms, including body temperature, locomotor activity, and other rhythms, compared to healthy aged-matched controls. This suggests that AD-related pathology alters the ability of the master circadian pacemaker (the suprachiasmatic nucleus of the hypothalamus, SCN), to synchronize such rhythms to the daily light-dark cycle. A particular form of circadian dysfunction in around 20% of AD/ADRD patients is “sundowning”, characterized by agitation, aggression, and wandering during the late afternoon and early evening. The neurobiology of sundowning remains unknown, but our lab has developed a working model for how disruption of circadian pathways in mice may lead to temporal disturbances relevant to sundowning. The SCN is known to regulate body temperature and locomotor activity rhythms by a pathway through its major postsynaptic target, the subparaventricular zone (SPZ). We recently showed that aggression propensity in mice also follows a daily rhythm regulated by the SCN and SPZ through a separate downstream pathway. Importantly, disrupting this pathway increases aggression around the active-to-rest phase transition, which is temporally analogous to when sundowning patients show agitation and aggression. AD-associated disruptions to the SCN, SPZ, or their input pathways, may thus lead to disturbances in body temperature, locomotor activity (in the form of wandering), and also sundowning-related aggression. To address potential mechanistic connections between AD-related pathology and circadian function, we conducted behavioral and neuroanatomical analyses in the TAPP mouse model of AD. We identified the lateral parabrachial nucleus (LPB) in the brainstem as a major site of pTau, found that the LPB projects to both the SCN and SPZ, and reveal strong evidence of a role for LPB pTau in AD-related circadian dysfunction and aggression. Here, we will test our hypotheses that the LPBàSCN/SPZ pathway is required for normal circadian function and that pTau in this pathway underlies AD- related circadian dysfunction and sundowning-related behavioral disturbances. We will use retrograde delivery of Cre recombinase from the SCN and SPZ, and Cre-dependent vectors in the LPB to specifically manipulate LPBàSCN/SPZ neurons. We will determine if chemogenetic manipulations of LPBàSCN/SPZ neurons acutely ameliorate or exacerbate circadian dysfunction and increased aggression in TAPP mice. We will also express the P301L mutation (and subsequently pTau) in only LPBàSCN/SPZ neurons in wild-type mice and in mice with high levels of a-beta to examine interactions between pTau and a-beta in this pathway. Finally, we will use Cre-mouse lines to target specific LPB subpopulations that differentially project to the circadian system to determine their respective roles in normal circadian function and pTau-related circadian dysfunction.