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的电路机制。 阿尔茨海默病（AD）和阿尔茨海默病中的功能障碍和相关行为障碍 相关性痴呆（ADRD）AD/ADRD与昼夜节律的进行性破坏有关， 包括体温，运动活动和其他节奏，与健康的年龄匹配相比， 对照这表明AD相关的病理改变了主昼夜节律起搏器的能力（ 下丘脑的视交叉上核，SCN），以使这种节律与每日的光-暗周期同步。 在大约20%的AD/ADRD患者中，昼夜节律功能障碍的一种特殊形式是“日落”，其特征在于： 在下午晚些时候和傍晚早些时候的躁动、侵略和徘徊。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，用于研究昼夜节律的破坏是如何发生的。 在小鼠中的信号通路可能导致与日落有关的时间干扰。众所周知，SCN调节 体温和运动活动节律的途径，通过其主要的突触后靶点， 室旁带（SPZ）。我们最近表明，小鼠的攻击倾向也遵循每天的 由SCN和SPZ通过单独的下游途径调节的节律。重要的是， 在活动到休息的阶段过渡期间，这条通路增加了攻击性，这在时间上类似于 当日落病人表现出激动和攻击性时与AD相关的SCN、SPZ或其 输入途径，因此可能导致体温、运动活动（以 流浪），也日落有关的侵略。为了解决潜在的机械联系， AD相关的病理学和昼夜节律功能，我们对这些患者进行了行为和神经解剖学分析。 AD的TAPP小鼠模型。我们发现，外侧臂旁核（LPB）在脑干作为一个主要的 pTau的网站，发现LPB项目的SCN和SPZ，并揭示了强有力的证据， LPB pTau在AD相关的昼夜节律功能障碍和攻击中的作用在这里，我们将测试我们的假设， LPB_SCN/SPZ通路是正常昼夜节律功能所必需的，并且该通路中的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。我们将使用逆行交付 来自SCN和SPZ的Cre重组酶，以及LPB中的Cre依赖性载体，以特异性地操纵 LPBàSCN/SPZ神经元。我们将确定LPBàSCN/SPZ神经元的化学遗传学操作是否急性 改善或加重TAPP小鼠的昼夜节律功能障碍和增加的攻击性。我们还将表达 在野生型小鼠和具有P301 L突变的小鼠中，仅在LPBàSCN/SPZ神经元中存在P301 L突变（以及随后的pTau突变）。 更高水平的α-β以检查该途径中pTau和α-β之间的相互作用。最后，我们将使用 Cre-mouse系针对特定的LPB亚群，这些亚群差异性地投射到昼夜节律系统， 确定它们在正常昼夜节律功能和pTau相关的昼夜节律功能障碍中各自的作用。

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.