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

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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.