Determining the role of a novel brainstem pathway in normal circadian function and in Alzheimer's disease related dysfunction and sundowning-associated behavior

University Of Wyoming, Laramie WY

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Abstract

The long-term goal of this project is to strengthen our understanding of the neural circuitry underlying circadian dysfunction in Alzheimer’s disease (AD) and Alzheimer’s disease related dementias (ADRD). AD and ADRD are associated with progressive disruption of circadian rhythms, including locomotor activity (LMA) and other rhythms, compared to healthy aged-matched controls – suggesting 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 prevalent in around 20% of AD and ADRD patients is “sundowning”, characterized by aggression and increased LMA (wandering) during the early evening. Such symptoms are detrimental to quality of life for both patients and their caretakers and often lead to institutionalization, and given the aging US population, this is problem that continues to grow. The neurobiology of the sundowning remains unknown, and the paucity of animal models to understand its mechanisms presents a major roadblock to progress. However, our lab has developed a working model for how disruption of particular circadian pathways in mice may lead to behavioral disturbances similar to those seen in sundowning. The SCN is known to regulate LMA rhythms by a pathway through its major postsynaptic target, the subparaventricular zone (SPZ), and we recently showed that aggression propensity in mice follows a daily rhythm regulated by the SCN and SPZ through a separate downstream pathway. Importantly, we found that disrupting this pathway increases aggression during the early resting phase, which is temporally analogous to when aggression occurs during sundowning. Thus, AD-associated disruptions to the function of the SCN and SPZ may lead to altered timing of LMA in the form of sundowning-related wandering, while also leading to sundowning-related aggression. To address potential mechanistic connections between AD-related pathology and circadian function, we conducted behavioral and pathological analyses in a mouse model of AD and retrograde tracing from circadian structures. We identified the lateral parabrachial nucleus (LPB) in the brainstem as a major site of Tau pathology (a hallmark of AD), found that the LPB projects to both the SCN and SPZ, and provided evidence that strongly supports a role for Tau-related dysfunction in the LPB in circadian disruptions. Here, we will test our hypotheses that the LPBSCN/SPZ pathway is necessary for normal behavioral rhythms, and that Tau pathology in this pathway is sufficient for the circadian dysfunction associated with sundowning. We will use retrograde delivery of Cre recombinase injected in the SCN and SPZ, and Cre-dependent vectors injected in the LPB to specifically ablate LPBSCN/SPZ neurons or transfect them with Tau pathology. We will also determine if chemogenetic manipulations of LPBSCN/SPZ neurons acutely ameliorate circadian dysfunction and increased aggression in our AD mouse model, suggesting a potential therapeutic target for treating sundowning that may improve quality of life for both patients and caretakers.