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

> **NIH NIH P20** · UNIVERSITY OF WYOMING · 2022 · $208,058

## 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 ci...

## Key facts

- **NIH application ID:** 10495800
- **Project number:** 2P20GM121310-06
- **Recipient organization:** UNIVERSITY OF WYOMING
- **Principal Investigator:** William David Todd
- **Activity code:** P20 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $208,058
- **Award type:** 2
- **Project period:** 2017-09-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495800

## Citation

> US National Institutes of Health, RePORTER application 10495800, Determining the role of a novel brainstem pathway in normal circadian function and in Alzheimer's disease related dysfunction and sundowning-associated behavior (2P20GM121310-06). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10495800. Licensed CC0.

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