# The Nigral Molecular Clock and Vulnerability to Neurodegeneration

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $450,883

## Abstract

Dopaminergic neurons of the substantia nigra are particularly susceptible to dysfunction and loss with aging
and disease. A potential contributor to this vulnerability is the requirement for the maintenance of intrinsic
pacemaking activity. However, little is known about how this pacemaking activity is regulated in physiological
and pathological states. Understanding how nigral neurons maintain their firing rate and adapt to cellular
stressors has the potential to reveal novel pathways for prevention of cellular damage and death. In this
application, we are proposing to test the novel hypotheses that the molecular clock is a key regulator of
pacemaking activity and other processes required for normal function of dopaminergic neurons and that
disruption of this clock contributes to cell dysfunction and death in models of Parkinson Disease (PD). In
support of these hypotheses, we have found that dopaminergic neuron firing rate varies with time of day and
that this variation is abolished in mice with midbrain-specific deletion of the obligate transcriptional regulator of
circadian function, Bmal1. Furthermore, we have found day/night differences in the expression of genes
involved in pacemaking activity in the substantia nigra, suggesting that pathways important for nigral function
may be regulated at the transcriptional level by the molecular clock. Interestingly, we have discovered alpha
synuclein mouse models of PD display disrupted day/night differences in pacemaking activity, leading to the
hypothesis that the impairment of circadian-regulated processes could contribute to neuronal dysfunction and
death in disease. In Aim 1, experiments are designed to determine the mechanisms by which the molecular
clock regulates dopaminergic neuron function at the transcriptional, electrophysiological, and behavioral levels,
using recently developed tools to evaluate molecular clock rhythmicity and transcription in a cell-specific way.
In Aim 2, experiments will utilize approaches to reset the molecular clock in a time-of-day-dependent manner in
mice with α-synuclein- induced pathology to determine the role for circadian dysregulation in the progression of
α-synuclein-mediated neurotoxicity and behavioral impairment. Altogether, these experiments have the
potential to reveal a novel regulatory mechanism of nigral function and vulnerability and could give critical
insight into disease progression and pathogenesis.

## Key facts

- **NIH application ID:** 9928136
- **Project number:** 5R01NS108713-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Rita Marie Cowell
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $450,883
- **Award type:** 5
- **Project period:** 2018-07-15 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928136

## Citation

> US National Institutes of Health, RePORTER application 9928136, The Nigral Molecular Clock and Vulnerability to Neurodegeneration (5R01NS108713-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928136. Licensed CC0.

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