Nucleus Incertus: Mapping its Anatomy in Alzheimer’s Disease Pathology

About the Research Project
Program
Award Type
Postdoctoral Fellowship
Award Amount
$169,856
Active Dates
July 01, 2021 - December 31, 2023
Grant ID
A2021006F
Goals
The main goal of this project is to investigate the nucleus incertus of the brain in humans and elucidate its role in dementia and Alzheimer’s disease pathology. This project aims to: (i) characterize the human nucleus incertus (NI) at the molecular level in post-mortem tissue from subjects without a history of dementia or other neurological disorders; and (ii) identify the gene expression profile of NI neurons in post-mortem tissue from Alzheimer’s disease and control subjects.
Note: This grant was terminated by the investigator on October 13, 2022, when she transferred to the Arizona Board of Regents for and on behalf of Arizona State University for an industry position.
Summary
By 2050 over 1115 million people worldwide will be living with Alzheimer’s disease (AD). Current treatments only marginally attenuate symptoms, and have little effect on slowing disease progression. Therefore, more research is required to discover further details about the neural networks that control cognition and related processes, and in turn, develop better treatments to slow the progress and reduce the symptoms of dementia leading to AD. In our brain, the brainstem region receives sensory information about our surroundings from the peripheral nervous system and relays this neural information throughout the forebrain. Certain areas in the brainstem, such as the locus coeruleus, are highly vulnerable to neurodegenerative conditions, including AD; and consequently, are the focus of intense preclinical and translational research. Critically for this project, a recent landmark paper published in Science established a key role for the brainstem region known as the nucleus incertus (NI) in memory, by confirming in mice strong neural communication between the NI and the hippocampus, a brain region crucial for learning and memory. However in humans, the specific functions of NI neurons and their chemical messengers, precise distribution, and connectivity, are currently unknown. The main goal of this project is to investigate the NI in humans and elucidate the role of the NI in dementia and Alzheimer’s disease pathology. These findings should have major therapeutic implications.
Unique and Innovative
The anatomy and key aspects of the neurochemistry of the nucleus incertus (NI) and its connections throughout the brain have been systematically mapped in rat, mouse and in primate, but not in humans. In my proposal, I will characterize the human NI at the molecular level in post-mortem human tissue.
Foreseeable Benefits
The study will lay the foundation for comparative studies of nucleus incertus samples from Alzheimer’s disease and matched control subjects; the data will lay the foundation for future multi-omics studies.
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