R01AG070831

Mechanisms of Pathology and Neuronal Hyperactivity in a Memory Circuit in Alzheimer's Disease

Previous work from the Tsai Lab (Canter et al., 2019) identified the mammillary body (MB) as one of the first sites of amyloid deposition in 5XFAD model mice. This region also correlates with dementia severity in human patients. Single-cell RNA sequencing of the mouse MB revealed two distinct neuronal populations within the MB, with segregated distribution, target projection, and unique electrophysiology. Analysis of these populations in the 5XFAD mice found that the lateral MB (LM) population is uniquely susceptible to hyperactivity and neurodegeneration, while the medial MB (MM) population is largely unaffected. The activity of the LM population directly contributes to mouse performance in memory tasks.

Additionally, using iterative direct-expansion microscopy (IDEXM) from the Boyden Lab, intriguing patterns of amyloid associated with specific projections in the fornix, the white matter tract from the subiculum with axonal inputs to the MB, have been identified. This grant proposes to investigate the links between amyloid and excitability changes in the MB and fornix, including the development of tools necessary to achieve this goal.

The hypothesis to be tested in this application is that amyloid preferentially associates with the subiculum-LM projection, and that these axons exhibit hyperexcitability.

Aim 1 will map the connections between this new population of LM neurons and its upstream inputs from the hippocampus, using a newly developed in situ sequencing technique. Additionally, pathology in the white matter projection regions of this circuit in 5XFAD mice and human brain samples will be explored using recently developed expansion microscopy.

Aim 2 will characterize the source and location of hyperactivity found in the LM neurons through advanced voltage imaging. This work will also be expanded to other mouse models of Alzheimer's disease.

Aim 3 will use optogenetics and pharmacological approaches to determine if specific aberrant circuit activity drives the pathology and behavioral changes seen in the Alzheimer's disease model mice.

Massachusetts Institute Of Technology

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Cambridge, Massachusetts 021394301 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 387% from $662,151 to $3,226,012.