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Principal Investigator: Amy Monasterio
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2024
Award: $48,694
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Defining how we form, store, and retrieve memories is one of neuroscience’s most researched areas. The
hippocampus is a well-characterized forebrain structure with a crucial role in the formation and retrieval of
episodic memory, and is known to be vulnerable to age-related memory dysfunction. Cognitive decline in age
and neurodegenerative disease is an increasing burden on healthcare systems and society at large. To treat the
causes of memory decline in age and age-related disease, the mechanisms by which hippocampal cell
populations form and maintain individual memories over time must be characterized. Decades of research have
shown that new learning results in strengthened synaptic connections between networks of hippocampal
neurons. These distributed connections between cells are believed to make up the physical basis for memories,
often defined as an engram. Significant progress has been made in finding the engram in the brain with the
application of activity-dependent genetic strategies, which isolate populations of cells expressing immediate-
early genes (IEGs), to identify the neurons activated by learning. Subpopulations of neurons expressing the IEG
c-Fos are activated during learning and reactivated during memory recall, so they are often referred to as engram
neurons. Previous studies demonstrated the crucial role of hippocampal engram neurons in memory recall
behavior, and artificial reactivation of these cells in mouse models of aging and Alzheimer’s disease rescued
memory retrieval deficits, pointing to engram cells as a promising target for future interventions to treat memory
deficits. However, the in vivo mechanisms by which these cells store associations, and how their reactivation
drives memory retrieval, have yet to be explored. To address this gap in knowledge, this project will utilize novel
two-photon imaging to combine an inducible c-Fos tagging strategy with large-scale calcium imaging, to
investigate how these cell populations contribute to memory formation. Aim 1 of this project is to characterize
the dynamics of engram cell populations across learning in order to inform our understanding of circuit
mechanisms underlying memory formation in healthy states. This mechanistic understanding will then be utilized
in Aim 2 to define how these processes are negatively impacted by aging. Overall, the aims of this proposal will
contribute to the advancement of our understanding of the circuit mechanisms of hippocampal memory formation
in health and disease, with the potential to inform current treatment strategies for cognitive decline.
Terms: <2-photon><AD dementia><Address><Affect><Age><Age-associated cognitive decline><Age-associated memory impairment><Age-related cognitive decline><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Ammon Horn><Area><Behavior><Benign senescent forgetfulness><Brain><Brain Nervous System><Brain region><Calcium><Cell Body><Cells><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Computer Models><Computerized Models><Cornu Ammonis><Cues><Data><Degenerative Neurologic Disorders><Disease><Disorder><Disturbance in cognition><Dysfunction><Educational process of instructing><Employment Application><Encephalon><Environment><Episodic memory><FOS gene><Faculty><Fellowship><Fore-Brain><Forebrain><Fostering><Functional disorder><Future><G0S7><Genetic><Genetic Technics><Genetic Techniques><Goals><Grant><Health><Health Care Systems><Healthcare Systems><Hippocampus><Image><Immediate-Early Genes><Impaired cognition><Impairment><Individual><Intervention><Intervention Strategies><Investigators><Job Application><Knowledge><Label><Learning><Life><Memory><Memory Deficit><Memory Loss><Memory impairment><Mentors><Methods><Mice><Mice Mammals><Modeling><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neurons><Neurosciences><Pattern><Phase><Physiology><Physiopathology><Population><Postdoc><Postdoctoral Fellow><Preparation><Primary Senile Degenerative Dementia><Process><Professional Competence><Prosencephalon><Protooncogene FOS><R-Series Research Projects><R01 Mechanism><R01 Program><Research><Research Associate><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Retrieval><Rodent><Rodentia><Rodents Mammals><Role><Scientist><Societies><Structure><Synapses><Synaptic><Teaching><Techniques><Technology><Testing><Time><Training><Viral Genetics><age associated><age associated disease><age associated disorder><age associated impairment><age associated memory decline><age correlated><age dependent><age dependent disease><age dependent disorder><age dependent impairment><age linked><age related><age related cognitive deficit><age related cognitive impairment><age related human disease><age related memory dysfunction><age specific><age-induced cognitive decline><age-related decline in cognition><age-related decline in cognitive function><age-related disease><age-related disorder><age-related impairment><ages><awake><c fos><c-fos Gene><c-fos Proto-Oncogenes><career><career skill><cell type><cognitive dysfunction><cognitive function><cognitive loss><computational modeling><computational models><computer based models><computerized modeling><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><experience><experiment><experimental research><experimental study><experiments><genetic approach><genetic strategy><hippocampal><imaging><imaging approach><imaging based approach><imaging genetics><in vivo><insight><interventional strategy><life span><lifespan><memory decline><memory dysfunction><memory recall><memory retrieval><mouse model><murine model><neurodegenerative illness><neuronal><new approaches><novel><novel approaches><novel strategies><novel strategy><optic imaging><optical imaging><pathophysiology><post-doc><post-doctoral><post-doctoral trainee><preparations><primary degenerative dementia><recruit><research associates><senile dementia of the Alzheimer type><social role><success><synapse><treatment strategy><two-photon><v-FOS FBJ Murine Osteosarcoma Viral Oncogene Homolog><virus genetics>