[K99] Enhancing hippocampal parvalbumin interneuron function ameliorates age-dependent cognitive decline
Ente: National Institute on Aging
Scadenza: 2028-08-31
Importo max: $134,740
Paese: US
Descrizione
Project Summary/Abstract
Human life expectancy has increased as medical science, public health measures, nutrition, and standards of
living continue to improve. Despite these advances, aging remains one of the most significant risk factors for
many chronic diseases and conditions, specifically cognitive decline. To improve treatments and identify novel
therapeutics for age-related cognitive decline, it is of critical importance that we understand mechanisms of
resilience and functional maintenance of cognition in the aging brain. A fundamental component of cognition is
memory. The hippocampus is known as the circuit hub for memory processing. Within the hippocampus,
parvalbumin inhibitory interneurons (PV INs) contribute to critical functions that are important for memory
processing. Human and animal research demonstrate that PV IN function declines in parallel with cognition in
the aging brain. Therapeutic interventions that subsequently enhance hippocampal PV IN function improve
memory and cognition. Therapeutic approaches to minimize cognitive decline are largely ineffective, further
research is needed toward more effective and targeted treatment. To this end, the Sahay Lab identified a unique
form of experience-dependent structural plasticity exhibited by hippocampal PV INs. Our research led to the
generation of a genetic blueprint for experience-dependent PV IN plasticity. Among this list is the transcription
factor Myeloid Ecotropic Insertion Site 2 (MEIS2). Our preliminary data demonstrates that selective expression
of MEIS2 in PV INs along the stratum lucidum of the dorsal hippocampus, restores circuit and cognitive function
in a neurodevelopmental disorder mouse model that is characterized by impaired PV IN function and cognition.
Accordingly, the proposed work will test the central hypothesis that enhancing hippocampal PV IN circuit function
ameliorates cognitive decline in aging and in AD. In Aim 1 (K99 year 1-2), I will determine if boosting MEIS2 in
hippocampal PV INs restores inhibitory circuit function and prevents age-related aberrant neural oscillation
patterns in the dentate gyrus (DG)→CA3/2 of aged mice. I will use ex vivo patch-clamp electrophysiology
combined with cell type-specific optogenetics to characterize PV IN properties and functions in 3- 12- and 20-
month-old mice, and in 20-month-old mice injected at 16-months-old with a PV specific viral vector that boosts
MEIS2 expression. I will also record in vivo local field potentials from the DG and CA subfields in behaving mice.
In Aim 2 (K99 year 2), I will determine if restoring hippocampal PV IN function prevents age-related cognitive
impairment. Within these same groups, I will assess memory performance in DG- and aging-sensitive memory
behavior tasks in conjunction with machine learning software to track natural homecage behaviors. In my final
Aim 3 (R00), I will employ experimental strategies established in Aims 1-2 to determine if enhancing hippocampal
PV IN-mediated
Istituzione: MASSACHUSETTS GENERAL HOSPITAL
PI: Jason Bondoc Alipio
Progetto: 1K99AG097925-01A1
Settori: National Institute on Aging
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