Project Summary We propose to investigate the contribution of the long non-coding RNA (lncRNA) Neat1 in astrocytes and identify the epigenetic mechanisms in these glia cells involved in enhancing memory resiliency with age. Interventions to enhance memory resilience within the aging population are possible. However, research studies that inform resiliency in this area are still lacking. Within the aging hippocampus, it is now clear that abnormal epigenetic control of gene transcription contributes to memory deficits. Nearly all the suggested epigenetic mechanisms controlling memory formation have mostly been attributed to neuronal cells within the hippocampus, largely disregarding these mechanisms in astrocytes. Thus, little is known about how astrocytic epigenetic mechanisms influence memory resiliency with age. Our long-term goal is to study the role of lncRNAs in astrocytes and to identify how these powerful epigenetic regulators impact memory formation with aging. Our pilot data demonstrate that Neat1 expression is decreased in area CA1 of young adult mice and overexpressed in aged mice. Furthermore, we demonstrate that inhibiting Neat1 expression in area CA1 of the hippocampus of aged mice reverses memory impairments. Pilot studies also suggest a strong relationship between G9a mediated H3K9me2 hypermethylation with Neat1 overexpression in aged adults. Based on these preliminary results, we plan to rigorously investigate the effects of manipulating Neat1 in astrocytes and determine effects on age-related memory decline. To gain further mechanistic insight into Neat1 mediated gene transcription in astrocytes in the aging hippocampus, we will use state-of-the-art approaches such as CRISPR reprogramming and chemogenetics to elucidate the epigenetic mechanisms in astrocytes in our aging animal model system. Our overarching hypothesis is that Neat1 contributes to age-associated changes in hippocampal astrocyte diversity, astrocyte function and vulnerability to memory dysfunction. Our Specific Aims are as follows: Specific Aim 1: Test the hypothesis that Neat1 is associated with astrocyte diversity with aging; Specific Aim 2: To determine the mechanism by which Neat1 acts to influence chromatin restructuring in astrocytes from young versus aged animals; and Specific Aim 3: To determine the contribution of astrocytic Neat1 to memory resiliency with age. Collectively, these studies will identify epigenetic mechanisms in astrocytes involved in age-related memory decline, with broad implications for treatment options for age-related dementia and Alzheimer’s disease.