Summary Astrocytes play diverse and indispensable roles in brain function. Participating as a component of the ‘tripartite synapse’, a single astrocyte is estimated to contact up to 100,000 neuronal synapses in the hippocampus. Notably, studies have identified essential functions of astrocytes in hippocampal circuits, where astrocytes are required for regulating synaptic plasticity including LTP, a key process associated with learning and memory. Recent studies have shown that enhancing Gq-signaling in astrocytes promotes LTP and enhances acute memory, while impairing astrocyte function suppresses LTP and memory, highlighting central roles for astrocytes in memory-dependent tasks. Learning events invoke activity and plasticity among a discrete ensemble of cells. Activation of these ensembles by learning and reactivated during memory recall constitute the physical substrate of memory and are referred to as engrams. Despite the critical involvement of astrocytes in learning and memory processes, the study of memory engrams has been limited exclusively to neuronal ensembles. The goal of this proposal is to study the potential of astrocyte engrams as a substrate of memory and to understand the nature and function of hippocampal astrocyte ensembles. We have created a host of mouse lines and associated AAV-viral tools the enable us to label and manipulate astrocytes during learning events in the hippocampus. Preliminary studies with these tools indicate that we can label ensembles of astrocytes after learning and that reactivation of these same astrocytes promotes memory recall. Based on the strength of these preliminary data and the associated tools we have built, we propose the following specific aims. In specific aim1, we will label astrocyte ensembles after learning and characterize whether they exhibit engram properties. In specific aim2, we will manipulate the prospective engram astrocyte populations and determine whether they encode memory storage and recall. In specific aim3, we will characterize the cellular and molecular properties of these labeled astrocyte engram populations.

Narrative The focal point of this project is to understand cellular ensembles that contribute to storage and retrieval of memory. Given that astrocytes directly contribute to neuronal circuit function associated with memory, our studies are likely to identify new cellular mechanisms that regulate memory formation and also provide new insights into astrocyte-neuron interactions in the brain. Alterations, impairment, and dysfunction of memory formation and retrieval underlies a host of neurological disorders, including dementia, amnesia, and Alzheimer’s disease (AD) to anxiety- or trauma-related disease such as posttraumatic stress disorders (PTSD), and roles for astrocytes have been implicated in each of these disorders.