EXPLORING BRAIN-WIDE ASTROCYTIC ENSEMBLES ACROSS DIVERSE EXPERIENCES​

Astrocytes support brain homeostasis and information processing through interactions with diverse cellular and subcellular domains across the CNS. Although their dysfunction is implicated and/or postulated in a broad range of human CNS disorders, how astrocytes dynamically and mal/adaptively remodel their molecular/cellular programs in response to experience and disease remains unclear. Using a newly developed approach to capture behaviorally relevant astrocyte ensembles (BAE) brain-wide in mice, we sought to anatomically map, molecularly dissect and functionally assess astrocyte ensembles across multiple behavioral paradigms and disease models. First, we found a profound recruitment of BAEs in the amygdala during fear memory recall. The recruitment mechanisms involved days-long astrocyte molecular state changes, including elevated expression of Adrb1, encoding the β1-adrenergic receptor. Deleting Adrb1 from astrocytes abolished BAE induction, demonstrating its requirement for formation of astrocyte ensemble. Second, we examined the brain-wide distribution of BAE during reward memory. Fear- and reward-related BAEs showed distinct anatomical positioning across multiple regions, with overlap in select areas including the amygdala. Using fiber photometry, we revealed behavior-specific patterns of noradrenergic and astrocytic cAMP signaling in the amygdala during fear and reward experiences. Third, reinforcing such noradrenaline-astrocyte cAMP signaling by overexpressing Adrb1 in amygdalar astrocytes was sufficient to stabilize both fear and reward memories. Finally, single-cell transcriptomic analysis functionally identified the astrocytic neuromodulatory factor Igfbp2 as a stabilizing cue for memories. Together, these findings demonstrate that experience-dependent astrocytic molecular adaptations regulate memory stability, providing insight into mechanisms underlying maladaptively stabilized memories in disorders such as PTSD and addiction.