Neuropeptide Y co-opts neuronal ensembles for memory lability and stability

Abstract

AbstractMemory engrams are formed by activity-dependent recruitment of distinct subsets of excitatory principal neurons (or neuronal ensembles) whereas inhibitory neurons pivot memory lability and stability1–5. However, the molecular logic for memory engrams to preferentially recruit specific type of interneurons over other subtypes remains enigmatic. Using activity-dependent single-cell transcriptomic profiling6–8in mice with training of cued fear memory and extinction, we discovered that neuropeptide Y (NPY)-expressing (NPY+) GABAergic interneurons in the ventral hippocampal CA1 (vCA1) region exert fast GABAergic inhibition to facilitate the acquisition of memory, but bifurcate NPY-mediated slow peptidergic inhibition onto distinct sub-ensembles underlying the extinction of single memory trace. Genetically encoded calcium and NPY sensors revealed that both calcium dynamics of NPY+neurons and their NPY release in vCA1 ramp up as extinction learning progresses while behavioral state switches from “fear-on” to “fear-off”. Bidirectional manipulations of NPY+neurons or NPY itself demonstrated NPY is both necessary and sufficient to control the rate and degree of memory extinction by acting on two physically non-overlapping sub-ensembles composed of NPY1R- and NPY2R-expressing neurons. CRISPR/Cas9-mediated knockout of NPY2R or NPY1R further unravels that NPY co-opts its actions on these two sub-ensembles to gate early fast and late slow stages of extinction. These findings exemplify the intricate spatiotemporal orchestration of slow peptidergic inhibitions from single subtype of GABAergic interneurons to fine-tune engram lability verse stability of memory.