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

Engrams are formed by activity-dependent recruitment of subsets of excitatory principal neurons, whereas inhibitory neurons mediate memory lability and stability. It remains elusive whether specific types of interneurons are preferentially engaged in determining the fate of memory. Here we show, in male mice undergoing cued fear memory training and extinction, that neuropeptide Y (NPY)-expressing (NPY⁺) GABA-ergic interneurons in ventral CA1 (vCA1) exert both fast GABA-ergic inhibition to facilitate memory acquisition and slow NPY-mediated inhibition to facilitate extinction. Specifically, the calcium dynamics of NPY⁺ neurons and NPY release in vCA1 ramp up as extinction learning progresses and the behavioral state switches from 'fear-on' to 'fear-off'. We show that NPY is necessary and sufficient to control the rate and degree of memory extinction by acting on two nonoverlapping subensembles composed of NPY receptor 1 (NPY1R)-expressing and NPY2R-expressing neurons, thereby gating early fast and late slow stages of extinction, respectively. Thus, subtype-specific, slow peptidergic inhibition from interneurons regulates engram lability versus stability.