INHIBITORY MECHANISMS OF MEMORY REACTIVATION

Episodic memory formation relies on neural assembly reactivation during hippocampal sharp-wave ripples (SPW-Rs). However, the mechanisms governing the formation and stabilization of neural assemblies remain poorly understood. Here, we introduce an approach to generate synthetic neural assemblies in vivo and use it to dissect the circuit mechanisms underlying assembly formation. Using silicon probes with miniaturized LEDs, we selectively coactivated groups of CA1 pyramidal neurons in behaving mice.
Across multiple stimulation protocols, only fast gamma–like bursting induced long-lasting assembly formation, as evidenced by increased pairwise co-firing, mutual information, and ICA-defined neuronal assemblies among coactivated neurons. Notably, other protocols produced similar or even stronger excitation during induction but failed to generate persistent assemblies. Instead, fast gamma stimulation uniquely enhanced inhibitory responses during coactivation through short-term facilitation at pyramidal-to-interneuron synapses.
This increase in inhibition persisted into subsequent sleep, selectively suppressing co-firing among unrelated neurons and thereby promoting the emergence and stabilization of induced assemblies. Using a ground-truth–based cell-type classifier, we identified somatostatin (Sst) and a subset of parvalbumin (Pvalb) interneurons as the main contributors to this facilitating inhibition, and found that the strength of inhibitory recruitment predicted assembly formation.
To generalize these findings, we examined spontaneously emerging assemblies during learning. Neurons encoding behavioral variables were more strongly inhibited during SPW-Rs than non-related neurons, and Sst recruitment during SPW-Rs was selectively enhanced during post-learning sleep. Finally, chemogenetic perturbation of CA1 interneurons reorganized population activity and disrupted memory reactivation, identifying inhibitory plasticity as a key mechanism organizing neural assemblies during memory consolidation