Natural hypothalamic circuit dynamics underlying object memorization

Abstract

Memorizing encountered objects is fundamental for normal life, but the underlying natural brain activity remains poorly understood. The hypothalamus is historically implicated in memory disorders, but whether and how its endogenous real-time activity affects object memorization remains unknown. We found that upon self-initiated object encounters, hypothalamic melanin-concentrating hormone (MCH) neurons emit dynamic, object-encounter-associated signals encoding object novelty. Optosilencing of these signals, performed in closed-loop with object encounters selectively during object memory acquisition, prevented the ability to recognize the previously encountered objects. Optogenetic and chemogenetic connectivity analyses demonstrated that local GAD65 neurons form an inhibitory GAD65[->]MCH microcircuit that controls the object-encounter-associated MCH cell signals. GAD65 cell optosilencing during object memory acquisition enhanced future object recognition through MCH-receptor-dependent pathways. These results provide causal evidence that natural, object-associated signals in genetically-distinct but interacting hypothalamic neurons differentially control whether the brain forms object memories.