Neuropeptidergic-glutamatergic circuit regulates selective forgetting of olfactory learning

Forgetting is an active and essential process for adapting to constantly changing environments, yet the molecular and circuit mechanisms underlying selective forgetting remain poorly understood. Our previous studies in the nematode Caenorhabditis elegans suggested that non-cell-autonomous neurosecretory signals accelerate forgetting of olfactory memory for diacetyl, an attractive odorant, by erasing its memory trace, which can be detected as changes in odor-evoked Ca²⁺ responses in sensory neurons. However, the identity of the forgetting signal, the circuit through which it acts to erase the sensory memory trace, and the time window in which forgetting occurs have remained elusive. Here, we identify a neuropeptidergic-glutamatergic circuit in C. elegans that drives the selective forgetting of olfactory memory. Our genetic and imaging analyses revealed that the gonadotropin-releasing hormone (GnRH)-related neuropeptide NLP-47, secreted from AWC neurons, acts on its receptor GNRR-1 in AIZ interneurons. Glutamatergic neurotransmission from AIZ interneurons then erases the sensory memory trace in AWA neurons via GLR-4, an AMPA-type receptor expressed in AWA. Optogenetic silencing of AWC and AIZ showed that this circuit acts during the recovery phase following conditioning, defining a critical temporal window for active forgetting. This neuropeptidergic-glutamatergic pathway selectively promotes forgetting of a specific odorant memory without affecting another formed simultaneously. Together, our findings demonstrate that neuropeptidergic signaling promotes selective forgetting via a glutamatergic circuit, highlighting that active forgetting is regulated within a critical temporal window and with remarkable specificity.