Work

A prefrontal cortex-piriform cortex circuit mediates diminished interest

Year: 2026

Type: article

Abstract: Diminished interest constitutes a core behavioral deficit across multiple neuropsychiatric conditions, yet its neural mechanism remains poorly understood. Here, we identify projection-biased and transcriptionally distinct subsets of glutamatergic neurons in the ventromedial prefrontal cortex (vmPFC) that preferentially innervate the anterior piriform cortex (APC) and posterior piriform cortex (PPC). By establishing a behavioral paradigm that selectively captures interest-related behaviors, we reveal that the vmPFC glu -PPC, but not the vmPFC glu -APC, circuit governs interest-related engagement without affecting olfactory function. This regulation is encoded by AMPAR-dependent burst firing in PPC neurons. Chronic stress selectively weakens this cortico-cortical pathway, reducing glutamatergic transmission and impairing burst firing in PPC neurons, thereby leading to deficits in interest-related behavior in mice. Targeted reactivation of the vmPFC glu -PPC circuit rescues these behavioral impairments. Collectively, our findings uncover a previously unrecognized cortical pathway dedicated to interest encoding and establish a circuit-level framework for explaining the selective vulnerability of interest under chronic stress.

Source: Molecular Psychiatry

DOI: 10.1038/s41380-026-03836-5