A prefrontal cortex-piriform cortex circuit mediates diminished interest.
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 vmPFCglu-PPC, but not the vmPFCglu-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 vmPFCglu-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.