Distinct orbitofrontal circuits with dorsal and ventral CA1 differentially regulate spatial memory and emotional...

The orbitofrontal cortex (OFC) and hippocampus are critically involved in cognitive and affective functions. However, the circuit architecture and functional organization linking the OFC with distinct hippocampal subregions, particularly dorsal CA1 (dCA1) and ventral CA1 (vCA1), remain poorly understood.

We combined viral circuit tracing with a bilateral disconnection strategy to investigate the anatomical and functional organization of OFC-CA1 connectivity in mice. Dual viral tracing was used to map direct and polysynaptic pathways, and taCasp3-mediated targeted neuronal ablation was employed to assess circuit-specific functional contributions. Behavioral effects were evaluated using spatial memory assays (Y-maze and object location recognition) and emotion-related tests (open field, elevated plus maze, tail suspension, and forced swim tests).

We identified a unidirectional indirect pathway linking OFC to dCA1 via the claustrum (OFC → claustrum→dCA1), with no evidence of reciprocal dCA1 → OFC connectivity. In contrast, vCA1 exhibited a distinct connectivity profile, including a direct monosynaptic projection to OFC and multiple indirect pathways through the anterior thalamic nuclei, basolateral amygdala, and entorhinal cortex, while no OFC → vCA1 projection was detected. Functionally, disconnection of OFC-dCA1 connectivity selectively impaired spatial memory without affecting anxiety- or depression-like behaviors. Conversely, disconnection of vCA1-OFC connectivity induced anxiety- and depression-like phenotypes while preserving spatial memory.

These findings demonstrate that the OFC interacts with dorsal and ventral CA1 subregions through anatomically distinct circuits with dissociable behavioral functions. This study provides circuit-level insight into how OFC-CA1 interactions differentially regulate spatial memory and affect-related behaviors.