Hippocampus-evoked polysynaptic responses in the medial prefrontal cortex are attenuated in aged rats.

Abstract

The hippocampus-medial prefrontal cortex (mPFC) circuit is critical for spatial working-memory and decision-making. Age-associated changes to these functions are attributed to alterations in this circuit, although the exact mechanisms remain unclear. These regions are connected via monosynaptic projections from the intermediate (iHC) and ventral (vHC) hippocampus to the mPFC. We examined the functional connection between these regions in young (10-12 months) and aged (23-26 months) male F344 rats. High-density Neuropixels probes were used to record mPFC field excitatory postsynaptic potentials (fEPSPs) and single-unit responses to electrical stimulation of iHC and vHC. We observed that hippocampal stimulation evoked both short-latency (5-35 ms) monosynaptic and long-latency (35-100 ms) polysynaptic responses across the dorsoventral mPFC axis. Monosynaptic fEPSP amplitude increased with mPFC depth for iHC and vHC stimulation sites. Age did not affect hippocampal-prefrontal monosynaptic transmission as measured by fEPSP amplitude and evoked neural firing. In contrast, polysynaptic responses, reflecting local mPFC circuit recruitment, were larger than monosynaptic responses in young but not aged rats. Polysynaptic fEPSPs increased toward ventral mPFC in young but not aged rats, and polysynaptic evoked firing was reduced with age, most prominently at ventral mPFC depths. Our findings demonstrate that aging preserves the functional direct synaptic transmission but impairs polysynaptic recruitment of local mPFC circuits, with ventral mPFC showing particular vulnerability. These circuit-level deficits may contribute to age-related impairments in cognitive flexibility.