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

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 infralimbic (IL) and prelimbic (PL) regions of 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 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 in PL and IL cortices. Monosynaptic responses, reflecting direct hippocampal-prefrontal synaptic transmission, had lower vHC-evoked IL fEPSP amplitude in aged rats, while other subregional HC-mPFC connections and evoked neural firing were preserved. The polysynaptic responses, reflecting local mPFC circuit recruitment, also had lower IL fEPSP amplitude in aged rats, while evoked neural firing in the polysynaptic window was diminished in both mPFC regions. Age-associated polysynaptic changes in mPFC neural responses differed by the HC stimulation site. In aged rats, iHC stimulation resulted in a lower proportion of recruited neurons, while vHC stimulation resulted in diminished evoked mPFC firing rates, compared to young rats. Our findings demonstrate that aging selectively impairs vHC-mPFC direct synaptic transmission and mPFC local responses, with infralimbic circuits showing particular vulnerability. These circuit-level deficits may contribute to age-related impairments in cognitive flexibility.