Viral Tracing Identifies Parallel Disynaptic Pathways to the Hippocampus

Electrophysiological and lesion studies in rodents have shown that the dorsal (septal) and ventral (temporal) segments of the hippocampus have functional specializations that can be understood in terms of their anatomical connections with distinct brain areas. Here we explore the circuitry associated with the hippocampus using the pseudorabies virus-Bartha strain (PRV-Bartha) tracer in the rat to examine both direct (first-order) and indirect (second-order) projections to the hippocampus. Based on analysis of PRV-Bartha infection density, we demonstrate two parallel pathways from the limbic cortex to the hippocampus. A dorsal spatial cognition pathway provides disynaptic input from the retrosplenial, anterior cingulate, and orbital cortex to the dorsal hippocampus, with potential synaptic relays in the anterior thalamic nuclei and dorsolateral entorhinal cortex. A ventral executive control pathway provides disynaptic input from the prelimbic, infralimbic, and orbital cortex to the ventral hippocampus, with potential synaptic relays in the midline thalamic nuclei and the rostral caudo-medial entorhinal cortex. These data suggest a new anatomical framework for understanding the functional interactions between the cortex and hippocampus, especially in cognitive disorders that involve both structures, such as frontotemporal dementia.