Non-Canonical Projections from Ventral CA1 and Subicular Complex to CA3 Augments the Feedforward Hippocampal Trisynaptic Pathway

Abstract

The hippocampal formation is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the hippocampal formation, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral-genetic mapping techniques enhances our ability to determine the detailed complexity of hippocampal formation circuitry. In earlier work, we mapped a subiculum back-projection to CA1 prompted by the discovery of theta wave back-propagation from the subiculum to CA1 and CA3. We reason that this circuitry may represent multiple extended non-canonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant non-canonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1, perirhinal cortex, and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3. Together, our data provide a circuit foundation to explore novel functional roles contributed by these non-canonical hippocampal circuit connections to hippocampal dynamics and behavior.