Differentiated Presynaptic Input to OLMɑ2 Cells Along the Hippocampal Dorsoventral Axis: Implications for Hippocampal Microcircuit Function

Abstract

The dorsal and ventral hippocampus have distinct processing properties, but it remains unclear if interneuron subtypes differ in connectivity along the dorsoventral axis. Oriens lacunosum-moleculare (OLM) interneurons, identified by the Chrna2 gene, are known to regulate memory processes differently along this axis. OLMɑ2 cells bidirectionally modulate risk-taking behavior, while ventral hippocampal medial prefrontal cortex (mPFC)-projecting neurons regulate approach and avoidance behaviors. Using rabies virus-mediated monosynaptic retrograde tracing, we show that OLMɑ2 cells receive differential innervation across the dorsal, intermediate, and ventral hippocampus. We find that CA1 and CA3 inputs differ between hippocampal poles, suggesting that OLMɑ2 cells may have distinct feedback and feed-forward inhibitory roles in the hippocampal microcircuit. Intermediate OLMɑ2 cells uniquely receive substantial input from the subiculum and dorsal/medial raphe nuclei, as well as widespread CA2 inputs potentially linked to social memory. The medial septum and diagonal band of Broca provide cholinergic, GABAergic, and glutamatergic inputs across the axis, likely influencing disinhibition and oscillatory activity during various behavioral states. Excitatory input to intermediate-ventral OLMɑ2 cells partly arises from CA1 projection neurons targeting the mPFC. This suggests a gate-switching function that favors CA3 input to projection neurons by two different mechanisms related to feedback and feed-forward inhibition. In conclusion, OLMɑ2 cells exhibit distinct presynaptic input profiles along the dorsoventral axis, with major differences in the proportions of intrahippocampal inputs, highlighting their diverse roles in hippocampal microcircuits.