Conserved inhibitory motifs yield distinct hippocampal functions through regional circuit embedding

Abstract

The ventral hippocampus (vHipp) is increasingly recognized for its role in processing probabilistic threats and emotional salience, yet the circuit mechanisms underlying these computations remain unclear. Here, we investigated how oriens-lacunosum moleculare interneurons expressing the 2 subunit of the nicotinic acetylcholine receptor (OLM2 cells) contribute to hippocampal function along the longitudinal axis. Combining cell-type specific optogenetics, behavioral assays, monosynaptic and transsynaptic viral tracing, we compared intermediate hippocampal (iHipp) and vHipp OLM2 populations. We show that OLM2 cells exert regionally distinct control over behavior. Manipulation of iHipp OLM2 cells selectively influenced object-directed exploration and novel object processing without affecting anxiety-like behavior, whereas vHipp OLM2 cells modulated arousal and emotionally driven avoidance without contributing to object memory. Circuit tracing revealed that this functional double dissociation is paralleled by distinct connectivity profiles: iHipp is preferentially embedded in sensory cortical networks, whereas vHipp is strongly connected to limbic structures, including the basolateral amygdala and nucleus accumbens. Notably, despite robust regional amygdala-hippocampal connectivity, OLM2 interneurons themselves received sparse direct amygdala input, indicating that emotional modulation is mediated indirectly via hippocampal pyramidal cell pathways. In contrast, stimulation of basolateral amygdala projections to vHipp promoted approach behavior without inducing generalized aversion, further supporting pathway- and cell-type specific encoding of valence and salience. Together, our findings demonstrate that OLM2 interneurons implement a longitudinally organized inhibitory framework in which conserved microcircuit motifs yield distinct behavioral outcomes, depending on their embedding within region specific input and output networks. This work identifies a mechanistic basis for functional specialization along the hippocampal axis and highlights interneuron positioning as a key determinant of hippocampal contributions to cognition and emotion.