Functional specialization of OLM α2 interneurons emerges from differential longitudinal hippocampal-amygdala wiring

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 α2 subunit of the nicotinic acetylcholine receptor (OLMα2 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 OLMα2 populations. We show that OLMα2 interneurons exert regionally distinct control over behavior. Manipulation of iHipp OLMα2 cells selectively influenced object-directed exploration and novel object processing without affecting anxiety-like behavior, whereas vHipp OLMα2 cells modulated arousal and emotionally driven avoidance without contributing to object memory. Circuit tracing revealed that these functional differences are 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, OLMα2 interneurons themselves received sparse direct amygdalar 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 OLMα2 interneurons implement a longitudinally organized inhibitory framework in which identical 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. Competing Interest Statement The authors have declared no competing interest. List of abbreviations - dHipp - Dorsal hippocampus - iHipp - Intermediate hippocampus - vHipp - Ventral hippocampus - OLM - Oriens lacunosum-moleculare - BLA - Basolateral amygdala - nAcc - Nucleus accumbens - NOR - Novel object recognition - COP - Conditioned odor preference - ChR2 - Channelrhodopsin-2 - Arch - Archaerhodopsin - POA - Predator odor aversion - eYFP - Enhanced yellow fluorescent protein - GFP - Green fluorescent protein - CamKII - Calmodulin-dependant Kinase II - AAV - Adeno-associated virus