INTERPEDUNCULAR NUCLEUS–VENTRAL HIPPOCAMPUS CIRCUIT CONTRIBUTIONS TO SOCIAL STRESS

Social stress elevates brain nerve growth factor (NGF) levels, which can reshape the activity of stress-sensitive circuits. The midbrain interpeduncular nucleus (IPN), a regulator of anxiety and social behavior, robustly expresses the NGF receptor TrkA and densely innervates the ventral hippocampus (vHPC); a hub for social and anxiety-related signalling and important NGF source. Despite this anatomical link, behavioural relevance and mechanistic role of the IPN–vHPC pathway remains unclear. Accordingly, we sought to define the electrophysiological properties and functional role of vHPC innervating IPN neurons. RNAscope in situ hybridization allowed molecular characterization of IPN neurons. Viral based tract tracing was used to map IPN-vHPC innervation. Electrophysiological whole cell patch clamp and multielectrode array recordings allowed verification of IPN neurons’ sensitivity to NGF. Resident-intruder protocol was used to determine whether vHPC-projecting IPN neurons encode aggression-related information. RNAscope showed that IPN neurons expressing mRNA for TrkA are localized in rostral, intermediate and lateral parts, consistent with tract-tracing studies identifying numerous vHPC-projecting cells in these regions. Patch-clamp recordings from anterior IPN showed no detectable response to NGF. Electrophysiological recordings with optogenetic tagging of IPN neurons innervating vHPC, revealed a small subset of identified neurons responding to NGF with inward currents. Multielectrode array recordings showed heterogeneous effects of NGF on IPN neurons. In the resident-intruder test increased c-Fos expression in IPN cells was observed. Our findings reveal that the IPN-vHPC circuit is enriched in TrkA-expressing subregions, shows selective, heterogeneous NGF sensitivity and is recruited by social stress, supporting its role in stress-linked behavioural modulation.