One Peptide to Rule Them All: Deciphering Intricated Oxytocinergic Neuromodulation in the Hippocampus and Striatum Across Health and Huntington's Disease

Oxytocin (OT) has emerged as a multifunctional neuropeptide in the central nervous system (CNS), capable of coordinating different brain regions to adapt animal behaviours to both individual needs and environmental demands. From invertebrates to mammals, OT has evolved to modulate social, reproductive, and emotional behaviours and the existence of an oxytocinergic system in the brain is now well-established. This complex modulation is achieved through the neuromodulation of specific brain region to elicits the desired behaviours. However, the mechanism by which OT affects individual neuron processing and neural circuits activity remains unclear. In this study, we investigated the neuromodulatory effects of OT on single neurons and studied the region-specific oxytocinergic modulation by comparing two brain area, the CA1 region of hippocampus and the dorsal portion of striatum in mice. OT’s role in hippocampus has been well-characterized, providing a strong basis for examining its neuromodulatory effects on neurons. In contrast, role of OT in the dorsal striatum remains poorly studied, despite evidence suggesting its involvement in this region. Investigating OT’s effects on striatal cells and comparing their responses to those in the CA1 hippocampal region may help elucidate the specific roles of OT in these two areas. Our results from CA1 GABAergic interneurons (INs) -the neuronal population expressing the oxytocin receptor (OTR) in the CA1 area- revealed that, in addition to its known effects of inducing membrane depolarization and increasing firing rate, OT significantly affects neuronal processing by enhancing membrane excitability and altering action potential (AP) morphology. Additionally, linear mixed-effects models (LMMs) were employed to study how OT interacts with AP parameters to determine the observed spike changes and to functionally explain such modifications. The obtained results indicate that all these effects are independent of one another, suggesting that OT dramatically influence neuronal physiology and information processing. Next, we investigate OT’s neuromodulatory action on neurons in the dorsal striatum of mice of different sexes and ages. We observed two distinct OT-responding subpopulations of striatal medium spiny neurons (MSNs): one that was depolarized by OT (dMSNs), and another inhibited (iMSNs). These effects are consistent across sexes and developmental stages. Importantly, OT had a direct inhibitory action on iMSNs, suggesting that these neurons express functioning OTRs. We also found that OT directly inhibited fast-spiking interneurons (FS-INs) in the dorsal striatum, contrasting with its excitatory effects on CA1 INs. Our data demonstrate a role for OT modulation in dorsal striatum and highlight OT’s region-specific effects on neuronal population in different brain areas. Given the oxytocinergic system involvement in various human disease, we also explored whether the OT neuromodulation is affected by pathological conditions. Specifically, we examined OT's effects on MSNs in the dorsal striatum in a mouse model of Huntington’s disease (HD) at both early and late stages of pathology. We again observed a bimodal modulation of OT on MSNs, with a direct inhibition of iMSNs. Very importantly, OT-induced MSN activity was preserved in HD mice, showing no significant differences compared to wild-type mice. As hyperactivation of the striatum is reported in HD and OT is known to modulate the dopaminergic system (which is disrupted in this disease), our findings suggest that the oxytocinergic system could serve as a therapeutic target, potentially normalizing striatal activity or influencing dopaminergic release. Overall, our study provides new insights into the neuromodulatory actions of OT in the brain, highlighting its region-specific regulatory effects and potential therapeutic implications for neurodegenerative diseases like Huntington’s disease.