Somatodendritic release of oxytocin from the hypothalamic supraoptic nucleus (SON) can reach the central amygdala (CeA) to act in a hormone-like manner

Authors: Elba C. Lira 1,2 , Manuel B. Ongolo 1,2 and, Javier E. Stern 1,2 1 Neuroscience Institute and 2 Center for Neuroinflammation and Cardiometabolic Diseases, Georgia State University, Atlanta GA, USA In addition to releasing their peptidergic cargo from axonal terminals in the posterior pituitary and other brain areas, oxytocin (OT) and vasopressin magnocellular neurons (MCNs) also release their peptides from somatodendritic compartments (i.e., somatodendritic release, SDR). It is known that the SDR of these peptides fulfills autocrine and paracrine functions, including mediating interpopulation communication among functionally distinct populations of neurons within the hypothalamic paraventricular nucleus (Son et al., 2013, de Kloet et al., 2017). Still, whether SDR of OT/VP can reach much more distant targets, acting in a hormone-like manner within the brain, remains unknown. Here, we tested whether SDR of OT from the supraoptic nucleus (SON) can reach the central amygdala (CeA), a brain region located ~1.5 mm from the SON, where OT regulates anxiety-like behaviors. We used electrophysiology, laser photolysis of caged glutamate, and OT sniffer biosensor cells in an ex-vivo slice preparation. Local glutamate uncaging within the SON in the presence of TTX (which evokes SDR but not axonal release of neuropeptides (Pitra et al., 2019)) evoked rapid and robust OT-SDR, as shown by biosensor responses (incidence: 43.3 ± 8.6% of responsive biosensors, latency: 0.3 ± 1.0 min). To determine if OT-SDR within the SON diffused sufficiently to reach the CeA, biosensors were placed in the CeA while glutamate uncaging was performed in the SON. Initially, experiments were done in the absence of TTX to maximize the release of OT. Surprisingly, we observed CeA biosensor responses following SON stimulation. However, their incidence and latency were significantly lower and slower than those observed within the SON (incidence: 7.0 ± 1.4% of responsive biosensors, latency: 2.8 ± 0.5.min, p< 0.001 compared to SON). Given that the slice is under constant unidirectional flow, we tested whether CeA responses depended on the flow's direction. We found similar responses regardless of whether the OT-SDR diffused in favor or against the perfusion flow. To determine whether the CeA responses following SON stimulation reflected SDR and/or axonal release, we repeated SON stimulations in the presence of TTX. The incidence of responses was not affected; however, the latency of CeA biosensor responses was significantly slower in TTX (p= 0.01), suggesting that CeA responses may involve a combination of both SDR and axonal release. Our studies indicate that somatodendritically-released OT can diffuse relatively long distances to reach remote targets, including the amygdala. These results suggest that in addition to acting in an autocrine and paracrine manner, SDR OT can also act in a hormone-like manner within the brain. Whether a similar phenomenon is observed in vivo, however, remains to be determined. 1R01HL162575-01 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.