Calcium dynamics in hypothalamic paraventricular oxytocin neurons and astrocytes associated with social and stress stimuli

Abstract

Activation of hypothalamic paraventricular oxytocin (OXT^PVN) neurons by social or stress stimuli triggers OXT release to respectively promote social investigation or buffer adverse effects of stress. Astrocytes, a type of glial cells, can bidirectionally interact with hypothalamic neurons to participate in local activity regulation within the paraventricular nucleus (PVN). It remains unknown whether contextual factors related to stimuli, as well as biological factors such as sex, influence OXT^PVN neuronal or astrocyte activity and/or their interactions. To address this question, we performed dual-color fiber photometry in freely behaving male and female mice to simultaneously record Ca²⁺ dynamics in OXT^PVN neurons and astrocytes during acute social (i.e. interactions with familiar vs. unfamiliar conspecifics) and stress (i.e. looming shadow) stimuli. During social stimuli, we observed most pronounced Ca²⁺ changes in OXT^PVN neurons in females, revealing sex- and familiarity context-specificity. No astrocyte Ca²⁺ changes were detected in either sex regardless of conspecific familiarity. In contrast, looming shadow stress increased Ca²⁺ in both OXT^PVN neurons and astrocytes in both sexes during an active escape (“run”) strategy. Ca²⁺ level changes in OXT^PVN neurons and astrocytes were significantly correlated during social investigations in both sexes regardless of conspecific familiarity. During looming shadow, this functional coupling was only observed in females during active escape. Together, our results suggest that sex, context, and behavioral strategy serve as major factors that shape the activity of OXT^PVN neurons and astrocytes, as well as their functional coupling, to potentially aid the adaptive response to social or stress stimuli.

Significance Statement Social or stress stimuli activate paraventricular OXT (OXT^PVN) neurons; however, it is unknown whether the neighbouring astrocytes show similar activity responses to these stimuli. To investigate this and examine the influence of context and sex, we performed dual-color fiber photometry recordings in freely behaving mice. Increased activity of OXT^PVN neurons, but not astrocytes, was pronounced in female mice while interacting with unfamiliar conspecifics. In contrast, both cell types were robustly activated while male and female mice actively escaped the looming shadow stress stimulus. OXT^PVN-astrocyte functional coupling was more robust during social investigation compared to looming shadow stress. In conclusion, social or stress stimuli activate OXT^PVN neurons and astrocytes and modify their functional coupling in a context- and sex-dependent manner.