Neuronal circuits, neurophysiology and optogenetic approaches

Publication date: 20/10/2025

Authors: Buron J., Linossier A., Gestreau C., Schaller F., Tyzio R., Felix M. S., Matarazzo V., Thoby-Brisson M., Muscatelli F. & Menuet C.

Journal: Nature Neuroscience

Commentary: Respiratory heart rate variability (RespHRV), the cyclical modulation of heart rate by respiration, is a robust index of cardiac parasympathetic activity and is enhanced during relaxation and positive socio-emotional states. Although oxytocin (OT) has been implicated in increasing RespHRV in humans, the central neuronal mechanisms responsible for this modulation remained unresolved. Using complementary anatomical tracing, optogenetics, chemogenetics, in vivo electrophysiology, whole-body plethysmography, telemetry, and ex vivo brainstem preparations in rodents, Buron et al. identify a dedicated hypothalamus–brainstem–heart circuit through which OT selectively amplifies RespHRV without altering respiratory rhythm. The authors demonstrate that a caudal subpopulation of paraventricular nucleus OT neurons projects preferentially to the pre-Bötzinger complex (preBötC), where OT acts on Oxtr-expressing glycinergic inspiratory neurons. Activation of these neurons strengthens inspiratory inhibitory input onto cardiac vagal neurons of the nucleus ambiguus, thereby increasing the respiratory gating of parasympathetic cardiac outflow. This mechanism selectively enlarges the inspiratory modulation of vagal activity and heart rate while preserving baseline heart rate and respiratory frequency, indicating that OT regulates cardiorespiratory coupling rather than respiratory rhythm generation itself. Functional experiments further establish the physiological relevance of this circuit during stress recovery. Chemogenetic inhibition of hypothalamic OT neurons impairs the restoration of RespHRV following acute restraint stress, demonstrating that endogenous OT signaling contributes to the transition from stress to a calm autonomic state. Collectively, the study defines a previously unrecognized hypothalamus–brainstem–heart pathway linking emotional state to cardiac autonomic regulation. These findings provide a mechanistic framework for the beneficial effects of oxytocin on autonomic homeostasis and identify a neural substrate that may be therapeutically targeted in disorders characterized by reduced RespHRV, including anxiety, depression, autism spectrum disorder, hypertension, and heart failure.

Commented by: Federica Antonelli

DOI: https://doi.org/10.1038/s41593-025-02074-2