Corticosterone inhibits vagal afferent glutamate release in the Nucleus of the Solitary Tract via retrograde endocannabinoid signaling.

Circulating blood glucocorticoid levels are dynamic and responsive to stimuli that impact autonomic function. In the brainstem, vagal afferent terminals release the excitatory neurotransmitter glutamate onto neurons in the nucleus of the solitary tract (NTS). Vagal afferents integrate direct visceral signals and circulating hormones with ongoing NTS activity to control autonomic function and behavior. Here we investigated the effects of corticosterone (CORT) on glutamate signaling in the NTS using patch-clamp electrophysiology on brainstem slices containing the NTS and central afferent terminals from male C57BL/6 mice. We found that CORT rapidly decreased both action-potential evoked and spontaneous glutamate signaling. The effects of CORT were phenocopied by dexamethasone and blocked by mifepristone, consistent with glucocorticoid receptor (GR) mediated signaling. While mRNA for GR was present in both the NTS and vagal afferent neurons, selective intracellular quenching of G-protein signaling in postsynaptic NTS neurons eliminated the effects of CORT. We then investigated the contribution of retrograde endocannabinoid (eCB) signaling, which has been reported to transduce non-genomic GR effects. Pharmacological or genetic elimination of the cannabinoid type 1 (CB1) receptor signaling blocked CORT suppression of glutamate release. Together our results detail a mechanism whereby the NTS integrates endocrine CORT signals with fast neurotransmission to control autonomic reflex pathways.