Cortical–brainstem circuitry attenuates physiological stress reactivity

Abstract Exposure to stressful stimuli promotes multi‐system biological responses to restore homeostasis. Catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) facilitate sympathetic activity and promote physiological adaptations, including glycaemic mobilization and corticosterone release. While it is unclear how brain regions involved in the cognitive appraisal of stress regulate RVLM neural activity, recent studies found that the rodent ventromedial prefrontal cortex (vmPFC) mediates stress appraisal and physiological stress responses. Thus, a vmPFC–RVLM connection could represent a circuit mechanism linking stress appraisal and physiological reactivity. The current study investigated a direct vmPFC–RVLM circuit utilizing genetically encoded anterograde and retrograde tract tracers. Together, these studies found that stress‐activated vmPFC neurons project to catecholaminergic neurons throughout the ventrolateral medulla in male and female rats. Next, we utilized optogenetic terminal stimulation to evoke vmPFC synaptic glutamate release in the RVLM. Photostimulating the vmPFC–RVLM circuit during restraint stress suppressed glycaemic stress responses in males, without altering the female response. However, circuit stimulation decreased corticosterone responses to stress in both sexes. Circuit stimulation did not modulate affective behaviour in either sex. Further analysis indicated that circuit stimulation preferentially activated non‐catecholaminergic medullary neurons in both sexes. Additionally, vmPFC terminals targeted medullary inhibitory neurons. Thus, both male and female rats have a direct vmPFC projection to the RVLM that reduces endocrine stress responses, likely by recruiting local RVLM inhibitory neurons. Ultimately, the excitatory/inhibitory balance of vmPFC synapses in the RVLM may regulate stress reactivity and stress‐related health outcomes. image Key points Glutamatergic efferents from the ventromedial prefrontal cortex target catecholaminergic neurons throughout the ventrolateral medulla. Partially segregated, stress‐activated ventromedial prefrontal cortex populations innervate the rostral and caudal ventrolateral medulla. Stimulating ventromedial prefrontal cortex synapses in the rostral ventrolateral medulla decreases stress‐induced glucocorticoid release in males and females. Stimulating ventromedial prefrontal cortex terminals in the rostral ventrolateral medulla preferentially activates non‐catecholaminergic neurons. Ventromedial prefrontal cortex terminals target medullary inhibitory neurons.