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 glycemic 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-reactive 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 glycemic 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 behavior 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 through the recruitment of local RVLM inhibitory neurons. Ultimately, the excitatory/inhibitory balance of vmPFC synapses in the RVLM may regulate stress reactivity as well as stress-related health outcomes.
Organismal survival and adaptation to stress rely on brainstem catecholaminergic neurons. In particular, catecholaminergic neurons in the rostral ventrolateral medulla (RVLM) drive sympathetic activity and enable physiological adaptations, including vasoconstriction, corticosterone release, and glycemic mobilization. However, it is unclear how brain regions involved in the cognitive appraisal of stress regulate the activity of RVLM neurons. Our previous studies found that the rodent infralimbic prefrontal cortex (IL) integrates behavioral and physiological responses to stress. Thus, a potential IL‐to‐RVLM connection would represent a crucial link between stress appraisal and sympathetic reactivity. In the current study, we investigated a direct IL‐to‐RVLM circuit by targeting a genetically‐encoded anterograde tracer under the control of the CaMKIIα promoter to the IL of adult male and female rats. Analysis revealed that IL terminals apposed RVLM neurons expressing the catecholamine‐synthesizing enzyme dopamine beta hydroxylase. Further, IL input to catecholamine cells was widespread throughout the rostral to caudal extent of the VLM in both male and female rodents. Quantification of innervation density revealed that males had a larger proportion of VLM catecholamine neurons receiving IL inputs relative to female rats. Additionally, IL appositions were identified on GABAergic and glycinergic neurons in both sexes. Accordingly, we hypothesized that IL projections may activate local RVLM inhibitory cells to limit sympathetic output. To test this hypothesis, we injected a viral vector coding for channelrhodopsin‐2 (ChR2) in the IL of males and females. Next, a fiber optic cannula was implanted dorsal to the RVLM to evoke IL synaptic glutamate release. Animals then received photostimulation during restraint stress with blood sampled to determine stress reactivity. Compared to controls, male rats expressing ChR2 on IL terminals had suppressed glycemic stress responses (p < 0.05). In contrast, stimulation of the IL‐RVLM circuit in females did not affect glucose mobilization (p < 0.05). However, ChR2 decreased corticosterone responses to stress relative to control rats in both sexes (males, p < 0.01; females, p < 0.05). Thus, both male and female rats have a direct circuit from the IL portion of the mPFC to catecholamine‐synthesizing cells of the RVLM that limits glucocorticoid stress responses, likely through the activation of local inhibitory neurons. However, the density of this circuit is greater in males, potentially accounting for reduced glycemic responses. Ultimately, excitatory/inhibitory balance at IL synapses in the RVLM may be critical for the health consequences of stress.
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