Pace Sebastian A, Lukinic Ema, Wallace Tyler, McCartney Carlie, Myers Brent
Department of Biomedical Sciences, Colorado State University, Fort Collins, CO, USA.
J Physiol. 2024 Mar;602(5):949-966. doi: 10.1113/JP285627. Epub 2024 Feb 14.
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. 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.
暴露于应激刺激会促进多系统的生物反应以恢复体内平衡。延髓头端腹外侧区（RVLM）的儿茶酚胺能神经元促进交感神经活动并促进生理适应，包括血糖动员和皮质酮释放。虽然尚不清楚参与应激认知评估的脑区如何调节RVLM神经活动，但最近的研究发现啮齿动物腹内侧前额叶皮层（vmPFC）介导应激评估和生理应激反应。因此，vmPFC-RVLM连接可能代表一种将应激评估与生理反应联系起来的神经回路机制。当前的研究利用基因编码的顺行和逆行示踪剂研究了直接的vmPFC-RVLM神经回路。综合这些研究发现，应激激活的vmPFC神经元投射到雄性和雌性大鼠整个腹外侧髓质的儿茶酚胺能神经元。接下来，我们利用光遗传学终末刺激来诱发vmPFC在RVLM中的突触谷氨酸释放。在束缚应激期间光刺激vmPFC-RVLM神经回路可抑制雄性大鼠的血糖应激反应，而不改变雌性大鼠的反应。然而，神经回路刺激可降低两性对应激的皮质酮反应。神经回路刺激在两性中均未调节情感行为。进一步分析表明，神经回路刺激在两性中均优先激活非儿茶酚胺能髓质神经元。此外，vmPFC终末靶向髓质抑制性神经元。因此，雄性和雌性大鼠均有从vmPFC到RVLM的直接投射，这可能通过募集局部RVLM抑制性神经元来降低内分泌应激反应。最终，RVLM中vmPFC突触的兴奋/抑制平衡可能调节应激反应性和与应激相关的健康结果。要点：腹内侧前额叶皮层的谷氨酸能传出纤维靶向整个腹外侧髓质的儿茶酚胺能神经元。部分分离的、应激激活的腹内侧前额叶皮层群体支配头端和尾端腹外侧髓质。刺激头端腹外侧髓质中的腹内侧前额叶皮层突触可降低雄性和雌性大鼠应激诱导的糖皮质激素释放。刺激头端腹外侧髓质中的腹内侧前额叶皮层终末优先激活非儿茶酚胺能神经元。腹内侧前额叶皮层终末靶向髓质抑制性神经元。
