Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States.
Department of Pharmacology, Physiology, and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States.
Brain Behav Immun. 2019 Jul;79:102-113. doi: 10.1016/j.bbi.2019.01.021. Epub 2019 Jan 29.
Exposure to psychosocial stress is known to precipitate the emergence of stress related psychiatric disorders such as depression and anxiety. While mechanisms by which this occurs remain largely unclear, recent evidence points towards a causative role for inflammation. Neurotransmitters, such as norepinephrine (NE), are capable of regulating expression of proinflammatory cytokines and thus may contribute to the emergence of stress-related disorders. The locus coeruleus (LC) is the major source of norepinephrine (NE) to the brain and therefore the current study utilized N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), an LC selective noradrenergic neurotoxin, to determine the discrete involvement of the LC-NE system in social defeat-induced inflammation in LC projection regions including the central amygdala (CeA), dorsal raphe (DR) and plasma. In the current study, rats were exposed to brief social defeat or control manipulations on 5 consecutive days. To determine whether a history of social defeat enhanced or "primed" the inflammatory response to a subsequent defeat exposure, all rats regardless of stress history were exposed to an acute social defeat challenge immediately preceeding tissue collection. As anticipated, prior history of social defeat primed inflammatory responses in the plasma and CeA while neuroinflammation in the DR was markedly reduced. Notably, DSP-4 treatment suppressed stress-induced circulating inflammatory cytokines independent of prior stress history. In contrast, neuroinflammation in the CeA and DR were greatly augmented selectively in DSP-4 treated rats with a history of social defeat. Together these data highlight the dichotomous nature of NE in stress-induced inflammatory priming in the periphery and the brain and directly implicate the LC-NE system in these processes.
已知心理社会应激会引发与应激相关的精神疾病，如抑郁症和焦虑症。虽然其发生的机制在很大程度上尚不清楚，但最近的证据表明炎症起着致病作用。神经递质，如去甲肾上腺素（NE），能够调节促炎细胞因子的表达，因此可能有助于应激相关疾病的出现。蓝斑（LC）是大脑中去甲肾上腺素（NE）的主要来源，因此本研究利用 N-(2-氯乙基)-N-乙基-2-溴苯甲胺（DSP-4），一种 LC 选择性去甲肾上腺素能神经毒素，来确定 LC-NE 系统在 LC 投射区（包括中央杏仁核（CeA）、背侧中缝核（DR）和血浆）中与社会挫败引起的炎症的离散关系。在本研究中，大鼠连续 5 天接受短暂的社会挫败或对照处理。为了确定社会挫败的历史是否增强或“启动”了随后的挫败暴露后的炎症反应，所有大鼠无论其应激史如何，都在组织采集前立即暴露于急性社会挫败挑战。正如预期的那样，先前的社会挫败史启动了血浆和 CeA 的炎症反应，而 DR 的神经炎症则明显减少。值得注意的是，DSP-4 治疗独立于先前的应激史抑制了应激诱导的循环炎症细胞因子。相比之下，在有社会挫败史的 DSP-4 处理大鼠中，CeA 和 DR 中的神经炎症被选择性地大大增强。这些数据共同强调了 NE 在应激诱导的外周和大脑炎症启动中的双重性质，并直接涉及 LC-NE 系统在这些过程中的作用。
