Center for the Study of Complementary and Alternative Therapies, University of Virginia School of Nursing, Charlottesville, VA 22908, USA.
Brain Behav Immun. 2011 Mar;25(3):443-60. doi: 10.1016/j.bbi.2010.11.005. Epub 2010 Nov 12.
Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from immune-sensory caudal brainstem sources target distinct populations of forebrain neurons that likely mediate different aspects of sickness. The caudal medullary catecholaminergic projections to the hypothalamus may significantly contribute to brain mechanisms that induce behavioral "fatigue" in the context of physiological stressors.
免疫挑战会导致明显的行为改变，包括疲劳、社交兴趣减少、厌食和嗜睡，但导致疾病行为的确切神经元机制仍难以捉摸。影响与疾病相关的行为的部分神经回路可能包括位于脑桥尾部的内脏感觉核，这是基于失活背侧迷走复合体 (DVC) 可以防止社交退缩的发现。这些脑干核团提供了多个神经元投射，这些投射靶向自主和应激相关神经回路的不同组成部分。特别是，延髓腹外侧部 (VLM) 和 DVC 中的儿茶酚胺神经元靶向下丘脑，并驱动神经内分泌对免疫挑战的反应，但它们在疾病行为中的特定作用尚不清楚。为了测试这条儿茶酚胺通路是否也介导了疾病行为，我们比较了 DVC 失活与儿茶酚胺通路的靶向损伤对探索行为的影响，探索行为提供了动机和疲劳的指标，以及通过 c-Fos 蛋白免疫组织化学检测评估的相关大脑激活模式。LPS 处理显著降低了探索行为，并在与应激和自主调节相关的脑区增加了 c-Fos 表达，包括室旁下丘脑 (PVN)、终纹床核 (BST)、中央杏仁核 (CEA)，而在涉及探索行为的脑区，激活减少了（海马、背侧纹状体、腹侧结节乳头核和腹侧被盖区）。DVC 失活和儿茶酚胺损伤都阻止了探索行为的减少，并完全阻止了 LPS 对行为相关区域 c-Fos 表达的抑制作用。相比之下，DVC 失活抑制了 LPS 诱导的 CEA 和 BST 中的激活，但儿茶酚胺损伤没有。这些发现支持了这样一种观点，即来自免疫感觉性脑桥尾部的平行通路靶向前脑神经元的不同群体，这些神经元可能介导了疾病的不同方面。尾髓的儿茶酚胺投射到下丘脑可能对诱导生理应激下的行为“疲劳”的大脑机制有重要贡献。
