Gut to Brain Pathways for Infection-Induced Anxiety

描述（由申请人提供）：本申请中提出的实验 应用程序检查感染性微生物在 胃肠道对情感和行为的影响，可能介导的影响 通过刺激通向中枢神经系统的内脏感觉通路 （CNS）。这项建议是基于证明低剂量 （“亚临床”）感染食源性病原体空肠弯曲菌 在经口激发的小鼠中诱导焦虑样行为。因此， 从目前对管理能力的机制的理解来看， 感染影响行为，因为这些感染引起的行为 改变发生在没有明显的身体疾病症状，通常 伴随着感染引起的行为改变。此外，新数据 证明这种亚临床感染导致特异性激活 大脑中与焦虑相关的区域， 肠-脑通路抑制C.空肠感染引起的脑激活。 因此，我们的具体目标是：1）确定周边伴随物 参与肠道水平，可能是负责的能力， 亚临床C.空肠感染以诱导小鼠的焦虑样行为。的 对C. 空肠将结合组织化学和免疫分析进行评估 感染的动物来扩展以前的工作。我们还将研究 局部免疫激活在没有全身反应的情况下发生; 2） 确定从肠道到中枢神经系统的特定内脏感觉通路 在口腔细菌攻击后被激活。我们将评估 激活标志物c-fos在肠和迷走神经感觉神经元中的表达 以及脊髓中的感觉神经元，并确定 选择性肝和腹腔迷走神经切断术;和3）确定连接性， 神经化学特性的神经元驱动的C。空肠感染形成a 特定的神经回路导致感染引起的行为改变。 总的来说，上述目标将寻求建立某些行为可能 在某种程度上，通过肠道内的感染性微生物， 涉及内脏感觉输入的“肠-脑”轴。一个链接之间的共同 胃肠道感染的发生，尤其是那些不 产生表明感染的明显临床症状，焦虑可能 因此，确定一个以前未确定的情况， 在调节行为方面的作用。

DESCRIPTION (provided by applicant): The experiments proposed in this application examine the effects of infectious microorganisms in the gastrointestinal tract on affect and behavior, effects posited to be mediated by stimulation of a visceral sensory pathway to the central nervous system (CNS). This proposal is based on the demonstration that a low-dose ("subclinical") infection with the food-borne pathogen Campylobacter jejuni induces anxiety-like behavior in orally challenged mice. As such, it differs from the current understanding of the mechanisms that govern the ability of infection to influence behavior since these infection-induced behavioral alterations occur in absence of obvious physical sickness symptoms that usually accompany infection-induced behavioral alterations. Further, new data demonstrate that such subclinical infection results in the specific activation of regions within the brain associated with anxiety and that interruption of gut-brain pathways inhibits C. jejuni infection-induced brain activation. Thus, our Specific Aims are: 1) To determine the peripheral concomitants involved at the gut level that may be responsible for the ability of subclinical C. jejuni infection to induce anxiety-like behavior in mice. The degree of behavioral alterations induced in response to oral challenge with C. jejuni will be assessed in conjunction with histochemical and immune analysis of infected animals to extend previous work. We will also examine whether a localized immune activation occurs in the absence of a systemic response; 2) To identify the specific visceral sensory pathways leading from the gut to the CNS that are activated following oral bacterial challenge. We will assess the expression of the activation marker c-fos in enteric and vagal sensory neurons as well as sensory neurons in the spinal chord, and determine the impact of selective hepatic and celiac vagotomy; and 3) To determine connectivity and neurochemical identities of neurons driven by C. jejuni infection that form a specific neurocircuitry leading to infection-induced alterations of behavior. Collectively, the above aims will seek to establish that certain behaviors may be modulated, in part, by infectious microorganisms within the gut through the "gut-to-brain" axis involving visceral sensory input. A link between the common occurrence of gastrointestinal infections, especially those which do not produce overt clinical symptoms indicative of infection, with anxiety may therefore identify a previously unidentified circumstance which may play a contributing role in regulating behavior.