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 应用检验感染性微生物对环境的影响 胃肠道对情绪和行为的影响，被认为是中介效应 通过刺激内脏感觉通路到达中枢神经系统 (CNS)。这项提议的基础是，低剂量的 (“亚临床”)食源性致病菌空肠弯曲菌感染 在口服挑战的小鼠中诱导焦虑样行为。因此，它是不同的 从目前对支配能力的机制的理解来看 感染影响行为，因为这些感染导致行为 在没有明显的躯体疾病症状的情况下，通常会发生变化 伴随着感染引起的行为改变。此外，新的数据 证明这种亚临床感染导致了特定的激活 大脑中与焦虑相关的区域，并中断 肠脑通路抑制空肠弯曲菌感染诱导的脑激活。 因此，我们的具体目标是：1)确定外围伴随 在肠道水平参与，这可能是负责的能力 空肠弯曲菌亚临床感染诱导小鼠焦虑样行为。这个 口服液刺激引起的行为改变程度。 将结合组织化学和免疫分析对空肠进行评估 对受感染动物的研究，以扩展之前的工作。我们还将研究是否存在 局部免疫激活发生在没有全身反应的情况下；2) 确定从肠道到中枢神经系统的特定内脏感觉通路 在口腔细菌挑战后被激活。我们将评估 激活标记c-fos在肠和迷走神经感觉神经元中的表达 以及脊髓脊索中的感觉神经元，并确定 选择性肝和腹腔迷走神经切断术；以及3)确定连接性和 空肠弯曲菌感染所致神经元的神经化学特性 导致感染引起的行为改变的特定神经回路。 总而言之，上述目标将寻求确定某些行为可能 在一定程度上由肠道内的感染性微生物通过 涉及内脏感官输入的“肠脑”轴。共同利益之间的纽带 胃肠道感染的发生，特别是那些没有 产生明显的临床症状，表明感染，并伴有焦虑 因此确定以前未确定情况，它可能会对 在规范行为方面的贡献作用。

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.