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.
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