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Infection-induced viscerosensory signals from the gut enhance anxiety: Implications for psychoneuroimmunology

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Abstract

Infection and inflammation lead to changes in mood and cognition. Although the “classic” sickness behavior syndrome, involving fatigue, social withdrawal, and loss of appetites are most familiar, other emotional responses accompany immune activation, including anxiety. Recent studies have shown that gastrointestinal bacterial infections lead to enhanced anxiety-like behavior in mice. The bacteria-induced signal is most likely carried by vagal sensory neurons, and occurs early on (within 6 h) during the infection. These signals induce evidence of activation in brain regions that integrate viscerosensory information with mood, and potentiate activation in brain regions established as key players in fear and anxiety. The findings underline the importance of viscerosensory signals arising from the gastrointestinal tract in modulation of behaviors appropriate for coping with threats, and suggest that these signals may contribute to affective symptoms associated with gastrointestinal disorders.

Section snippets

1. Introduction

In the late 1800s William James, a psychologist at Harvard University, published a provocative theory of emotion: that the perception of emotions follows from perception of our physical responses to cognitive apprehension of external threats (or more pleasant stimuli). That is: the experience of emotion is integrated with somato- and viscerosensory signals that result from cognitively driven motor, neuroendocrine, or autonomic responses, in a kind of brain–body–brain “loop” communication

2. Infection-induced anxiety

We first became involved with these issues when one of us (ML) observed that mice treated per-orally with live bacteria (Campylobacter jejuni) seemed more anxious than saline-treated control mice (Lyte et al., 1998). This observation was confirmed by comparing the behavior of C. jejuni-treated mice and control mice on the elevated plus maze. However, there was no evidence that the bacteria had reached the systemic circulation (and thus the brain), or that the infection induced circulating

3. Brain substrates for infection-induced anxiety-like behavior

As James predicted and as recent studies now support, brain regions involved in emotions are associated with viscerosensory and autonomic (visceral motor) processing (Craig, 2003, Nauta, 1971, Price, 1999, Zagon, 2001). Previous studies using immune challenges with bacterial products (LPS) or cytokines, such as IL-1, that usually induce symptoms of behavioral depression have indicated that, indeed, these immune stimuli also activate brain regions involved in viscerosensory processing (Goehler

4. What may be the adaptive value of enhanced anxiety during gut infection?

An important issue to keep in mind regarding experiments investigating emotional states in animals, especially anxiety, is that the characteristics of the testing procedure influence the findings. In the case of the open field/hole board, this apparatus represents a possibly dangerous novel environment. It can be thought of as analogous to that which an animal might encounter when foraging in an unknown area for food, or in any other exploratory behavior in the wild. The open character of the

5. Bidirectional interactions of bacteria/immune-brain-gut axis: “Bottom–up” and “top–down” influences on gastrointestinal health and mood

One of the core principles of psychoneuroimmunology is the bidirectional influence of the immune and nervous systems on mood and health. That is, affective symptoms associated with illness or inflammation follow not only from stress of dealing with a medical condition, or personality factors (“top–down” brain-mediated) but also from the effects of cytokines, or other products of inflammation, induced by infection or inflammation (“bottom–up” immune and viscerosensory mediated). In the case of

6. Conclusion

It seems reasonable to assert that linking emotions to homeostatic mechanisms conveys powerful adaptive advantages, as this is a salient way for conditions within the body to influence behavior. In the case of infection-induced anxiety, increasing cautiousness in an animal that may soon become ill could save its life. In a similar way, the development of a conditioned taste aversion (a learned negative association of recently eaten food with illness) following the survival of food poisoning

Acknowledgments

This work was supported by NIH Grants MH50431, MH64648, and MH68834.

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