Parasites have evolved various mechanisms for manipulating host behavior for the benefit of the parasite. This proposal concerns an example relevant to understanding fear and anxiety. The protozoan Toxoplasma gondii reproduces sexually in a two-species life cycle. The parasite reproduces in cats, and is then excreted. Infected feces are eaten by rodents, in which Toxoplasma forms cysts in muscle and the CNS. The life cycle is completed when the rodent is predated by a cat. Recent reports indicate that Toxoplasma alters the behavior of infected rodents so as to increase the likelihood of their being predated by cats. Specifically, the parasite blunts the innate aversion of rats for the urine of cats, producing instead an attraction towards cat pheromones. This appears to be a rather specific effect (rather than merely being secondary to damage to the olfactory system or to the CNS in general). Moreover, additional observations suggest that Toxoplasma decreases ethologically-relevant fear in other mammals as well. These findings suggest that Toxoplasma is selectively able to interfere with circuits of fear and anxiety in the rodent, a possibility unstudied to date, to my knowledge. The purpose of this exploratory grant is to examine how broadly Toxoplasma is able to suppress fear-related behaviors in rodents, and to begin to understand the neurobiology of this effect; potentially, this could pave the way for novel approaches to the treatment of anxiety disorders.
In Specific Aim 1, we will test the generality of these Toxoplasma effects, examining the behavior of infected rats with a battery of tests of differing facets of fear and anxiety. Controls will be mocked infected or infected with Sarcocystis neurona, a related protozoa that does not reproduce in a carnivore.
In Specific Aim 2, we will use a Toxoplasma strain that expresses a reporter gene during its phase of forming CNS cysts in order to do a detailed examination of the neuroanatomy of infection. We hypothesize that Toxoplasma infects brain regions involved in the circuitry of fear and anxiety (in particular, the amygdala).
In Specific Aim 3, we will examine the effects of Toxoplasma infection on cell number and volume, and on dendritic morphology in brain regions implicated in the prior two Specific Aims in the effects of Toxo.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Neuroendocrinology, Neuroimmunology, and Behavior Study Section (NNB)
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Winsky, Lois M
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Stanford University
Schools of Arts and Sciences
United States
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Vyas, A; Kim, S-K; Sapolsky, R M (2007) The effects of toxoplasma infection on rodent behavior are dependent on dose of the stimulus. Neuroscience 148:342-8
Vyas, Ajai; Kim, Seon-Kyeong; Giacomini, Nicholas et al. (2007) Behavioral changes induced by Toxoplasma infection of rodents are highly specific to aversion of cat odors. Proc Natl Acad Sci U S A 104:6442-7