Toxoplasma infection and dopamine signaling-dependent behaviors
McFarland, Ross Douglas
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Toxoplasma gondii is an apicomplexan obligate intracellular parasite, capable of infecting a wide range of hosts and cell types. Human infection with the parasite involves an acute replicative phase followed by long term chronic neurotropic infection that may persist for decades and is generally observed as asymptomatic. Clinical interest in the parasite and the accompanying disease of toxoplasmosis, generally centers around infection of immune naïve or immune compromised patients, such as in utero infections and late stage AIDS cases. However, comprehensive examinations of patient serology suggest that antibodies to T. gondii are significantly correlated with some psychiatric disorders. Hampering the study of the putative link between infection and psychiatric disease, animal models of T. gondii infection have suffered from inconsistent behavioral phenotypes. Robust and reproducible behavioral phenotypes consistently altered during parasitic infection have been largely lacking in the field. The thesis presented here centers around my work to characterize a consistent and significant behavioral change associated with T. gondii infection in mice. We have pioneered a stimulant induced activity assay wherein infected mice show significantly blunted response to cocaine or amphetamine administration, two stimulants that produce hyperactivity by increasing the release of dopamine from pre-synaptic terminals. We have established that blunted response to stimulants are independent of mouse sex or strain, the duration of infection or the strain of the parasite. The failure of these drugs to induce hyperactive in infected mice led us to hypothesize that infection affects host dopamine signaling. Consistent with this hypothesis, we have found that chronic T. gondii infection is associated with a significant decrease in expression of vesicular monoamine transporter and dopamine transporter, host factors that mediate the behavioral and synaptic effects of psychostimulants. These molecular changes are not associated with gross abnormalities in the brain morphology, cortical layering or overall architectonics. In addition, we found no synaptic damage, and no significant damage to brain morphology through inflammation or parasitic proliferation. Along with the characterization of the behavioral effects described in this thesis, I also work to answer a persistent question about the role of the parasite in dopamine signaling which has existed in the field of T. gondii biology and host behavior. This question stems from the observation that the T. gondii parasite genome contains two genetic homologues of tyrosine hydroxylase (TH), the rate limiting enzyme in the production of dopamine in mammalian brains. Previous studies have shown that TH expression in the host brain is increased in and around the encysted parasites, along with levels of extra-cellular dopamine. Considerable speculation persists in the field about whether the Toxoplasma TH that is upregulated during brain specific infection is responsible for a direct impact of infection on host brain function, leading to behavioral change. In order to address this question, a collaborating lab provided me with parasites deleted for the TH homolog gene. Applying these mutant parasites to my model of behavioral change, I was able to conclusively show that the impact of infection on reaction to dopaminergic drugs is wholly independent of Toxoplasma TH expression. Additionally, TH expression by the host, not the parasite, is responsible for any measurable changes in in vivo dopamine release in the striatum. Together, the thesis work represents a thorough analysis of the behavioral impacts that T. gondii infection has on host response to dopaminergic drugs, and then the role that pre-synaptic dopamine signaling has in creating those impacts. The results provide a strong indication that host brain functions, particularly dopamine signaling, is significantly impacted by infection. Those impacts appear to be linked to expression of the traditionally defined markers of presynaptic dopamine release, reuptake and vesicular transport. These results highlight how the parasite may directly or indirectly change host brain function, resulting in perturbation of human biology toward a psychiatric disease state.