Toxoplasma infection in male mice alters dopamine-sensitive behaviors and host gene expression patterns associated with neuropsychiatric disease

Abstract

During chronic infection, the single celled parasite, Toxoplasma gondii, can migrate to the brain where it has been associated with altered dopamine function and the capacity to modulate host behavior, increasing risk of neurocognitive disorders. Here we explore alterations in dopamine-related behavior in a new mouse model based on stimulant (cocaine)-induced hyperactivity. In combination with cocaine, infection resulted in heightened sensorimotor deficits and impairment in prepulse inhibition response, which are commonly disrupted in neuropsychiatric conditions. To identify molecular pathways in the brain affected by chronic T. gondii infection, we investigated patterns of gene expression. As expected, infection was associated with an enrichment of genes associated with general immune response pathways, that otherwise limits statistical power to identify more informative pathways. To overcome this limitation and focus on pathways of neurological relevance, we developed a novel context enrichment approach that relies on a customized ontology. Applying this approach, we identified genes that exhibited unexpected patterns of expression arising from the combination of cocaine exposure and infection. These include sets of genes which exhibited dampened response to cocaine in infected mice, suggesting a possible mechanism for some observed behaviors and a neuroprotective effect that may be advantageous to parasite persistence. This model offers a powerful new approach to dissect the molecular pathways by which T. gondii infection contributes to neurocognitive disorders.

Author summary

Infecting 1 in 3 worldwide, the single-celled parasite T. gondii causes a chronic infection whereby it can migrate to the brain and promote low-grade neuroinflammation. Given this intimate association, infection with T. gondii has the capacity to induce changes in brain morphology and behavior as well as modulate the production of neurotransmitters, such as dopamine. Consequently, T. gondii has been linked with several neurocognitive disorders including schizophrenia, dementia, and Parkinson’s disease, in addition to a loss of fear response. To examine how infection impacts pathways utilizing neurotransmitters, we used a mouse model, based on stimulant-induced (cocaine) hyperactivity. Infection with T. gondii did not alter fear behavior but did impact motor activity and neuropsychiatric-related behaviors. Gene expression analysis revealed an initial enrichment of uninformative immune-response pathways. By applying a novel context enrichment approach, we identified significant associations with neurologically relevant genes involved in multiple pathways. These include sets of genes which exhibited dampened response to cocaine exposure in the context of T. gondii infection, suggestive of a neuroprotective effect that may be advantageous to parasite persistence. We suggest this novel mouse model offers a new perspective to dissect the molecular pathways by which T. gondii infection contributes to neuropsychiatric disorders.