Toxoplasma gondii-altered host behaviour: elucidating the role of parasite-produced dopamine

Certain parasites appear to manipulate their host’s behaviour for their own selective benefit. The mechanisms behind such behavioural alterations in vertebrate hosts remain elusive, despite their profound implications, particularly for those parasites with a broad host range. Toxoplasma gondii, the causative agent of the globally important toxoplasmosis, is a canonical example for parasite-altered behaviour in its rodent intermediate host. Such behavioural alterations, from subtle to severe, are also displayed across a broad spectrum of infected secondary hosts, including humans. Dopamine dysregulation has been proposed as one potential mechanistic explanation. Furthermore, T. gondii was found to encode tyrosine hydroxylases, TgTH, suggesting that the parasite itself may be a source of dopamine. The role of TgTH in behaviour change, however, remains controversial, with currently no behavioural studies supporting a direct link. Here, using the biologically and clinically appropriate rat (Rattus norvegicus) model, with subtle and specific behavioural and biostatistical assays and analyses, we aimed to elucidate the role of TgTH on host behavioural change. For this purpose, we developed two differentially (middle and high) over-expressing (OE) Prugniaud T. gondii lines, for comparison with both a true wildtype and a recombinant wildtype, without TgTH modification, as well as uninfected negative (sham exposed) controls. Our results indicated that, whilst all genetically modified parasite lines induced smaller intensities of behavioural change relative to true wild-type T. gondii, potentially indicative of lowered fitness of the recombinant lines in general, the severity of behavioural changes were dose-dependent on the level of TgTH expression. Our findings thereby provide unique support for the hypothesis of a contributing mechanistic role of TgTH in T. gondii-associated behavioural changes, and we discuss these findings in terms of their theoretical and applied implications.