The role of parasite-produced dopamine in Toxoplasma gondii-altered host behaviour

Beatriz Calvo-Urbano; Maya Kaushik; An-Chi Cheng; Greg C. Bristow; Emese Prandovszky; Martin Walker; Poppy H. L. Lamberton; Glenn A. McConkey; Joanne P. Webster

doi:10.1038/s41467-025-66139-3

AI summary · DOI: 10.1038/s41467-025-66139-3 · Immunology and Microbiology

The role of parasite-produced dopamine in Toxoplasma gondii-altered host behaviour

Beatriz Calvo-Urbano (University of London, Royal Veterinary College), Maya Kaushik (Imperial College London), An-Chi Cheng (University of London, Royal Veterinary College), Greg C. Bristow (University of Leeds, University of Bradford), Emese Prandovszky (University of Leeds, Johns Hopkins University), Martin Walker (University of London, Royal Veterinary College), Poppy H. L. Lamberton (Imperial College London, University of Glasgow), Glenn A. McConkey (University of Leeds),

and 1 more author

Joanne P. Webster (University of London, Royal Veterinary College)

Original paper Published on 05 Dec. 2025 Nature Communications License: CC BY

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The essentials

In rats, greater parasite TgTH expression was associated with stronger Toxoplasma gondii-related behavioural changes, supporting a contributory role for TgTH.

Question

Does parasite-produced tyrosine hydroxylase (TgTH) contribute to behavioural changes in Toxoplasma gondii-infected hosts? The authors tested whether the intensity of those changes varies with parasite TgTH expression.

Method

The study infected 85 Lister-hooded rats (41 male and 44 female) with true wildtype, recombinant control, or one of two TgTH-overexpressing Prugniaud parasite lines, or sham-exposed them. Six weeks after infection, rats completed a 2.5-hour four-choice cat-urine behavioural assay; outcomes were analysed using Bayesian regression and model comparison.

Findings

Result Infected rats spent more time in the cat zone than uninfected controls, with time in that zone increasing across the recombinant control, mid-expression, and high-expression lines.
Result Velocity in the cat zone was lower in the wildtype and high-expression groups than in the control and mid-expression groups.
See the passage in the paper
The velocity (cm/s) in the cat zone was highest in the uninfected Control group, lowest in both WT and TgTH-HIGH, and showed intermediate values in TgTH0 and TgTH-MID (Fig. 2; Table S5).
Result Female rats travelled farther in the cat zone and entered it approximately twice as frequently as males.
See the passage in the paper
Sex was the main factor associated with frequency of entering the cat zone, with females entering approximately twice as frequently as males (Fig. 5; Tables 11 and 12).
Authors’ interpretation The authors interpret the expression-dependent behavioural pattern as evidence that TgTH contributes to, but may not be sufficient to explain, T. gondii-associated behavioural change.

Limitations

The study did not measure dopamine levels in rat brains in vivo, limiting direct assessment of the proposed dopamine pathway.
See the passage in the paper
Our study may have been improved by using methods such as high-performance liquid chromatography to measure the dopamine level in the rats’ brains in vivo, in complement to our in vitro here.
All recombinant parasite lines caused smaller behavioural changes than true wildtype, so effects of TgTH expression are difficult to separate fully from possible costs of genetic modification.

Why it matters

The authors argue that the findings provide support for TgTH as one contributor to parasite-associated behavioural manipulation, while recognizing that the phenotype likely reflects multiple interacting pathways. If confirmed, this could inform understanding of parasite effects on vertebrate host behaviour across infected hosts.

Written by AI from the paper. Passages are checked word for word against the text we analysed; the rest may contain errors.

AI-generated keywords: Toxoplasma gondii tyrosine hydroxylase dopamine host behaviour predator odour

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Comprehensive Summary
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Original abstract

The study examined whether tyrosine hydroxylase produced by *Toxoplasma gondii* (TgTH) contributes to the parasite’s effects on host behaviour. Previous research had suggested that *T. gondii* may alter dopamine signalling, but evidence directly linking TgTH to behavioural changes remained inconclusive. The authors tested this possibility in rats, which they considered more suitable than mice for detecting subtle effects of chronic infection. The researchers compared four infected groups: rats carrying unmodified wild-type parasites (WT), a recombinant control line without TgTH overexpression (TgTH0), and two recombinant lines engineered to express medium or high levels of TgTH (TgTH-MID and TgTH-HIGH). Uninfected, sham-injected rats served as controls. The study included 85 Lister-hooded rats—41 males and 44 females. Behavioural testing took place six weeks after infection, once chronic infection had been established. Each rat completed a 2.5-hour, four-choice odour test. Separate zones contained cat urine, rabbit urine, water, and the rat’s own urine-soiled bedding. Automated tracking measured time spent in the cat-odour zone, movement speed in that zone and relative to the other zones, distance travelled, and the number of entries. The authors compared Bayesian statistical models that included parasite line, sex, and their interaction. Infected rats differed behaviourally from uninfected controls, including spending more time near cat odour, consistent with reduced innate aversion to a feline predator cue. Across the infected groups, several behavioural changes generally increased with TgTH expression, progressing from TgTH0 through TgTH-MID to TgTH-HIGH. Time spent in the cat zone was lowest in uninfected controls and highest in WT rats; the authors also reported an increasing pattern across the recombinant lines. Cat-zone velocity was highest in controls, lowest in WT and TgTH-HIGH rats, and intermediate in TgTH0 and TgTH-MID rats. Controls and TgTH-MID rats moved faster in the cat zone than WT and TgTH-HIGH rats. The difference between velocity in the cat and non-cat zones was positive for controls and the TgTH0 and TgTH-MID groups, while WT and TgTH-HIGH rats showed no clear difference. Parasite line and sex were associated with distance travelled in the cat zone. Males travelled shorter distances than females, while controls and TgTH0 rats travelled shorter distances than WT and TgTH-HIGH rats. Females entered the cat zone about twice as often as males, regardless of infection status. Overall, the recombinant lines produced smaller behavioural changes than the wild-type parasites. The authors suggest that genetic modification may have reduced parasite fitness, complicating interpretation of the TgTH-related pattern. They conclude that the dose-related differences support a contributory role for TgTH, but do not show that TgTH is the sole cause of the behavioural effects or is sufficient to produce them. They also emphasize that infection may affect behaviour through multiple pathways and neurotransmitters. A central limitation is that dopamine was not measured in the rats’ brains in vivo. The findings therefore support, but do not directly demonstrate, a dopamine-mediated mechanism. The study also did not test TgTH knockout lines and used only one parasite strain. The authors recommend further experiments using the same behavioural assays, improved genetic comparisons, and direct measurements of dopamine or its turnover.

Can a parasite enzyme change how rats respond to danger?

The parasite Toxoplasma gondii can infect many warm-blooded animals, including humans. In rodents, chronic infection has been linked to changes in responses to cat odours—a notable finding because cats are the parasite’s definitive hosts. One proposed explanation is that the parasite affects dopamine signalling, perhaps through its own tyrosine hydroxylase enzyme, known as TgTH.

In “The role of parasite-produced dopamine in Toxoplasma gondii-altered host behaviour,” Beatriz Calvo-Urbano, Maya Kaushik, An-Chi Cheng, Greg C. Bristow, Emese Prandovszky, Martin Walker et al. investigated whether TgTH contributes to behavioural changes in infected rats. Their results offer evidence for a possible role, while also showing why the mechanism is not yet settled.

Testing the TgTH hypothesis

Earlier research had suggested that T. gondii might influence dopamine, a chemical messenger involved in many brain functions. But evidence directly connecting parasite-produced TgTH to altered behaviour was inconclusive. To test the idea, the researchers compared rats infected with parasites that differed in TgTH expression.

The study included 85 Lister-hooded rats: 41 males and 44 females. Some rats received sham injections and remained uninfected. The infected animals carried one of four parasite lines:

WT: unmodified wild-type parasites.
TgTH0: a recombinant control line without TgTH overexpression.
TgTH-MID: a recombinant line engineered to express a medium level of TgTH.
TgTH-HIGH: a recombinant line engineered to express a high level of TgTH.

The researchers chose rats because they considered them better suited than mice for detecting subtle effects of chronic infection. Behaviour was tested six weeks after infection, when chronic infection had been established.

A four-choice odour test

Each rat explored an arena for 2.5 hours. Four zones offered different scents: cat urine, rabbit urine, water, and the animal’s own urine-soiled bedding. Automated tracking recorded how much time each rat spent in the cat-odour zone, how quickly it moved there, how its speed compared with other zones, how far it travelled, and how often it entered the zone.

This setup let the team examine not only whether infected rats approached cat odour, but also how they behaved once they were near it. Their statistical models considered parasite line, sex, and the possibility that parasite-line effects differed between males and females.

What the researchers found

Infected rats differed from uninfected controls. In particular, they spent more time near cat odour, consistent with a reduction in the usual aversion to a feline predator cue. Several behavioural changes generally became more pronounced across the recombinant lines as TgTH expression increased, from TgTH0 through TgTH-MID to TgTH-HIGH.

Time in the cat-odour zone was lowest in uninfected controls and highest in rats carrying WT parasites. The researchers also described an increasing pattern across the recombinant lines. Movement speed showed a more complex picture: rats in the control and TgTH-MID groups moved faster in the cat zone than WT and TgTH-HIGH rats. The difference between speed in the cat zone and speed elsewhere was clearly positive for controls, TgTH0, and TgTH-MID rats, but less clear for WT and TgTH-HIGH rats.

Distance travelled in the cat zone was associated with both parasite line and sex. Males travelled shorter distances than females. Controls and TgTH0 rats also travelled shorter distances than WT and TgTH-HIGH rats. Females entered the cat zone about twice as often as males, regardless of infection status.

A suggestive pattern, not a complete explanation

The progression across TgTH-expression levels supports the idea that the parasite enzyme may contribute to behavioural effects. However, the recombinant lines generally produced smaller changes than WT parasites. The authors suggest that genetic modification may have reduced the parasites’ fitness, making it difficult to interpret the differences as a straightforward effect of TgTH alone.

The findings do not establish that TgTH is the sole cause of altered behaviour, or that TgTH by itself is sufficient to produce the changes. Infection could affect behaviour through several biological pathways and neurotransmitters. A key limitation is that dopamine was not measured directly in the rats’ brains in vivo. The results therefore support a possible dopamine-related mechanism but do not demonstrate it.

The study also used only one parasite strain and did not test TgTH knockout lines, which would help assess what happens when the enzyme is absent. The authors recommend further experiments using improved genetic comparisons, the same behavioural tests, and direct measurements of dopamine or its turnover.

Why the study matters

This research adds a carefully structured test of a long-standing hypothesis: that a parasite-produced enzyme may help shape a host’s response to predator cues. Its results point toward a contributory role for TgTH, but leave open how the enzyme fits into the broader effects of infection. Pinning down that relationship will require stronger genetic controls and direct evidence about dopamine activity in the brain.

Abstract 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, Tg TH, suggesting that the parasite itself may be a source of dopamine. The role of Tg TH 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 Tg TH 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 Tg TH 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 Tg TH expression. Our findings thereby provide unique support for the hypothesis of a contributing mechanistic role of Tg TH in T. gondii -associated behavioural changes, and we discuss these findings in terms of their theoretical and applied implications.

Created on 30 Oct. 2026

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The role of parasite-produced dopamine in Toxoplasma gondii-altered host behaviour

The essentials

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Method

Findings

Limitations

Why it matters

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Definitions

Can a parasite enzyme change how rats respond to danger?

Testing the TgTH hypothesis

A four-choice odour test

What the researchers found

A suggestive pattern, not a complete explanation

Why the study matters

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