SummaryParasite location has been proposed as an important factor in the behavioural changes observed in rodents infected with the protozoan Toxoplasma gondii. During the chronic stages of infection, encysted parasites are found in the brain but it remains unclear whether the parasite has tropism for specific brain regions. Parasite tissue cysts are found in all brain areas with some, but not all, prior studies reporting higher numbers located in the amygdala and frontal cortex. A stochastic process of parasite location does not, however, seem to explain the distinct and often subtle changes observed in rodent behaviour. One factor that could contribute to the specific changes is increased dopamine production by T. gondii. Recently, it was found that cells encysted with parasites in the brains of experimentally infected rodents have high levels of dopamine and that the parasite encodes a tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of this neurotransmitter. A mechanism is proposed that could explain the behaviour changes due to parasite regulation of dopamine. This could have important implications for T. gondii infections in humans.

SummaryWe examine the role of the protozoan Toxoplasma gondii as a manipulatory parasite and question what role study of infections in its natural intermediate rodent hosts and other secondary hosts, including humans, may elucidate in terms of the epidemiology, evolution and clinical applications of infection. In particular, we focus on the potential association between T. gondii and schizophrenia. We introduce the novel term ʻT. gondii-rat manipulation-schizophrenia modelʼ and propose how future behavioural research on this model should be performed from a biological, clinical and ethically appropriate perspective.

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26The parasitic protozoan Toxoplasma gondii becomes encysted in brain and muscle tissue 27 during chronic infection, a stage that was previously thought to be dormant but has been 28 found to be active and associated with physiological effects in the host. Dysregulation of 29 catecholamines in the CNS has previously been observed in chronically-infected animals. In 30 the study described here, the noradrenergic system was suppressed with decreased levels of 31 norepinephrine in brains of infected animals and in infected neuronal cells in vitro. 32 Expression of dopamine β-hydroxylase (DBH), essential for synthesis of norepinephrine 33 from dopamine, was the most differentially-expressed gene in infections in vitro and was 34 down-regulated in infected brain tissue, particularly in the prefrontal cortex and dorsal locus 35 coeruleus/pons region. The down-regulated DBH expression in infected rat 36 catecholaminergic and human neuronal cells corresponded with decreased norepinephrine 37 and increased dopamine. As the DBH suppression was observed in vitro, this effect is not 38 caused by neuroinflammation. Silencing of DBH expression was specific for T. gondii infection 39 and was not observed with CMV infection. The noradrenergic-linked behaviors of sociability 40 and arousal were altered in chronically-infected animals, with a high correlation between 41 DBH expression and infection intensity. These findings together provide a plausible 42 mechanism to explain prior discrepancies in changes to CNS neurotransmitters levels with 43 infection. The suppression of norepinephrine synthesis observed here may, in part, explain 44 behavioural effects of infection, associations with mental illness, and neurological 45 3 consequences of infection such as the loss of coordination and motor impairments associated 46 with human toxoplasmosis. 47 48T. gondii infects warm-blooded animals and is characterised by a transient acute infection 49 wherein vegetative tachyzoite forms rapidly replicate in tissues followed by a persistent 50 chronic infection. Chronic stages of infection can persist for years and potentially the lifetime 51 of the host with the bradyzoite-stage parasites encysted in cells within immunoprivileged 52 tissues, including muscle, eyes, and brain. Several reports have published host behavioral 53 changes with infection. A selective loss of aversion to feline urine and increased motor 54 activity has been observed in rodents, specifically manipulating behavior that will enhance 55 the probability of parasite transmission (1, 2). 56Toxoplasmosis can be a severe disease in immunocompromised individuals and in utero. 57Infection can cause retinochoroiditis and congenital hydrocephalus and cerebral 58 calcifications. T. gondii was recently ranked the second most important food-borne parasite 59 in Europe and is classified as a Neglected Parasitic Infection (CDC, Atlanta) (3). It has also 60 been linked by epidemiological studies to cognitive impairment and major mental illnesses. 61Severe cases are ass...