Toxoplasma gondii infection reduces predator aversion in rats through epigenetic modulation in the host medial amygdala

Abstract

Male rats (Rattus novergicus) infected with protozoan Toxoplasma gondii relinquish their innate aversion to the cat odours. This behavioural change is postulated to increase transmission of the parasite to its definitive felid hosts. Here, we show that the Toxoplasma gondii infection institutes an epigenetic change in the DNA methylation of the arginine vasopressin promoter in the medial amygdala of male rats. Infected animals exhibit hypomethylation of arginine vasopressin promoter, leading to greater expression of this nonapeptide. The infection also results in the greater activation of the vasopressinergic neurons after exposure to the cat odour. Furthermore, we show that loss of fear in the infected animals can be rescued by the systemic hypermethylation and recapitulated by directed hypomethylation in the medial amygdala. These results demonstrate an epigenetic proximate mechanism underlying the extended phenotype in the Rattus novergicus-Toxoplasma gondii association.

Host Manipulation by Parasites: Cases, Patterns, and Remaining Doubts

“…This finding might explain why enhanced levels of testosterone have been observed only in infected men (Flegr et al, 2008;Shirbazou et al, 2011), and for the multiple behavioral and psychological traits in which men and women with latent toxoplasmosis exhibit opposite trends (Flegr et al, 2011;Flegr, 2013b). Recently, T. gondii has been reported to hypomethylate the arginine vasopressin promoters in the medial amygdala of rats (Hari Dass and Vyas, 2014), an epigenetic manipulation that could cause a stronger activation of vasopressinergic neurons after exposure to cat odor (Flegr and Markos, 2014). However, it remains an open question whether and to what degree these findings are also applicable to the brain of infected humans and, more importantly, the relevance of these effects in the interaction of the natural intermediate hosts with the natural final hosts of T. gondii has yet to be determined.…”

Toxoplasma gondii Infection in Mice Impairs Long-Term Fear Memory Consolidation through Dysfunction of the Cortex and Amygdala

“…Moreover, treatment of T. gondii-infected rats with haloperidol, an antipsychotic that is known to affect the dopaminergic system, reverses the behavioral effect of T. gondii infection (23). In their recent study, Hari Dass et al indicated that T. gondii infection induces hypomethylation of the arginine vasopressin promoter in the medial amygdala (21). They also showed that decreased aversion to cat odors in the T. gondii-infected rat is recovered by systemic hypermethylation (21).…”

“…However, another study found that tissue cyst density in amygdalar areas (the medial and basolateral amygdala) is 2-fold higher than that in nonamygdalar areas (9), whereas the presence of tissue cysts in the forebrain contributes to the attenuation of predator odor aversion and anxiety-like behavior (16). Overall, these studies suggest that the T. gondii cyst distribution contributes to behavioral changes, but this still requires further investigation.Second, research on the mechanisms underlying behavioral changes following T. gondii infection has examined the effect of the infection on neuronal cell biology, including neurotransmitter synthesis, signal transduction, gene expression, and epigenetic modulation (14,(17)(18)(19)(20)(21). One study reported that dopaminergic cells are upregulated by infection, suggesting that T. gondii affects the central nervous system to manipulate host behavior (22).…”

“…Second, research on the mechanisms underlying behavioral changes following T. gondii infection has examined the effect of the infection on neuronal cell biology, including neurotransmitter synthesis, signal transduction, gene expression, and epigenetic modulation (14,(17)(18)(19)(20)(21). One study reported that dopaminergic cells are upregulated by infection, suggesting that T. gondii affects the central nervous system to manipulate host behavior (22).…”

Toxoplasma gondii and Schizophrenia: A Relationship That Is Not Ruled Out

“…It may be due to a direct effect on tissue cysts in specific brain areas such as the amygdala or hippocampus, given that the host response to predator odors was changed by the parasite in male rats infected with T. gondii by inducing hypomethylation of the neuropeptide arginine vasopressin in the posterodorsal part of the medial amygdala, an important node of the extrahypothalamic vasopressin system that contains a large number of arginine vasopressin neurons. This epigenetic manipulation produced a greater activation of vasopressinergic neurons after exposure to cat odor, leading to the reversion of fear into attraction [86]. It may also result from the effect of a more diffuse and wider involvement of brain tissues, with no apparent changes, that nevertheless give rise to a series of neurophysiological disorders.…”