Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice

Gatkowska, Justyna; Wieczorek, Marek; Dziadek, Bożena; Dzitko, Katarzyna; Długońska, Henryka

doi:10.1016/j.exppara.2012.10.005

Cited by 74 publications

(71 citation statements)

References 49 publications

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“…In support of this finding, dopamine (DA) levels in T. gondii-infected mice are higher than those in control mice (17). Furthermore, increased DA release is observed in acutely infected male mice (18), and increased DA levels are observed in the striatum of infected mice at 6 days postinfection (dpi) (20). 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).…”

supporting

confidence: 62%

“…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).…”

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confidence: 99%

“…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).…”

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

et al. 2016

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cChronic infection with Toxoplasma gondii becomes established in tissues of the central nervous system, where parasites may directly or indirectly modulate neuronal function. Epidemiological studies have revealed that chronic infection in humans is a risk factor for developing mental diseases. However, the mechanisms underlying parasite-induced neuronal dysfunction in the brain remain unclear. Here, we examined memory associated with conditioned fear in mice and found that T. gondii infection impairs consolidation of conditioned fear memory. To examine the brain pathology induced by T. gondii infection, we analyzed the parasite load and histopathological changes. T. gondii infects all brain areas, yet the cortex exhibits more severe tissue damage than other regions. We measured neurotransmitter levels in the cortex and amygdala because these regions are involved in fear memory expression. The levels of dopamine metabolites but not those of dopamine were increased in the cortex of infected mice compared with those in the cortex of uninfected mice. In contrast, serotonin levels were decreased in the amygdala and norepinephrine levels were decreased in the cortex and amygdala of infected mice. The levels of cortical dopamine metabolites were associated with the time spent freezing in the fear-conditioning test. These results suggest that T. gondii infection affects fear memory through dysfunction of the cortex and amygdala. Our findings provide insight into the mechanisms underlying the neurological changes seen during T. gondii infection.T oxoplasma gondii is one of the most successful brain parasites, infecting approximately one-third of the human population (1). T. gondii can persist in brain and muscle throughout the host's life, and chronic infection is asymptomatic in immunocompetent humans (2). However, recent studies have suggested that T. gondii infection is a risk factor for developing mental diseases, such as schizophrenia and depression, as well as human behavior and personality changes and suicide (3, 4). Interestingly, T. gondii infection increases the risk of schizophrenia roughly 2.7 times, which is higher than that for genes associated with schizophrenia (5). Several studies have also suggested that rodents infected with T. gondii exhibit decreased avoidance behavior in response to cat odors, indicating manipulation of the host's behavior by T. gondii to facilitate the parasite's transmission and complete sexual replication in the definitive host (6-11).To date, research on the mechanism(s) underlying behavioral changes following T. gondii infection has been conducted primarily from two points of view. First, the relationship between parasite localization in the brain and behavioral changes has been investigated, with a previous study reporting that T. gondii has no obvious tropism in the brain (12-15). 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 cy...

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confidence: 99%

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confidence: 99%

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

et al. 2016

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“…Similarly, Gatkowska et al (37) noted profound changes in the ratios of dopamine, serotonin, and norepinephrine to their metabolites during acute infection, but which returned to baseline upon the establishment of chronic infection. Additionally, we did not observe differences in dopamine or related metabolite levels in the striatum, a region of the brain rich in dopaminergic terminals.…”

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confidence: 99%

Reassessment of the Role of Aromatic Amino Acid Hydroxylases and the Effect of Infection by Toxoplasma gondii on Host Dopamine

et al. 2015

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Toxoplasma gondii infection has been described previously to cause infected mice to lose their fear of cat urine. This behavioral manipulation has been proposed to involve alterations of host dopamine pathways due to parasite-encoded aromatic amino acid hydroxylases. Here, we report successful knockout and complementation of the aromatic amino acid hydroxylase AAH2 gene, with no observable phenotype in parasite growth or differentiation in vitro and in vivo. Additionally, expression levels of the two aromatic amino acid hydroxylases were negligible both in tachyzoites and in bradyzoites. Finally, we were unable to confirm previously described effects of parasite infection on host dopamine either in vitro or in vivo, even when AAH2 was overexpressed using the BAG1 promoter. Together, these data indicate that AAH enzymes in the parasite do not cause global or regional alterations of dopamine in the host brain, although they may affect this pathway locally. Additionally, our findings suggest alternative roles for the AHH enzymes in T. gondii, since AAH1 is essential for growth in nondopaminergic cells. The protozoan parasite Toxoplasma gondii is an obligate intracellular parasite that is capable of infecting most warmblooded animals. It is a member of the phylum Apicomplexa, which also contains Plasmodium falciparum, the causative agent of malaria. Toxoplasma gondii is one of the most widely distributed parasites in the world, both in geographic location and in the diversity of its host range (1). Its only definitive hosts are members of the genus Felis. Exclusively within enterocytes of the gut, it undergoes a sexual reproductive cycle to form environmentally resistant and infectious oocysts that are shed in cat feces (2). In all other hosts, Toxoplasma gondii infection begins as a fast-growing lytic stage called the tachyzoite. Innate and adaptive immune responses restrict the growth of tachyzoites, which can respond by differentiating into bradyzoites, a semidormant stage that exists as quiescent intracellular cysts in brain and muscle tissue. This chronic infection can persist for the lifetime of the host (3). Infections spread among incidental hosts through carnivorism, vertical transmission, and ingestion of T. gondii oocysts (4).Rodents that become infected by T. gondii exhibit an unusual behavioral response: they lose their instinctive aversion to the odor of cats and instead become mildly attracted to the scent (5-13). This behavioral manipulation appears specific to the cat (7, 8), and it has been speculated that this facilitates transmission (9). The exact mechanism of this behavioral manipulation is unknown, but parasite stimulation of host dopamine pathways in the brain has been suggested as a cause (14-16). It was observed that infection of mice by T. gondii caused a 14% increase in wholebrain dopamine levels upon establishment of chronic infection (17). Additionally, dopamine receptor antagonist drugs used for the treatment of schizophrenia block cat attraction in infected rodents (18,19). T. gondii ...

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“…In these animals, acute infection is accompanied by a decrease in noradrenergic system activity in females and a slight increase in some areas of males' brains. Infection induced elevation in serotonin and dopamine activity in acutely infected males (GATKOWSKA et al, 2013). Rats infected with Toxoplasma manifest symptoms similar to schizophrenia, present a reduction in learning and memory capacity, as well as depression (WANG et al, 2013).…”

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confidence: 99%

Behavioral Changes Induced by Toxoplasmosis in Animals and Humans.

Bichuette¹,

Costa²,

Torres³

et al. 2017

IJAR

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Sex-dependent neurotransmitter level changes in brains of Toxoplasma gondii infected mice

Cited by 74 publications

References 49 publications

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

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

Reassessment of the Role of Aromatic Amino Acid Hydroxylases and the Effect of Infection by Toxoplasma gondii on Host Dopamine

Behavioral Changes Induced by Toxoplasmosis in Animals and Humans.

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