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

Abstract

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...

Downregulation of the central noradrenergic system by Toxoplasma gondii infection

“…The level of NE was significantly changed with infection (p=0.0019) with a 50±14% decrease in NE level in the brain (Figure 1A). Decreased NE in T. gondii -infected mice has been observed in other studies (11, 13). The suppression observed with infection (Figure 1A) is analogous to decreases in CNS NE levels observed with high affinity DBH inhibitors (24).…”

“…Early studies found changes in dopaminergic neurotransmission associated with infection, with high levels of dopamine (DA) in brain tissue cysts and abrogation of infection-induced behavior changes when animals were treated with dopamine antagonists, haloperidol and GBR-12909 (8–10). Perturbations in catecholaminergic signalling with chronic infection have been observed, with elevated DA metabolites in the cortex and decreased NE in the cortex and amygdala and loss of amphetamine-induced locomotor activity (11,12). There are discrepancies in observations of changes in dopamine levels in the brain with T. gondii infection (13–17).…”

Microglia in neuropathology caused by protozoan parasites

“…Interestingly, numerous studies have revealed that toxoplasma‐infected mice lose their inborn aversion to cat odors (reviewed in Ingram et al ., ), suggesting parasite‐induced reorganization of neuronal synapses. In support of this, a recent study found clear indications for changes in fear memory by analyzing neurotransmitter levels in different brain areas as well as cortex and amygdala interactions (Ihara et al ., ). It thus seems that T. gondii have evolved adaptations to influence their transmission success by changing the brain functions of their hosts.…”

Toxoplasmainduces stripping of perisomatic inhibitory synapses

“…In addition to seizures, a large number of studies, including a recent case-control study with over 80,000 individuals, have revealed a strong association between Toxoplasma gondii infection and neuropsychiatric disorders, including schizophrenia (Dickenson et al 2007(Dickenson et al , 2014Flegr and Horacek 2018;Burgdorf et al 2019). Given that Toxoplasma parasites are known to increase dopamine metabolism in their hosts and even generate dopamine themselves (Prandovszky et al 2011;Ihara et al 2016;Gaskell et al 2009) and neuropsychiatric illnesses have long been attributed to dopamine dysfunction (Brisch et al 2014), it has been hypothesized that the association between persistent Toxoplasma infection and schizophrenia is due to altered dopamine signaling (Skallova et al 2006;Elsheikha et al 2016;Stock et al 2017; but see also Wang et al 2015Wang et al , 2017. However, it is noteworthy that the impairment of Parv + interneurons and GABAergic perisomatic synapses has also been strongly associated with the development of neuropsychiatric disorders, such as schizophrenia (Belforte et al 2010;Marin 2012;Gonzalez-Burgos et al 2010Sgado et al 2011;Gonzalez-Burgos and Lewis 2012;Lewis et al 2012).…”

“…A number of cellular and molecular mechanisms have been proposed to underlie behavioral changes in schizophrenia, many of which point to alterations in the assembly, maintenance and function of synapses (Birnbaum and Weinberger 2017). In addition to its association with schizophrenia, persistent Toxoplasma infection in animal models leads to seizures (Brooks et al 2015;David et al 2016), altered neurotransmitter levels (Alsaady et al 2019;Skallova et al 2006;Gatkowska et al 2013), altered neural connectivity (Brooks et al 2015;Ihara et al 2016;Parlog et al 2015;Lang et al 2018) and altered neuronal function (Haroon et al 2012), all phenotypes that are associated with impaired synaptic organization or function.…”