Toxoplasma gondii is a sexually transmissible parasite in humans and induces host behavioral change in rodents via the medial amygdala arginine vasopressin system

• Main Author: Tong, Wen Han
• Other Authors: Ajai Vyas
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2018
• Subjects: DRNTU::Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/89203; http://hdl.handle.net/10220/47073
• Institution: Nanyang Technological University

Basic innate defensive responses such as fear of predators are hardwired to preserve the survival of an individual. Nonetheless, a parasite, Toxoplasma gondii, can cause rodents to lose their innate aversion to predators. This behavioral change plausibly facilitates trophic transmission of the parasite to its definitive feline host. This is an important event in view of the two-stage life cycle of Toxoplasma gondii which requires predation of rodents by cats. My thesis is motivated by this intriguing loss of fear which is detrimental to the evolutionary fitness of an individual. I start from the idea that Toxoplasma gondii changes the approach-avoidance continuum of its host. I posit a crucial role for the medial amygdala (MeA) neurons containing neuropeptide arginine vasopressin (AVP) in mediating innate fear. The broad aim of this thesis is to ask if the MeA-AVP system is necessary and sufficient to reduce innate aversion in rodents akin to that observed during chronic Toxoplasma gondii infection. AVP and its homologues are critical mediators of socio-sexual behavior in a range of species. This is especially true for extra-hypothalamic AVP-containing neurons within extended medial amygdala. Moreover, AVP transcription within MeA is dependent on the level of the circulating sex hormone, testosterone. This is achieved by an androgen-dependent epigenetic change of the AVP promoter in rats. As I intend to use transgenic mice in my experiments, it is first crucial to establish if biochemical machinery linking MeA-AVP with testosterone exist in mice. In parallel, testosterone is thought to be an anxiolytic hormone but its effects on innate fear of predators remains understudied. To this end, I demonstrate that testosterone reduces innate fear of predator odor when castrated male mice are supplemented with chronic exogenous testosterone. Congruently, I show that supplementation of testosterone causes DNA hypomethylation in AVP promoter both in MeA and bed nucleus of stria terminalis (BNST). My results suggest that testosterone via MeA-AVP neurons reduces innate aversion by co-opting pre-existing trade-off between fear and socio-sexual behaviors. Reproductive opportunities are often interleaved in the environment with predation risk. Therefore, the fear to cues of the predators is often titrated with reproductive cues in the environment. The MeA is the main site where such emotional stimuli are processed. This is due to an abundance of AVP neurons which are critically involved in an extensive range of male sexual and social behaviors. However, it is inconclusive if MeA-AVP neurons are involved in the modulation of the neural circuits for innate fear. In this regard, I use chemogenetic approaches to demonstrate that AVP neurons within MeA are necessary and sufficient to modulate fear to olfactory cues of the predator. Circumscribed overexpression of AVP in these neurons reduces innate fear in mice towards cat urine. Similarly, specific ablation of these neurons facilitates innate fear. My results suggest that MeA-AVP neurons serve as an interface between internal hormonal milieu and external reproductive opportunities within the brain. Beside animals, Toxoplasma gondii also infects human beings and this infection is known as Toxoplasmosis. Toxoplasma gondii is known to be sexually transmitted in multiple non-human mammals. This is surprising because the blood-testes barrier is conceivably the most impervious mammalian blood-tissue barriers. However, increasing evidences suggest Toxoplasma gondii can breach this barrier as evidenced by the presence of Toxoplasma cyst in the epididymis and ejaculate post-infection in laboratory rats, dogs and sheep. It gives rise to the claim that Toxoplasma gondii may indeed transmit sexually in humans as well. This possibility is perplexing given the high prevalence of Toxoplasma gondii in many countries and increased probability of developing neuropsychiatric disorders such as Schizophrenia in Toxoplasma gondii-infected individuals. To reinforce this claim, I also investigate if Toxoplasma gondii cysts can be found in ejaculates of immune-competent and chronically infected male humans. My results suggest a possible breach of the human blood-testes barrier as evidenced by high concordance between seropositivity for anti-Toxoplasma gondii antibodies and the presence of Toxoplasma gondii cysts in human semen samples. Overall, research findings in this thesis point to a possible role of MeA-AVP neurons in mediating innate fear. Results also suggest Toxoplasma gondii to be a sexually transmissible parasite in humans.