Acquired infection with Toxoplasma gondii in adult mice results in sensorimotor deficits but normal cognitive behavior despite widespread brain pathology

Abstract

Toxoplasma gondii is a ubiquitous intracellular parasite which chronically infects 30-50% of the human population. While acquired infection is primarily asymptomatic several studies have suggested that such infections may contribute to neurological and psychiatric symptoms. Previous studies in rodents have demonstrated that T. gondii infection does not just kill its host, but alters the behavioral repertoire of an infected animal, making it more likely that predation with occur completing the parasite life cycle. The aim of the present study was to evaluate the behavioral changes in C57BL/6 mice chronically infected with the avirulent T. gondii (ME49, a Type II strain), in a comprehensive test battery. Infected mice demonstrated profound and widespread brain pathology, motor coordination and sensory deficits. In contrast, cognitive function, anxiety levels, social behavior and the motivation to explore novel objects were normal. The observed changes in behavior did not represent "gross" brain damage or dysfunction and were not due to targeted destruction of specific areas of the brain. Such changes point out the subtle interaction of this parasite with its intermediate hosts and are consistent with ideas about increased predation being an outcome of infection.

Figure 1

Histological findings in brain stained with hematoxylin and eosin. (A) Normal brainstem (25x magnification). (B) Toxoplasma treated mouse brainstem. There is extensive lymphocytic perivascular inflammation (arrows) and focally extensive inflammation at the base of the brainstem (boxed area) (25x magnification). (C) Normal brainstem (200x magnification). (D) T. gondii infected mouse brainstem. There are nodules of glial cells (arrows), rarefaction of white matter (*), infiltrates of lymphocytes (arrow heads), and axonal swelling (a). (200x magnification). (E) T. gondii infected mouse cortex. There are glial cell aggregates (surrounded by arrows) and a protozoal cyst (large arrowhead) (200x magnification). (F) T. gondii infected mouse brainstem. There is a single large protozoal cyst (arrow) with no apparent inflammatory reaction (200x magnification).

Figure 2

Motor coordination deficits assessed as the number of slips (A) and the time to cross (B) a 120 cm long and 2.5 cm diameter beam. * indicates significant differences between T. gondii infected and control mice, p< 0.001.

Figure 3

Gait deficits assessed as the number of mis-steps (A) and the mean stride length (B) and the number of rear paw drags (C). * indicates significant differences between T. gondii infected and control mice, p< 0.05. Representative footprints of a control mouse (D) compared to T. gondii infected mice (E and F) clearly show examples of the shorter and more variable stride pattern, paw misplacements, weaving gait and other abnormalities. Examples of foot drag (G), paw misplacement (H), and gross ataxia (I) from T. gondii infected mice are also illustrated.

Figure 4

Open field behavior in a 6 min test period indicates that T. gondii infected mice have lower levels of general locomotor activity (A: grid crosses) and exploratory activity (B: number of rears) and the number of rear paw drags. * indicates significant differences between T. gondii infected and control mice, p< 0.005.

Figure 5

Cognitive deficits were not evident in T. gondii infected mice (Toxo) in either spatial memory (A) or in recognition memory (B) in the novel object recognition and object placement tasks. Extent of object exploration (sec) was also normal during the trial 1 of each task (D and E) in both T. gondii infected and control mice