Cognitive dysfunction in mice infected with Plasmodium berghei strain ANKA

Abstract

Cerebral malaria complicated by cognitive sequelae is a major cause of morbidity in humans infected with Plasmodium falciparum. To model cognitive function after malaria, we created a rodent model of cerebral malaria by infecting C57BL/6 mice with Plasmodium berghei strain ANKA. After 7 days, an object-recognition test of working memory revealed a significant impairment in the visual memory of infected mice. This impairment was observed in the absence of confounding effects of infection. The cognitive dysfunction correlated with hemorrhage and inflammation. Furthermore, microglial activity and morphological changes detected throughout the brains of infected mice were absent from the brains of control mice, and this correlated with the measured cognitive defects. Similar testing methods in human studies could help identify subjects at risk for an adverse cognitive outcome. This murine model should facilitate the study of adjunctive methods to ameliorate adverse neurological outcomes in cerebral malaria.

Figure 1

A, Infected mice performed worse in the object recognition test of working memory by 7 days after infection (P < .01). Infected animals had significantly worse visual memory than the noninfected control. Infected mice and control mice demonstrated similar levels of novel object exploration (B) and locomotor activity (C).

Figure 2

A, Hematoxylin-eosin staining of cerebellum of an infected mouse demonstrating dilated vessels with leukocyte margination (arrowheads) and an area of microhemorrhage (arrow). B, Ionized calcium-binding adaptor molecule 1 (Iba-1) immunostaining of the same cerebellar region, demonstrating Iba-1 positive leukocytes (arrows) and activated microglial cells (arrowheads).

Figure 3

Infected mice (B) demonstrated hemorrhage in the fornix (arrow), which was absent in uninfected mice (A). Sections taken at bregma −1.86 in control mice and Bregma −1.94 in infected mice. A and B show the CA2 region of the hippocampus.

Figure 4

Ionized calcium-binding adaptor molecule 1 (Iba-1) staining of the cortex and hippocampus of uninfected control mice and infected mice. In the cortex (A) and hippocampus (C) of control mice, Iba-1–positive microglial cells are small with delicate fine processes (arrows). In the cortex (B) and hippocampus (D) of infected mice, microglial cells undergo morphological changes that reflect activation, such as thickening of the processes and strong Iba-1 reactivity (arrows).