Immune System Challenge Improves Cognitive-Behavioural Responses and Reverses Malaria-Induced Cognitive Impairment in Mice

Abstract

22The immune and nervous systems can be categorized as cognitive plastic systems for 23 their ability to know and recognize "real world objects", including microbes, and 24 because of their prerogative of constant self-reorganization as they live learning 25 experiences. After each antigenic or sensory occurrence, vertebrate organisms 26 experience changes in the cellular connections of their immune and nervous systems 27 altering their abilities and structures. Elements of the immune machinery are necessary 28 for neurocognitive function, and the pattern of the immune response triggered by 29 different stimuli may induce regulator or deregulator signals for the nervous functions. 30 Here we show, for the first time, that the immune modulation with anti-inflammatory 31 stimuli can positively regulate the behavior of healthy mice and mitigate the cognitive-32 behavioral deficits induced by a mild infection of C57BL/6 animals with Plasmodium 33 berghei ANKA.34 35 To address the effect of immune responses on locomotion and on long-term 87 habituation, mice were submitted to the open field task (OFT), with a training and a 88 test sessions, 24 hours apart, assessed in a well-established protocol 32 . Locomotion is 89 evaluated when mice access the open field arena for the first time. At the training 90 session, a high rate of locomotor activity is commonly observed. Surprisingly, Pool and 91 T1 immunized mice showed a reduced total OFT1 locomotion, when compared to non-92 immunized mice, and T2 immunized animals showed a clear trend towards a 93 decreased locomotion (Extended data, Fig1a) Commonly, after the training session, 94the exploratory behavior decreases, as the stress related to the novelty disappears, 95 and is significantly lower after 10 minutes of task performance 32,[48][49] . Control and all 96 immunized groups of mice presented a decreased locomotion in the test session 97 (OFT2) as compared to the training session (Extended data, Fig1a). These results 98 indicate that the immunization did not affect the long-term habituation memory 99 accessed 24 hours after training.100 101 Mice were then subjected to the novel object recognition test (NORT) in the same Open 102 Field arena. On the training session, a similar exploratory activity of both familiar (FO1 103 or FO2) objects is expected and was observed in all groups (Control, Pool, T1 and T2) 104 of mice (Fig.1a; Extended data, Fig.1c), exploring them for a mean of 25 seconds (data 105 not shown). Remarkably, as we hypothesized, the groups of mice immunized with the 106 Pool and T2 strategies presented significantly higher recognition memory performance 107 in relation to the control group of non-immunized mice during the test session (Fig.1c; 108 Extended data Fig.1e). These data indicate, for the first time, that an immune response 109 classically categorized as anti-inflammatory (induced by T2 stimuli) may enhance long-110 term recognition memory in healthy mice. 111 112Immunization of healthy mice did not influence their anxiety-like state 11...