Interferon-α-induced deficits in novel object recognition are rescued by chronic exercise
Introduction
Interferons are a family of multi-functional, pleiotropic proteins belonging to the cytokine family of proteins. They are produced by the body in response to viral infections and tumors; key functions include anti-viral activities, inhibition of cell growth and control of apoptosis. While IFN-α is currently a mainstay of treatment for a variety of viral diseases, cancers and other disorders (comprehensively reviewed in [1]), there are considerable problems regarding the emergence of psychiatric adverse events during patient treatment. Although systemic effects such as myalgia and chills normally regress after about two weeks of treatment and do not tend to interfere with treatment compliance [2], serious psychiatric and cognitive phenomena emerge later on in the course of treatment and can even necessitate treatment cessation [3].
Clinical studies have documented a wide range of IFN-α-related psychiatric disturbances including depression [4], [5], [6], [7], psychoses [8] and aggressive tendencies [9]. Few have investigated the effects of IFN-α on neurocognitive function, but significant findings have been made: both numerical working memory function [10] and verbal recall abilities [11] have been found to be significantly impaired in IFN-α patients, independent of depressive symptoms. Further, prefrontal cortical hypometabolism has been detected using PET imaging in patients receiving low-dose IFN-α treatment [12]. In contrast, Capuron et al. [13], found no effect of four weeks high-dose IFN-α on spatial working memory accuracy or spatial planning ability.
Suggestions of IFN-α-generated cognitive dysregulation are also found in the animal literature. Mice that over-express IFN-α in astrocytes have significantly impaired spatial learning abilities and deficits in the induction of hippocampal LTP [14]. One might hypothesize that systemic IFN-α administration could exert similar effects on spatial learning behaviors in rodents.
There has been a lack of consensus in the literature on the ability of systemic administration of human IFN-α in rodents to provoke a CNS syndrome that mimics the patient condition [15], [16], [17], [18], [19]. However, our laboratory has recently described a clinically-relevant animal model of IFN-α affective dysregulation [20]: our procedure involves sustained (> 3 weeks) systemic administration of IFN-α with a dose and regime similar to that used in humans. Here, we first set about investigating cognitive effects of IFN-α in this model using the object exploration (OE) task which has long been used to investigate animals' ability to encode spatial representations [21].
Chronic physical activity has been found to confer significant benefits in terms of brain wellbeing. In both clinical and analogous animal populations, exercise may act as a neuroprotectant in aging, Parkinson's disease (PD) traumatic brain injury (TBI), cerebral ischemia/stroke and kainic acid-induced neurodegeneration (for recent examples and discussions see [22], [23], [24], [25], [26], [27], [28], [29], [30]). Even in pathology-free animals, exercise can alter several cognition-related parameters, as indexed by variety of behavioral (watermaze [31], [32], object recognition [32], DNMS [33], radial arm maze [34]) and neurobiological (LTP [32], neurogenesis [35]) measures. On a molecular level, alterations in a number of plasticity-related, synaptic, anti-apoptotic and immune response gene expression profiles are seen following chronic wheel-running in rats [36]. In the study presented here, we also evaluated the efficacy of a chronic, forced treadmill running regime in preventing predicted IFN-α-induced learning deficits.
Section snippets
Animals
Thirty-two male Wistar rats (215–330 g at the beginning of the experiment, BioResources Unit, Trinity College Dublin; n = 8 per group) were housed in groups of three (standard hard-bottomed, polypropylene cages, cage dimensions — 44 × 28 × 18 cm) or four (cage dimensions — 55 × 30 × 25 cm) in a temperature-controlled vivarium (20 to 22 °C), with a 12:12 h light:dark cycle, and allowed free access to food and water. Animals were given at least 5 days to acclimate to their environment and receive gentle
Object exploration task
The OE task was performed towards the end of week six of IFN-α treatment. OE testing for each treatment group began approximately 14 h after the last exercise session of that group and 24 h after the last IFN-alpha injection to ensure that the acute effects of the drug did not interfere with behavioral assessment. Each group was tested on separate days, testing was thus carried out across four days.
Habituation and reactions to spatial change and novel object introduction were evaluated by the
Open field exploration
One-way ANOVA analyses did not reveal any significant effect of treatment group on locomotion in the open field (trial 0) in terms of distance traveled, velocity or thigmotaxis; data not shown.
Habituation
Over trials 1–3 of this task, all groups showed habituation to their environment as expected, with total exploration time decreasing across trials (Fig. 1B); a mixed-factorial ANOVA revealed a significant effect of trial (F(2, 52) = 9.41, p < 0.001), but no significant trial × group interaction (F(2, 52) = 1.36, p
Discussion
The aims of this study were to evaluate the impact of chronic, systemic IFN-α treatment on cognitive function in the rat, and to assess the potential of chronic forced exercise to prevent the induction of IFN-α-induced cognitive deficits. Previous data indicate the positive prophylactic effects of exercise against neuronal insult (see Introduction). We found that our treatment regime of IFN-α (which has previously been shown to induce an affective-like syndrome in rodents, [20]) had a
Acknowledgements
This research was funded by the Programme for Research in Third-Level Institutions (PRTLI) of the Higher Education Authority, Ireland.
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Now at St. George' s University, Grenada, West Indies.