Interferon-α-induced deficits in novel object recognition are rescued by chronic exercise

Abstract

The anti-viral drug interferon-alpha (IFN-α) is widely-known to induce psychiatric and cognitive effects in patients. Previous work has shown that physical exercise can have a positive effect against brain insult. We investigated the effects of a clinically-comparable treatment regime of IFN-α on cognitive function in male Wistar rats and assessed the impact of chronic treadmill running on the deficits generated by IFN-α. We found that IFN-α induced significant impairments in performance on both spatial novelty and object novelty recognition. Chronic forced exercise did not protect against IFN-α-induced learning deficits in reactivity to spatial change, but did restore the capacity for novel object recognition in IFN-α-treated animals.

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.