A comparison of voluntary and forced exercise in protecting against behavioral asymmetry in a juvenile hemiparkinsonian rat model

Highlights

• Starting exercise after weaning before an adult 6-OHDA lesion is a novel design.

• Preconditioning of exercise did not prevent motor asymmetry in a 6-OHDA rat model.

• No differences between forced and voluntary exercise were observed.

• These results are inconsistent with research showing exercise to be neuroprotective.

Abstract

Several studies have found a neuroprotective effect of forced exercise in rodent Parkinson's disease models; however, the evidence for the protective effect of voluntary exercise is mixed. Most of these studies have initiated the exercise after toxin-induced hemiparkinsonism. Few studies have investigated the role of a preconditioning of exercise prior to neurotoxic insult. Therefore, the purpose of this study was to explore the neuroprotective effect of regular forced and voluntary exercise in recently weaned rat pups prior to an adult hemiparkinsonian lesion. Recently weaned rat pups were randomized into four 6-week experimental groups: forced exercise, voluntary exercise, control, and a sham surgery control. After participation in a 6-week experimental condition, hemiparkinsonism was induced using a unilateral injection of 6-hydroxydopamine (6-OHDA). Parkinsonian behavioral tests (i.e., apomorphine rotations, forelimb placement asymmetry, exploratory rearing) demonstrated significant motor asymmetry for all three 6-OHDA group; however, there were no significant differences among them. The sham control rats did not show motor impairment consistent with nigrostriatal motor deficits. Neither a preconditioning of forced nor voluntary exercise was neuroprotective of a future 6-OHDA lesion. These results are in contrast to the literature and suggest that exercise neuroprotection may not be so straightforward.

Introduction

Exercise produces a plethora of benefits in those who have been diagnosed with Parkinson's disease (PD) [1], [2], [3]. In fact, many national and international panels on the topic have recommended the use of exercise to improve outcomes, activities of daily living and motor performance in those with PD [4], [5], [6]. Others have suggested the type of exercise is an important prescriptive consideration in PD [7]. While these studies collectively suggest that functional outcomes are indeed improved with general exercise, they add little knowledge as to how exercise and different exercise parameters influence the underlying disease processes of PD. For this reason, studies using comparative-control designs with animal models of PD are needed to explore these relationships.

In animal models, there are two different exercise modalities, forced exercise and voluntary exercise. While several studies have found a neuroprotective effect on PD with forced exercise [8], [9], [10], [11], the results with voluntary exercise are not as well developed. O’Dell et al. [17] found that voluntary wheel running facilitated motor recovery following toxin-induced PD but did so without sparing of dopamine terminals. Mabandla et al. [16] found that voluntary running using the same PD model did prevent apomorphine-induced contralateral rotations suggesting a sparing of dopaminergic neurons. Much like forced exercise, these latter two studies suggest that voluntary exercise may also offer some benefit in rodent models of PD.

One of the key differences between these two exercise modalities is that voluntary exercise allows the animal freedom to choose the timing and dosage of the exercise, whereas forced exercise removes this aspect and usually relies on an aversive stimulus to condition the behavior. In the case of rat forced exercise models, this often means an electrical grid on the back of a rodent treadmill that administers an electrical shock should the rat slow down or stop running. Unpleasant “encounters” with the electrical grid due to running noncompliance is what conditions running behavior. While this aversive stimulus is effective at conditioning running behavior, it can create a stressful atmosphere for the animal. Voluntary running occurs when the animal decides, usually in the dark cycle; whereas, forced running usually occurs during the light cycle for researcher convenience. The light cycle is typically a time of less activity for the animal and so it is plausible that this may add to the already stressful environment of forced running. Importantly, stress has received traction in the literature as a key factor in the loss of dopaminergic neurons that underlies PD [12]. In support of this notion, even mildly stressful conditions have been shown to negate the neuroprotective effect of exercise in a rat model of PD [13].

A recent review from the literature [14] suggests that forced exercise and voluntary exercise have different effects on brain neurochemistry and behavior. Leasure and Jones [15] found that rats in a forced exercise condition ran about the same distance as rats that voluntarily exercised. However, they report that voluntary exercise rats ran faster and for less total time than rats that were forced. Additionally, they found that rats in the forced exercise condition exhibited more anxiety-like behaviors compared to the voluntary exercisers despite the fact that there was no difference in corticosterone between the two groups. Leasure and Jones [15] further suggest that it is imperative that neural and behavioral effects of different forms of exercise using the similar parameters need to be addressed in greater detail scientifically.

Almost all of the aforementioned studies on the effect of exercise neuroprotection have administered the experimental exercise condition after the onset of toxin-induced PD. Only a few studies have utilized a design wherein exercise was administered to rats before a 6-OHDA-induced PD [8], [16], [17]. While the designs of these studies certainly make sense from a neuroprotective perspective, they may not capture the true neuroprotective effect of exercise throughout the life of the animal as they were all administered to adult rats. This is akin to having humans start an exercise program later in adult life with the hopes that it will provide neuroprotection. Perhaps an important “window of opportunity” may have been missed by not starting exercise earlier while the brain was developing. While implementation of exercise prior to disease onset in adult rats certainly makes sense from a neuroprotective perspective, these previous designs may not have captured the neuroprotective effect of exercise throughout the life of the animal. The administration of exercise in adolescence prior to disease onset is an attractive neuroprotective strategy because neurodevelopment is most robust in young and adolescent brains. Thus, it was felt that an important neuroprotective window of opportunity may have not been appropriately vetted scientifically. For this reason, the purpose of this study was to explore the neuroprotective effect in terms of parkinsonian behavioral signs of regular forced and voluntary exercise in recently weaned rat pups until they received an adult, neurotoxin-induced PD lesion.