The glucocorticoid system is required for the voluntary exercise-induced enhancement of learning and memory in rats

doi:10.1016/j.bbr.2010.12.005

Behavioural Brain Research

Volume 219, Issue 1, 16 May 2011, Pages 75-81

https://doi.org/10.1016/j.bbr.2010.12.005 Get rights and content

Abstract

Although it is well established that voluntary exercise can improve cognitive functions, the underlying mechanisms are largely unknown. Glucocorticoids play an important role in learning and memory functions. This study addressed whether the glucocorticoid system would play a role in the exercise-induced enhancement of learning and memory. Intact rats or those that were either adrenalectomized or daily given the corticosterone-synthesis inhibitor metyrapone were allowed to freely exercise in a running wheel for 10 days. Control animals were kept sedentary for this period. After this period, they were trained and tested on a water-maze spatial task using three-trial per day for 5 consecutive days, succeeded by a probe trial two days later. Exercise increased plasma corticosterone levels, as assessed after this 10-day period. Both adrenalectomy and metyrapone slightly reduced running-wheel activity. Adrenalectomy reduced the plasma corticosterone levels to almost zero whereas metyrapone selectively blocked the exercise-induced increase in corticosterone levels. Exercise significantly improved performance during both training and retention of the water-maze task whereas this effect was absent in both adrenalectomized and metyrapone-treated rats. These findings indicate that the glucocorticoid system play a crucial role in the beneficial effects of voluntary exercise on cognitive functions in rats.

Research highlights

▶ Voluntary exercise enhances cognitive functions. ▶ Glucocorticoids play a crucial role in regulation of learning and memory functions. ▶ Voluntary exercise increases production of glucocorticoids. ▶ Blocking the glucocorticoid system reverses the exercise-induced improvement in learning and memory.

Introduction

Voluntary exercise has been shown to facilitate learning and memory in a wide variety of hippocampus-dependent tasks such as the water maze, radial-arm maze, contextual fear conditioning, and passive avoidance conditioning in animals [2], [3], [34], [39]. Voluntary exercise has also been shown to recover functional loss after central nervous system damage [17], and to reduce cognitive decline during aging [20]. Although the biological mechanisms that underlie such beneficial effects are still to be completely elucidated, possible mechanisms are an enhancement of neurogenesis, synaptic plasticity and brain-derived neurotrophic factor levels in the hippocampus [38], [39], activation of noradrenergic and serotonergic systems [13], [15], [19] or increased neuronal uptake of circulating insulin like growth factor-I [6], [10].

Physical exercise is known to correlate with striking metabolic changes and elicits neuro-endocrine responses, including that of the hypothalamic–pituitary–adrenal (HPA) axis [21]. Recent studies have shown that long-term voluntary wheel running, like other stressors, activates the HPA axis and results in glucocorticoid production [11], [16], [24], [26]. Voluntary exercise appears to exert its stimulatory effects at multiple levels of the HPA axis [35]. In addition to supporting physical activity via metabolic modulation [8], glucocorticoids also have complex effects on the central nervous system, including effects on learning and memory. In fact, extensive evidence from animals and humans studies indicates that the administration of low doses of glucocorticoid hormones enhances memory for stressful or emotionally arousing events. These enhancing effects depend on the integrity of the amygdala noradrenergic system [31].

As voluntary exercise activates the HPA axis resulting in glucocorticoid production, this study investigated whether the glucocorticoid system might play a role in the exercise-induced enhancement of learning and memory. We used a water maze (WM) task to study the possible interaction between the voluntary exercise-induced glucocorticoid activity and the spatial learning and memory enhancement. Two experimental approaches were used to reduce the concentration of circulating corticosterone; pharmacologically, by an inhibition of its synthesis using metyrapone, and surgically, by adrenalectomy (ADX).

Section snippets

Animals

Adult, male Wistar rats (210 ± 10 g) were individually housed in cages (50 cm × 26 cm × 25 cm) in a 12-h light/dark cycle at 22–24 °C, with food and water available ad libitum. All experimental procedures were conducted in accordance with the National Institutes of Health's Guide for the care and use of laboratory animals. Additionally, care was taken to minimize the number of animals used in each experiment.

Exercise paradigm

Each of the exercising rats was given access to a cage that was equipped with a running wheel

Discussion

These experiments examined whether metyrapone and ADX influenced the enhancing effect of voluntary exercise on spatial learning and memory. Voluntary wheel running for 10 days prior to the onset of behavioral testing enhanced subsequent spatial learning and memory in rats. Both metyrapone treatment and ADX blocked the cognitive-enhancing effects of voluntary exercise. These findings demonstrate a crucial role for the glucocorticoid system in mediating the exercise-induced enhancement of

Acknowledgments

This work was supported by grants from Semnan University of Medical Sciences and Iranian Neuroscience Research Network. We would like to thank Dr. B. Roozendaal for his critical review and language editing of the manuscript.

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Research reportThe glucocorticoid system is required for the voluntary exercise-induced enhancement of learning and memory in rats

Abstract

Research highlights

Introduction

Section snippets

Animals

Exercise paradigm

Discussion

Acknowledgments

Neuroscience

Physiol Behav

Neurobiol Learn Mem

Neurosci Lett

Pharmacol Biochem Behav

Front Neuroendocrinol

Neuroscience

Behav Brain Res

Neuroscience

Arch Phys Med Rehabil

Behav Neur Biol

Pharmacol Biochem Behav

Physiol Behav

Physiol Behav

Psychoneuroendocrinology

Pharmacol Biochem Behav

Neuroscience

Neurobiol Aging

Steroids

Research report
The glucocorticoid system is required for the voluntary exercise-induced enhancement of learning and memory in rats