Accepted Manuscript The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels Chong Chen, Shin Nakagawa, Yan An, Koki Ito, Yuji Kitaichi, Ichiro Kusumi PII: DOI: Reference:
S0091-3022(16)30061-9 http://dx.doi.org/10.1016/j.yfrne.2016.12.001 YFRNE 651
To appear in:
Frontiers in Neuroendocrinology
Received Date: Revised Date: Accepted Date:
27 July 2016 26 November 2016 1 December 2016
Please cite this article as: C. Chen, S. Nakagawa, Y. An, K. Ito, Y. Kitaichi, I. Kusumi, The exercise-glucocorticoid paradox: How exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels, Frontiers in Neuroendocrinology (2016), doi: http://dx.doi.org/10.1016/j.yfrne.2016.12.001
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Review
The exercise-glucocorticoid paradox: how exercise is beneficial to cognition, mood, and the brain while increasing glucocorticoid levels
Chong Chen 1,2, Shin Nakagawa 1,*, Yan An 1, Koki Ito 1, Yuji Kitaichi 1, Ichiro Kusumi 1 1
Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan
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Present address: RIKEN Brain Science Institute, Wako, Saitama, 351-0198, Japan
∗ Corresponding author. Tel.: +81 11 706 5160; Fax: +81 11 706 5081. E-mail address:
[email protected] (S. Nakagawa)
Abstract: 147; Manuscript: 10013; References: 361; Figures: 9; Tables: 1; Supplementary material:0.
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Abstract Exercise is known to have beneficial effects on cognition, mood, and the brain. However, exercise also activates the hypothalamic–pituitary–adrenal axis and increases levels of the glucocorticoid cortisol (CORT). CORT, also known as the “stress hormone,” is considered a mediator between chronic stress and depression and to link various cognitive deficits. Here, we review the evidence that shows that while both chronic stress and exercise elevate basal CORT levels leading to increased secretion of CORT, the former is detrimental to cognition/memory, mood/stress coping, and brain plasticity, while the latter is beneficial. We propose three preliminary answers to the exercise-CORT paradox. Importantly, the elevated CORT, through glucocorticoid receptors, functions to elevate dopamine in the medial prefrontal cortex under chronic exercise but not chronic stress, and the medial prefrontal dopamine is essential for active coping. Future inquiries may provide further insights to promote our understanding of this paradox.
Keywords: brain plasticity, chronic stress, corticosterone, cortisol, depression, dopamine, exercise, glucocorticoid receptor, medial prefrontal cortex, wheel running
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Contents 1. Introduction 2. Stress and exercise increase CORT 2.1 Stress increases CORT: acute stress increases CORT levels, while chronic stress increases basal CORT levels 2.2 Exercise increases CORT: acute exercise increases CORT, while chronic exercise increases basal CORT levels 3. The exercise-CORT paradox 3.1 Chronic stress or CORT administration induce depression, impair memory/cognition, and damage the structural and functional plasticity of the brain 3.2 Chronic exercise prevents/reverses depression, improves memory/cognition, and promotes the structural and functional plasticity of the brain 4. Preliminary solutions to the paradox 4.1 Chronic exercise buffers, while chronic stress enhances the HPA-axis response to novel stress 4.2 Chronic exercise increases, while chronic stress decreases medial prefrontal cortex dopamine 4.3 Chronic stress but not exercise downregulates mineralocorticoid and glucocorticoid receptor expression 5. Concluding remarks and future directions Acknowledgements References Tables Figure captions
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1. Introduction
In order for man to succeed in life, God provided him with two means, education and physical activity. Not separately, one for the soul and the other for the body, but for the two together. With these two means, man can attain perfection. ― Plato
Aerobic exercise, also known as endurance activity or cardiovascular exercise, involves a sustained period of rhythmic movement of large muscles, and requires pumping of oxygenated blood by the heart to deliver oxygen to the muscles to generate energy. Aerobic exercise (exercise is used synonymously below), such as running, whether acute or chronic (habitual/repeated), has been shown to improve cognition, memory, and mental health in humans as well as in rodents (Hillman, et al 2008; Ratey & Hagerman, 2008; Change et al 2012; Novak et al 2012. For a detailed review see below). Two examples in humans are 1) exercise prevents cognitive decline and improves cognitive functioning in elderly people (Heyn et al 2004; Hindin & Zelinski, 2012), and 2) exercise shows comparable therapeutic effects in relation to pharmacological treatment or psychological therapy in the treatment of patients with depressive disorders (Cooney et al 2013). However, while the benefits of exercise are well established, its mechanism of action remains largely unknown (Hillman, et al 2008; Hötting and Röder 2013; Voss et al 2013). More importantly a paradox also exists (Figure 1). As such, despite being ultimately beneficial for cognition, mood and the brain, exercise activates the hypothalamic–pituitary–adrenal (HPA)-axis and increases levels of the well known “stress hormone,” the glucocorticoid cortisol (CORT; the primary CORT in humans is cortisol, while in mice and rats it is corticosterone). Numerous studies have shown that acute exercise increases CORT levels immediately, while chronic exercise may also elevate basal CORT levels (Kanaley & Hartman, 2002; Stranahan et al 2008. For a detailed review see below). Elevated CORT levels, generally occurring after stressful events, impairs cognition/memory and stress coping, and reduces the structural and functional plasticity of the brain (McEwen, 2007, 2008; Lupien et al
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2009. For a detailed review see below). Contrary to the two examples suggesting the benefits of exercise, elevated CORT has been defined as one of the key features or causes of cognitive decline in aging and depression (Sapolsky et al 1986; Sapolsky, 2000). Several authors have pointed to the existence of an “Exercise-Glucocorticoid Paradox” (see Adlard and Cotman 2004; Schoenfeld and Gould 2012; Chen et al 2016). Here, we provide an extensive review of the existing literature regarding the effects of exercise on CORT and postulate the “Exercise-Glucocorticoid Paradox.” Here, we wish to encourage further investigations to unearth this paradox and determine how exercise counters the detrimental effects of CORT. We believe studies investigating potential solutions to the paradox would further our understanding of exercise physiology and the neuropathophysiology of stress and depression, and would also be of great benefit for developing methods to reduce stress, treat depression and develop new pharmacological therapies. 2. Stress and exercise increase CORT 2.1 Stress increases CORT: acute stress increases CORT, while chronic stress increases basal CORT levels The acute effects of stress on CORT levels have been well established (Ulrich-Lai and Herman 2009; Allen et al 2014). Dickerson and Kemeny (2004) performed a meta-analysis of 208 human laboratory studies of acute psychological stressors, including cognitive tasks, public speaking tasks, noise exposure, and emotion induction. They concluded that various acute stressors significantly increase circulating CORT levels in plasma and saliva, which peaks at 21–40 min from the onset of stress. This is true in both male and female individuals and in adults and older people. However, the nature of the stressor employed (Dickerson and Kemeny 2004), and the subjects examined (Foley and Kirschbaum 2010) can moderate the effect size. For instance, social-evaluative threat and uncontrollable tasks elicit a significantly larger CORT response than controllable tasks and those without social-evaluation (Dickerson and Kemeny 2004). In addition, children, adolescents and adults all show a similar increase in CORT levels, while men show a greater increase in CORT than women (Foley and Kirschbaum 2010). Since CORT shows diurnal variation, peaking in the morning
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in humans, studies conducted in the afternoon have generally found a larger effect size than those conducted in the morning (Dickerson and Kemeny 2004). Similarly in rodents, various acute stressors (Cockrem et al 2013), either physical stressors such as restraint (Buynitsky and Mostofsky 2009) or psychological stressors such as social defeat (Hammels et al 2015), consistently increase CORT levels in both male and female young (< 8 weeks) and adult (≥ 8 weeks) animals. While repeated exposure to the same stressor may induce habituation, i.e., reduce any subsequent CORT response to the same stressor (Grissom and Bhatnagar 2009; Herman et al 2013), chronic stress causes hyperactivity of the HPA-axis and a resulting elevation in CORT levels in both humans and rodents. For instance, in adult humans chronic stress, especially chronic psychosocial stress, results in an overall increase in CORT levels in plasma, saliva, and hair (CORT levels in hair reflect long-term secretion) in both male and female individuals (Charmandari et al 2005; Chrousos 2009; Staufenbiel et al 2013). However, insignificant results have also been reported occasionally. As such, the effect seems to be intensity-dependent. For instance, Kalra et al (2007) reported a correlation between perceived stress levels and CORT levels in the hair in pregnant women, whereas Gow et al (2011) found a similar correlation in male but not female older adult patients with adrenal insufficiency (mean age 55 years) receiving hydrocortisone replacement therapy. Furthermore, in older people (mean age >70 years), Stalder et al (2014) reported a correlation between caregiving burden and CORT levels in the hair, and also a correlation between CORT levels in the hair and the degree of depressive symptoms. Notably, a positive association has also been reported between CORT levels in the hair and socioemotional problems in one-year-old children (Palmer et al 2013). With regard to the diurnal pattern of CORT secretion, a meta-analysis of 107 studies found that, in both men and women (mean age 38.39 years, SD 16.23), various chronic stressors, e.g., social threat such as unemployment, physical threat such as disease/injury, natural disaster, etc., increase afternoon/evening CORT levels consistently, while studies examining morning CORT levels report either increases, decreases or no influence on CORT levels (Miller et al 2007). Additional recent studies also support this observation (Chandola et al 2010; Corrêa et al 2015). Most of the rodent studies have been performed in male animals. These studies have almost
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consistently shown that various chronic stress paradigms, such as chronic mild stress (Figure 2a), chronic restraint stress (Figure 2b), repeated water-immersion combined with restraint stress (Miyata et al 2011), repeated electric shock (Ottenweller et al 1989), and chronic social defeat stress (Klein et al 1992; Keeney et al 2001), lead to increased basal CORT levels across the light-dark cycle in both young (
