The effectiveness of continuous and interval exercise preconditioning against chronic unpredictable stress: Involvement of hippocampal PGC-1α/FNDC5/BDNF pathway

https://doi.org/10.1016/j.jpsychires.2021.02.006Get rights and content

Highlights

  • Continuous and interval exercise trainings increased the hippocampal PGC-1α/FNDC5/BDNF proteins.

  • Continuous and interval exercise training improved the anxiety- and depression-like behaviors in the rats.

  • Chronic unpredictable stress decreased the hippocampal PGC-1α/FNDC5/BDNF proteins.

  • Chronic unpredictable stress induced the anxiety- and depression-like behaviors in the rats.

  • Continuous and interval exercise preconditioning had a protective effect against chronic unpredictable stress.

Abstract

Various exercise-training types are known to prevent depression, but mechanisms underlying their beneficial effects remain unknown. In the present study, the preconditioning effect of continuous and interval exercise on stress-induced depression was evaluated. Adult male Wistar rats in the exercise groups were made to run on a motorized treadmill, five sessions per week for six weeks. After that, to induce the depression model, the rats were exposed to chronic unpredictable stress for three weeks. Behavioral tests were assessed by open field, elevated plus maze, and forced swim tests. Hippocampal PGC-1α, FNDC5, and BDNF protein expression by Western blot and serum corticosterone by ELISA were detected. In the present results, after continuous and interval exercise periods, locomotor activity, the number of entries and time spent in the open arms were increased, and immobility time was significantly reduced. PGC-1α, FNDC5, and BDNF protein levels had a significant increase, and serum corticosterone did not change. Also, interval exercise training increased PGC-1α and FNDC5 more than continuous. Chronic unpredictable stress reduced the positive changes caused by exercise training, although, except FNDC5, exercise preconditioned groups experienced less significant adverse changes in most variables. These findings showed that both continuous and interval exercise preconditioning with increasing hippocampal PGC-1α, FNDC5, and BDNF proteins and improve the anxiety- and depression-like behaviors have a protective effect against chronic unpredictable stress.

Introduction

Depression is a common mental disorder that more than 322 million people live with this disease in the world. In 2020, depression was a significant contributor to the overall global burden and the second leading cause of disability worldwide, according to the World Health Organization (James et al., 2018). Depression causes many negative changes in the brain, especially the hippocampus, including hippocampal volume reduction (Roddy et al., 2019; Chen et al., 2020), disruption of memory function (Dillon and Pizzagalli, 2018), neuronal atrophy (Khan et al., 2019), and decreased neurotrophic factors (Gross and Seroogy, 2020) contribute to depressive behaviors. The hippocampus plays an essential role in learning and memory and is a significant site where changes occur induce by exercise. Depression can often ensue after exposure to chronic stress. Chronic unpredictable stress (CUS) is probably the most valid animal model of depression and involves the exposure of animals to a series of mild and unpredictable stressors during at least two weeks. The model has been reported to result in long-lasting changes in behavioral and neurochemical variables (Willner, 2005).

Probably performing physical exercise before exposure to stressful conditions prevents, attenuates, and possibly reverses biochemical and behavioral negative changes induced by depression (Mammen and Faulkner, 2013; Schuch et al., 2016; Stavrakakis et al., 2013). A large part of the positive effects of physical exercise is believed to be mediated by the increased brain-derived neurotrophic factor (BDNF), one of the most critical neurotrophic factors in the brain from the neurotrophin family (Szuhany et al., 2015; Dinoff et al., 2018). BDNF involved in neuronal differentiation, plasticity, cell survival, hippocampal function, learning, neuronal sprouting, synaptic reorganization, and neurogenesis plays a critical role in the development and maintenance of the peripheral and central nervous system (Kowiański et al., 2018; Szuhany and Otto, 2020). Reduced brain BDNF levels are also associated with CUS and depression (Murakami et al., 2005; LI et al., 2007), while, in contrast, exercise training appears to increase BDNF levels (Fang et al., 2013; Toups et al., 2011). However, the exact mechanism of exercise effects on BDNF has not been established.

There are many exercise dependent signaling pathway to activate BDNF. The newly discovered pathway is related to Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). This protein was first discovered as a transcriptional co-modulator of mitochondrial biogenesis and oxidative metabolism in brown fat (Spiegelman, 2007; Puigserver et al., 1998). It has shown that PGC-1α has a vital role in the brain. The deficiency of PGC-1α is associated with neurodegeneration (Lin et al., 2004; Ma et al., 2010). Also, chronic forced treadmill running increases Pgc1a expression in various areas of the brain (Steiner et al., 2011). During exercise and in response to contraction, PGC-1α-dependent myokine, Fibronectin type III domain-containing protein 5 (FNDC5), is cleaved and secreted from muscle induces some major metabolic benefits of exercise (Boström et al., 2012). FNDC5 is also expressed in the brain, especially the hippocampus (Wrann et al., 2013). There is a strong correlation between PGC-1a and FNDC5 gene expression as PGC-1α is a transcriptional regulator of Fndc5 gene expression. However, very little is known about the function of FNDC5 in the brain. It was shown that PGC-1α−/− mice exhibit low FNDC5 expression in the brain. FNDC5 deficiency impairs neuronal development (Hashemi et al., 2013). Recent research has shown that exercise-induced BDNF gene expression in the hippocampus is relevant to PGC1α/FNDC5/BDNF pathway, and on the other hand, BDNF through FNDC5/BDNF feedback loop negatively regulates FNDC5 (Wrann et al., 2013; Wrann, 2015; Xu, 2013). Therefore, these components form an essential and complex signaling pathway in the hippocampus.

A variety of exercise training methods for brain health against many diseases are recommended. Many recent studies have compared two types of them on treadmill, continuous, and interval exercise training. Therefore, in the present study, we tried to answer two main questions: (1) If the male Wistar rats perform two types of exercise training, continuous and interval, for six weeks and then exposure to three weeks of chronic unpredictable stress, whether PGC1α/FNDC5/BDNF protein expression will be changed? (2) Is there any difference between continuous and interval exercise training? In this study, cognitive function changes based on locomotion, anxiety- and depression-like behaviors were analyzed.

Section snippets

Animals

Animals were two-month-old adult male Wistar rats (Pasteur Institute, Tehran, Iran) weighing 175–200g. They were maintained under standard laboratory conditions on 22 ± 2 °C under 12-h light/dark cycles and 50 ± 5% humidity with food and water available ad libitum except when they were submitted to CUS. Upon entering the lab, all rats were allowed to adapt to the environment for a week. The experimental protocol was approved by the Ethical Review Board of Shahid Beheshti University of Medical

Results

In this study, by comparing Control + Non-Stress and Control + Stress groups with each other by unpaired two-sample t-test, it was indicated three weeks chronic unpredictable stress had significance negative effect on most behavioral variables (Table 2) include total distance traveled [t(10) = −4.592, p = 0.001] and velocity [t(10) = 1.347, p = 0.208] in OF, percent of entries to open arms [t(10) = −4.142, p = 0.031], time spent on open arms [t(10) = −17.516, p = 0.001] and time spent on close

Discussion

The present study investigated the effect of continuous and interval exercise preconditioning against chronic unpredictable stress on hippocampal PGC-1α/FNDC5/BDNF protein expression and some male rats’ behaviors. The findings have shown: (1) Both types of exercise training, interval and continuous, similarly improved locomotion, depression- and anxiety-like behaviors in male rats, (2) It was observed that after the exercise phase, hippocampal levels of PGC-1α, BDNF, and FNDC5 increased in

Conclusion

Generally, the six-week continuous and interval exercise training increases PGC-1α/FNDC5/BDNF protein expression of male rat's hippocampus and improves anxiety- and depression-like behaviors, although the interval training increases the PGC-1α and FNDC5 more than continuous training. After exercise training, the three weeks' chronic unpredictable stress reduced PGC-1α, FNDC5, and BDNF protein levels and behavioral scores. However, exercise preconditioning, except the FNDC5, has a significant

CRediT authorship contribution statement

Ayyub Babaei: Funding acquisition, contributed to the acquisition of behavioral and molecular data, Formal analysis, assisted with data analysis and interpretation of findings, Writing - original draft. Maryam Nourshahi: Conceptualization, were responsible for the study concept and design, Formal analysis, assisted with data analysis and interpretation of findings, provided critical revision of the manuscript for important intellectual content. Maryam Fani: Funding acquisition, contributed to

Declaration of competing interest

The authors declare that they have no conflict of interest.

Acknowledgment

The authors would like to thank the Department of Biological Sciences in Sport, Faculty of Sports Sciences and Health, Shahid Beheshti University and Neuroscience and Neurobiology Research Centers, School of Medicine, Shahid Beheshti University of Medical Sciences for their cooperation in conducting this study.

References (75)

  • R.S. Duman et al.

    Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid-acting agents

    Trends Neurosci.

    (2012)
  • Z.H. Fang

    Effect of treadmill exercise on the BDNF-mediated pathway in the hippocampus of stressed rats

    Neurosci. Res.

    (2013)
  • C. Gross et al.

    Neuroprotective roles of neurotrophic factors in depression

  • M.-S. Hashemi

    Fndc5 knockdown significantly decreased neural differentiation rate of mouse embryonic stem cells

    Neuroscience

    (2013)
  • M. Hei

    Effects of chronic mild stress induced depression on synaptic plasticity in mouse hippocampus

    Behav. Brain Res.

    (2019)
  • Z. Huang

    Curcumin reverses corticosterone-induced depressive-like behavior and decrease in brain BDNF levels in rats

    Neurosci. Lett.

    (2011)
  • S. Jung et al.

    Exercise-induced PGC-1α transcriptional factors in skeletal muscle

    Integrative medicine research

    (2014)
  • L. Khedr

    TLR4 signaling modulation of PGC1-α mediated mitochondrial biogenesis in the LPS-Chronic mild stress model: effect of fluoxetine and pentoxiyfylline

    Life Sci.

    (2019)
  • J. Lin

    Defects in adaptive energy metabolism with CNS-linked hyperactivity in PGC-1α null mice

    Cell

    (2004)
  • W. Liu et al.

    Corticosterone reduces brain mitochondrial function and expression of mitofusin, BDNF in depression-like rodents regardless of exercise preconditioning

    Psychoneuroendocrinology

    (2012)
  • D. Ma

    Neuronal inactivation of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) protects mice from diet-induced obesity and leads to degenerative lesions

    J. Biol. Chem.

    (2010)
  • G. Mammen et al.

    Physical activity and the prevention of depression: a systematic review of prospective studies

    Am. J. Prev. Med.

    (2013)
  • O. Martí et al.

    Effects of chronic stress on food intake in rats: influence of stressor intensity and duration of daily exposure

    Physiol. Behav.

    (1994)
  • K. Mikkelsen

    Exercise and mental health

    Maturitas

    (2017)
  • S. Murakami

    Chronic stress, as well as acute stress, reduces BDNF mRNA expression in the rat hippocampus but less robustly

    Neurosci. Res.

    (2005)
  • P. Nasrallah

    Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling

    Neurobiology of stress

    (2019)
  • G. Patki

    Novel mechanistic insights into treadmill exercise based rescue of social defeat-induced anxiety-like behavior and memory impairment in rats

    Physiol. Behav.

    (2014)
  • A. Pietrelli

    Aerobic exercise prevents age-dependent cognitive decline and reduces anxiety-related behaviors in middle-aged and old rats

    Neuroscience

    (2012)
  • P. Puigserver

    A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis

    Cell

    (1998)
  • D.W. Roddy

    The hippocampus in depression: more than the sum of its parts? Advanced hippocampal substructure segmentation in depression

    Biol. Psychiatr.

    (2019)
  • F.B. Schuch

    Exercise as a treatment for depression: a meta-analysis adjusting for publication bias

    J. Psychiatr. Res.

    (2016)
  • A. Siteneski

    Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice

    Prog. Neuro Psychopharmacol. Biol. Psychiatr.

    (2018)
  • N. Stavrakakis

    Physical activity and onset of depression in adolescents: a prospective study in the general population cohort TRAILS

    J. Psychiatr. Res.

    (2013)
  • K.L. Szuhany et al.

    Assessing BDNF as a mediator of the effects of exercise on depression

    J. Psychiatr. Res.

    (2020)
  • K.L. Szuhany et al.

    A meta-analytic review of the effects of exercise on brain-derived neurotrophic factor

    J. Psychiatr. Res.

    (2015)
  • J.P. Tiano et al.

    SMAD3 negatively regulates serum irisin and skeletal muscle FNDC5 and peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) during exercise

    J. Biol. Chem.

    (2015)
  • M.S. Toups

    Effects of serum Brain Derived Neurotrophic Factor on exercise augmentation treatment of depression

    J. Psychiatr. Res.

    (2011)
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