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