The exercise-derived myokine, irisin, as a stress-counteracting agent



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Psychological stress is one of the main events to change the structure, function, and activity of the brain. Organs respond to stress in different ways to enable the body to maintain homeostasis. Depending on the type of stress—acute or chronic—the CNS shows a wide range of behavioral and physiological changes. The hippocampus is the most vulnerable region of the brain, and it is affected by stress immensely. Emotion, spatial navigation, and memory are controlled by the hippocampus and are influenced by psychological stress. Conveying the information from stressors activates the sympathetic-adreno-medullar (SAM) axis and the hypothalamus-pituitary-adrenal (HPA) axis, which are the major components of the stress response. The SAM axis is the initial response to stress for adjusting the body to a traumatic condition. Activation of SAM by stress leads to stimulation of target organs (e.g., increased heart rate), adrenaline secretion, energy utilization and immune reactions. The second phase of response to stress is the activation of the HPA axis. An active HPA axis results in corticosteroids secretion from adrenal cortex. Secreted corticosteroids initiate structural and functional changes in the hippocampus through their receptors. In addition to structural change, different signaling pathways are modulated by active HPA axis in the hippocampus. Responding to stress is different between males and females. In females the estrous cycle has a crucial role in the level of response to stress. But the mechanism of action in the hippocampus of male and female rodents in response to stress is not fully understood. Acute stress is a short-term sudden and unpredictable threat such as car accident. Acute stress changes energy homeostasis in the hippocampus. Disruption in glucose metabolism and energy homeostasis in the hippocampus correspond to behavioral impairments such as memory loss, anxiety, and depression-like behaviors. The Akt/GSK3β axis is the central signaling pathway in neurons and hippocampus for sensing the glucose uptake and energy homeostasis. Fluctuating glucose metabolism alters Akt/GSK3β status in the hippocampus. At a behavioral level, hippocampal the Akt/GSK3β axis corresponds to emotion and memory formation. Interestingly, acute stress decreases glucose uptake in the hippocampus of male mice without impacting female subjects. But the influences of the hippocampal Akt/GSK3β axis by acute stress have not been studied. In addition, determining the difference between sexes in molecular level in the hippocampus is still not completely understood. Finding a strategy to alleviate stress outcomes is one of the main challenges in the neuroscience research field. Exercise has wide ranges of beneficial effects on physical and mental health. For minimizing the symptoms of neurological diseases such as Alzheimer’s and Parkinson’s diseases (AD and PD), exercise is one of the main remedies. Exercise can make connections between different tissues through secreting hormones and growth factors. Myokines, which are secreted from skeletal muscles during exercise, strengthen the muscle-brain axis. Irisin is a cleaved region of FNDC5—a recently discovered myokine which controls energy homeostasis in different tissues. FNDC5 has abundant expression in the skeletal muscle and brain with divergent expression in males and females. But the sex-dependency for Irisin has not been studied yet. Increasing the expression of the FNDC5/Irisin in the hippocampus rescues memory impairment in AD models. But the role of exercise and Irisin in suppressing acute stress-induced behavioral and physiological impairments is still unknown. In this study we show how exercise and Irisin exercise play a protective role in protecting against acute stress. Hence, we show Irisin administration into the hippocampus has sex-dependent manner in suppressing acute stress-induced abnormalities. In addition, we show swimming exercise has beneficial effects on behavior and enable mice to cope with acute stress. In conclusion, finding the strategy or medication to help to cope with psychological stress is crucial for controlling neuropsychiatric diseases. Our study shows Irisin secretion during exercise has the potential to suppress acute stress and support adjusting to it. Therefore, our demonstration of Irisin and exercise as therapeutic agents, as documented in this dissertation, opens new avenues in the stress research field.



Irisin, Stress, Hippocampus, Exercise