Long-term light and moderate exercise intervention similarly prevent both hippocampal and glycemic dysfunction in presymptomatic type 2 diabetic rats.

A prediabetic population has an increased risk of cognitive decline and type 2 diabetes mellitus (T2DM). This study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with 4 mo of exercise intervention from the presymptomatic stage in a T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the presymptomatic stage of Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a T2DM model, with Long-Evans Tokushima (LETO) rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for 4 mo with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the presymptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the presymptomatic stage of T2DM normalized glycemic parameters and hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A 4-mo exercise regimen from the presymptomatic stage of T2DM at a light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement.NEW & NOTEWORTHY Type 2 diabetes mellitus is an independent risk factor for hippocampal memory dysfunction, which would progress since the prediabetic stage. We found that 4 mo of exercise both at the light and moderate intensity prevented the progression of memory dysfunction with an improvement of hippocampal MCT2 expression in presymptomatic diabetes, implying that light intensity exercise could be a therapeutic approach, and the alteration of hippocampal MCT2 would be a therapeutic target of memory dysfunction from presymptomatic diabetes.

Exercise-Induced Adrenocorticotropic Hormone Response Is Cooperatively Regulated by Hypothalamic Arginine Vasopressin and Corticotrophin-Releasing Hormone.

INTRODUCTION: Exercise becomes a stress when performed at an intensity above the lactate threshold (LT) because at that point the plasma adrenocorticotropic hormone (ACTH), a marker of stress response, increases. It is possible that the exercise-induced ACTH response is regulated at least by arginine vasopressin (AVP) and possibly by corticotropin-releasing hormone (CRH), but this remains unclear. To clarify the involvement of these factors, it is useful to intervene pharmacologically in the regulatory mechanisms, with a physiologically acceptable exercise model. METHODS: We used a special stress model of treadmill running (aerobic exercise) for male Wistar rats, which mimic the human physiological response, where plasma ACTH levels increase at just above the LT for 30 min. Animals were administered the AVP V1b receptor antagonist SSR149415 (SSR) and/or the CRH type 1 receptor antagonist CP154526 (CP) intraperitoneally before the exercise, which allowed the monitoring of exercise-induced ACTH response. Immunohistochemical evaluation of activated AVP and CRH neurons with exercise was performed for the animals' hypothalami. RESULTS: A single injection of either antagonist, SSR or CP, resulted in inhibited ACTH levels after exercise stress. Moreover, the combined injection of SSR and CP strongly suppressed ACTH secretion during treadmill running to a greater extent than each alone. The running-exercise-induced activation of both AVP and CRH neurons in the hypothalamus was also confirmed. CONCLUSION: These results lead us to hypothesize that AVP and CRH are cooperatively involved in exercise-induced ACTH response just above the LT. This may also reflect the stress response with moderate-intensity exercise in humans.

Leptin in hippocampus mediates benefits of mild exercise by an antioxidant on neurogenesis and memory.

Regular exercise and dietary supplements with antioxidants each have the potential to improve cognitive function and attenuate cognitive decline, and, in some cases, they enhance each other. Our current results reveal that low-intensity exercise (mild exercise, ME) and the natural antioxidant carotenoid astaxanthin (AX) each have equivalent beneficial effects on hippocampal neurogenesis and memory function. We found that the enhancement by ME combined with AX in potentiating hippocampus-based plasticity and cognition is mediated by leptin (LEP) made and acting in the hippocampus. In assessing the combined effects upon wild-type (WT) mice undergoing ME with or without an AX diet for four weeks, we found that, when administrated alone, ME and AX separately enhanced neurogenesis and spatial memory, and when combined they were at least additive in their effects. DNA microarray and bioinformatics analyses revealed not only the up-regulation of an antioxidant gene, ABHD3, but also that the up-regulation of LEP gene expression in the hippocampus of WT mice with ME alone is further enhanced by AX. Together, they also increased hippocampal LEP (h-LEP) protein levels and enhanced spatial memory mediated through AKT/STAT3 signaling. AX treatment also has direct action on human neuroblastoma cell lines to increase cell viability associated with increased LEP expression. In LEP-deficient mice (ob/ob), chronic infusion of LEP into the lateral ventricles restored the synergy. Collectively, our findings suggest that not only h-LEP but also exogenous LEP mediates effects of ME on neural functions underlying memory, which is further enhanced by the antioxidant AX.

Preventive role of regular low-intensity exercise during adolescence in schizophrenia model mice with abnormal behaviors.

Schizophrenia is probably ascribed to perinatal neurodevelopmental deficits, and its onset might be affected by environmental factors. Hypofrontality with glutamatergic and dopaminergic neuronal dysfunction are known factors, but a way to mitigate abnormalities remains unfound. An early enriched environment such as a wheel running in rodents may contribute to the prevention, but its clinical applicability is very limited. From our studies, low-intensity exercise training (LET) based on physiological indices, such as lactate threshold, easily translates to humans and positively affects the brains. Hence, LET during adolescence may ameliorate abnormalities in neurodevelopment and prevent the development of schizophrenia. In the current study, LET prevented sensitization to phencyclidine (PCP) treatment, impairment of cognition, and affective behavioral abnormalities in an animal model of schizophrenia induced by prenatal PCP treatment. Further, LET increased dopamine turnover and attenuated the impairment of phosphorylation of ERK1/2 after exposure to a novel object in the prenatal PCP-treated mice. These results suggest that LET during adolescence completely improves schizophrenia-like abnormal behaviors associated with improved glutamate uptake and the dopamine-induced ERK1/2 signaling pathway in the PFC.

Mild exercise improves executive function with increasing neural efficiency in the prefrontal cortex of older adults.

This study examined whether a 3-month mild-exercise intervention could improve executive function in healthy middle-aged and older adults in a randomized control trial. Ultimately, a total of 81 middle-aged and older adults were randomly assigned to either an exercise group or a control group. The exercise group received 3 months of mild cycle exercise intervention (3 sessions/week, 30-50 min/session). The control group was asked to behave as usual for the intervention period. Before and after the intervention, participants did color-word matching Stroop tasks (CWST), and Stroop interference (SI)-related reaction time (RT) was assessed as an indicator of executive function. During the CWST, prefrontal activation was monitored using functional near-infrared spectroscopy (fNIRS). SI-related oxy-Hb changes and SI-related neural efficiency (NE) scores were assessed to examine the underlying neural mechanism of the exercise intervention. Although the mild-exercise intervention significantly decreased SI-related RT, there were no significant effects of exercise intervention on SI-related oxy-Hb changes or SI-related NE scores in prefrontal subregions. Lastly, changes in the effects of mild exercise on NE with advancing age were examined. The 81 participants were divided into two subgroups (younger-aged subgroup [YA], older-aged subgroup [OA], based on median age [68 years.]). Interestingly, SI-related RT significantly decreased, and SI-related NE scores in all ROIs of the prefrontal cortex significantly increased only in the OA subgroup. These results reveal that a long-term intervention of very light-intensity exercise has a positive effect on executive function especially in older adults, possibly by increasing neural efficiency in the prefrontal cortex.

Accelerated Fear Extinction by Regular Light-Intensity Exercise: A Possible Role of Hippocampal BDNF-TrkB Signaling.

PURPOSE: Growing concern exists worldwide about stress-related mental disorders, such as posttraumatic stress disorder (PTSD), often linked to hippocampal dysfunctions. Recognizing this connection, regular light-intensity exercise (LIE)-such as yoga, walking, or slow jogging-may offer a solution. Easily accessible even to vulnerable individuals, LIE has been found to enhance hippocampus-based cognitive functions through the stimulation of neurotrophic factors like brain-derived neurotrophic factor (BDNF). A prior study that demonstrated BDNF's role in extinguishing original fear memory further leads us to propose that a consistent LIE training might drive fear extinction learning, offering potential therapeutic benefits through BDNF signaling. METHODS: Eleven-week-old Wistar rats underwent 4 wk of training under conditions of sedentary, LIE, or moderate-intensity exercise (MOE) after contextual or auditory fear conditioning. Subsequently, fear extinction tests were performed. We then administered intraperitoneal (i.p.) ANA-12, a selective antagonist of tropomyosin receptor kinase B (TrkB), or a vehicle to explore the role of BDNF signaling in exercise-induced fear extinction among the LIE rats. Following the regular exercise training, further fear extinction tests were conducted, and hippocampal protein analysis was performed using Western blotting. RESULTS: Both LIE and MOE over 4 wk accelerated hippocampus-associated contextual fear extinction compared with sedentary. In addition, 4 wk of LIE with i.p. administered vehicle increased hippocampal BDNF and TrkB protein levels. In contrast, i.p. ANA-12 administration fully blocked the LIE-enhanced protein levels and its effect on contextual fear extinction. CONCLUSIONS: Our findings reveal that LIE regimen promotes fear extinction learning, at least partially tied to hippocampal BDNF-TrkB signaling. This suggests that even regular light exercise could alleviate the excessive fear response in anxiety disorders and PTSD, providing hope for those affected.

Benefits of Exercise and Astaxanthin Supplementation: Are There Additive or Synergistic Effects?

A healthy lifestyle is essential for maintaining physical and mental health. Health promotion, with a particular emphasis on regular exercise and a healthy diet, is one of the emerging trends in healthcare. However, the way in which exercise training and nutrients from dietary intake interact with each other to promote additive, synergistic, or antagonistic effects on physiological functions leading to health promotion, and the possible underlying biomolecular mechanisms of such interactions, remain poorly understood. A healthy diet is characterized by a high intake of various bioactive compounds usually found in natural, organic, and fresh foodstuffs. Among these bioactive compounds, astaxanthin (ASX), a red carotenoid pigment especially found in seafood, has been recognized in the scientific literature as a potential nutraceutical due to its antioxidant, anti-inflammatory, and neurotrophic properties. Therefore, scientists are currently exploring whether this promising nutrient can increase the well-known benefits of exercise on health and disease prevention. Hence, the present review aimed to compile and summarize the current scientific evidence for ASX supplementation in association with exercise regimes, and evaluate the additive or synergistic effects on physiological functions and health when both interventions are combined. The new insights into the combination paradigm of exercise and nutritional supplementation raise awareness of the importance of integrative studies, particularly for future research directions in the field of health and sports nutrition science.

[Mild Exercise Results in Robust Brain Activation and Increased Memory Function].

Exercise increases adult hippocampal neurogenesis (AHN) and enhances memory function. To elucidate optimal exercise, especially exercise intensity, on hippocampus-based cognition, we established treadmill running animal model, in which running speed was defined using the blood lactate threshold (LT). Using this exercise model, we found for the first time that hippocampal neurons were activated after acute mild exercise (ME) below the LT with running stress minimized. In addition, chronic ME enhanced AHN and spatial memory function. We review the beneficial effects of ME and discuss several molecular factors underlying ME-enhanced hippocampal function.