Non-pharmacological interventions including ipRGC-sensitive flickering blue light and physical exercise exert beneficial effects on cognitive function. However, whether their combined application confers additional benefits within a short intervention window where single interventions lack obvious efficacy remains unclear, and the underlying neural oscillatory mechanisms are poorly defined. This study aimed to characterize the behavioral and electrophysiological effects of short-term combined blue light and exercise in cognitive disorder mice. 5×FAD mice and their wild-type littermates were randomized into 5 groups (n = 8 each): wild-type control (CTRL), AD control (AD), AD with blue light (AD + B), AD with exercise (AD + E), and AD with combined intervention (AD + BE). All mice completed 7 days of exercise acclimatization before formal intervention. Cognitive function was assessed via Y-maze and novel object recognition (NOR) tests. Wireless electrophysiology recorded hippocampal CA1 local field potential (LFP) during rest and behavioral tasks. A one-week combined intervention effectively rescued cognitive deficits in AD mice, whereas single blue light or exercise alone produced no detectable behavioral improvement. The combined regimen corrected pathological elevation of δ band power, restored γ band deficits, and selectively enhanced cognition-related θ–γ phase-amplitude coupling (PAC). Notably, neural and PAC restoration exhibited clear task-dependent patterns: additional elevation of θ power in the NOR task, and concurrent improvement of δ–γ and θ–γ PAC in the Y-maze task. Short-term combined intervention with ipRGC-sensitive blue light and physical exercise ameliorates cognitive impairment at a time point when monotherapies have not yet produced significant beneficial effects. In addition, this combinatorial regimen remodels hippocampal oscillatory activity and phase-amplitude coupling, rendering combined treatment a promising therapeutic strategy for mitigating cognitive impairment.
Obesity has been increasingly linked to differences in working memory (WM), yet the neurophysiological mechanisms linking metabolic state to cognitive function remain unclear. Here, we investigated whether alterations in cortical information transmission are associated with obesity-related differences in working memory. Using resting-state fMRI data from the Human Connectome Project, we applied an information-theoretic framework to quantify synergistic and redundant connectivity among key brain regions supporting working memory. We examined whether network-level and edge-level connectivity features were associated with BMI and working memory performance and further assessed their moderating relationships with the BMI–WM association, together with exploratory indirect-effect analyses. Higher BMI was associated with poorer WM performance (β = − 0.149, 95
Aging is associated with progressive alterations in mitochondrial function, metabolic regulation, vascular integrity, neuromuscular performance, and cognitive function, contributing to increased vulnerability to frailty, cardiometabolic disorders, and neurodegenerative diseases. Lifestyle interventions combining regular physical activity with targeted nutritional strategies have attracted increasing attention as potential approaches to support healthy aging. Among dietary polyphenols, green tea catechins and cocoa flavanols have been extensively investigated because of their antioxidant, neuroprotective, and vasculoprotective properties. This narrative review provides a comparative neurobiological framework to examine the available evidence regarding the combined effects of catechins or cocoa flavanols with exercise on brain aging and neurodegeneration, with particular emphasis on mitochondrial bioenergetics, apoptosis and cell survival, neuromuscular function and sarcopenia, and cardiovascular regulation. Current evidence suggests that catechins may exert more direct intracellular effects by supporting mitochondrial function, reducing oxidative stress, modulating apoptotic signaling, and influencing neuroinflammatory pathways, whereas cocoa flavanols appear to predominantly improve vascular function through enhanced nitric oxide bioavailability, endothelial function, and tissue perfusion. Existing studies also suggest that both compounds may interact with exercise-induced adaptations, although catechins have been more consistently associated with mitochondrial biogenesis and muscle regeneration, while cocoa flavanols have shown greater effects on vascular and cardiorespiratory function. Nevertheless, much of the available evidence is derived from preclinical studies, and further well-designed clinical trials are needed to clarify comparative efficacy, long-term safety, and underlying mechanisms. Overall, the available evidence supports the potential complementary roles of these interventions in healthy brain aging; however, additional high-quality clinical and mechanistic studies are required before definitive conclusions can be drawn.
Chronic opioid exposure and subsequent abstinence are associated with persistent cognitive impairment and disrupted neuroplasticity, which may be further aggravated by opioid-induced hypogonadism. Brain-derived neurotrophic factor (BDNF) is a key regulator of neuronal plasticity in memory-related brain regions; however, the combined effects of exercise intensity and testosterone replacement during morphine abstinence remain poorly understood. This study investigated whether mild- and moderate-intensity treadmill exercise, alone or in combination with testosterone replacement, could ameliorate cognitive deficits and restore BDNF levels in morphine-abstinent castrated male rats. Rats underwent sham surgery or bilateral castration, followed by a 30-day recovery period, induction of morphine dependence (10 mg/kg, twice daily for 10 days), and a 28-day intervention consisting of sedentary conditions or treadmill exercise with or without testosterone treatment. Spatial learning and memory were evaluated using the Morris water maze, and avoidance memory was assessed using the shuttle box task. BDNF levels in the hippocampus, prefrontal cortex, and serum were quantified by ELISA. Morphine abstinence and castration impaired spatial learning, spatial memory, and avoidance memory and significantly reduced hippocampal and prefrontal cortex BDNF levels. Both mild- and moderate-intensity exercise improved cognitive performance and increased hippocampal and prefrontal cortex BDNF levels, with moderate-intensity exercise generally producing greater benefits. Testosterone replacement partially ameliorated the adverse effects of castration and improved selected behavioral and neurochemical outcomes, although its effects varied across experimental conditions. These findings suggest that appropriately prescribed exercise is an effective non-pharmacological strategy for promoting cognitive recovery and restoring neurotrophic signaling during morphine abstinence, while testosterone replacement may provide additional benefit under hypogonadal conditions. Chronic morphine and castration impair spatial and avoidance memory. Exercise improves cognition and restores brain BDNF during morphine abstinence. Moderate exercise produces greater cognitive benefits than mild exercise. Testosterone partially restores cognition and BDNF after castration. Exercise and testosterone may aid cognitive recovery during opioid abstinence.
Nandrolone decanoate (ND) exposure has been associated with impairments in hippocampal-dependent learning and memory, potentially involving alterations in intracellular calcium signaling and Calcineurin protein expression. Given the distinct functional contributions of the dorsal hippocampus (dHPC) and ventral hippocampus (vHPC) to cognitive and emotional processes, this study investigated whether ND-induced behavioral changes are associated with alterations in Calcineurin protein levels in these hippocampal subregions. Twenty-seven male rats were randomly assigned to three groups (n = 9 per group) and received intraperitoneal injections of ND (5 or 15 mg/kg) or sesame oil as the vehicle control every third day for 22 days. Behavioral assessments included the Morris water maze (MWM) for spatial learning and memory, the open field test (OFT) for locomotor activity and anxiety-like behavior, and the passive avoidance test (PAT) for aversive memory. Following completion of behavioral testing, the animals were deeply anesthetized, and the brains were removed. The hippocampus was dissected from the right hemisphere and further separated into dorsal and ventral regions according to standard stereotaxic coordinates relative to Bregma. Tissue samples were homogenized, and Calcineurin protein levels in the dHPC and vHPC were quantified using a commercial ELISA kit according to the manufacturer’s instructions. ND administration impaired both spatial and avoidance memory and was associated with increased Calcineurin protein levels in the dHPC and vHPC. These findings suggest an association between increased Calcineurin protein levels and Nandrolone-induced cognitive deficits in both hippocampal subregions. Additionally, Nandrolone did not significantly alter locomotor activity but reduced anxiety-like behavior in rats. These findings suggest that ND-associated learning and memory impairments are accompanied by alterations in Calcineurin protein levels in both the dHPC and vHPC. The region-dependent effects of ND on Calcineurin may contribute to the differential vulnerability of hippocampal subregions to ND exposure and provide further insight into the potential molecular mechanisms underlying the cognitive effects of anabolic-androgenic steroid exposure.
