Brain Plasticity

Although muscular strength has been linked to greater cognitive function across different cognitive domains, the mechanism(s) through which this occurs remain(s) poorly understood. Indeed, while an emerging body of literature suggests peripheral myokines released from muscular contractions may play a role in this relationship, additional research is needed to understand this link. Accordingly, this study sought to compare the influences of a particular myokine, Cathepsin B (CTSB), and muscular strength on hippocampal-dependent relational memory and cognitive control in 40 adults (age = 50.0±7.3 yrs). Overnight fasted venous blood draws were taken to assess plasma CTSB and muscular strength was assessed as maximal isokinetic strength testing using a Biodex dynamometer. Cognitive performance was assessed using a Spatial Reconstruction Task to assess relational memory and a modified Flanker task to assess cognitive control. Neuroelectric function for cognitive control was assessed using event-related potentials (ERPs) recorded during the Flanker task. Initial bivariate correlational analyses revealed that neither sex, age, lean body mass, or muscular strength was associated with CTSB. However, CTSB was inversely associated with reaction time and fractional peak latency of the P3 component of the Flanker task. Muscular strength was also inversely associated with reaction time and positively associated with relational memory performance. However, the influence of muscular strength on relational memory did not persist following adjustment for covariates. Greater circulating CTSB was selectively associated with greater cognitive control as well as faster information processing speed. These findings are the first to link circulating CTSB to both cognitive control and neuroelectric function. Future intervention studies are needed to examine the effects of changes in muscular strength, circulating myokines, and different domains of cognitive function.

Skeletal muscle health and function are important determinants of systemic metabolic homeostasis and organism-wide responses, including disease outcome. While it is well known that exercise protects the central nervous system (CNS) from aging and disease, only recently this has been found to depend on the endocrine capacity of skeletal muscle. Here, we review muscle-secreted growth factors and cytokines (myokines), metabolites (myometabolites), and other unconventional signals (e.g. bioactive lipid species, enzymes, and exosomes) that mediate muscle-brain and muscle-retina communication and neuroprotection in response to exercise and associated processes, such as the muscle unfolded protein response and metabolic stress. In addition to impacting proteostasis, neurogenesis, and cognitive functions, muscle-brain signaling influences complex brain-dependent behaviors, such as depression, sleeping patterns, and biosynthesis of neurotransmitters. Moreover, myokine signaling adapts feeding behavior to meet the energy demands of skeletal muscle. Contrary to protective myokines induced by exercise and associated signaling pathways, inactivity and muscle wasting may derange myokine expression and secretion and in turn compromise CNS function. We propose that tailoring muscle-to-CNS signaling by modulating myokines and myometabolites may combat age-related neurodegeneration and brain diseases that are influenced by systemic signals.

Physical activity is a powerful lifestyle factor capable of improving cognitive function, modifying the risk for dementia associated with neurodegeneration and possibly slowing neurodegenerative disease progression in both men and women. However, men and women show differences in the biological responses to physical activity and in the vulnerabilities to the onset, progression and outcome of neurodegenerative diseases, prompting the question of whether sex-specific regulatory mechanisms might differentially modulate the benefits of exercise on the brain. Mechanistic studies aimed to better understand how physical activity improves brain health and function suggest that the brain responds to physical exercise by overall reducing neuroinflammation and increasing neuroplasticity. Here, we review the emerging literature considering sex-specific differences in the immune system response to exercise as a potential mechanism by which physical activity affects the brain. Although the literature addressing sex differences in this light is limited, the initial findings suggest a potential influence of biological sex in the brain benefits of exercise, and lay out a scientific foundation to support very much needed studies investigating the potential effects of sex-differences on exercise neurobiology. Considering biological sex and sex-differences in the neurobiological hallmarks of exercise will help to enhance our understanding of the mechanisms by which physical activity benefits the brain and also improve the development of treatments and interventions for diseases of the central nervous system.

Brain plasticity and metabolism are tightly connected by a constant influx of peripheral glucose to the central nervous system in order to meet the high metabolic demands imposed by neuronal activity. Metabolic disturbances highly affect neuronal plasticity, which underlies the prevalent comorbidity between metabolic disorders, cognitive impairment, and mood dysfunction. Effective pro-cognitive and neuropsychiatric interventions, therefore, should consider the metabolic aspect of brain plasticity to achieve high effectiveness. The adipocyte-secreted hormone, adiponectin, is a metabolic regulator that crosses the blood-brain barrier and modulates neuronal activity in several brain regions, where it exerts neurotrophic and neuroprotective properties. Moreover, adiponectin has been shown to improve neuronal metabolism in different animal models, including obesity, diabetes, and Alzheimer’s disease. Here, we aim at linking the adiponectin’s neurotrophic and neuroprotective properties with its main role as a metabolic regulator and to summarize the possible mechanisms of action on improving brain plasticity via its role in regulating the intracellular energetic activity. Such properties suggest adiponectin signaling as a potential target to counteract the central metabolic disturbances and impaired neuronal plasticity underlying many neuropsychiatric disorders.

The birth, maturation, and integration of new neurons in the adult hippocampus regulates specific learning and memory processes, responses to stress, and antidepressant treatment efficacy. This process of adult hippocampal neurogenesis is sensitive to environmental stimuli, including peripheral signals from certain cytokines, hormones, and metabolites, which can promote or hinder the production and survival of new hippocampal neurons. The trillions of microorganisms resident to the gastrointestinal tract, collectively known as the gut microbiota, also demonstrate the ability to modulate adult hippocampal neurogenesis. In doing so, the microbiota-gut-brain axis can influence brain functions regulated by adult hippocampal neurogenesis. Unlike the hippocampus, the gut microbiota is highly accessible to direct interventions, such as prebiotics, probiotics, and antibiotics, and can be manipulated by lifestyle choices including diet. Therefore, understanding the pathways by which the gut microbiota shapes hippocampal neurogenesis may reveal novel targets for non-invasive therapeutics to treat disorders in which alterations in hippocampal neurogenesis have been implicated. This review first outlines the factors which influence both the gut microbiome and adult hippocampal neurogenesis, with cognizance that these effects might happen either independently or due to microbiota-driven mechanisms. We then highlight approaches for investigating the regulation of adult hippocampal neurogenesis by the microbiota-gut-brain axis. Finally, we summarize the current evidence demonstrating the gut microbiota’s ability to influence adult hippocampal neurogenesis, including mechanisms driven through immune pathways, microbial metabolites, endocrine signalling, and the nervous system, and postulate implications for these effects in disease onset and treatment.

The term “neural plasticity” was first used to describe non-pathological changes in neuronal structure. Today, it is generally accepted that the brain is a dynamic system whose morphology and function is influenced by a variety of factors including stress, diet, and exercise. Neural plasticity involves learning and memory, the synthesis of new neurons, the repair of damaged connections, and several other compensatory mechanisms. It is altered in neurodegenerative disorders and following damage to the central or peripheral nervous system. Understanding the mechanisms that regulate neural plasticity in both healthy and diseased states is of significant importance to promote cognition and develop rehabilitation techniques for functional recovery after injury. In this minireview, we will discuss the mechanisms by which environmental factors promote neural plasticity with a focus on exercise- and diet-induced factors. We will highlight the known circulatory factors that are released in response to exercise and discuss how all factors activate pathways that converge in part on the activation of BDNF signaling. We propose to harness the therapeutic potential of exercise by using BDNF as a biomarker to identify novel endogenous factors that promote neural plasticity. We also discuss the importance of combining exercise factors with dietary factors to develop a lifestyle pill for patients afflicted by CNS disorders.