Muscle-to-Brain Signaling Via Myokines and Myometabolites

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.

Traditional Chinese Mind-Body Exercise Baduanjin Modulate Gray Matter and Cognitive Function in Older Adults with Mild Cognitive Impairment: A Brain Imaging Study

Background: Previous studies found traditional Chinese mind-body exercise Baduanjin could modulate cognition of community older adults. Objective: This study aims to investigate the effect of 6 months of Baduanjin exercise on brain structure and cognitive function in older adults with mild cognitive impairment (MCI). Methods: The MCI older adults were randomly assigned into either Baduanjin training, brisk walking training or usual physical activity control group. Magnetic Resonance Imaging (MRI), Montreal Cognitive Assessment (MoCA) and Wechsler Memory Scale-Chinese Revised (WMS-CR) were applied to measure gray matter volume (GMV), global cognitive ability and memory at baseline and end of intervention. Results: Compared to usual physical activity, Baduanjin exercise significantly improved MoCA, WMS-CR scores, WMS-MQ, and mental control and comprehension memory subscores of the WMS-CR; significantly increased the GMV in the temporal gyrus, frontal gyrus, parietal gyrus, medial occipital gyrus, cingulate gyrus and angular gyrus after 6 months of intervention. Compared to brisk walking, Baduanjin significantly improved MoCA scores and picture reproduction subscores of memory, and significantly increased the GMV in the right frontal gyrus, precentral gyrus, occipital gyrus. Furthermore, the increased GMV in the right medial temporal gyrus was significantly associated with improvement in the MoCA scores. Conclusion: The present study suggested that regular Baduanjin training could have a positive effect in increasing brain gray matter and improving cognitive function in older adults with MCI.

Simultaneous Exercise and Cognitive Training in Virtual Reality Phase 2 Pilot Study: Impact on Brain Health and Cognition in Older Adults

Background: Aerobic exercise and environmental enrichment have been shown to enhance brain function. Virtual reality (VR) is a promising method for combining these activities in a meaningful and ecologically valid way. Objective: The purpose of this Phase 2 pilot study was to calculate relative change and effect sizes to assess the impact of simultaneous exercise and cognitive training in VR on brain health and cognition in older adults. Methods: Twelve cognitively normal older adults (64.7±8.8 years old, 8 female) participated in a 12-week intervention, 3 sessions/week for 25–50 minutes/session at 50–80%HRmax. Participants cycled on a custom-built stationary exercise bike while wearing a VR head-mounted display and navigating novel virtual environments to train spatial memory. Brain and cognitive changes were assessed using MRI imaging and a cognitive battery. Results: Medium effect size (ES) improvements in cerebral flow and brain structure were observed. Pulsatility, a measure of peripheral vascular resistance, decreased 10.5%(ES(d) = 0.47). Total grey matter volume increased 0.73%(ES(r) = 0.38), while thickness of the superior parietal lobule, a region associated with spatial orientation, increased 0.44%(ES(r) = 0.30). Visual memory discrimination related to pattern separation showed a large improvement of 68%(ES(ηp2) = 0.43). Cognitive flexibility (Trail Making Test B) (ES(r) = 0.42) and response inhibition (ES(W) = 0.54) showed medium improvements of 14%and 34%, respectively. Conclusions: Twelve weeks of simultaneous exercise and cognitive training in VR elicits positive changes in brain volume, vascular resistance, memory, and executive function with moderate-to-large effect sizes in our pilot study.

The Perfect Cytokine Storm: How Peripheral Immune Challenges Impact Brain Plasticity & Memory Function in Aging

Precipitous declines in cognitive function can occur in older individuals following a variety of peripheral immune insults, such as surgery, infection, injury, and unhealthy diet. Aging is associated with numerous changes to the immune system that shed some light on why this abrupt cognitive deterioration may occur. Normally, peripheral-to-brain immune signaling is tightly regulated and advantageous; communication between the two systems is bi-directional, via either humoral or neural routes. Following an immune challenge, production, secretion, and translocation of cytokines into the brain is critical to the development of adaptive sickness behaviors. However, aging is normally associated with neuroinflammatory priming, notably microglial sensitization. Microglia are the brain’s innate immune cells and become sensitized with advanced age, such that upon immune stimulation they will mount more exaggerated neuroimmune responses. The resultant elevation of pro-inflammatory cytokine expression, namely IL-1β, has profound effects on synaptic plasticity and, consequentially, cognition. In this review, we (1) investigate the processes which lead to aberrantly elevated inflammatory cytokine expression in the aged brain and (2) examine the impact of the pro-inflammatory cytokine IL-1β on brain plasticity mechanisms, including its effects on BDNF and AMPA and NMDA receptor-mediated long-term potentiation.

Preliminary Evidence of Improvement in Adolescent and Young Adult Cancer Survivors’ Brain Health Following Physical Activity: A Proof-of-Concept Sub-Study

Background: Cognitive impairment is common among adolescent and young adult (AYA) cancer survivors. Physical activity (PA) may help mitigate cognitive impairment post- treatment by positively impacting two indicators of general brain health: fractional anisotropy (FA) and functional connectivity (FC). As part of a two-arm, mixed-methods pilot randomized controlled trial (RCT), this sub-study was designed to provide preliminary proof-of-concept evidence for the effects of PA on FA and FC among AYA cancer survivors post-treatment to help inform decisions about proceeding to larger trials. Methods: AYA cancer survivors who had completed cancer treatment and who were enrolled in a larger pilot RCT testing a 12-week PA intervention or waitlist control group, were invited to participate in this sub-study. Sub-study participants completed diffusion tensor imaging and resting-state functional magnetic resonance imaging prior to randomization and post-PA intervention. Data were analyzed with descriptive statistics, independent component analysis, and paired sample t-tests. Results: Post-intervention, participants showed increases in the FA of the bilateral hippocampal cingulum, left anterior corona radiata, middle cingulum, left anterior thalamic radiation, and left cerebellum. A decrease in overall FC of the default mode network and increases in the cerebellar and visual networks were also noted post-intervention (p < .05). Conclusion: Results provide preliminary evidence for the possible positive effects of PA on FA and FC among AYA cancer survivors post-treatment. On the basis of these results, larger trials assessing the effects of PA on specific brain health indicators, as captured by FA and FC, among AYA cancer survivors are appropriate and warranted.

TAM Signaling in the Nervous System

Tyro3, Axl and Mertk are members of the TAM family of tyrosine kinase receptors. TAMs are activated by two structurally homologous ligands GAS6 and PROS1. TAM receptors and ligands are widely distributed and often co-expressed in the same cells allowing diverse functions across many systems including the immune, reproductive, vascular, and the developing and adult nervous systems. This review will focus specifically on TAM signaling in the nervous system, highlighting the essential roles they play in maintaining cell survival and homeostasis, cellular functions such as phagocytosis, immunity and tissue repair. Dysfunctional TAM signaling can cause complications in development, disruptions in homeostasis which can rouse autoimmunity, neuroinflammation and neurodegeneration. The development of therapeutics modulating TAM activities in the nervous system has great prospects, however, foremost we need a complete understanding of TAM signaling pathways.

Metabotropic Glutamate Receptor Trafficking and its Role in Drug-Induced Neurobehavioral Plasticity

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system that guides developmental and experience-dependent changes in many cellular substrates and brain circuits, through the process collectively referred to as neurobehavioral plasticity. Regulation of cell surface expression and membrane trafficking of glutamate receptors represents an important mechanism that assures optimal excitatory transmission, and at the same time, also allows for fine-tuning neuronal responses to glutamate. On the other hand, there is growing evidence implicating dysregulated glutamate receptor trafficking in the pathophysiology of several neuropsychiatric disorders. This review provides up-to-date information on the molecular determinants regulating trafficking and surface expression of metabotropic glutamate (mGlu) receptors in the rodent and human brain and discusses the role of mGluR trafficking in maladaptive synaptic plasticity produced by addictive drugs. As substantial evidence links glutamatergic dysfunction to the progression and the severity of drug addiction, advances in our understanding of mGluR trafficking may provide opportunities for the development of novel pharmacotherapies of addiction and other neuropsychiatric disorders.

EEG Resting-State and Event-Related Potentials as Markers of Learning Success in Older Adults Following Second Language Training: A Pilot Study

In this pilot study, we evaluated the use of electrophysiological measures at rest as paradigm-independent predictors of second language (L2) development for the first time in older adult learners. We then assessed EEG correlates of the learning outcome in a language-switching paradigm after the training, which to date has only been done in younger adults and at intermediate to advanced L2 proficiency. Ten (Swiss) German-speaking adults between 65–74 years of age participated in an intensive 3-week English training for beginners. A resting-state EEG was recorded before the training to predict the ensuing L2 development (Experiment 1). A language-switching ERP experiment was conducted after the training to assess the learning outcome (Experiment 2). All participants improved their L2 skills but differed noticeably in their individual development. Experiment 1 showed that beta1 oscillations at rest (13–14.5 Hz) predicted these individual differences. We interpret resting-state beta1 oscillations as correlates of attentional capacities and semantic working memory that facilitate the extraction and processing of novel forms and meanings from the L2 input. In Experiment 2, we found that language switching from the L2 into the native language (L1) elicited an N400 component, which was reduced in the more advanced learners. Thus, for learners beginning the acquisition of an L2 in third age, language switching appears to become less effortful with increasing proficiency, suggesting that the lexicons of the L1 and L2 become more closely linked. In sum, our findings extend the available evidence of neurological processes in L2 learning from younger to older adults, suggesting that electrophysiological mechanisms are similar across the lifespan.