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Exercise has the unique aptitude to benefit overall health of body and brain. Evidence indicates that the effects of exercise can be saved in the epigenome for considerable time to elevate the threshold for various diseases. The action of exercise on epigenetic regulation seems central to building an "epigenetic memory" to influence long-term brain function and behavior. As an intrinsic bioenergetic process, exercise engages the function of the mitochondria and redox pathways to impinge upon molecular mechanisms that regulate synaptic plasticity and learning and memory. We discuss how the action of exercise uses mechanisms of bioenergetics to support a "epigenetic memory" with long-term implications for neural and behavioral plasticity. This information is crucial for directing the power of exercise to reduce the burden of neurological and psychiatric disorders., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The complex pathology of mild traumatic brain injury (mTBI) is a main contributor to the difficulties in achieving a successful therapeutic regimen. Thyroxine (T4) administration has been shown to prevent the cognitive impairments induced by mTBI in mice but the mechanism is poorly understood. To understand the underlying mechanism, we carried out a single cell transcriptomic study to investigate the spatiotemporal effects of T4 on individual cell types in the hippocampus and frontal cortex at three post-injury stages in a mouse model of mTBI. We found that T4 treatment altered the proportions and transcriptomes of numerous cell types across tissues and timepoints, particularly oligodendrocytes, astrocytes, and microglia, which are crucial for injury repair. T4 also reversed the expression of mTBI-affected genes such as Ttr, mt-Rnr2, Ggn12, Malat1, Gnaq, and Myo3a, as well as numerous pathways such as cell/energy/iron metabolism, immune response, nervous system, and cytoskeleton-related pathways. Cell-type specific network modeling revealed that T4 mitigated select mTBI-perturbed dynamic shifts in subnetworks related to cell cycle, stress response, and RNA processing in oligodendrocytes. Cross cell-type ligand-receptor networks revealed the roles of App, Hmgb1, Fn1, and Tnf in mTBI, with the latter two ligands having been previously identified as TBI network hubs. mTBI and/or T4 signature genes were enriched for human genome-wide association study (GWAS) candidate genes for cognitive, psychiatric and neurodegenerative disorders related to mTBI. Our systems-level single cell analysis elucidated the temporal and spatial dynamic reprogramming of cell-type specific genes, pathways, and networks, as well as cell-cell communications as the mechanisms through which T4 mitigates cognitive dysfunction induced by mTBI., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) often results in a reduction of the capacity of cells to sustain energy demands, thus, compromising neuronal function and plasticity. Here we show that the mitochondrial activator humanin (HN) counteracts a TBI-related reduction in mitochondrial bioenergetics, including oxygen consumption rate. HN normalized the disruptive action of TBI on memory function, and restored levels of synaptic proteins (synapsin 1 and p-CREB). HN also counteracted TBI-related elevations of pro-inflammatory cytokines in plasma (TNF-α, INF-y, IL 17, IL 5, MCP 5, GCSF, RANNETS, sTNFRI) as well as in the hippocampus (gp-130 and p-STAT3). Gp-130 is an integral part of cytokine receptor impinging on STAT3 (Tyr-705) signaling. Furthermore, HN reduced astrocyte proliferation in TBI. The overall evidence suggests that HN plays an integral role in normalizing fundamental aspects of TBI pathology which are central to energy balance, brain function, and plasticity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) is major neurological burden globally, and effective treatments are urgently needed. TBI is characterized by a reduction in energy metabolism and synaptic function that seems a primary cause of neuronal dysfunction. R13, a small drug and BDNF mimetic showed promising results in improving spatial memory and anxiety-like behavior after TBI. Additionally, R13 was found to counteract reductions in molecules associated with BDNF signaling (p-TrkB, p-PI3K, p-AKT), synaptic plasticity (GluR2, PSD95, Synapsin I) as well as bioenergetic components such as mitophagy (SOD, PGC-1α, PINK1, Parkin, BNIP3, and LC3) and real-time mitochondrial respiratory capacity. Behavioral and molecular changes were accompanied by adaptations in functional connectivity assessed using MRI. Results highlight the potential of R13 as a therapeutic agent for TBI and provide valuable insights into the molecular and functional changes associated with this condition., Competing Interests: Declaration of competing interest The authors declare that they have no competing financial and personal interest that would influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Clinical evidence indicates that injury to the brain elicits systemic metabolic disturbances that contributes to the brain pathology. Since dietary fructose is metabolized in the liver, we explored mechanisms by which traumatic brain injury (TBI) and dietary fructose influence liver function and their possible repercussions to brain. Consumption of fructose contributed to the detrimental effects of TBI on liver operation, in terms of glucose and lipid metabolism, de novo lipogenesis, lipid peroxidation. Thyroid hormone (T4) is metabolized in the liver and found that T4 supply improved lipid metabolism by reducing de novo lipogenesis, lipid accumulation, lipogenic enzymes (ACC, AceCS1, FAS), lipid peroxidation in liver in response to fructose and fructose-TBI. T4 supply also helped to normalize glucose metabolism and improve insulin sensitivity. Furthermore, T4 counteracted elevations of the pro-inflammatory cytokines, Tnfα and Mcp-1 after TBI and/or fructose intake in liver and circulation. T4 also exerted an effect on isolated primary hepatocytes by potentiating phosphorylation of AMPKα and AKT substrate, AS160, leading to increased glucose uptake. In addition, T4 restored the metabolism of DHA in the liver disrupted by TBI and fructose, adding important information to optimize the action of DHA in therapeutics. The overall evidence seems to indicate that the liver works as a gate for the regulation of the effects of brain injury and foods on brain pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Traumatic brain injury (TBI) results in metabolic deficits and functionally compromised tissue. The BDNF mimetic R13 has a significant positive effect on both tissue metabolism and behavioral outcome after TBI, indicating a promising therapeutic. To understand the mechanism of action for this intervention, we determined whether there was any association between the underlying metabolic insult and any improvement in resting state functional connectivity (FC) with MRI, or whether R13 acts through mechanisms unrelated to metabolic recovery. We found perfusion deficits could be reasonably approximated by reductions in mean diffusivity (MD) acutely after injury, because a majority of regions with low perfusion matched to regions of low MD, indicative of cell swelling. Injury alone resulted in reduced cross-brain FC and contralateral hyperconnectivity at 1d compared to sham and these were spatially coincident with regions of low MD. R13 intervention at 1-7d altered the tissue trajectory of MD pathology away from pseudo-normalization so that a greater volume of tissue remained with low MD at 7d. These same regions were associated with significant changes in cross-brain and contralateral FC in R13 treated rats compared to injured vehicle-treated rats. These data indicate a likely metabolic effect of R13 acutely after injury.

Background: The etiology of mild traumatic brain injury (mTBI) remains elusive due to the tissue and cellular heterogeneity of the affected brain regions that underlie cognitive impairments and subsequent neurological disorders. This complexity is further exacerbated by disrupted circuits within and between cell populations across brain regions and the periphery, which occur at different timescales and in spatial domains., Methods: We profiled three tissues (hippocampus, frontal cortex, and blood leukocytes) at the acute (24-h) and subacute (7-day) phases of mTBI at single-cell resolution., Results: We demonstrated that the coordinated gene expression patterns across cell types were disrupted and re-organized by TBI at different timescales with distinct regional and cellular patterns. Gene expression-based network modeling implied astrocytes as a key regulator of the cell-cell coordination following mTBI in both hippocampus and frontal cortex across timepoints, and mt-Rnr2, which encodes the mitochondrial peptide humanin, as a potential target for intervention based on its broad regional and dynamic dysregulation following mTBI. Treatment of a murine mTBI model with humanin reversed cognitive impairment caused by mTBI through the restoration of metabolic pathways within astrocytes., Conclusions: Our results offer a systems-level understanding of the dynamic and spatial regulation of gene programs by mTBI and pinpoint key target genes, pathways, and cell circuits that are amenable to therapeutics., (© 2022. The Author(s).)

Physical rehabilitation is an effective therapy to normalize weaknesses encountered with neurological disorders such as traumatic brain injury (TBI). However, the efficacy of exercise is limited during the acute period of TBI because of metabolic dysfunction, and this may further compromise neuronal function. Here we discuss the possibility to normalize brain metabolism during the early post-injury convalescence period to support functional plasticity and prevent long-term functional deficits. Although BDNF possesses the unique ability to support molecular events involved with the transmission of information across nerve cells through activation of its TrkB receptor, the poor pharmacokinetic profile of BDNF has limited its therapeutic applicability. The flavonoid derivative, 7,8-dihydroxyflavone (7,8-DHF), signals through the same TrkB receptors and results in the activation of BDNF signaling pathways. We discuss how the pharmacokinetic limitations of BDNF may be avoided by the use of 7,8-DHF, which makes it a promising pharmacological agent for supporting activity-based rehabilitation during the acute post-injury period after TBI. In turn, docosahexaenoic acid (C22:6n-3; DHA) is abundant in the phospholipid composition of plasma membranes in the brain and its action is important for brain development and plasticity. DHA is a major modulator of synaptic membrane fluidity and function, which is fundamental for supporting cell signaling and synaptic plasticity. Exercise influences DHA function by normalizing DHA content in the brain, such that the collaborative action of exercise and DHA can be instrumental to boost BDNF function with strong therapeutic potential for reducing the deleterious effects of TBI on synaptic plasticity and cognition., Competing Interests: The authors declare that do not have conflicts of interest relevant to this review., (© 2022 Chengdu Sport University. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. Ltd.)

High consumption of fructose has paralleled an explosion in metabolic disorders including obesity and type 2 diabetes. Even more problematic, sustained consumption of fructose is perceived as a threat for brain function and development of neurological disorders. The action of fructose on peripheral organs is an excellent model to understand how systemic physiology impacts the brain. Given the recognized action of fructose on liver metabolism, here we discuss mechanisms by which fructose can impact the brain by interacting with liver and other organs. The interaction between peripheral and central mechanisms is a suitable target to reduce the pathophysiological consequences of neurological disorders., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Introduction: Traumatic brain injury (TBI) is considered as the most robust environmental risk factor for Alzheimer's disease (AD). Besides direct neuronal injury and neuroinflammation, vascular impairment is also a hallmark event of the pathological cascade after TBI. However, the vascular connection between TBI and subsequent AD pathogenesis remains underexplored., Methods: In a closed-head mild TBI (mTBI) model in mice with controlled cortical impact, we examined the time courses of microvascular injury, blood-brain barrier (BBB) dysfunction, gliosis and motor function impairment in wild type C57BL/6 mice. We also evaluated the BBB integrity, amyloid pathology as well as cognitive functions after mTBI in the 5xFAD mouse model of AD., Results: mTBI induced microvascular injury with BBB breakdown, pericyte loss, basement membrane alteration and cerebral blood flow reduction in mice, in which BBB breakdown preceded gliosis. More importantly, mTBI accelerated BBB leakage, amyloid pathology and cognitive impairment in the 5xFAD mice., Discussion: Our data demonstrated that microvascular injury plays a key role in the pathogenesis of AD after mTBI. Therefore, restoring vascular functions might be beneficial for patients with mTBI, and potentially reduce the risk of developing AD.