Treadmill Exercise Reshapes Cortical Astrocytic and Neuronal Activity to Improve Motor Learning Deficits Under Chronic Alcohol Exposure.

Alcohol abuse induces various neurological disorders including motor learning deficits, possibly by affecting neuronal and astrocytic activity. Physical exercise is one effective approach to remediate synaptic loss and motor deficits as shown by our previous works. In this study, we unrevealed the role of exercise training in the recovery of cortical neuronal and astrocytic functions. Using a chronic alcohol injection mouse model, we found the hyperreactivity of astrocytes along with dendritic spine loss plus lower neuronal activity in the primary motor cortex. Persistent treadmill exercise training, on the other hand, improved neural spine formation and inhibited reactive astrocytes, alleviating motor learning deficits induced by alcohol exposure. These data collectively support the potency of endurance exercise in the rehabilitation of motor functions under alcohol abuse.

Flexible Piezoresistive Sensors Based on PPy Granule-Anchored Multilayer Fibrous Membranes with a Wide Operating Range and High Sensitivity.

The employment of flexible piezoresistive sensors has sparked growing interest within the realm of wearable electronic devices, specifically in the fields of health detection and e-skin. Nevertheless, the advancement of piezoresistive sensors has been impeded by their limited sensitivity and restricted operating ranges. Consequently, it is imperative to fabricate sensors with heightened sensitivity and expanded operating ranges through the utilization of the appropriate methodologies. In this paper, piezoresistive sensors were fabricated utilizing electrospun polyvinylidene fluoride/polyacrylonitrile/polyethylene-polypropylene glycol multilayer fibrous membranes anchored with polypyrrole granules as the sensing layer, while electrospun thermoplastic polyurethane (TPU) fibers were employed as the flexible substrate. The sensitivity of the sensor is investigated by varying the fiber diameter of the sensing layer. The experimental findings reveal that a concentration of 14 wt % in the spinning solution exhibits high sensitivity (996.7 kPa-1) within a wide working range (0-10 kPa). This is attributed to the favorable diameter of the fibers prepared at this concentration, which facilitates the uniform in situ growth of pyrrole. The highly deformable TPU flexible fibers and multilayer sensing layer structure enable different linear responses across a broad pressure range (0-1 MPa). Furthermore, the sensor demonstrates good cyclic stability and can detect human movements under different pressures. These results suggest that the piezoresistive sensor with a wide operating range and high sensitivity has significant potential for future health monitoring and artificial intelligence applications.

Secretin-dependent signals in the ventromedial hypothalamus regulate energy metabolism and bone homeostasis in mice.

Secretin, though originally discovered as a gut-derived hormone, is recently found to be abundantly expressed in the ventromedial hypothalamus, from which the central neural system controls satiety, energy metabolism, and bone homeostasis. However, the functional significance of secretin in the ventromedial hypothalamus remains unclear. Here we show that the loss of ventromedial hypothalamus-derived secretin leads to osteopenia in male and female mice, which is primarily induced by diminished cAMP response element-binding protein phosphorylation and upregulation in peripheral sympathetic activity. Moreover, the ventromedial hypothalamus-secretin inhibition also contributes to hyperphagia, dysregulated lipogenesis, and impaired thermogenesis, resulting in obesity in male and female mice. Conversely, overexpression of secretin in the ventromedial hypothalamus promotes bone mass accrual in mice of both sexes. Collectively, our findings identify an unappreciated secretin signaling in the central neural system for the regulation of energy and bone metabolism, which may serve as a new target for the clinical management of obesity and osteoporosis.

Mechanisms for enhanced lignin humification with reduced organic matter loss by goethite in biogas residue composting.

In this study, effects of three iron (oxyhydr)oxides on the biogas residue composting, i.e., composting with goethite (CFe1), hematite (CFe2) or magnetite (CFe3), were investigated. Results showed that composting performance of CFe1 was much better than those of CFe2 and CFe3. Addition of goethite increased temperature of CFe1 and enhanced lignin humification. More than 31.49% of Fe(III) in goethite was reduced to amorphous Fe(II) during the composting, suggesting that goethite worked as electron acceptor for microbial metabolism and heat generation. The functional bacteria Chloroflexi and Actinobacteria, and genes encoding key enzymes (AA1 family), which play essential roles in humification of lignin, were enriched in CFe1. Besides, goethite reduced 10.96% organic matter (OM) loss probably by increasing the molecular size and aggregation of OM for its protection during the composting. This study shows that adding goethite is an efficient strategy to enhancing the humification of lignin-rich biowaste.

Genome-wide investigation and expression profiling of LOR gene family in rapeseed under salinity and ABA stress.

The Brassica napus (B. napus) LOR (Lurp-One-Related) gene family is a little-known gene family characterized by a conserved LOR domain in the proteins. Limited research in Arabidopsis showed that LOR family members played important roles in Hyaloperonospora parasitica (Hpa) defense. Nevertheless, there is a paucity of research investigating the role of the LOR gene family towards their responses to abiotic stresses and hormone treatments. This study encompassed a comprehensive survey of 56 LOR genes in B. napus, which is a prominent oilseed crop that holds substantial economic significance in China, Europe, and North America. Additionally, the study evaluated the expression profiles of these genes in response to salinity and ABA stress. Phylogenetic analysis showed that 56 BnLORs could be divided into 3 subgroups (8 clades) with uneven distribution on 19 chromosomes. 37 out of 56 BnLOR members have experienced segmental duplication and 5 of them have undergone tandem repeats events with strong evidence of purifying selection. Cis-regulatory elements (CREs) analysis indicated that BnLORs involved in process such as light response, hormone response, low temperature response, heat stress response, and dehydration response. The expression pattern of BnLOR family members revealed tissue specificity. RNA-Seq and qRT-PCR were used to validate BnLOR gene expression under temperature, salinity and ABA stress, revealing that most BnLORs showed inducibility. This study enhanced our comprehension of the B. napus LOR gene family and could provide valuable information for identifying and selecting genes for stress resistant breeding.

Food additive glycerol monocaprylate modulated systemic inflammation and gut microbiota without stimulating metabolic dysfunction in high-fat diet fed mice.

Recent findings imply that great consideration should be given to the potential health risks of food additives on gut microbiota. Glycerol monocaprylate (GMC) is a widely consumed food preservative and emulsifier. Our results indicated that GMC significantly ameliorated visceral fat accumulation and systemic inflammation in high-fat diet (HFD)-fed mice. Furthermore, GMC induced improvements on the composition and function of gut microbiota, resulting in increased beneficial gut bacteria (Bifidobacterium and Lactobacillus) and promoted production of short chain fatty acids. Notably, GMC-induced metabolic amelioration is closely related to the regulation in gut microbiota. Overall, our findings supported that unlike the emulsifiers previously reported to damage intestinal health, GMC performed the potential on attenuating HFD-induced metabolic disorders and gut microbiota dysbiosis, which also refined on the safety evaluation of GMC on gut microbiota. Our findings suggest that when evaluating the safety of food additives with regards to gut microbiota, it is important to take into account the specific characteristics of the additive in question, rather than simply relying on its classification.

Physical exercise modulates the microglial complement pathway in mice to relieve cortical circuitry deficits induced by mutant human TDP-43.

The aggregation of TAR DNA binding protein 43 kDa (TDP-43) is related to different neurodegenerative diseases, which leads to microglial activation and neuronal loss. The molecular mechanism driving neuronal death by reactive microglia, however, has not been completely resolved. In this study, we generated a mouse model by overexpressing mutant human TDP-43 (M337V) in the primary motor cortex, leading to prominent motor-learning deficits. In vivo 2-photon imaging shows an active approach of microglia toward parvalbumin interneurons, resulting in disrupted cortical excitatory-inhibitory balance. Proteomics studies suggest that activation of the complement pathway induces microglial activity. To develop an early interventional strategy, treadmill exercise successfully prevents the deterioration of motor dysfunction under enhanced adipocytic release of clusterin to block the complement pathway. These results demonstrate a previously unrecognized pathway by which TDP-43 induces cortical deficits and provide additional insights for the mechanistic explanation of exercise training in disease intervention.

Amygdala neural ensemble mediates mouse social investigation behaviors.

Innate social investigation behaviors are critical for animal survival and are regulated by both neural circuits and neuroendocrine factors. Our understanding of how neuropeptides regulate social interest, however, is incomplete at the current stage. In this study, we identified the expression of secretin (SCT) in a subpopulation of excitatory neurons in the basolateral amygdala. With distinct molecular and physiological features, BLASCT+ cells projected to the medial prefrontal cortex and were necessary and sufficient for promoting social investigation behaviors, whilst other basolateral amygdala neurons were anxiogenic and antagonized social behaviors. Moreover, the exogenous application of secretin effectively promoted social interest in both healthy and autism spectrum disorder model mice. These results collectively demonstrate a previously unrecognized group of amygdala neurons for mediating social behaviors and suggest promising strategies for social deficits.

A gut-brain axis mediates sodium appetite via gastrointestinal peptide regulation on a medulla-hypothalamic circuit.

Salt homeostasis is orchestrated by both neural circuits and peripheral endocrine factors. The colon is one of the primary sites for electrolyte absorption, while its potential role in modulating sodium intake remains unclear. Here, we revealed that a gastrointestinal hormone, secretin, is released from colon endocrine cells under body sodium deficiency and is indispensable for inducing salt appetite. As the neural substrate, circulating secretin activates specific receptors in the nucleus of the solitary tracts, which further activates the downstream paraventricular nucleus of the hypothalamus, resulting in enhanced sodium intake. These results demonstrated a previously unrecognized gut-brain pathway for the timely regulation of sodium homeostasis.

Planar cell polarity protein Celsr2 maintains structural and functional integrity of adult cortical synapses.

A few developmental genes remain persistently expressed in the adult stage, whilst their potential functions in the mature brain remain underappreciated. Here, we report the unexpected importance of Celsr2, a core Planar cell polarity (PCP) component, in maintaining the structural and functional integrity of adult neocortex. Celsr2 is highly expressed during development and remains expressed in adult neocortex. In vivo synaptic imaging in Celsr2 deficient mice revealed alterations in spinogenesis and reduced neuronal calcium activities, which are associated with impaired motor learning. These phenotypes were accompanied with anomalies of both postsynaptic organization and presynaptic vesicles. Knockout of Celsr2 in adult mice recapitulated those features, further supporting the role of Celsr2 in maintaining the integrity of mature cortex. In sum, our data identify previously unrecognized roles of Celsr2 in the maintenance of synaptic function and motor learning in adulthood.

Celsr2 regulates NMDA receptors and dendritic homeostasis in dorsal CA1 to enable social memory.

Social recognition and memory are critical for survival. The hippocampus serves as a central neural substrate underlying the dynamic coding and transmission of social information. Yet the molecular mechanisms regulating social memory integrity in hippocampus remain unelucidated. Here we report unexpected roles of Celsr2, an atypical cadherin, in regulating hippocampal synaptic plasticity and social memory in mice. Celsr2-deficient mice exhibited defective social memory, with rather intact levels of sociability. In vivo fiber photometry recordings disclosed decreased neural activity of dorsal CA1 pyramidal neuron in Celsr2 mutants performing social memory task. Celsr2 deficiency led to selective impairment in NMDAR but not AMPAR-mediated synaptic transmission, and to neuronal hypoactivity in dorsal CA1. Those activity changes were accompanied with exuberant apical dendrites and immaturity of spines of CA1 pyramidal neurons. Strikingly, knockdown of Celsr2 in adult hippocampus recapitulated the behavioral and cellular changes observed in knockout mice. Restoring NMDAR transmission or CA1 neuronal activities rescued social memory deficits. Collectively, these results show a critical role of Celsr2 in orchestrating dorsal hippocampal NMDAR function, dendritic and spine homeostasis, and social memory in adulthood.

Physical Exercise Prevented Stress-Induced Anxiety via Improving Brain RNA Methylation.

Physical exercise is effective in alleviating mental disorders by improving synaptic transmission; however, the link between body endurance training and neural adaptation has not yet been completely resolved. In this study, the authors investigated the role of RNA N6 -methyladenosine (m6A), an emerging epigenetic mechanism, in improved resilience against chronic restraint stress. A combination of molecular, behavioral, and in vivo recording data demonstrates exercise-mediated restoration of m6A in the mouse medial prefrontal cortex, whose activity is potentiated to exert anxiolytic effects. Furthermore, it is revealed that hepatic biosynthesis of one methyl donor is necessary for exercise to improve brain RNA m6A to counteract environmental stress. This novel liver-brain axis provides an explanation for brain network changes upon exercise training and provides new insights into the diagnosis and treatment of anxiety disorders.

Celsr3 Inactivation in the Brainstem Impairs Rubrospinal Tract Development and Mouse Behaviors in Motor Coordination and Mechanic-Induced Response.

Inactivation of Celsr3 in the forebrain results in defects of longitudinal axonal tracts such as the corticospinal tract. In this study, we inactivated Celsr3 in the brainstem using En1-Cre mice (Celsr3 cKO) and analyzed axonal and behavioral phenotypes. Celsr3 cKO animals showed an 83% reduction of rubrospinal axons and 30% decrease of corticospinal axons in spinal segments, associated with increased branching of dopaminergic fibers in the ventral horn. Decreases of spinal motoneurons, neuromuscular junctions, and electromyographic signal amplitude of the biceps were also found in mutant animals. Mutant mice had impaired motor coordination and defective response to heavy mechanical stimulation, but no disability in walking and food pellet handling. Transsynaptic tracing demonstrated that rubrospinal axons synapse on spinal neurons in the deep layer of the dorsal horn, and mechanical stimulation of hindpaws induced strong calcium signal of red nuclei in control mice, which was less prominent in mutant mice. In conclusion, Celsr3 regulates development of spinal descending axons and the motor network in cell and non-cell autonomous manners, and the maturation of the rubrospinal system is required for motor coordination and response to mechanical stimulation.

Physical exercise rescues cocaine-evoked synaptic deficits in motor cortex.

Drug exposure impairs cortical plasticity and motor learning, which underlies the reduced behavioral flexibility in drug addiction. Physical exercise has been used to prevent relapse in drug rehabilitation program. However, the potential benefits and molecular mechanisms of physical exercise on drug-evoked motor-cortical dysfunctions are unknown. Here we report that 1-week treadmill training restores cocaine-induced synaptic deficits, in the form of improved in vivo spine formation, synaptic transmission, and spontaneous activities of cortical pyramidal neurons, as well as motor-learning ability. The synaptic and behavioral benefits relied on de novo protein synthesis, which are directed by the activation of the mechanistic target of rapamycin (mTOR)-ribosomal protein S6 pathway. These findings establish synaptic functional restoration and mTOR signaling as the critical mechanism supporting physical exercise training in rehabilitating the addicted brain.

A Functionalized Octahedral Palladium Nanozyme as a Radical Scavenger for Ameliorating Alzheimer's Disease.

Oxidative stress is always mentioned as a pathologic appearance of Alzheimer's disease (AD). It is attributed to mitochondrial dysfunction closely linked to Aß deposition and neurofibrillary tangles (NFTs). Octahedral palladium nanoparticles (Pd NPs) exhibited excellent antioxidant enzyme-like activity and outstanding biocompatibility, but the poor blood-brain barrier (BBB) permeability limits their application in the treatment of Alzheimer's disease. Herein, we constructed a borneol (Bor)-modified octahedral palladium (Pd@PEG@Bor) nanozyme platform to eliminate intracellular reactive oxygen species (ROS) and elevate epithelial cell penetrability. Based on in vitro and in vivo studies, we demonstrate that the Pd@PEG@Bor could efficiently reduce ROS and Ca2+ contents, maintain the mitochondrial membrane potential, and further protect the mitochondria in SH-SY5Y cells. Furthermore, the nanozymes could quickly accumulate in the brain of AD mice and alleviate pathological characteristics such as Aß plaque deposition, neuron loss, and neuroinflammation. The learning ability and memory function of AD mice are also significantly improved. Overall, this work indicates that the Pd@PEG@Bor nanozymes could delay the progression of AD by regulating ROS levels and also provides a new strategy for the treatment of AD.

Metabonomics Study on the Infertility Treated With Zishen Yutai Pills Combined With In Vitro Fertilization-embryo Transfer.

Zishen Yutai Pills (ZYP) is a safe and well quality-controlled TCM preparation with promising effects in many fields of reproduction, including prevention of miscarriage, increase of pregnancy rate during in vitro fertilization-embryo transfer (IVF-ET). The plasma of patients was collected from a clinical trial, namely, "Effect of Traditional Chinese Medicine vs placebo on live births among women undergoing in vitro fertilization, a multi-center randomized controlled trial." Plasma samples were analyzed with metabonomics method. UPLC-MS technology was used to establish the plasma metabolic fingerprint. Multivariate statistical analysis was applied for comparing the differences of plasma metabolites between ZYP group and placebo group, 44 potential metabolites were screen out and identified. Pathway analysis was conducted with database mining. Compared with placebo, chemicals were found to be significantly down-regulated on HCG trigger day and 14 days after embryo transplantation, including trihexosylceramide (d18:1/26:1), glucosylceramide(d18:1/26:0), TG(22:6/15:0/22:6), TG(22:4/20:4/18:4). Compared with placebo, some chemicals were found to be significantly up-regulated on HCG trigger day and 14 days after embryo transplantation, i.e., PIP3(16:0/16:1), PIP2(18:1/18:1), tauroursodeoxycholic acid, L-asparagine, L-glutamic acid, kynurenic acid, 11-deoxycorticosterone, melatonin glucuronide, hydroxytyrosol. These metabolites were highly enriched in pathways including sphingolipid metabolism, alanine, aspartic acid and glutamic acid metabolism, aminoacyl tRNA biosynthesis, taurine and hypotaurine metabolism. This study revealed metabolic differences between subjects administered with ZYP and placebo. Relating metabolites were identified and pathways were enriched, providing basis on the exploration on the underlying mechanisms of ZYP combined with IVF-ET in the treatment of infertility.

Mass spectrometry-based metabolomics to reveal chicken meat improvements by medium-chain monoglycerides supplementation: Taste, fresh meat quality, and composition.

This study was conducted to reveal the differences of chicken fresh meat quality, composition and taste induced by medium-chain monoglycerides (MG) supplementation. Results demonstrated that both chicken broth and meat taste were improved by MG supplementation. The up-regulated l-carnosine, sarcosine, uridine and nicotinamide in the chicken broth of the MG group contributed to the umami and meaty taste. Dietary MG increased the total superoxide dismutase activity and amino acid content in the muscle of chicken breast and reduced the malondialdehyde content and drip loss. Moreover, meat metabolome revealed that creatine, betaine, l-anserine, inosine 5'-monophosphate, hypoxanthine, inosine and phospholipid, as well as amino acid and purine metabolism pathway connected to the improvements of meat quality, composition and taste of broilers by MG addition. In conclusion, these findings provide convincing evidence regarding the improvements of fresh meat quality, composition and taste of broilers by MG supplementation.

Electroacupuncture activates inhibitory neural circuits in the somatosensory cortex to relieve neuropathic pain.

Electroacupuncture (EA) has been accepted to effectively relieve neuropathic pain. Current knowledge of its neural modulation mainly covers the spinal cord and subcortical nuclei, with little evidence from the cortical regions. Using in vivo two-photon imaging in mice with chronic constriction injury, we found that EA treatment systemically modulated the Ca2+ activity of neural circuits in the primary somatosensory cortex, including the suppression of excitatory pyramidal neurons, potentiation of GABAergic somatostatin-positive interneurons, and suppression of vasoactive intestinal peptide-positive interneurons. Furthermore, EA-mediated alleviation of pain hypersensitivity and cortical modulation were dependent on the activation of endocannabinoid receptor 1. These findings collectively reveal a cortical circuit involved in relieving mechanical or thermal hypersensitivity under neuropathic pain and identify one molecular pathway directing analgesic effects of EA.

Metabonomics Study on Serum Characteristic Metabolites of Psoriasis Vulgaris Patients With Blood-Stasis Syndrome.

Psoriasis is a chronic, refractory, systemic inflammatory skin disease. Traditional Chinese medicine (TCM) shows unique advantage in the treatment of psoriasis based on syndrome differentiation. An untargeted high-throughput metabonomics method based on liquid chromatography coupled to mass spectrometry was applied to study the serum metabolic characteristics in different TCM syndrome types in patients with psoriasis vulgaris (PV), and to discover potential serum biomarkers for its pathogenesis on the endogenous metabolite differentiation basis. The serum metabolic profiles of 45 healthy controls and 124 patients with PV (50 in the blood-stasis group, 30 in the blood-heat group, and 44 in the blood-dryness group) were acquired. The raw spectrometric data were processed using multivariate statistical analysis, and 14 biomarkers related to TCM syndrome differentiation and psoriasis types were screened and identified. The blood-stasis syndrome group showed abnormal lipid metabolism, which was characterized by a low level of phosphatidylcholine (PC) and a high level of lysophosphatidylcholine (LPC). We propose that platelet-activating factor can be applied as a potential biomarker in clinical diagnosis and differentiation of PV with blood-stasis syndrome. The difference in the serum metabolites among PV types with different TCM syndromes and healthy control group illustrated the objective material basis in TCM syndrome differentiation and classification of psoriasis.

Intelligently thermoresponsive flower-like hollow nano-ruthenium system for sustained release of nerve growth factor to inhibit hyperphosphorylation of tau and neuronal damage for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) seriously affects human health and life and lacks effective treatments. The lessons of many clinical trial failures suggest that targeting amyloid beta to treat AD is difficult, and finding new targets is an important direction for AD drug research. The neurofibrillary tangles formed by hyperphosphorylation of tau protein induce the production of cytotoxic reactive oxygen species (ROS) and cause neuronal apoptosis. Therefore, inhibition of hyperphosphorylation of tau protein and reduction of neuronal damage have become promising methods for the treatment of AD. We herein designed a novel nanocomposite with high stability and good biocompatibility by using flower-shaped hollow nano-ruthenium (Ru NPs) as a carrier, loading nerve growth factor (NGF) and sealing with phase change material (PCM). Due to its excellent photothermal effect, under the near-infrared (NIR) irradiation, the nanocomposite could effectively penetrate the blood-brain barrier (BBB) and respond to phase changes in the lesion area, releasing NGF, which inhibited tau hyperphosphorylation, reduced oxidative stress, and more importantly restored nerve damage and maintained neuronal morphology, thereby significantly improving learning and memory in AD mice. Thus, the experimental results indicate that multifunctional nanocomposites may be a promising drug in the treatment of AD.