Development Of Nervous System Research Articles

The Nervous System Development Regulator Neuropilin-1 as a Potential Prognostic Marker and Therapeutic Target in Brain Cancer.

Neuropilins are transmembrane glycoproteins that regulate developmental processes in the nervous system and other tissues. Overexpression of neuropilin-1 (NRP1) occurs in many solid tumor types and, in several instances, may predict patient outcome in terms of overall survival. Experimental inhibition of NRP1 activity can display antitumor effects in different cancer models. Here, we review NRP1 expression and function in adult and pediatric brain cancers, particularly glioblastomas (GBMs) and medulloblastomas, and present analyses of NRP1 transcript levels and their association with patient survival in GBMs. The case of NRP1 highlights the potential of regulators of neurodevelopment as biomarkers and therapeutic targets in brain cancer.

Preeclampsia and Its Impact on Human Milk Activin A Concentration.

It is known that preeclampsia affects lactogenesis. However, data on the effects of this pathology on human milk neurobiomarker composition are not available. The aim of this study is to investigate the effects of this gestational pathology on activin A levels, a neurobiomarker known to play an important role in the development and protection of the central nervous system. The women recruited were divided in two different study groups: preeclamptic or normotensive women. All the human milk samples were collected using the same procedure. Activin A was quantified using an Enzyme-linked immunosorbent assay (ELISA) test. To investigate the effect of preeclampsia on the activin A concentration in the three lactation phases, a mixed linear model with a unistructural covariance structure, with the mother as the random effect, and fixed effects were performed. Activin A was detected in all samples. There were no significant differences between preeclamptic and normotensive women. The only significant effect is related to the lactation phase: the difference between colostrum and mature milk (p < 0.01) was significant. In conclusion, these results allow us to affirm that breast milk's beneficial properties are maintained even if preeclampsia occurs.

Super-enhancer hijacking drives ectopic expression of hedgehog pathway ligands in meningiomas

Hedgehog signaling mediates embryologic development of the central nervous system and other tissues and is frequently hijacked by neoplasia to facilitate uncontrolled cellular proliferation. Meningiomas, the most common primary brain tumor, exhibit Hedgehog signaling activation in 6.5% of cases, triggered by recurrent mutations in pathway mediators such as SMO. In this study, we find 35.6% of meningiomas that lack previously known drivers acquired various types of somatic structural variations affecting chromosomes 2q35 and 7q36.3. These cases exhibit ectopic expression of Hedgehog ligands, IHH and SHH, respectively, resulting in Hedgehog signaling activation. Recurrent tandem duplications involving IHH permit de novo chromatin interactions between super-enhancers within DIRC3 and a locus containing IHH. Our work expands the landscape of meningioma molecular drivers and demonstrates enhancer hijacking of Hedgehog ligands as a route to activate this pathway in neoplasia.

A Versatile, Behavioral Method to Investigate Thyroid Hormone Effects on Cerebellar Function.

Thyroid hormone (TH) action is essential during the development of the central nervous system, including the cerebellum. In case of TH deficiency in early life such as congenital hypothyroidism, patients display neurological disorders such as cognitive retardation and motor deficits. There are various studies using mouse models with tissue- or cell-specific TH deficiency to investigate the role of TH in the cerebellum. Compared to generalized congenital hypothyroid mice, cerebellar cell-specific TH-deficient mice display milder and subtler ataxic features, making the assessment of motor function difficult when using conventional tests such as the rotarod test. Due to the need for an alternative tool to assess motor function in TH-related animal models, we developed a versatile behavioral method called the "ladder beam test," in which we can design the various ladder tests depending on the severity of ataxia in model mice. We utilized transgenic mice expressing a dominant-negative TH receptor specifically in the cerebellar Purkinje cell, a sole output neuron in the cerebellar cortex modulating motor performance. The newly-built ladder beam test successfully detected robust impairments in motor performance in the transgenic mice at a greater level compared to the rotarod test. Disruption of motor learning was also detected in the ladder beam test but not in the rotarod test. The protocol with this novel behavioral apparatus can be applied to other animal models that may show mild ataxic phenotype to examine subtle changes in cerebellar function.

Selective extraction of phospholipids from human milk using glass fabric modified with zirconium-based metal organic framework

Phospholipids (PLs) are important and complex trace lipids in milk, which have positive effects on the infants' nervous and immune system development. Herein, a new method for selective extraction of PLs using glass fabric @ MOF-808 was proposed. Based on Lewis acid-base interaction, MOF-808 containing abundant Zr-OH groups was selected as the adsorption body, and glass fabric was used as a substrate to make the adsorbent easy to remove and reuse. The influencing factors such as loading solution, extraction time, eluent and elution time were further investigated. The adsorbent showed high adsorption capacity (3.31–6.54 mg/g for PLs) and good reusability (reused at least five times). The method showed low detection limits (1.61 μg/L - 10.24 μg/L) and quantification limits (5.24 μg/L–51.21 μg/L) for eight classes of PLs. The analysis of PLs in human milk at different lactation stages by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry could obtain up to 206 PLs, indicating that the method has extremely high extraction and anti-interference capabilities. This work is the first time to introduce MOF materials to selectively extract PLs and use glass fabric as a substrate for MOF-808, which has the advantages of easy recovery and high sensitivity. It provides technical support for the discovery of more PL species and has potential applications in phospholipidomics.

Mikroglijos reikšmė išsėtinės sklerozės patogenezėje ir sąsajos su imunomoduliuojančiu gydymu

Multiple sclerosis is a chronic autoimmune disease of the central nervous system. Multiple sclerosis causes demyelination, impaired nervous system function, and eventually neurodegeneration. Microglia are cells of the central nervous system that develop from yolk sac macrophages during embryogenesis. These cells perform important functions in the development of the central nervous system and the retina, in the formation of synapses, protect against pathogens, and are involved in the removal of damaged structures. In response to environmental factors, microglia can acquire an inflammatory or anti-inflammatory phenotype. Microglia also play an important role in the pathogenesis of multiple sclerosis, and these cells are thought to be involved in both demyelination and remyelination processes. Microglial cells phagocytose harmful myelin remnants, promote remyelination, and control the proper response of peripheral immune cells, but disruption of these functions can lead to demyelination and neurodegeneration. Many of the disease-modifying drugs used to treat multiple sclerosis also affect microglial cells and inhibit their inflammatory response. Currently, new drugs are being researched that could be used to treat multiple sclerosis promoting the transition of microglia to an anti-inflammatory phenotype. The latest advanced cell therapy drugs have a broader spectrum of action – they inhibit inflammation, promote angiogenesis, perform trophic function, and inhibit oxidative damage.

Glial plasticity at nervous system transition zones.

The central and peripheral nervous systems (CNS and PNS, respectively) are two separate yet connected domains characterized by molecularly distinct cellular components that communicate via specialized structures called transition zones to allow information to travel from the CNS to the periphery, and vice versa. Until recently, nervous system transition zones were thought to be selectively permeable only to axons, and the establishment of the territories occupied by glial cells at these complex regions remained poorly described and not well understood. Recent work now demonstrates that transition zones are occupied by dynamic glial cells and are precisely regulated over the course of nervous system development. This review highlights recent work on glial cell migration in and out of the spinal cord, at motor exit point (MEP) and dorsal root entry zone (DREZ) transition zones, in the physiological and diseased nervous systems. These cells include myelinating glia (oligodendrocyte lineage cells, Schwann cells and motor exit point glia), exit glia, perineurial cells that form the perineurium along spinal nerves, as well as professional and non-professional phagocytes (microglia and neural crest cells).

Rejection of inappropriate synaptic partners in mouse retina mediated by transcellular FLRT2-UNC5 signaling.

During nervous system development, neurons choose synaptic partners with remarkable specificity; however, the cell-cell recognition mechanisms governing rejection of inappropriate partners remain enigmatic. Here, we show that mouse retinal neurons avoid inappropriate partners by using the FLRT2-uncoordinated-5 (UNC5) receptor-ligand system. Within the inner plexiform layer (IPL), FLRT2 is expressed by direction-selective (DS) circuit neurons, whereas UNC5C/D are expressed by non-DS neurons projecting to adjacent IPL sublayers. Invivo gain- and loss-of-function experiments demonstrate that FLRT2-UNC5 binding eliminates growing DS dendrites that have strayed from the DS circuit IPL sublayers. Abrogation of FLRT2-UNC5 binding allows mistargeted arbors to persist, elaborate, and acquire synapses from inappropriate partners. Conversely, UNC5C misexpression within DS circuit sublayers inhibits dendrite growth and drives arbors into adjacent sublayers. Mechanistically, UNC5s promote dendrite elimination by interfering with FLRT2-mediated adhesion. Based on their broad expression, FLRT-UNC5 recognition is poised to exert widespread effects upon synaptic partner choices across the nervous system.

Transcriptome-wide analysis of trigeminal ganglion and subnucleus caudalis in a mouse model of chronic constriction injury-induced trigeminal neuralgia.

Trigeminal neuropathic pain (TNP) induces mechanical allodynia and hyperalgesia, which are known to alter gene expression in injured dorsal root ganglia primary sensory neurons. Non-coding RNAs (ncRNAs) have been linked to TNP. However, the functional mechanism underlying TNP and the expression profile of ncRNAs in the trigeminal ganglion (TG) and trigeminal subnucleus caudalis (Sp5C) are still unknown. We used RNA sequencing and bioinformatics analysis to examine the TG and Sp5C transcriptomes after infraorbital nerve chronic constrictive injury (IoN-CCI). The robust changes in the gene expression of lncRNAs, circRNAs, and mRNAs were observed within the TG and Sp5C from mice that underwent IoN-CCI and the sham-operated mice (day 7). In total, 111,003 lncRNAs were found in TG and 107,157 in Sp5C; 369 lncRNAs were differentially expressed in TG, and 279 lncRNAs were differentially expressed in Sp5C. In addition, 13,216 circRNAs in TG and 21,658 circRNAs in Sp5C were identified, with 1,155 circRNAs and 2,097 circRNAs differentially expressed in TG and Sp5C, respectively. Furthermore, 5,205 DE mRNAs in TG and 3,934 DE mRNAs in Sp5C were differentially expressed between IoN-CCI and sham groups. The study revealed a high correlation of pain-related differentially expressed genes in the TG and Sp5C to anxiety, depression, inflammation, neuroinflammation, and apoptosis. Gene Ontology analysis revealed that binding-related molecular functions and membrane-related cell components were significantly enriched. Kyoto Encyclopedia of Genes and Genomes analysis shows the most significant enrichments in neurogenesis, nervous system development, neuron differentiation, adrenergic signaling, cAMP signaling, MAPK signaling, and PI3K-Akt signaling pathways. Furthermore, protein-protein interaction analysis showed that hub genes were implicated in neuropeptide signaling pathways. Functional analysis of DE ncRNA-targeting genes was mostly enriched with nociception-related signaling pathways underpinning TNP. Our findings suggest that ncRNAs are involved in TNP development and open new avenues for research and treatment.

From Glands to Nerves: Hypothyroidism’s Underexplored Influence on Neurological Well Being-A Narrative Review

Hypothyroidism is a clinical health condition in which the thyroid gland secretes insufficient levels of the thyroid hormones T3 and T4, resulting in high thyroid stimulating hormone (TSH) readings. The thyroid gland plays a key role in the development of the central nervous system. These hormones are essential for brain development and function. It has been found that thyroid disorders are among the most common diseases in worldwide. Thyroid disorders are one of the primary causes of cognitive decline, including Alzheimer's disease (AD). In this review, we had discussed about the various neurological complications that develops due to hypothyroidism.

Defective phagocytosis leads to neurodegeneration through systemic increased innate immune signaling

In nervous system development, disease, and injury, neurons undergo programmed cell death, leaving behind cell corpses that are removed by phagocytic glia. Altered glial phagocytosis has been implicated in several neurological diseases including Alzheimer's disease. To untangle the links between glial phagocytosis and neurodegeneration, we investigated Drosophila mutants lacking the phagocytic receptor Draper. Loss of Draper leads to persistent neuronal cell corpses and age-dependent neurodegeneration. Here we investigate whether the phagocytic defects observed in draper mutants lead to chronic increased immune activation that promotes neurodegeneration. We found that the antimicrobial peptide Attacin-A is highly upregulated in the fat body of aged draper mutants and that the inhibition of the Immune deficiency (Imd) pathway in the glia and fat body of draper mutants led to reduced neurodegeneration. Taken together, these findings indicate that phagocytic defects lead to neurodegeneration via increased immune signaling, both systemically and locally in the brain.

Genes Involved by Dexamethasone in Prevention of Long-Term Memory Impairment Caused by Lipopolysaccharide-Induced Neuroinflammation.

Inflammatory activation within the brain is linked to a decrease in cognitive abilities; however, the molecular mechanisms implicated in the development of inflammatory-related cognitive dysfunction and its prevention are poorly understood. This study compared the responses of hippocampal transcriptomes 3 months after the striatal infusion of lipopolysaccharide (LPS; 30 µg), resulting in memory loss, or with dexamethasone (DEX; 5 mg/kg intraperitoneal) pretreatment, which abolished the long-term LPS-induced memory impairment. After LPS treatment, a significant elevation in the expression of immunity/inflammatory-linked genes, including chemokines (Cxcl13), cytokines (Il1b and Tnfsf13b), and major histocompatibility complex (MHC) class II members (Cd74, RT1-Ba, RT1-Bb, RT1-Da, and RT1-Db1) was observed. DEX pretreatment did not change the expression of these genes, but significantly affected the expression of genes encoding ion channels, primarily calcium and potassium channels, regulators of glutamate (Slc1a2, Grm5, Grin2a), and GABA (Gabrr2, Gabrb2) neurotransmission, which enriched in such GO biological processes as "Regulation of transmembrane transport", "Cognition", "Learning", "Neurogenesis", and "Nervous system development". Taken together, these data suggest that (1) pretreatment with DEX did not markedly affect LPS-induced prolonged inflammatory response; (2) DEX pretreatment can affect processes associated with glutamatergic signaling and nervous system development, possibly involved in the recovery of memory impairment induced by LPS.

SASH1 contributes to glial cell migration in the early development of the central nervous system

SAM and SH3 domain-containing 1 (SASH1), a member of the SLy protein family, is a tumor suppressor gene that has been studied for its association with various cancers. SASH1 is highly expressed in the mammalian central nervous system, particularly in glial cells, and is expressed in the central nervous system during zebrafish embryo development. However, SASH1's role in brain development has rarely been investigated. In this study, Morpholino oligonucleotides (MO) were used to down-regulate sash1a expression in zebrafish to observe morphological changes in the brain. Three transgenic zebrafish lines, Tg(gfap:eGFP), Tg(hb9:eGFP), and Tg(coro1a:eGFP) were selected to observe changes in glial cells, neurons, and immune cells after sash1a knockdown. Our results showed that the number of microglia residing in the developmental brain was reduced, whereas the axonal growth of caudal primary motor neurons was unaffected by sash1a downregulation. And more significantly, the gfap + glia presented abnormal arrangements and disordered orientations in sash1a morphants. The similar phenotype was verified in the mutation induced by the injection of cas9 mRNA and sash1a sgRNA. We further performed behavioral experiments in zebrafish larvae that had been injected with sash1a MO at one-cell stage, and found them exhibiting abnormal behavior trajectories. Moreover, injecting the human SASH1 mRNA rescued these phenomena in sash1a MO zebrafish. In summary, our study revealed that the downregulation of SASH1 leads to malformations in the embryonic brain and disorganization of glial cell marshalling, suggesting that SASH1 plays an important role in the migration of glial cells during embryonic brain development.

Rapid and Efficient Enrichment of Mouse Spinal Cord Microglia.

The vertebral column defines a vertebrate and shapes the spinal canal, a cavity that encloses and safeguards the spinal cord. Proper development and function of the mammalian central nervous system rely significantly on the activity of resident macrophages known as microglia. Microglia display heterogeneity and multifunctionality, enabling distinct gene expression and behavior within the spinal cord and brain. Numerous studies have explored cerebral microglia function, detailing purification methods extensively. However, the purification of microglia from the spinal cord in mice lacks a comprehensive description. In contrast, the utilization of a highly purified collagenase, as opposed to an unrefined extract, lacks reporting within central nervous system tissues. In this study, the vertebral column and spinal cord were excised from 8-10 week-old C57BL/6 mice. Subsequent digestion employed a highly purified collagenase, and microglia purification utilized a density gradient. Cells underwent staining for flow cytometry, assessing viability and purity through CD11b and CD45 staining. Results yielded an average viability of 80% and a mean purity of 95%. In conclusion, manipulation of mouse microglia involved digestion with a highly purified collagenase, followed by a density gradient. This approach effectively produced substantial spinal cord microglia populations.

Transcriptomics analysis unveils key potential genes associated with brain development and feeding behavior in the hypothalamus of L-citrulline-fed broiler chickens

High ambient temperature is a major environmental stressor affecting poultry production, especially in the tropical and subtropical regions of the world. Nutritional interventions have been adopted to combat thermal stress in poultry, including the use of amino acids. L-citrulline is a nonessential amino acid that is involved in nitric oxide generation and thermoregulation, however, the molecular mechanisms behind L-citrulline's regulation of body temperature are still unascertained. This study investigated the global gene expression in the hypothalamus of chickens fed either basal diet or L-citrulline-supplemented diets under different housing temperatures. Ross 308 broilers were fed with basal diet (CON) or 1% L-citrulline diet (LCT) from day-old, and later subjected to 2 environmental temperatures in a 2 by 2 factorial arrangement as follows; basal diet-fed chickens housed at 24°C (CON-TN); L-citrulline diet-fed chickens housed at 24°C (LCT-TN); basal diet-fed chickens housed at 35°C (CON-HS), and L-citrulline diet-fed chickens housed at 35°C (LCT-HS) from 22 to 42 d of age. At 42-days old, hypothalamic tissues were collected for mRNA analyses and RNA sequencing. A total of 1,019 million raw reads were generated and about 82.59 to 82.96% were uniquely mapped to genes. The gene ontology (GO) term between the CON-TN and LCT-TN groups revealed significant enrichments of pathways such as central nervous system development, and Wnt signaling pathway. On the other hand, GO terms between the CON-HS and LCT-HS groups revealed enrichments in the regulation of corticosteroid release, regulation of feeding behavior, and regulation of inflammatory response. Several potential candidate genes were identified to be responsible for central nervous system development (EMX2, WFIKKN2, SLC6A4 Wnt10a, and PHOX2B), and regulation of feed intake (NPY, AgRP, GAL, POMC, and NMU) in chickens. Therefore, this study unveils that L-citrulline can influence transcripts associated with brain development, feeding behavior, energy metabolism, and thermoregulation in chickens raised under different ambient temperatures.

Functional, Morphological and Molecular Changes Reveal the Mechanisms Associated with Age-Related Vestibular Loss.

Age-related loss of vestibular function and hearing are common disorders that arise from the loss of function of the inner ear and significantly decrease quality of life. The underlying pathophysiological mechanisms are poorly understood and difficult to investigate in humans. Therefore, our study examined young (1.5-month-old) and old (24-month-old) C57BL/6 mice, utilizing physiological, histological, and transcriptomic methods. Vestibular sensory-evoked potentials revealed that older mice had reduced wave I amplitudes and delayed wave I latencies, indicating reduced vestibular function. Immunofluorescence and image analysis revealed that older mice exhibited a significant decline in type I sensory hair cell density, particularly in hair cells connected to dimorphic vestibular afferents. An analysis of gene expression in the isolated vestibule revealed the upregulation of immune-related genes and the downregulation of genes associated with ossification and nervous system development. A comparison with the isolated cochlear sensorineural structures showed similar changes in genes related to immune response, chondrocyte differentiation, and myelin formation. These findings suggest that age-related vestibular hypofunction is linked to diminished peripheral vestibular responses, likely due to the loss of a specific subpopulation of hair cells and calyceal afferents. The upregulation of immune- and inflammation-related genes implies that inflammation contributes to these functional and structural changes. Furthermore, the comparison of gene expression between the vestibule and cochlea indicates both shared and distinct mechanisms contributing to age-related vestibular and hearing impairments. Further research is necessary to understand the mechanistic connection between inflammation and age-related balance and hearing disorders and to translate these findings into clinical treatment strategies.

Fibroblast Growth Factor Receptor 2 (FGFR2), a New Gene Involved in the Genesis of Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a long-known complex neurodevelopmental disorder, and over the past decades, with the enhancement of the research genomic techniques, has been the object of intensive research activity, and many genes involved in the development and functioning of the central nervous system have been related to ASD genesis. Herein, we report a patient with severe ASD carrying a G > A de novo variant in the FGFR2 gene, determining a missense mutation. FGFR2 encodes for the ubiquitous fibroblast growth factor receptor (FGFR) type 2, a tyrosine kinase receptor implicated in several biological processes. The mutated version of this protein is known to be responsible for several variable overlapping syndromes. Even if there still is only sparse and anecdotal data, recent research highlighted a potential role of FGFR2 on neurodevelopment. Our findings provide new insights into the potential causative role of FGFR2 gene in complex neurodevelopmental disorders.

"Beyond transcription: How post-transcriptional mechanisms drive neural crest EMT".

The neural crest is a stem cell population that originates from the ectoderm during the initial steps of nervous system development. Neural crest cells delaminate from the neuroepithelium by undergoing a spatiotemporally regulated epithelial-mesenchymal transition (EMT) that proceeds in a coordinated wave head-to-tail to exit from the neural tube. While much is known about the transcriptional programs and membrane changes that promote EMT, there are additional levels of gene expression control that neural crest cells exert at the level of RNA to control EMT and migration. Yet, the role of post-transcriptional regulation, and how it drives and contributes to neural crest EMT, is not well understood. In this mini-review, we explore recent advances in our understanding of the role of post-transcriptional regulation during neural crest EMT.

The ameliorative effects of choline on ethanol-induced cell death in the neural tube of susceptible BXD strains of mice.

Fetal alcohol spectrum disorders (FASD) are the leading preventable cause of intellectual disability, providing the impetus for evaluating various potential treatments to ameliorate ethanol's teratogenic effects, particularly in the nervous system. One treatment is the dietary supplement choline which has been shown to mitigate at least some of ethanol's teratogenic effects. The present study was designed to investigate the effects of genetics on choline's efficacy in ameliorating cell death in the developing neural tube. Previously, we examined BXD recombinant inbred mice, and their parental C57BL/6 J (B6) and DBA/2 J strains, and identified strains that were sensitive to ethanol's teratogenic actions. Thus, we used these strains to identify response to choline treatment. Timed pregnant mice from 4 strains (B6, BXD51, BXD73, BXD2) were given either ethanol or isocaloric maltose-dextrin (5.8 g/kg in two administrations separated by 2 h) with choline at one of 3 doses: 0, 100 or 250 mg/kg. Subjects were exposed via intragastric gavage on embryonic day 9 and embryos were collected 7 h after the initial ethanol administrations. Cell death was analyzed using TUNEL staining in the developing forebrain and brainstem. Choline ameliorated the ethanol-induced cell death across all 4 strains without causing enhanced cell death in control mice. Choline was effective in both the developing telencephalon and in the brainstem. Both doses diminished cell death, with some differences across strains and brain regions, although the 100 mg/kg dose was most consistent in mitigating ethanol-related cell death. Comparisons across strains showed that there was an effect of strain, particularly in the forebrain at the higher dose. These results show that choline is effective in ameliorating ethanol-induced cell death at this early stage of nervous system development. However, there were some strain differences in its efficacy, especially at the high dose, providing further evidence of the importance of genetics in influencing the ability of choline to protect against prenatal alcohol exposure.

Transcriptomics and biochemical evidence of trigonelline ameliorating learning and memory decline in the senescence-accelerated mouse prone 8 (SAMP8) model by suppressing proinflammatory cytokines and elevating neurotransmitter release

In recent years, exploring natural compounds with functional properties to ameliorate aging-associated cognitive decline has become a research priority to ensure healthy aging. In the present study, we investigated the effects of Trigonelline (TG), a plant alkaloid, on memory and spatial learning in 16-week-old senescence-accelerated mouse model SAMP8 using an integrated approach for cognitive and molecular biology aspects. After 30 days of oral administration of TG at the dose of 5 mg/kg/day, the mice were trained in Morris Water Maze task. TG-treated SAMP8 mice exhibited significant improvement in the parameters of escape latency, distance moved, and annulus crossing index. Next, we performed a whole-genome transcriptome profiling of the mouse hippocampus using microarrays. Gene ontology analyses showed that a wide range of biological processes, including nervous system development, mitochondrial function, ATP synthesis, and several signaling pathways related to inflammation, autophagy, and neurotransmitter release, were significantly enriched in TG-treated SAMP8 compared to nontreated. Further, a nonlinear dimensionality reduction technique, Uniform Manifold Approximation and Projection (UMAP), was applied to identify clusters of functions that revealed TG primarily regulated pathways related to inflammation, followed by those involved in neurotransmitter release. In addition, a protein–protein interaction network analysis indicated that TG may exert its biological effects through negatively modulating Traf6-mediated NF-κB activation. Finally, ELISA test showed that TG treatment significantly decreased proinflammatory cytokines- TNFα and IL6 and increased neurotransmitters- dopamine, noradrenaline, and serotonin in mouse hippocampus. Altogether, our integrated bio-cognitive approach highlights the potential of TG in alleviating age-related memory and spatial impairment.