Human Brain Research Articles

The normalizing properties of intracranial volume across race and sex

Abstract In volumetric analysis of the human brain with MRI, intracranial volume is an important covariate as it has a strong correlation with the volume of regions of interest in the brain. Therefore, accurate adjustment for intracranial volume (e.g., by division) is essential to mitigate the impact of head size on brain measurements. In this study, we assess the effects of intracranial volume normalization on differences across sex and racial groups, using a diverse cohort with 5,977 subjects from three different (self-reported) races. We show that (i) differences in intracranial volume across sex are consistent across race and vice versa; and (ii) intracranial volume normalization almost completely accounts for differences by race and sex. These results suggest that subjects of different sexes and races can be safely aggregated in volumetric studies by normalizing the volume of regions of interest to intracranial volume.

Evidence for trans-synaptic propagation of oligomeric tau in human progressive supranuclear palsy

Abstract In the neurodegenerative disease progressive supranuclear palsy (PSP), tau pathology progresses through the brain in a stereotypical spatiotemporal pattern, and where tau pathology appears, synapses are lost. We tested the hypothesis that pathological tau contributes to synapse loss and may spread through the brain by moving from presynapses to postsynapses. Using postmortem PSP brain samples and a living human brain slice culture model, we observe pathological tau in synaptic pairs and evidence that oligomeric tau can enter live human postsynapses. Proteomics revealed increased clusterin in synapses in PSP, and super-resolution imaging showed clusterin colocalized with tau in synapses in close enough proximity to be binding partners, which may mediate tau spread. Accumulation of tau in synapses correlated with synapse loss, and synaptic engulfment by astrocytes was observed, suggesting that astrocytes contribute to synapse loss. Together, these data indicate that targeting synaptic tau is a promising approach to treat PSP.

The dietary ligands, omega-3 fatty acid endocannabinoids and short-chain fatty acids prevent cytokine-induced reduction of human hippocampal neurogenesis and alter the expression of genes involved in neuroinflammation and neuroplasticity

Abstract The dietary ligands, omega-3 fatty acid endocannabinoids (eCBs) eicosapentaenoyl ethanolamide (EPEA) and docosahexaenoyl ethanolamide (DHEA), and short-chain fatty acids (SCFAs) acetate, propionate and butyrate, have anti-inflammatory and antidepressant properties. However, the molecular mechanisms underlying their action in the human brain remain elusive. Here, we treated human hippocampal neurons (HPC0A07/03 C) with eCBs (EPEA (300 pM) or DHEA (700 pM)), or SCFAs (acetate (200 uM), propionate (30 uM), butyrate (20 uM)), followed by interleukin (IL)1β (10,000 pg/ml) or IL6 (50 pg/ml). We found that treatment with either eCBs or SCFAs prevented IL1β- and IL6-induced reduction in neurogenesis and increase in apoptosis. These effects were mediated by IL1β-induced production of IL6, interferon-gamma (IFNγ) and tumour necrosis factor-alpha (TNFα), and by IL6-induced IL1β, IL8 and IL13, all of which were prevented by treatment with eCBs. In contrast, IL1β-induced production of IL6, IL12 and fractalkine (CX3CL1), and IL6-induced production of CX3CL1, were prevented by SCFAs. Treatment with IL1β and IL6 also increased the production of candidate kynurenine pathway metabolites, such as kynurenine (KYN) and nicotinic acid (NICA), which again were prevented by eCBs and SCFAs. We then conducted mRNA sequencing analysis to investigate cellular genes and signalling pathways relevant for the neuro-inflammatory changes previously observed, and putatively prevented by eCB and SCFA treatment. We found that IL1β decreased the expression of the neuroplasticity gene, FRY microtubule binding gene (FRY), and increased the expression of the neuroinflammation gene, U3 small nucleolar ribonucleoprotein homolog C subunit processome component (UTP14C), and both these effects were prevented by either acetate or propionate. Similarly, the expression of the proinflammatory gene, ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), was increased by IL6, an effect that was prevented by either EPEA or acetate. Altogether, we identify novel anti-inflammatory and neurogenic mechanisms mediating the effect of eCBs and SCFAs on human hippocampal neurogenesis, which can be significant as potential future treatment candidates in the context of neuropsychiatric disorders.

The impact of citicoline on brain mitochondrial dysfunction induced in rats after head irradiation

Abstract Head irradiation is a common treatment for brain cancer; however, it can cause side effects in healthy brain tissue. This study aimed to test whether citicoline administration modulates radiation-induced brain mitochondrial dysfunction in rats. The head of the animal was exposed to 10 Gy γ-radiation. Citicoline (300 mg/kg body weight/day) was administered intraperitoneally for four weeks after irradiation. Some biochemical changes related to mitochondrial function in brain tissue were studied. The results showed that citicoline administration after head irradiation reduced oxidative stress, enhanced the activity of mitochondrial complexes (I and II), increased the aconitase enzyme activity, boosted ATP production, and restored the levels of calcium, iron, and caspase-3, compared to the corresponding values in irradiated rats. The levels of glucose and cholesterol in brain tissue were modulated. Citicoline also increased acetylcholine level and alpha-7 nicotinic receptor mRNA expression and decreased acetylcholinesterase activity in the brain tissue of irradiated-treated rats. We concluded that citicoline could attenuate the harmful effects of γ-radiation on the brain by modulating mitochondrial function, neurotransmission, and calcium & iron homeostasis, thus suppressing the mitochondrial-mediated apoptosis pathway. However, additional studies are required to validate and confirm these results before any clinical application can be recommended.

Functional alterations in parvalbumin-positive interneurons after traumatic brain injury in somatosensory cortex of mice

Traumatic brain injury (TBI) can lead to long lasting cognitive deficits in the human brain, with a considerable contribution of secondary morphological and functional sequela in cortical regions distant to the lesion site. In order to uncover the role of early functional alterations in parvalbumin-positive basket cells (PV-BCs), an interneuron population required to maintain inhibition of neocortical circuits, to this dysfunctional plasticity, we investigated anatomical and electrophysiological properties of PV-BCs in PV-IRES-Cre-tdTomato mice of both sexes 24h after a cortical impact. These experiments revealed that the number of PV-BCs was moderately decreased around the cortical impact site, while their morphology was unaffected. Patch-clamp experiments demonstrated that TBI increased the input-resistance of PV-BCs and the amplitude of hyperpolarization-activated inward currents (Ih). In addition, the maximal firing frequency upon depolarizing stimuli was decreased. The increase in Ih amplitude was paralleled by the appearance of somatic HCN-channels in immunohistochemical staining and the occurrence of somatic Ih in nucleated-patch recordings, suggesting that TBI induced a redistribution of HCN-channels from a purely axonal to an additional somatodendritic expression. Pharmacological experiments showed that inhibition of axonal HCN-mediated currents impairs the maximal firing frequency of PV-BCs. Additional in-silico simulations disclosed the general importance of axonal HCN-channels to maintain high-frequency firing of PV-BCs by counteracting Na+-K+-pump associated hyperpolarizing currents. In summary, our results suggest that the early loss of PV-BCs and the TBI induced distinct alterations in their electrophysiological properties can contribute to the establishment of disturbed network activity following TBI. Significance statement Brain injuries caused by a traumatic mechanical impact can lead to long lasting cognitive deficits in the human brain. Secondary functional changes substantially contribute to these cognitive deficits. Understanding how traumatic brain injuries (TBI) affect the function of neurons will help to understand the processes leading to cognitive deficits. In the present study we investigated how TBI affects properties of basket-cells, an important class of inhibitory interneurons that regulate brain circuits. We observed that TBI decreased the number of basket-cells and attenuated their action potential firing, mainly by a shift in a single membrane protein. Our results indicate that even subtle alterations in this important cell type can contribute to the impaired function of the brain after TBI.

Integrative Single-Cell Analysis Decodes Gene Expression and Chromatin Accessibility in the Developing Human Fetal Brain.

The brain is the core of the central nervous system, responsible for regulating and integrating various physiological and psychological functions. Abnormal disruptions in genes during brain development can lead to a range of neurodevelopmental disorders. In this study, we performed a systematic investigation of human fetal brain tissue from miscarriages between 8 and 17weeks of gestation using integrated single-cell RNA sequencing (scRNA-seq) and single-cell transposase-accessible chromatin sequencing (scATAC-seq). We constructed single-cell transcriptomic and epigenomic maps of neurodevelopment, revealing key signaling pathways involved in neural cell proliferation, differentiation, and functional maturation. Through pseudotime analysis, we reconstructed the developmental trajectory of neuronal differentiation and its dynamic regulatory mechanisms. Additionally, we identified cell type-specific chromatin accessibility regions during neurogenesis and, through integrated analysis, predicted potential regulatory elements involved in the process. Overall, the single-cell multi-omics integration map constructed in this study provides valuable resources for a deeper understanding of fetal brain development, cellular heterogeneity, lineage relationships, and transcriptional regulatory networks during neurogenesis.

Multiscale characterization of myelin distribution with polarized THG microscopy

Myelin is essential for axonal conduction and metabolic support. To better understand its role in health and disease, it is necessary to establish accurate methods for in situ mapping of myelin at scales ranging from submicrometer to centimeters. Third-harmonic generation (THG) microscopy has recently been proposed as an efficient label-free method to visualize myelin in thick and living tissue. However, the contrast mechanism of THG from myelinated axons is complex and poorly described, which has limited the development of THG as a quantitative probe of myelin distribution. Here, we present a systematic characterization and modeling of polarization-resolved THG (pTHG) signals from individual axons as a function of their diameter and myelin thickness, and we show that pTHG can be used to derive myelin scores in several biological systems. First, we confirm the sensitivity and specificity of the THG contrast for myelinated axons in mouse brain tissue and its ability to detect isolated micrometer-sized axons oriented both in-plane and out-of-plane. We then present a detailed characterization of the pTHG contrast of small and large axons in live zebrafish larvae at different developmental stages, and we demonstrate that pTHG detects early axon development in vivo. We show that classical models of coherent multiphoton microscopy fail to reproduce pTHG profiles of axons because they neglect myelin-induced optical aberrations, and we establish a numerical strategy based on finite-difference time-domain calculations that can accurately relate pTHG signal profiles to axonal diameter and myelin thickness. Finally, we illustrate the relevance of pTHG microscopy for characterizing myelin distribution at different scales in fixed mouse and human brain tissue.

The therapeutic effects of genistein in rats with epilepsy by influencing mitochondrial biogenesis and regulating apoptosis in brain tissue

Abstract PurposeEpilepsy is a widespread, long-term neurological condition triggered by an overabundance of electrical activity from the neurons in the brain. Genistein, a natural isoflavone found in soybeans, can prevent chronic diseases such as cardiovascular disease and osteoporosis. We aimed to investigate the potential protective effects of genistein on epilepsy using rat models through behavior analysis and investigation of key pathways, including antioxidant activity (Nrf2 and HO-1), promoting mitochondrial biogenesis (TFAM), and reducing brain tissue apoptosis (BCL2, BAX, and caspases).Main methodsPTZ was used to induce epilepsy in rats, and then they were treated with genistein. The hippocampus sections were stained with Nissl stain, and others were stained with anti-TFAM antibodies. Furthermore, TFAM, Nrf2, HO-1, BCL2, BAX, and caspases-3/8/9 gene expression and protein levels were quantified using quantitative real-time polymerase chain reaction (qRT-PCR) and complementary biochemical/functional assays.ResultsRats treated with genistein displayed notable progress in their behavior during behavioral tests. Sections stained with Nissl revealed that genistein increased the staining intensity of Nissl granules in the cerebral cortex. Additionally, genistein increased the expression of TFAM, Nrf2, HO-1, and BCL2, which reduced levels of BAX and caspase-3/8/9.ConclusionsGenistein safeguards against epilepsy in rats by enhancing their behavior and reinstating normal neuron structure. Its protective benefits may stem from its potential to boost antioxidant activity and promote mitochondrial biogenesis, which in turn decreases cell apoptosis.

Investigating the interplay of immune response and redox homeostasis in hypoxic brain injury at high altitude

Environments at high altitudes, where barometric pressure is low and oxygen levels are diminished, significantly heighten the risk of High-Altitude Cerebral Edema (HACE), a potentially life-threatening neurological disorder. HACE induces a robust inflammatory response, disrupting redox balance in the brain and causing neurocyte swelling and degeneration. This study evaluated changes in apoptotic cells, mast cells (MCs), and the expression of TNF-α, a key mediator of neuroinflammation, following acute hypobaric hypoxia. Furthermore, changes in the activities of superoxide dismutase (SOD), catalase (CAT), and lactate dehydrogenase (LDH) were examined to evaluate disruptions in the redox balance and potential disturbances in cell energy metabolism within the brain. The animals were exposed to hypobaric hypoxia for roughly 24 hours at an altitude of 7620m. The findings revealed a significant increase in MCs in the brain tissue (p<0.001), along with an elevated number of TNF-α and apoptotic cells, suggesting considerable neuronal degeneration (p<0.05). The activities of SOD and CAT were decreased (p<0.01), which shows weakened antioxidant defense mechanisms following the hypoxic exposure. However, the changes of LDH level remained unaltered. These results underscore the critical role of the immune reaction of the brain triggered by the hypoxic conditions that aggravate cerebral edema development. This study illustrates the interplay of inflammatory response with an antioxidant defense system in the context of blood-brain barrier (BBB) disruption, contributing to cerebral edema formation and neuronal dysfunction. This research deepens our understanding of the pathogenesis of HACE, highlighting the interactions between specific biomolecules that regulate the brain’s immune reaction and redox pathways under hypoxic conditions.

A Descriptive Study on the Students’ Perception Toward the Use of Board Race Game in Learning English at the Eleventh Grade of SMK PGRI 1 Giri Banyuwangi in the 2022/2023 Academic Year

Perceptions are the results of information which are expressed to other people who have different meanings in each human brain. The purpose of this research is to determine students’ perceptions of the use of the Board Race Game in learning English. This research used method research such as descriptive quantitative research. There were 52 students as respondents of a senior high schools on the eleventh grade at SMK PGRI 1 Giri Banyuwangi. The purposive sampling was one of the techniques used in this research. To find out the perceptions on the use Board Race Game in Learning English, the data collection method was done by filling out the questionnaire. Related to the result of research of the students’ perceptions on the eleventh grade at SMK PGRI 1 Giri Banyuwangi is a good category with overall percentage 78%. The researcher suggests that English teachers use the Board Race Game as a learning method. Through Games, English teachers can deliver the materials easily and creatively

Dysregulated calcium signaling in the aged primate association cortices: vulnerability to Alzheimer’s disease neuropathology

The common, late onset form of Alzheimer’s disease (AD) selectively impacts higher brain circuits, with tau pathology and neurodegeneration preferentially afflicting glutamatergic neurons in the limbic and association cortices. Understanding this selective vulnerability may help reveal the etiology of sporadic AD and therapeutic targets for prevention. The current review describes that these vulnerable circuits express magnified calcium signaling needed for higher cognition and memory, but that heightened calcium signaling becomes toxic when dysregulated by age and inflammation. Many of the earliest pathological events in AD are challenging to study in human brain, as proteins such as tau rapidly dephosphorylate postmortem. However, they can be studied in aging macaques, who are all APOE-ε4 homozygotes and naturally develop cognitive deficits, calcium dysregulation, synapse loss, tau and amyloid pathology and autophagic degeneration, including elevated plasma pT217Tau, a new blood biomarker of incipient AD. High resolution nanoscale imaging of aging macaque brains reveals the earliest stages of soluble tau pathology and its relationships with Aβ42 and calcium signaling. These data indicate that inflammation erodes regulation of calcium signaling leading to the activation of calpain-2, which drives tau hyperphosphorylation, APP cleavage to Aβ42 and autophagic degeneration. These in turn propel further calcium dysregulation to drive vicious cycles. Restoring calcium dysregulation, e.g., with calpain-2 inhibitors, thus may be a rational strategy for slowing or preventing AD pathology. Recent data show that an agent that reduces GCPII inflammation and restores mGluR3 regulation of calcium reduced tau pathology in aged macaques, encouraging this approach. Targeting inflammation and dysregulated calcium may be especially helpful for patients who are APOE-ε4 carriers and insufficiently aided by current anti-amyloid antibody treatments.

New Alzheimer's association workgroup criteria underestimate syndromes in Alzheimer's disease definition.

The biological definition of Alzheimer's disease promoted by the Alzheimer's Association Working Group's new criteria relegates cognitive impairment to the background when defining the disease. However, cognitive syndromes, as plaques and tangles, are important biological phenomena, are part of the disease and not of the illness, and are objectively investigable. When well delineated, they show a close correlation with brain anatomy and neuropathology and are also few, relatively invariable, well-defined and well distinguishable from each other. Therefore, their detection retains a high value in suggesting the presence of the disease, which still must be confirmed by principle of exclusion.

Molecular Docking and in vivo Toxicity Evaluations of Jopan Nanoherbal (Clibadium surinamense L.) Leaves in a Zebrafish Model

Nanotechnological advancements have significantly increased the effectiveness of herbal remedies, particularly Jopan (Clibadium surinamense L.) leaves, which are recognised for their anti-inflammatory, antimicrobial, and antioxidant characteristics. This study aims to assess the toxicological potential of nanoherbal C. surinamense leaves via computational (molecular docking) and in vivo toxicity evaluations in a zebrafish model. ProTox-III was employed for the toxicity classifications; molecular docking simulations, using the CYP450 enzyme (PDB ID: 4R20); and in vivo zebrafish toxicity testing. Zebrafish were exposed to nanoherbal C. surinamense leaves at concentrations of 0, 12.5, 25, 50, 100, 200, 400, and 800 mg/L for 96 hours following OECD Guideline 203. The acute toxicity was evaluated by determining the LC50 value, while the toxic effects on the brain, liver, and intestinal tissues were assessed via histopathological analysis. An LC50 value of 516.87 mg/L was obtained, indicating low toxicity, while concentrations ≥200 mg/L caused dose-dependent toxic effects, including Purkinje cell degeneration, hepatocellular necrosis, and villus fragmentation. Molecular docking simulations revealed 2-undecanone 2,4-dinitrophenylhydrazone as the most active compound, exhibiting the strongest binding affinity (-7.4 kcal/mol) for CYP450. In conclusion, while nanoherbal C. surinamense leaves show therapeutic potential, their toxicity at higher concentrations necessitates further investigation to establish safe dosages; further, their long-term effects and pharmacokinetic properties should be explored to ensure their safety for medical applications.

The impact of Sorbs2 on the progression of ventricular arrhythmias in mice

Objective: To investigate the impact potential mechanisms of Sorbin and SH3 domain-containing protein 2 (Sorbs2) on ventricular arrhythmias in mice. Methods: In the animal experiments, mating was performed using six 8-week-old Sorbs2+/- mice (3 males and 3 females) weighing 20-22 g. Wild-type (Sorbs2+/+, n=8) and homozygous (Sorbs2-/-, n=6) offspring were selected as experimental subjects through genotyping. Echocardiography was performed at 16 weeks of age to record cardiac function parameters in both groups. Resting-state and caffeine-dobutamine-induced electrocardiograms were also conducted. Real-time quantitative reverse transcription polymerase chain reaction was used to detect Sorbs2 messager RNA expression in the heart, liver, spleen, lung, kidney, brain, small intestine, and skeletal muscle tissues of wild-type mice. Western blotting was employed to measure the protein expression levels of Sorbs2 and voltage-dependent sodium channel alpha subunit 1.5 (Nav1.5) in myocardial tissues from both groups. In the cell experiments, H9C2 cells were transfected with Sorbs2 small interfering RNA as the si-Sorbs2 group, with a corresponding si-negative control group established. Western blot was performed to detect the protein expression levels of Sorbs2 and Nav1.5 in both groups. Results: Sorbs2 was abundantly expressed in cardiac tissue. Compared with wild-type mice, homozygous mice exhibited larger left ventricular end-systolic diameter, along with lower left ventricular ejection fraction and fractional shortening (P all<0.05). Resting-sate electrocardiograms revealed no spontaneous arrhythmias in either group; however, homozygous mice showed shorter RR intervals but longer QRS and QTc intervals versus wild-type mice (P all<0.05). Following caffeine and dobutamine induction, homozygous mice demonstrated a higher incidence of ventricular arrhythmias, longer arrhythmia duration, and higher ventricular arrhythmia scores than wild-type mice (P all<0.05). Western blot analysis revealed that Nav1.5 protein expression was markedly lower in myocardial tissues of homozygous mice compared to wild-type mice. Similarly, si-Sorbs2-transfected H9C2 cells exhibited lower Nav1.5 protein levels compared to the si-negative control group (P<0.05). Conclusion: Sorbs2 plays a critical role in maintaining normal cardiac electrophysiological function. Deficiency of Sorbs2 may lead to impaired cardiac function and increased susceptibility to ventricular arrhythmias in mice, which could be associated with reduced expression of Nav1.5 protein.

The addition of stereopsis to natural scenes enhances human brain activation in scene-selective regions

The addition of stereopsis to natural scenes enhances human brain activation in scene-selective regions

Penerapan Model CRISP-DM Untuk Klasifikasi Tumor Otak Menggunakan Algoritma CNN

In general, a tumor is an abnormal tissue growth in the body that occurs due to uncontrolled cell division. Tumors can be benign (non-cancerous) or malignant (cancerous). Benign tumors tend to grow locally without spreading to other tissues, while malignant tumors can invade surrounding tissues and spread to other parts of the body through the bloodstream. A brain tumor is a mass or growth of abnormal tissue in or around the brain. Specifically, brain tumors can be primary (originating from the brain cells themselves or surrounding tissues, such as the meninges, pituitary gland, or cranial nerves) or secondary (metastasis from cancer originating from other parts of the body). The main problem today is that brain tumors have many types, therefore research on the classification of brain tumor types is very valuable today. In order to improve accuracy and also speed up the diagnosis process. The results of this study, brain tumor image data classification has been carried out using the CNN Algorithm method with the CRISP-DM data mining technique. The dataset consists of 3,554 datasets, but from the results of testing this algorithm has good performance with an accuracy of 98% with Evaluation and validation using the Confusion Matrix test parameters. and successfully classified human brains affected by tumors and those not affected by tumors, in addition to being able to classify 3 different types of tumors, namely glioma, meningioma, and pituitary.

Protein-Altering Variants' Analysis in Autism Subgroups Uncovers Early Brain-Expressed Gene Modules Relevant to Autism Pathophysiology.

Understanding the functional implications of genes' variants in autism heterogeneity is challenging. Gene set analysis examines the cumulative effect of multiple functionally converging genes. Here we explored whether a multi-step analysis could identify gene sets with different loads of protein-altering variants (PAVs) between two subgroups of autistic children. After subdividing our sample (n = 71, 3-12 years) based on higher (> 80; n = 43) and lower ( 80; n = 28) intelligence quotient (IQ), a gene set variant enrichment analysis identified gene sets with significantly different incidence of PAVs between the two subgroups of autistic children. Significant gene sets were then clustered into modules of genes. Their brain expression was investigated according to the BrainSpan Atlas of the Developing Human Brain. Next, we extended each module by selecting the genes that were spatio-temporally co-expressed in the developing brain and physically interacting with those in modules. Last, we explored the incidence of autism susceptibility genes within original and extended modules. Our analysis identified 38 significant gene sets (FDR, q < 0.05). They clustered in four modules involved in ion cell communication, neurocognition, gastrointestinal function, and immune system. Those modules were highly expressed in specific brain structures across development. Spatio-temporal brain co-expression and physical interactions identified extended genes' clusters with over-represented autism susceptibility genes. Overall, our unbiased approach identified modules of genes functionally relevant to autism pathophysiology, possibly implicating them in phenotypic variability across subgroups. The findings also suggest that autism diversity likely originates from multiple interacting pathways. Future research could leverage this approach to identify genetic pathways relevant to autism subtyping.

Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells

Substrate stiffness and shear stress collectively regulate the inflammatory phenotype in cultured human brain microvascular endothelial cells

Visual-semantic representations within the distributed conceptual network of the human brain

Visual-semantic representations within the distributed conceptual network of the human brain

A Machine-Learning Approach Identifies Rejuvenating Interventions in the Human Brain.

The increase in life expectancy has caused a rise in age-related brain disorders. Although brain rejuvenation is a promising strategy to counteract brain functional decline, systematic discovery methods for efficient interventions are lacking. A computational platform based on a transcriptional brain aging clock capable of detecting age- and neurodegeneration-related changes is developed. Applied to neurodegeneration-positive samples, it reveals that neurodegenerative disease presence and severity significantly increase predicted age. By screening 43840 transcriptional profiles of chemical and genetic perturbations, it identifies 453 unique rejuvenating interventions, several of which are known to extend lifespan in animal models. Additionally, the identified interventions include drugs already used to treat neurological disorders, Alzheimer's disease among them. A combination of compounds predicted by the platform reduced anxiety, improved memory, and rejuvenated the brain cortex transcriptome in aged mice. These results demonstrate the platform's ability to identify brain-rejuvenating interventions, offering potential treatments for neurodegenerative diseases.