Pathological Processes In Brain Research Articles

Biomimetic mesoporous carbon-silica/AAO asymmetric nanochannel array for electrochemical sensing of K+ in rat brain microdialysates and serum

Acquirement of chemical expression in practical brain system is vital to understand the molecular mechanism involved in physiological and pathological processes in brain. Though nanochannels have been demonstrated to be promising platform for electrochemical sensor, it is a great challenge for nanochannels to be employed in practical brain biofluid. In this work, we rationally designed and created the biomimetic asymmetric nanochannels for sensing of K+ through integrating in situ modification of a two-component mesoporous carbon-silica (MCS) thin film with a pore size of ∼3.6 nm at anodic alumina nanochannel array (AAO) with the ∼40 nm pores (denoted as MCS/AAO). Apparent rectification phenomenon in such functionalized nanochannel array was achieved based on diode-like ion transport. Then, 4′-aminobenzeno-18-crown-6 (SP) was selected to be chemically decorated at MCS/AAO as the specific recognition for K+ (SP/MCS/AAO). The developed SP/MCS/AAO exhibited good selectivity towards K+ detection against the coexisting interferences in brain, and possessed a good linear response to K+ concentration in the range of 0.5–10 mM with a detection limit of 0.1 mM. Combined with microdialysis technique, the variation of K+ was successfully determined in rat brain microdialysates and serums. Compared with normal rats, the concentration of K+ was found to be greatly decreased in the cerebral microdialysates and serum of rats with hypertensive model (SHR). This work unveiled a powerful platform for K+, and promised to be extended to design new strategy for detecting other chemical species, in particular non-electroactive species in biofluid related to physiological and pathological events.

Immunogenetic Factors in the Pathogenesis of Schizophrenia

Human predisposition to neurological diseases such as schizophrenia, Alzheimer’s, Parkinson’s and other neuropathologies is associated with genetic and environmental factors. One of the promising directions in the area of molecular neurosciences is the study of the role of immunogenetic mechanisms in different types of pathological processes in brain. This review explores the role of complex histocompatibility genes in the pathogenesis of schizophrenia, evaluating changes in the immune repertoire of T- and B-cell receptors in neuroinflammation.

Lateralization of delta band power in magnetoencephalography (MEG) in patients with unilateral focal epilepsy and its relation to verbal fluency.

Delta power is a clinically established biomarker for abnormal brain processes. However, in patients with unilateral focal epilepsy (FE) it is still not well understood, how it relates to the epileptogenic zone and to neurocognitive functioning. The aim of the present study was thus to assess how delta power relates to the affected hemisphere, whether lateralization strength differs between the patients, and how changes in delta power correlate with cognitive functioning. We retrospectively studied patients with left (LFE) and right FE (RFE) who had undergone a resting-state magnetoencephalography measurement. We computed global and hemispheric delta power and lateralization indices and examined whether delta power correlates with semantic and letter verbal fluency (former being a marker for language and verbal memory, latter for executive functions) in 26 FE patients (15 LFE, 11 RFE) and 10 healthy controls. Delta power was increased in FE patients compared to healthy controls. However, the increase across hemispheres was related to the site of the epileptic focus: On group level, LFE patients showed higher delta power in both hemispheres, whereas RFE patients primarily exhibited higher delta power in the ipsilateral right hemisphere. Both groups showed co-fluctuations of delta power between the hemispheres. Besides, delta power correlated negatively only with letter verbal fluency. The findings confirm and provide further evidence that delta power is a marker of pathological activity and abnormal brain processes in FE. Delta power dynamics differ between patient groups, indicating that delta power could offer additional diagnostic value. The negative association of delta power and letter verbal fluency suggests that executive dysfunctions are related to low frequency abnormalities.

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid-β (Aβ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of Aβ plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with Aβ plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than Aβ and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with Aβ and tau.

Blood-based Aβ42 increases in the earliest pre-pathological stage before decreasing with progressive amyloid pathology in preclinical models and human subjects: opening new avenues for prevention

Blood-based (BB) biomarkers for Aβ and tau can indicate pathological processes in the brain, in the early pathological, even pre-symptomatic stages in Alzheimer’s disease. However, the relation between BB biomarkers and AD-related processes in the brain in the earliest pre-pathology stage before amyloid pathology develops, and their relation with total brain concentrations of Aβ and tau, is poorly understood. This stage presents a critical window for the earliest prevention of AD. Preclinical models with well-defined temporal progression to robust amyloid and tau pathology provide a unique opportunity to study this relation and were used here to study the link between BB biomarkers with AD-related processes in pre- and pathological stages. We performed a cross-sectional study at different ages assessing the link between BB concentrations and AD-related processes in the brain. This was complemented with a longitudinal analysis and with analysis of age-related changes in a small cohort of human subjects. We found that BB-tau concentrations increased in serum, correlating with progressive development of tau pathology and with increasing tau aggregates and p-tau concentrations in brain in TauP301S mice (PS19) developing tauopathy. BB-Aβ42 concentrations in serum decreased between 4.5 and 9 months of age, correlating with the progressive development of robust amyloid pathology in APP/PS1 (5xFAD) mice, in line with previous findings. Most importantly, BB-Aβ42 concentrations significantly increased between 1.5 and 4.5 months, i.e., in the earliest pre-pathological stage, before robust amyloid pathology develops in the brain, indicating biphasic BB-Aβ42 dynamics. Furthermore, increasing BB-Aβ42 in the pre-pathological phase, strongly correlated with increasing Aβ42 concentrations in brain. Our subsequent longitudinal analysis of BB-Aβ42 in 5xFAD mice, confirmed biphasic BB-Aβ42, with an initial increase, before decreasing with progressive robust pathology. Furthermore, in human samples, BB-Aβ42 concentrations were significantly higher in old (> 60 years) compared to young (< 50 years) subjects, as well as to age-matched AD patients, further supporting age-dependent increase of Aβ42 concentrations in the earliest pre-pathological phase, before amyloid pathology. Also BB-Aβ40 concentrations were found to increase in the earliest pre-pathological phase both in preclinical models and human subjects, while subsequent significantly decreasing concentrations in the pathological phase were characteristic for BB-Aβ42. Together our data indicate that BB biomarkers reflect pathological processes in brain of preclinical models with amyloid and tau pathology, both in the pathological and pre-pathological phase. Our data indicate a biphasic pattern of BB-Aβ42 in preclinical models and a human cohort. And most importantly, we here show that BB-Aβ increased and correlated with increasing concentrations of Aβ in the brain, in the earliest pre-pathological stage in a preclinical model. Our data thereby identify a novel critical window for prevention, using BB-Aβ as marker for accumulating Aβ in the brain, in the earliest pre-pathological stage, opening new avenues for personalized early preventive strategies against AD, even before amyloid pathology develops.

Roles of Nitric Oxide in Brain Ischemia and Reperfusion.

Brain ischemia and reperfusion (I/R) is one of the most severe clinical manifestations of ischemic stroke, placing a significant burden on both individuals and society. The only FDA-approved clinical treatment for ischemic stroke is tissue plasminogen activator (t-PA), which rapidly restores cerebral blood flow but can have severe side effects. The complex pathological process of brain I/R has been well-established in the past few years, including energy metabolism disorders, cellular acidosis, doubling of the synthesis or release of excitotoxic amino acids, intracellular calcium homeostasis, free radical production, and activation of apoptotic genes. Recently, accumulating evidence has shown that NO may be strongly related to brain I/R and involved in complex pathological processes. This review focuses on the role of endogenous NO in pathological processes in brain I/R, including neuronal cell death and blood brain barrier disruption, to explore how NO impacts specific signaling cascades and contributes to brain I/R injury. Moreover, NO can rapidly react with superoxide to produce peroxynitrite, which may also mediate brain I/R injury, which is discussed here. Finally, we reveal several therapeutic approaches strongly associated with NO and discuss their potential as a clinical treatment for ischemic stroke.

Photoacoustic Neuroimaging - Perspectives on a Maturing Imaging Technique and its Applications in Neuroscience.

A prominent goal of neuroscience is to improve our understanding of how brain structure and activity interact to produce perception, emotion, behavior, and cognition. The brain’s network activity is inherently organized in distinct spatiotemporal patterns that span scales from nanometer-sized synapses to meter-long nerve fibers and millisecond intervals between electrical signals to decades of memory storage. There is currently no single imaging method that alone can provide all the relevant information, but intelligent combinations of complementary techniques can be effective. Here, we thus present the latest advances in biomedical and biological engineering on photoacoustic neuroimaging in the context of complementary imaging techniques. A particular focus is placed on recent advances in whole-brain photoacoustic imaging in rodent models and its influential role in bridging the gap between fluorescence microscopy and more non-invasive techniques such as magnetic resonance imaging (MRI). We consider current strategies to address persistent challenges, particularly in developing molecular contrast agents, and conclude with an overview of potential future directions for photoacoustic neuroimaging to provide deeper insights into healthy and pathological brain processes.

Proteomics Profiling of Neuron-Derived Small Extracellular Vesicles from Human Plasma: Enabling Single-Subject Analysis.

Small extracellular vesicles have been intensively studied as a source of biomarkers in neurodegenerative disorders. The possibility to isolate neuron-derived small extracellular vesicles (NDsEV) from blood represents a potential window into brain pathological processes. To date, the absence of sensitive NDsEV isolation and full proteome characterization methods has meant their protein content has been underexplored, particularly for individual patients. Here, we report a rapid method based on an immunoplate covalently coated with mouse monoclonal anti-L1CAM antibody for the isolation and the proteome characterization of plasma-NDsEV from individual Parkinson’s disease (PD) patients. We isolated round-shaped vesicles with morphological characteristics consistent with exosomes. On average, 349 ± 38 protein groups were identified by liquid chromatography–tandem mass spectrometry (LC-MS/MS) analysis, 20 of which are annotated in the Human Protein Atlas as being highly expressed in the brain, and 213 were shared with a reference NDsEV dataset obtained from cultured human neurons. Moreover, this approach enabled the identification of 23 proteins belonging to the Parkinson disease KEGG pathway, as well as proteins previously reported as PD circulating biomarkers.

Preliminary Study of hsa-mir-626 Change in the Cerebrospinal Fluid in Parkinson's Disease.

A host of microRNAs have been reported to suppress tumor growth, invasion, and metastasis and play roles in neurodegeneration disorders. Moreover, microRNA changes are found in the peripheral blood, cerebrospinal fluid (CSF), and brain tissues of central nervous system diseases, including glioma, Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis, and depression. Compared with other body fluids, CSF can reflect the brain pathological processes more accurately. To understand whether microRNA expression may be misregulated in patients with PD, and further discover potential diagnostic biomarkers and promising therapeutic targets for PD. Here, through real-time reverse-transcription polymerase chain reaction (RT-PCR), we compared CSF microRNA from 15 PD patients, 11 AD patients, and 16 controls with other neurologic disorders, such as encephalitis and Guillain-Barre syndrome. Finally, we identified hsa-miR-626 changes in the CSF of PD patients. The mean expression level of hsa-miR-626 was significantly reduced in the CSF of PD patients compared with AD patients and controls. Our approach provides a preliminary research for identifying biomarkers in the CSF that could be used for the detection, diagnosis, and monitoring of PD.

What Can Local Transfer Entropy Tell Us about Phase-Amplitude Coupling in Electrophysiological Signals?

Modulation of the amplitude of high-frequency cortical field activity locked to changes in the phase of a slower brain rhythm is known as phase-amplitude coupling (PAC). The study of this phenomenon has been gaining traction in neuroscience because of several reports on its appearance in normal and pathological brain processes in humans as well as across different mammalian species. This has led to the suggestion that PAC may be an intrinsic brain process that facilitates brain inter-area communication across different spatiotemporal scales. Several methods have been proposed to measure the PAC process, but few of these enable detailed study of its time course. It appears that no studies have reported details of PAC dynamics including its possible directional delay characteristic. Here, we study and characterize the use of a novel information theoretic measure that may address this limitation: local transfer entropy. We use both simulated and actual intracranial electroencephalographic data. In both cases, we observe initial indications that local transfer entropy can be used to detect the onset and offset of modulation process periods revealed by mutual information estimated phase-amplitude coupling (MIPAC). We review our results in the context of current theories about PAC in brain electrical activity, and discuss technical issues that must be addressed to see local transfer entropy more widely applied to PAC analysis. The current work sets the foundations for further use of local transfer entropy for estimating PAC process dynamics, and extends and complements our previous work on using local mutual information to compute PAC (MIPAC).

Epigenetic modulation of AREL1 and increased HLA expression in brains of multiple system atrophy patients

Multiple system atrophy (MSA) is a rare disease with a fatal outcome. To date, little is known about the molecular processes underlying disease development. Its clinical overlap with related neurodegenerative movement disorders underlines the importance for expanding the knowledge of pathological brain processes in MSA patients to improve distinction from similar diseases. In the current study, we investigated DNA methylation changes in brain samples from 41 MSA patients and 37 healthy controls. We focused on the prefrontal cortex, a moderately affected area in MSA. Using Illumina MethylationEPIC arrays, we investigated 5-methylcytosine (5mC) as well as 5-hydroxymethylcytosine (5hmC) changes throughout the genome. We identified five significantly different 5mC probes (adj. P < 0.05), of which one probe mapping to the AREL1 gene involved in antigen presentation was decreased in MSA patients. This decrease correlated with increased 5hmC levels. Further, we identified functional DNA methylation modules involved in inflammatory processes. As expected, the decreased 5mC levels on AREL1 was concordant with increased gene expression levels of both AREL1 as well as MHC Class I HLA genes in MSA brains. We also investigated whether these changes in antigen-related processes in the brain associated with changes in peripheral mononuclear cells. Using flow cytometry on an independent cohort of MSA patients, we identified a decrease in circulating non-classical CD14+CD16++ blood monocytes, whereas T and NK cell populations were unchanged. Taken together, our results support the view of an active neuroimmune response in brains of MSA patients.

Just a very expensive breathing training? Risk of respiratory artefacts in functional connectivity-based real-time fMRI neurofeedback

Real-time functional magnetic resonance imaging neurofeedback (rtfMRI NFB) is a promising method for targeted regulation of pathological brain processes in mental disorders. But most NFB approaches so far have used relatively restricted regional activation as a target, which might not address the complexity of the underlying network changes. Aiming towards advancing novel treatment tools for disorders like schizophrenia, we developed a large-scale network functional connectivity-based rtfMRI NFB approach targeting dorsolateral prefrontal cortex and anterior cingulate cortex connectivity with the striatum.In a double-blind randomized yoke-controlled single-session feasibility study with N ​= ​38 healthy controls, we identified strong associations between our connectivity estimates and physiological parameters reflecting the rate and regularity of breathing. These undesired artefacts are especially detrimental in rtfMRI NFB, where the same data serves as an online feedback signal and offline analysis target.To evaluate ways to control for the identified respiratory artefacts, we compared model-based physiological nuisance regression and global signal regression (GSR) and found that GSR was the most effective method in our data.Our results strongly emphasize the need to control for physiological artefacts in connectivity-based rtfMRI NFB approaches and suggest that GSR might be a useful method for online data correction for respiratory artefacts.

Cross-Species Single-Cell Analysis Reveals Divergence of the Primate Microglia Program

Microglia, the brain-resident immune cells, are critically involved in many physiological and pathological brain processes, including neurodegeneration. Here we characterize microglia morphology and transcriptional programs across ten species spanning more than 450 million years of evolution. We find that microglia express a conserved core gene program of orthologous genes from rodents to humans, including ligands and receptors associated with interactions between glia and neurons. In most species, microglia show a single dominant transcriptional state, whereas human microglia display significant heterogeneity. In addition, we observed notable differences in several gene modules of rodents compared with primate microglia, including complement, phagocytic, and susceptibility genes to neurodegeneration, such as Alzheimer's and Parkinson's disease. Our study provides an essential resource of conserved and divergent microglia pathways across evolution, with important implications for future development of microglia-based therapies in humans.

Design Principles for Cationic, Astrocyte-Targeted Probes.

The brain's astrocytes play key roles in normal and pathological brain processes. Targeting small molecules to astrocytes in the presence of the many other cell types in the brain will provide useful tools for their visualization and manipulation. Herein, we explore the functional consequences of synthetic modifications to a recently described astrocyte marker composed of a bright rhodamine-based fluorophore and an astrocyte-targeting moiety. We altered the nature of the targeting moiety to probe the dependence of astrocyte targeting on hydrophobicity, charge, and pKa when exposed to astrocytes and neurons isolated from the mouse cortex. We found that an overall molecular charge of +2 and a targeting moiety with a heterocyclic aromatic amine are important requirements for specific and robust astrocyte labeling. These results provide a basis for engineering astrocyte-targeted molecular tools with unique properties, including metabolite sensing or optogenetic control.

RBPJ polymorphisms associated with cerebral infarction diseases in Chinese Han population: A Clinical Trial/Experimental Study (CONSORT Compliant).

Trial design:Cerebral small vessel diseases (CSVDs) are a group of brain pathological processes involving cerebral small arteries, brain venules, and capillaries. The recombination signal-binding protein Jκ (RBPJ) is implicated in the pathogenesis of these diseases but its actual roles need confirmation. The aim of this work was to evaluate variations in RBPJ gene for their possible associations with the disease.Methods:The RBPJ gene was sequenced for 400 patients with cerebral infarction disease and 600 normal controls. The statistical analyses and Hardy–Weinberg equilibrium tests of the patients and control populations were conducted using the SPSS software (version 19.0) and Plink (version 1.9), Haploview software, and online software SNPSpD.Results:We characterized variants rs2871198, rs1397731, rs3822223, rs2077777, rs2270226, and rs2788861 within or near the RBPJ gene. The genetic heterozygosity of rs2871198, rs1397731, rs3822223, rs2077777, and rs2270226 was very high. Statistical analysis showed that the variants rs2270226 and rs2077777 in the gene were associated with the risk of cerebral infarction diseases in the Chinese Han population.Conclusions:rs2270226 and rs2077777 in the RBPJ gene were associated with the risk of cerebral infarction diseases in the Chinese Han population.

Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer's disease

Cytochrome P450 46A1 (CYP46A1 or cholesterol 24-hydroxylase) controls cholesterol elimination from the brain and plays a role in higher order brain functions. Genetically enhanced CYP46A1 expression in mouse models of Alzheimer's disease mitigates the manifestations of this disease. We enhanced CYP46A1 activity pharmacologically by treating 5XFAD mice, a model of rapid amyloidogenesis, with a low dose of the anti-HIV medication efavirenz. Efavirenz was administered from 1 to 9 months of age, and mice were evaluated at specific time points. At one month of age, cholesterol homeostasis was already disturbed in the brain of 5XFAD mice. Nevertheless, efavirenz activated CYP46A1 and mouse cerebral cholesterol turnover during the first four months of administration. This treatment time also reduced amyloid burden and microglia activation in the cortex and subiculum of 5XFAD mice as well as protein levels of amyloid precursor protein and the expression of several genes involved in inflammatory response. However, mouse short-term memory and long-term spatial memory were impaired, whereas learning in the context-dependent fear test was improved. Additional four months of drug administration (a total of eight months of treatment) improved long-term spatial memory in the treated as compared to the untreated mice, further decreased amyloid-β content in 5XFAD brain, and also decreased the mortality rate among male mice. We propose a mechanistic model unifying the observed efavirenz effects. We suggest that CYP46A1 activation by efavirenz could be a new anti-Alzheimer's disease treatment and a tool to study and identify normal and pathological brain processes affected by cholesterol maintenance.

A novel approach for multiscale source analysis and modeling of epileptic spikes.

Multiscale recordings of brain electrical activity are often performed for presurgical evaluation in patients with focal epilepsy to facilitate the identification and precise delineation of the epileptogenic zone. However, data regarding the concordance of source models derived from recordings on different scales and their reciprocal validation against clinical outcomes remains scarce. This study aims to define a common source model that accurately depicts both scalp EEG and subdural EEG (ECoG) interictal spikes. To this purpose, the sLORETA method was applied to averaged spikes and source reconstruction results were implemented to outline the location and extent of an epileptic cortical patch. This estimated patch served as the basis for the spatiotemporal source model in a generative model of EEG. Spike activity was simulated on both scalp EEG and ECoG signal scales, with simulated traces resembling measured traces regarding their spatial distribution and amplitude compared to background. Simulated spikes served for the evaluation of source reconstruction with a known generator topography. The described setup allows for the validation and, ultimately, for the refinement of source reconstruction methods. It provides novel insights towards a thorough understanding of physiological and pathological brain processes and their representation in neuroelectric measurements.

MicroRNAs: Novel Mechanism Involved in the Pathogenesis of Microwave Exposure on Rats' Hippocampus.

Microwave-induced adverse health outcomes have been gaining much attention in recent years. The hippocampus is sensitive and vulnerable to microwave exposure. Studies from our group and others showed that microwave-induced structural and functional injury of hippocampus, accompanied with alteration of gene and protein expression. It has been demonstrated that microRNAs (miRNAs) were involved in the physiological and pathological processes of brain. In this study, the miRNAs expression profiles of microwave-exposed hippocampus were detected by microarray analysis and verified by real-time polymerase chain reaction (PCR). At 7 days after 30 mW/cm(2) microwave exposure, the expression of 12 miRNAs increased, while other 70 miRNAs decreased in rats' hippocampus. However, most of miRNAs restored to normal levels at 14 days after exposure, only two upregulated miRNAs and 14 downregulated miRNAs were detected. Gene transcription, neuroprotection and receptors function related target genes were predicated by miRDB, miRbase and miRanda. Moreover, these differentially expressed miRNAs were involved in brain-related signaling pathways, such as synaptic vesicle cycle, long-term depression, calcium signaling and neurotrophin signaling pathways. In conclusion, we successfully characterized the miRNA profiles in microwave-exposed hippocampus, and that will be helpful to clarify the molecular mechanism and provide potential therapeutic targets.

Windowed correlation: a suitable tool for providing dynamic fMRI-based functional connectivity neurofeedback on task difficulty.

The goal of neurofeedback training is to provide participants with relevant information on their ongoing brain processes in order to enable them to change these processes in a meaningful way. Under the assumption of an intrinsic brain-behavior link, neurofeedback can be a tool to guide a participant towards a desired behavioral state, such as a healthier state in the case of patients. Current research in clinical neuroscience regarding the most robust indicators of pathological brain processes in psychiatric and neurological disorders indicates that fMRI-based functional connectivity measures may be among the most important biomarkers of disease. The present study therefore investigated the general potential of providing fMRI neurofeedback based on functional correlations, computed from short-window time course data at the level of single task periods. The ability to detect subtle changes in task performance with block-wise functional connectivity measures was evaluated based on imaging data from healthy participants performing a simple motor task, which was systematically varied along two task dimensions representing two different aspects of task difficulty. The results demonstrate that fMRI-based functional connectivity measures may provide a better indicator for an increase in overall (motor) task difficulty than activation level-based measures. Windowed functional correlations thus seem to provide relevant and unique information regarding ongoing brain processes, which is not captured equally well by standard activation level-based neurofeedback measures. Functional connectivity markers, therefore, may indeed provide a valuable tool to enhance and monitor learning within an fMRI neurofeedback setup.

Environment and Brain Plasticity: Towards an Endogenous Pharmacotherapy

Brain plasticity refers to the remarkable property of cerebral neurons to change their structure and function in response to experience, a fundamental theoretical theme in the field of basic research and a major focus for neural rehabilitation following brain disease. While much of the early work on this topic was based on deprivation approaches relying on sensory experience reduction procedures, major advances have been recently obtained using the conceptually opposite paradigm of environmental enrichment, whereby an enhanced stimulation is provided at multiple cognitive, sensory, social, and motor levels. In this survey, we aim to review past and recent work concerning the influence exerted by the environment on brain plasticity processes, with special emphasis on the underlying cellular and molecular mechanisms and starting from experimental work on animal models to move to highly relevant work performed in humans. We will initiate introducing the concept of brain plasticity and describing classic paradigmatic examples to illustrate how changes at the level of neuronal properties can ultimately affect and direct key perceptual and behavioral outputs. Then, we describe the remarkable effects elicited by early stressful conditions, maternal care, and preweaning enrichment on central nervous system development, with a separate section focusing on neurodevelopmental disorders. A specific section is dedicated to the striking ability of environmental enrichment and physical exercise to empower adult brain plasticity. Finally, we analyze in the last section the ever-increasing available knowledge on the effects elicited by enriched living conditions on physiological and pathological aging brain processes.