The Nicotinic Acetylcholine Receptor and Its Pentameric Homologs: Toward an Allosteric Mechanism of Signal Transduction at the Atomic Level.

The nicotinic acetylcholine receptor has served, since its biochemical identification in the 1970s, as a model of an allosteric ligand-gated ion channel mediating signal transition at the synapse. In recent years, the application of X-ray crystallography and high-resolution cryo-electron microscopy, together with molecular dynamic simulations of nicotinic receptors and homologs, have opened a new era in the understanding of channel gating by the neurotransmitter. They reveal, at atomic resolution, the diversity and flexibility of the multiple ligand-binding sites, including recently discovered allosteric modulatory sites distinct from the neurotransmitter orthosteric site, and the conformational dynamics of the activation process as a molecular switch linking these multiple sites. The model emerging from these studies paves the way for a new pharmacology based, first, upon the occurrence of an original mode of indirect allosteric modulation, distinct from a steric competition for a single and rigid binding site, and second, the design of drugs that specifically interact with privileged conformations of the receptor such as agonists, antagonists, and desensitizers. Research on nicotinic receptors is still at the forefront of understanding the mode of action of drugs on the nervous system.

Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes.

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

Human prefrontal cortex gene regulatory dynamics from gestation to adulthood at single-cell resolution.

Human brain development is underpinned by cellular and molecular reconfigurations continuing into the third decade of life. To reveal cell dynamics orchestrating neural maturation, we profiled human prefrontal cortex gene expression and chromatin accessibility at single-cell resolution from gestation to adulthood. Integrative analyses define the dynamic trajectories of each cell type, revealing major gene expression reconfiguration at the prenatal-to-postnatal transition in all cell types followed by continuous reconfiguration into adulthood and identifying regulatory networks guiding cellular developmental programs, states, and functions. We uncover links between expression dynamics and developmental milestones, characterize the diverse timing of when cells acquire adult-like states, and identify molecular convergence from distinct developmental origins. We further reveal cellular dynamics and their regulators implicated in neurological disorders. Finally, using this reference, we benchmark cell identities and maturation states in organoid models. Together, this captures the dynamic regulatory landscape of human cortical development.

TRIM71 mutations cause a neurodevelopmental syndrome featuring ventriculomegaly and hydrocephalus.

Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.

In vivo base editing of a pathogenic Eif2b5 variant improves vanishing white matter phenotypes in mice.

Vanishing white matter (VWM) is a fatal leukodystrophy caused by recessive mutations in subunits of the eukaryotic translation initiation factor 2B. Currently, there are no effective therapies for VWM. Here, we assessed the potential of adenine base editing to correct human pathogenic VWM variants in mouse models. Using adeno-associated viral vectors, we delivered intein-split adenine base editors into the cerebral ventricles of newborn VWM mice, resulting in 45.9% ± 5.9% correction of the Eif2b5R191H variant in the cortex. Treatment slightly increased mature astrocyte populations and partially recovered the integrated stress response (ISR) in female VWM animals. This led to notable improvements in bodyweight and grip strength in females; however, locomotor disabilities were not rescued. Further molecular analyses suggest that more precise editing (i.e., lower rates of bystander editing) as well as more efficient delivery of the base editors to deep brain regions and oligodendrocytes would have been required for a broader phenotypic rescue. Our study emphasizes the potential, but also identifies limitations, of current in vivo base-editing approaches for the treatment of VWM or other leukodystrophies.

Cryptic mutations of PLC family members in brain disorders: recent discoveries and a deep-learning-based approach.

Phospholipase C (PLC) is an essential isozyme involved in the phosphoinositide signalling pathway, which maintains cellular homeostasis. Gain- and loss-of-function mutations in PLC affect enzymatic activity and are therefore associated with several disorders. Alternative splicing variants of PLC can interfere with complex signalling networks associated with oncogenic transformation and other diseases, including brain disorders. Cells and tissues with various mutations in PLC contribute different phosphoinositide signalling pathways and disease progression, however, identifying cryptic mutations in PLC remains challenging. Herein, we review both the mechanisms underlying PLC regulation of the phosphoinositide signalling pathway and the genetic variation of PLC in several brain disorders. In addition, we discuss the present challenges associated with the potential of deep-learning-based analysis for the identification of PLC mutations in brain disorders.

Modulation of autophagy by melatonin and its receptors: implications in brain disorders.

Autophagy plays a crucial role in maintaining neuronal homeostasis and function, and its disruption is linked to various brain diseases. Melatonin, an endogenous hormone that primarily acts through MT1 and MT2 receptors, regulates autophagy via multiple pathways. Growing evidence indicates that melatonin's ability to modulate autophagy provides therapeutic and preventive benefits in brain disorders, including neurodegenerative and affective diseases. In this review, we summarize the key mechanisms by which melatonin affects autophagy and explore its therapeutic potential in the treatment of brain disorders.

Developing Peripheral Biochemical Biomarkers of Brain Disorders: Insights from Zebrafish Models.

High prevalence of human brain disorders necessitates development of the reliable peripheral biomarkers as diagnostic and disease-monitoring tools. In addition to clinical studies, animal models markedly advance studying of non-brain abnormalities associated with brain pathogenesis. The zebrafish (Danio rerio) is becoming increasingly popular as an animal model organism in translational neuroscience. These fish share some practical advantages over mammalian models together with high genetic homology and evolutionarily conserved biochemical and neurobehavioral phenotypes, thus enabling large-scale modeling of human brain diseases. Here, we review mounting evidence on peripheral biomarkers of brain disorders in zebrafish models, focusing on altered biochemistry (lipids, carbohydrates, proteins, and other non-signal molecules, as well as metabolic reactions and activity of enzymes). Collectively, these data strongly support the utility of zebrafish (from a systems biology standpoint) to study peripheral manifestations of brain disorders, as well as highlight potential applications of biochemical biomarkers in zebrafish models to biomarker-based drug discovery and development.

Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders.

A variety of neurological and psychiatric disorders have recently been shown to be highly associated with the abnormal development and function of oligodendrocytes (OLs) and interneurons. OLs are the myelin-forming cells in the central nervous system (CNS), while interneurons are important neural types gating the function of excitatory neurons. These two types of cells are of great significance for the establishment and function of neural circuits, and they share similar developmental origins and transcriptional architectures, and interact with each other in multiple ways during development. In this review, we compare the similarities and differences in these two cell types, providing an important reference and further revealing the pathogenesis of related brain disorders.

Assessment of Mannitol-Induced Chronic Blood-Brain Barrier Dysfunction In Vivo Using Magnetic Resonance.

The blood-brain barrier (BBB) is essential for protection and plays a crucial role in chronic neurological disorders like small-vessel disease and Alzheimer's disease. Its complexity poses significant challenges for effective diagnostics and treatments, highlighting the need for novel animal models and comprehensive BBB dysfunction studies. This study investigates chronic BBB dysfunction induction using osmotic disruption via mannitol in healthy adult male Sprague Dawley rats over 12 weeks. Group 1 received 1 bolus/week (2.0 g/kg), Group 2 received 3 boluses/week (1.5 g/kg), and Group 3 received 3 boluses/week (2.5 g/kg). BBB dysfunction was assessed using gadolinium (Gd) infusion and MRI to evaluate location, severity, evolution, and persistence. MR spectroscopy (MRS) examined the brain metabolism changes due to intravenous mannitol, with T2-weighted MRI assessing brain lesions. Biomarkers of neuroinflammation were analyzed in the highest mannitol dose group. Our data show chronic BBB dysfunction primarily in the cortex, hippocampus, and striatum, but not in the corpus callosum of rats under periodic mannitol dosing in groups 1 and 2. MRS identified a distinctive metabolite signature, including changes in alanine, choline, and N-acetyl aspartate in the striatum of Group 1. No significant differences were found in the serum levels of all pro- and anti-inflammatory cytokines analyzed in the high-dose Group 3. This study underscores the feasibility and implications of using osmotic disruption to model chronic BBB dysfunction, offering insights for future neuroprotection and therapeutic strategies research.

Impact of TNF and IL-33 Cytokines on Mast Cells in Neuroinflammation.

Mast cells (MCs) are derived from hematopoietic progenitors, mature in vascularized tissues, and participate in innate and acquired immunity. Neuroinflammation is a highly debated topic in the biomedical literature; however, the impact of tumor necrosis factor (TNF) and IL-33 on MCs in the brain has not been widely addressed. MCs can be activated by IgE binding to FcεRI, as well as by different antigens. After activation, MCs mediate various immunological and inflammatory responses through TNF and IL-33. TNF has two receptors: TNFR1, a p55 molecule, and TNFR2, a p75 molecule. This cytokine is the only one of its kind to be stored in the granules of MCs and can also be generated by de novo synthesis via mRNA. In the central nervous system (CNS), TNF is produced almost exclusively by microglial cells, neurons, astrocytes, and, minimally, by endothelial cells. After its release into brain tissue, TNF rapidly induces the adhesion molecules endothelial leukocyte adhesion molecule 1 (ELAM-1), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) in endothelial cells. TNF causes the chemoattraction of neutrophils by inducing several molecules, including CXC chemokines (IL-8). Both MCs and microglial cells act as a primary barrier against foreign molecules in the CNS, producing pro-inflammatory cytokines such as IL-33. IL-33 belongs to the IL-1 family, is activated through the ST2L/IL1-RAcP receptor complex, and mediates both the innate and adaptive immune response. IL-33 is a nuclear transcription factor expressed in the brain, where it induces pro-inflammatory cytokines (TNF and IL-1) and chemokines (CCL2, CCL3, CCL5, and CXCL10). Therefore, MCs and microglia in the CNS are a source of pro-inflammatory cytokines, including TNF and IL-33, that mediate many brain diseases. The inhibition of TNF and IL-33 may represent a new therapeutic approach that could complement existing neuroinflammatory therapies.

Natural Products and Their Neuroprotective Effects in Degenerative Brain Diseases: A Comprehensive Review.

As the global population ages, the incidence of neurodegenerative diseases such as Alzheimer's and Parkinson's is rapidly rising. These diseases present a significant public health challenge, as they severely impair cognitive and motor functions, ultimately leading to a substantial reduction in quality of life and placing a heavy burden on healthcare systems worldwide. Although several therapeutic agents have been developed to manage the symptoms of these diseases, their effectiveness is often limited, and there remains an urgent need for preventive strategies. Growing evidence indicates that bioactive compounds from natural products possess neuroprotective properties through antioxidant and anti-inflammatory effects, modulating key pathways such as phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and brain-derived neurotrophic factor-tropomyosin receptor kinase B-cAMP response element-binding protein (BDNF-TrkB-CREB), which are crucial for neuronal survival. These compounds may also reduce amyloid-beta and tau pathology, as well as enhance cholinergic neurotransmission by inhibiting acetylcholinesterase activity. By targeting oxidative stress, neuroinflammation, and neurodegeneration, natural products offer a promising approach for both prevention and treatment. These findings suggest that natural products may be promising for preventing and treating neurodegenerative diseases. This review aims to explore the pathogenesis of neurodegenerative diseases, the limitations of current therapies, and the potential role of natural products as therapeutic agents.

Inferring the genetic relationship between brain imaging-derived phenotypes and risk of complex diseases by Mendelian randomization and genome-wide colocalization.

Observational studies consistently disclose brain imaging-derived phenotypes (IDPs) as critical markers for early diagnosis of both brain disorders and cardiovascular diseases. However, it remains unclear about the shared genetic landscape between brain IDPs and the risk of brain disorders and cardiovascular diseases, restricting the applications of potential diagnostic techniques through brain IDPs. Here, we reported genetic correlations and putative causal relationships between 921 brain IDPs, 20 brain disorders and six cardiovascular diseases by leveraging their large-scale genome-wide association study (GWAS) summary statistics. Applications of Mendelian randomization (MR) identified significant putative causal effects of multiple region-specific brain IDPs in relation to the increased risks for amyotrophic lateral sclerosis (ALS), major depressive disorder (MDD), autism spectrum disorder (ASD) and schizophrenia (SCZ). We also found brain IDPs specifically from temporal lobe as a putatively causal consequence of hypertension. The genome-wide colocalization analysis identified three genomic regions in which MDD, ASD and SCZ colocalized with the brain IDPs, and two novel SNPs to be associated with ASD, SCZ, and multiple brain IDPs. Furthermore, we identified a list of candidate genes involved in the shared genetics underlying pairs of brain IDPs and MDD, ASD, SCZ, ALS and hypertension. Our results provide novel insights into the genetic relationships between brain disorders and cardiovascular diseases and brain IDP, which may server as clues for using brain IDPs to predict risks of diseases.

Angiotensin-converting enzymes as druggable features of psychiatric and neurodegenerative disorders.

The renin-angiotensin system (RAS) plays essential roles in maintaining peripheral cardiovascular homeostasis, with its potential roles in the brain only being recognized more recently. Angiotensin-I-converting enzyme (ACE) is the main component of the RAS, and it has been implicated in various disorders of the brain. ACE and other RAS components, including the related enzyme ACE2, angiotensin peptides and their respective receptors, can participate in the pathological state, as well as with potential to contribute to neuroprotection and/or to complement existing treatments for psychiatric illness. In this narrative review, we aimed to identify the main studies describing the functions of the RAS and ACEs in the brain and their association with brain disorders. These include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, psychiatric illnesses such as schizophrenia, bipolar disorder, and depression. We also discuss the possible association of a functional polymorphism of the ACE gene with these brain diseases and the relevance of the neuroprotective and anti-inflammatory properties of ACE inhibitors (ACEis) and angiotensin receptor blockers (ARBs). Based on this, we conclude that there is significant potential value to the inclusion of ACEis and/or ARBs as a novel integrated approach for the treatment of various disorders of the brain, and particularly for psychiatric illness.

Significant heterogeneity in structural asymmetry of the habenula in the human brain: A systematic review and meta-analysis.

Understanding the evolutionarily conserved feature of functional laterality in the habenula has been attracting attention due to its potential role in human cognition and neuropsychiatric disorders. Deciphering the structure of the human habenula remains to be challenging, which resulted in inconsistent findings for brain disorders. Here, we present a large-scale meta-analysis of the left-right differences in the habenular volume in the human brain to provide a clearer picture of the habenular asymmetry. We searched PubMed, Web of Science, and Google Scholar for articles that reported volume data of the bilateral habenula in the human brain, and assessed the left-right differences. We also assessed the potential effects of several moderating variables including the mean age of the participants, magnetic field strengths of the scanners and different disorders by using meta-regression and subgroup analysis. In total 52 datasets (N = 1427) were identified and showed significant heterogeneity in the left-right differences and the unilateral volume per se. Moderator analyses suggested that such heterogeneity was mainly due to different MRI scanners and segmentation approaches used. While inversed asymmetry patterns were suggested in patients with depression (leftward) and schizophrenia (rightward), no significant disorder-related differences relative to healthy controls were found in either the left-right asymmetry or the unilateral volume. This study provides useful data for future studies of brain imaging and methodological developments related to precision habenula measurements, and also helps to further understand potential roles of the habenula in various disorders.

Parkinson's Disease Risk and Hyperhomocysteinemia: The Possible Link.

Parkinson's disease (PD) is one of the most common degenerative brain disorders caused by the loss of dopaminergic neurons in the substantia nigra (SN). Lewy bodies and -synuclein accumulation in the SN are hallmarks of the neuropathology of PD. Due to lifestyle changes and prolonged L-dopa administration, patients with PD frequently have vitamin deficiencies, especially folate, vitamin B6, and vitamin B12. These disorders augment circulating levels of Homocysteine with the development of hyperhomocysteinemia, which may contribute to the pathogenesis of PD. Therefore, this review aimed to ascertain if hyperhomocysteinemia may play a part in oxidative and inflammatory signaling pathways that contribute to PD development. Hyperhomocysteinemia is implicated in the pathogenesis of neurodegenerative disorders, including PD. Hyperhomocysteinemia triggers the development and progression of PD by different mechanisms, including oxidative stress, mitochondrial dysfunction, apoptosis, and endothelial dysfunction. Particularly, the progression of PD is linked with high inflammatory changes and systemic inflammatory disorders. Hyperhomocysteinemia induces immune activation and oxidative stress. In turn, activated immune response promotes the development and progression of hyperhomocysteinemia. Therefore, hyperhomocysteinemia-induced immunoinflammatory disorders and abnormal immune response may aggravate abnormal immunoinflammatory in PD, leading to more progression of PD severity. Also, inflammatory signaling pathways like nuclear factor kappa B (NF-κB) and nod-like receptor pyrin 3 (NLRP3) inflammasome and other signaling pathways are intricate in the pathogenesis of PD. In conclusion, hyperhomocysteinemia is involved in the development and progression of PD neuropathology either directly via induction degeneration of dopaminergic neurons or indirectly via activation of inflammatory signaling pathways.

Comparative Analysis of Behavioral Reactions and Morphological Changes in the Rat Brain After Exposure to Ionizing Radiation with Different Physical Characteristics.

The aim of this research was to study behavioral reactions and morphological changes in the brain of adult female Sprague Dawley rats after exposure to 170 MeV and 70 MeV protons and gamma radiation (60Co) at a dose of 1 Gy. The analysis of the behavioral reactions in the T-maze showed that exposure to ionizing radiation with different LETs led to an increase in number of repeated entries into the arms of the maze in the spontaneous alternation test. In the Open Field test a decrease in overall motor activity in the group of irradiated animals (70 MeV protons at the Bragg peak) was observed. A decrease in the number of standing positions was seen in all groups of irradiated animals. Morphological analysis showed the development of early amyloidosis, autolysis of the ependymal layer, an increase in the number of neurodegenerative changes in various structures of the brain, and the development of neuronal hypertrophy on the 30th day after irradiation in the cerebellum and hippocampal hilus. Exposure to protons at a dose of 1 Gy leads to the development of structural and functional disorders of the central nervous system of animals on the 30th day after irradiation. These data indicate a damage of short-term memory, a decrease in motor activity and exploratory behavior of animals. With an increase in LET, there is an increase in the number of amyloid plaques in the forebrain of rats, autolysis of the ependymal layer of the ventricles, and the development of dystrophic changes. Investigations of behavioral reactions and morphological changes in various parts of the brain of adult rats on the 30th day after influence of ionizing radiation with different physical characteristics at a dose of 1 Gy. Various negative patho-morphological and cognitive-behavioral changes observed.

Cannabidiol for the Treatment of Brain Disorders: Therapeutic Potential and Routes of Administration.

The use of cannabidiol (CBD) for treating brain disorders has gained increasing interest. While the mechanism of action of CBD in these conditions is still under investigation, CBD has been shown to affect numerous different drug targets in the brain that are involved in brain disorders. Here we review the preclinical and clinical evidence on the potential therapeutic use of CBD in treating various brain disorders. Moreover, we also examine various drug delivery approaches that have been applied to CBD. Due to the slow absorption and low bioavailability with the current oral CBD therapy, more efficient routes of administration to bypass hepatic metabolism, particularly pulmonary delivery, should be considered. Comparison of pharmacokinetic studies of different delivery routes highlight the advantages of intranasal and inhalation drug delivery over other routes of administration (oral, injection, sublingual, buccal, and transdermal) for treating brain disorders. These two routes of delivery, being non-invasive and able to achieve fast absorption and increase bioavailability, are attracting increasing interest for CBD applications, with more research and development expected in the near future.

A vision of 14 T MR for fundamental and clinical science.

OBJECTIVE: We outline our vision for a 14 Tesla MR system. This comprises a novel whole-body magnet design utilizing high temperature superconductor; a console and associated electronic equipment; an optimized radiofrequency coil setup for proton measurement in the brain, which also has a local shim capability; and a high-performance gradient set. RESEARCH FIELDS: The 14 Tesla system can be considered a 'mesocope': a device capable of measuring on biologically relevant scales. In neuroscience the increased spatial resolution will anatomically resolve all layers of the cortex, cerebellum, subcortical structures, and inner nuclei. Spectroscopic imaging will simultaneously measure excitatory and inhibitory activity, characterizing the excitation/inhibition balance of neural circuits. In medical research (including brain disorders) we will visualize fine-grained patterns of structural abnormalities and relate these changes to functional and molecular changes. The significantly increased spectral resolution will make it possible to detect (dynamic changes in) individual metabolites associated with pathological pathways including molecular interactions and dynamic disease processes. CONCLUSIONS: The 14 Tesla system will offer new perspectives in neuroscience and fundamental research. We anticipate that this initiative will usher in a new era of ultra-high-field MR.

Pathophysiological Roles of Auxiliary Calcium Channel α2δ Subunits.

α2δ proteins serve as auxiliary subunits of voltage-gated calcium channels, which are essential components of excitable cells such as skeletal and heart muscles, nerve cells of the brain and the peripheral nervous system, as well as endocrine cells. Over the recent years, α2δ proteins have been identified as critical regulators of synaptic functions, including the formation and differentiation of synapses. These functions require signalling mechanisms which are partly independent of calcium channels. Hence, in light of these features it is not surprising that the genes encoding for the four α2δ isoforms have recently been linked to neurological and neurodevelopmental disorders including epilepsy, autism spectrum disorders, schizophrenia, and depressive and bipolar disorders. Despite the increasing number of identified disease-associated mutations, the underlying pathophysiological mechanisms are only beginning to emerge. However, a thorough understanding of the pathophysiological role of α2δ proteins ideally serves two purposes: first, it will contribute to our understanding of general pathological mechanisms in synaptic disorders. Second, it may support the future development of novel and specific treatments for brain disorders. In this context, it is noteworthy that the antiepileptic and anti-allodynic drugs gabapentin and pregabalin both act via binding to α2δ proteins and are among the top sold drugs for treating neuropathic pain. In this book chapter, we will discuss recent developments in our understanding of the functions of α2δ proteins, both as calcium channel subunits and as independent regulatory entities. Furthermore, we present and summarize recently identified and likely pathogenic mutations in the genes encoding α2δ proteins and discuss potential underlying pathophysiological consequences at the molecular and structural level.