Pathophysiology Of Neurological Disorders Research Articles

Darier disease is associated with neurodegenerative disorders and epilepsy

Darier disease (DD) is a rare monogenetic skin disorder with limited data on its potential association with neurological disorders. This study aimed to investigate the association between DD and neurological disorders, specifically Parkinson's disease, dementias, and epilepsy. Using Swedish national registers in a period spanning between 1977 and 2013, 935 individuals with DD were compared with up to 100 comparison individuals each, randomly selected from the general population based on birth year, sex, and county of residence at the time of the first diagnosis of DD. Individuals with DD had increased risks of being diagnosed with Parkinson's disease (RR 2.1, CI 1.1; 4.4), vascular dementia (RR 2.1, CI 1.0; 4.2), and epilepsy, (RR 2.5, CI 1.8; 3.5). No association of DD with other dementias were detected. This study demonstrates a new association between DD and neurodegenerative disorders and epilepsy, underlining the need for increased awareness, interdisciplinary collaboration, and further research to understand the underlying mechanisms. Early identification and management of neurological complications in DD patients could improve treatment strategies and patient outcomes. The findings also highlight the role of SERCA2 in the pathophysiology of neurological disorders, offering new targets for future research and potentials for novel treatments.

Modulation of neural circuits by melatonin in neurodegenerative and neuropsychiatric disorders.

Neurodegenerative and neuropsychiatric disorders are two broad categories of neurological disorders characterized by progressive impairments in movement and cognitive functions within the central and peripheral nervous systems, and have emerged as a significant cause of mortality. Oxidative stress, neuroinflammation, and neurotransmitter imbalances are recognized as prominent pathogenic factors contributing to cognitive deficits and neurobehavioral anomalies. Consequently, preventing neurodegenerative and neuropsychiatric diseases has surfaced as a pivotal challenge in contemporary public health. This review explores the investigation of neurodegenerative and neuropsychiatric disorders using both synthetic and natural bioactive compounds. A central focus lies on melatonin, a neuroregulatory hormone secreted by the pineal gland in response to light-dark cycles. Melatonin, an amphiphilic molecule, assumes multifaceted roles, including scavenging free radicals, modulating energy metabolism, and synchronizing circadian rhythms. Noteworthy for its robust antioxidant and antiapoptotic properties, melatonin exhibits diverse neuroprotective effects. The inherent attributes of melatonin position it as a potential key player in the pathophysiology of neurological disorders. Preclinical and clinical studies have demonstrated melatonin's efficacy in alleviating neuropathological symptoms across neurodegenerative and neuropsychiatric conditions (depression, schizophrenia, bipolar disorder, and autism spectrum disorder). The documented neuroprotective prowess of melatonin introduces novel therapeutic avenues for addressing neurodegenerative and psychiatric disorders. This comprehensive review encompasses many of melatonin's applications in treating diverse brain disorders. Despite the strides made, realizing melatonin's full neuroprotective potential necessitates further rigorous clinical investigations. By unravelling the extended neuroprotective benefits of melatonin, future studies promise to deepen our understanding and augment the therapeutic implications against neurological deficits.

Targeting Gut Dysbiosis and Microbiome Metabolites for the Development of Therapeutic Modalities for Neurological Disorders.

The gut microbiota, composed of numerous species of microbes, works in synergy with the various organ systems in the body to bolster our overall health and well-being. The most well-known function of the gut microbiome is to facilitate the metabolism and absorption of crucial nutrients, such as complex carbohydrates, while also generating vitamins. In addition, the gut microbiome plays a crucial role in regulating the functioning of the central nervous system (CNS). Host genetics, including specific genes and single nucleotide polymorphisms (SNPs), have been implicated in the pathophysiology of neurological disorders, including Parkinson's disease (PD), Alzheimer's disease (AD), and autism spectrum disorder (ASD). The gut microbiome dysbiosis also plays a role in the pathogenesis of these neurodegenerative disorders, thus perturbing the gut-brain axis. Overproduction of certain metabolites synthesized by the gut microbiome, such as short-chain fatty acids (SCFAs) and p-cresyl sulfate, are known to interfere with microglial function and trigger misfolding of alpha-synuclein protein, which can build up inside neurons and cause damage. By determining the association of the gut microbiome and its metabolites with various diseases, such as neurological disorders, future research will pave the way for the development of effective preventive and treatment modalities.

Role of glymphatic system in neurological diseases - literature review

Abstract Introduction: The glymphatic system is the equivalent of the lymphatic system in the brain. This system is responsible for the exchange of metabolism waste products between the cerebrospinal fluid and the interstitial fluid. The glymphatic system functions mainly during sleep, and this is when the removal of interstitial metabolism waste products take place. A proper diet and physical activity are also needed for the glymphatic system to work effectively. Abnormal function of the glymphatic system can contribute to the development of diseases of the central nervous system, including neurodegenerative diseases and migraine. Aim of the study: The aim of our study is to review the latest knowledge linking the glymphatic system with the pathogenesis of selected neurological diseases and other lifestyle-related factors such as sleep, diet and physical activity. The study included Alzheimer’s disease, Parkinson’s disease, migraines and ischemic stroke. Materials and methods: We have reviewed the literature available in the pubmed database using keywords: “glymphatic system”; “aquaporin-4”; “Alzheimer’s disease”; “Parkinson’s disease”; “migraines”; “sleep” Conclusions: The studies discussed here show a clear correlation between the glymphatic system and neurological diseases. The glymphatic system may definitely be involved in the pathophysiology of neurological disorders. A thorough investigation of this issue will help uncover potentially new strategies for the prevention and treatment of neurological diseases. Key words: glymphatic system; aquaporin-4; Alzheimer’s disease; Parkinson’s disease; migraine; sleep

Amelioration of Parkinson's disease by pharmacological inhibition and knockdown of redox sensitive TRPC5 channels: Focus on mitochondrial health

AimsTransient receptor potential canonical 5 (TRPC5) channels are redox-sensitive cation-permeable channels involved in temperature and mechanical sensation. Increased expression and over-activation of these channels has been implicated in several central nervous system disorders such as epilepsy, depression, traumatic brain injury, anxiety, Huntington's disease and stroke. TRPC5 channel activation causes increased calcium influx which in turn activates numerous downstream signalling pathways involved in the pathophysiology of neurological disorders. Therefore, we hypothesized that pharmacological blockade and knockdown of TRPC5 channels could attenuate the behavioural deficits and molecular changes seen in CNS disease models such as MPTP/MPP+ induced Parkinson's disease (PD). Materials and methodsIn the present study, PD was induced after bilateral intranigral infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the Sprague Dawley rats. Additionally, SH-SY5Y neurons were exposed to 1-methyl-4-phenylpyridinium (MPP+) to further determine the role of TRPC5 channels in PD. Key findingsWe used clemizole hydrochloride, a potent TRPC5 channel blocker, to reverse the behavioural deficits, molecular changes and biochemical parameters in MPTP/MPP+-induced PD. Furthermore, knockdown of TRPC5 expression using siRNA also closely phenocopies these effects. We further observed restoration of tyrosine hydroxylase levels and improved mitochondrial health following clemizole treatment and TRPC5 knockdown. These changes were accompanied by diminished calcium influx, reduced levels of reactive oxygen species and decreased apoptotic signalling in the PD models. SignificanceThese findings collectively suggest that increased expression of TRPC5 channels is a potential risk factor for PD and opens a new therapeutic window for the development of pharmacological agents targeting neurodegeneration and PD.

Insights into the Hippocampus Proteomics Reveal Epigenetic Properties of Walnut-Derived Peptides in a Low-Grade Neuroinflammation Model.

Epigenetic mechanisms that dysregulate gene expressions may play a significant role in the development of neurological disorders. However, whether peptides can modulate epigenetic mechanisms remains elusive. This work aimed to investigate the impact of pretreatment with walnut-derived peptides─WHP and YVLLPSPK─on DNA methylation in a low-grade neuroinflammation model. The enriched KEGG pathways included oxidative phosphorylation, riboflavin metabolism, ribosome, and pyrimidine metabolism, which are associated with methylation modification by oral administration of YVLLPSPK in mice with scopolamine-induced cognitive deficits. Furthermore, when THP-1 cells (human acute monocytic leukemia cell line) were exposed to lipopolysaccharide (LPS)-induced inflammation responses, both WHP and YVLLPSPK markedly inhibited the level of Il-6 to 2.05 ± 0.76 and 1.29 ± 0.19 (p < 0.05) and also declined the mRNA expression of Mcp-1 to 1.64 ± 0.02 and 3.29 ± 1.21 (p < 0.01), respectively. Meanwhile, YVLLPSPK decreased the activities of DNA methyltransferases (DNMTs) to 1.03 ± 0.02 and 1.20 ± 0.31 (p < 0.05) based on Dnmt3b and Tet2, respectively. The results indicated that YVLLPSPK modulated DNA methylation in embryonic and neural precursor cells in creating new methylation patterns. Further trials are needed to assess the mechanisms underlying DNA methylation changes through peptides in the pathophysiology of neurological disorders.

Nutritional interventions for the prevention and treatment of neurological disorders such as anxiety, bipolar disorder, depression, epilepsy, multiple sclerosis, and schizophrenia

Neurological disorders are a significant cause of mortality and disability across the world. The current aging population and population expansion have seen an increase in the prevalence of neurological and psychiatric disorders such as anxiety, bipolar disorder, depression, epilepsy, multiple sclerosis and schizophrenia. These pose a significant societal burden, especially in low - and middle-income countries. Many neurological disorders have complex mechanisms and lack definitive cures; thus, improving our understanding of them is essential. The pathophysiology of neurological disorders often includes inflammation, mitochondrial dysfunction and oxidative stress. Oxidative stress processes, especially the generation of reactive oxygen species, are key mechanisms in the development of neurological disorders. Oxidative stress refers to an imbalance between the production of reactive oxygen species and antioxidants that can counteract them. Through their impacts on the pathophysiology of neurological disorders, nutrients with anti-inflammatory, neuroprotective and antioxidative properties have been suggested to prevent or mitigate these disorders. Certain vitamins, minerals, polyphenols and flavonoids may have therapeutic effects as adjuvant treatments for neurological disorders. Diet quality is also a risk factor for some neurological and psychiatric disorders and addressing nutritional deficiencies may alleviate symptoms. Therefore, optimizing nutritional intake may represent a potential treatment or prevention strategy. This review summarizes a selection of promising nutrients for the prevention and amelioration of neurological disorders to provide a summary for scientists, clinicians and patients, which may improve understanding of the potential benefits of nutrients in the treatment of neurological disorders.

Brain Connectomics.

A central tenet of modern neuroscience is the conceptualization of the brain as a collection of complex networks or circuits with a shift away from traditional "localizationist" theories. Connectomics seeks to unravel these brain networks and their role in the pathophysiology of neurologic diseases. This article discusses the science of connectomics with the examples of its potential role in clinical medicine and neuromodulation in multiple disorders, such as essential tremor, Parkinson's disease, obsessive-compulsive disorder, and epilepsy.

Is there a role of epigenetics in gut microbiome and neurological disorders?

Cross-talk between gut microbiota and the nervous system in the pathophysiology of neurological diseases has become a recent focus of interest. The underlying mechanisms are complex, and we suggest that they might involve gut bacterial metabolite-induced epigenetic modulations of neurodegenerative disorders. Advances in epigenetic techniques could provide the key to understanding the epigenetics of the gut-brain axis.

Basic considerations on magnesium in the management of neurocritical patients

Magnesium is an essential chemical element in human life. In the brain, it is physiologically responsible for a large number of processes involved in intracellular homeostasis, blood-brain barrier integrity, protein synthesis, neuronal proliferation, aging, and apoptosis. Considering that neurocritical care is a relatively new discipline in certain regions of the world and is an independent protective factor of neurological diseases in critical care, it is essential to disseminate basic concepts and utilities of tools that can positively impact the neurological disease burden. Magnesium and its use in neurocritical care are poorly understood. Therefore, this study aimed to review basic concepts regarding the physiology of magnesium in neurological dynamics, its role in the pathophysiology of neurological disorders, and the outcome of its use in the management of neurocritical illnesses.

Neuropharmacological investigation, ultra-high performance liquid chromatography analysis, and in silico studies of Phyla nodiflora.

The increasing burden of neurological disorders is becoming a worldwide health challenge and researchers are continuously struggling to cure them by utilizing the miraculous medicinal properties of plants. The crude methanolic extract of whole herb of Phyla nodiflora (Pn.Cr) was subjected to phytochemical, antioxidant and neuropharmacological assessment. The Pn.Cr was initially exposed to the in vitro examination for phytocomposition through ultra-high performance liquid chromatography (UHPLC). The Sprague Dawley rats were chronically administered with various doses (100, 200 and 300 mg/kg) of Pn.Cr for one month with subsequent exposure to neurobehavioral and biochemical experimentation. The Pn.Cr exhibited a dose-dependent anxiolytic effect (P < 0.05 in comparison to control) as rats preferred central, illuminated and open arm zones in open field (OFT), light/dark (L/D) and elevated plus maze (EPM) tests. Likewise, scopolamine-induced amnesia was noticeably reversed with P < 0.05 by Pn.Cr as animals showed improved spontaneous alternation, discrimination index and shorter escape latencies in Y-maze, novel object recognition (NOR) and Morris water maze (MWM) tests. Subsequently, in vivo enzymatic assays depicted the reduced acetylcholinesterase and malondialdehyde levels. The levels of oxidative stress combating enzymes (glutathione peroxidase and superoxide dismutase) were increased in a dose-dependent style. The UHPLC detected 22 phytocompounds were further investigated in silico studied to predict the interaction of blood-brain barrier (BBB) crossing phytocompounds with human acetylcholinesterase. The four BBB crossing phytocompounds belonging to flavonoids, chalcones and alkaloids showed possible interaction with the target enzyme. We found that the phytocompounds owned by Pn.Cr might be playing multiple roles in modulation of different pathways to hinder the pathophysiology of neurological disorders including anxiety and Alzheimer's disease.

NFIB induces functional astrocytes from human pluripotent stem cell-derived neural precursor cells mimicking in vivo astrogliogenesis.

The ability to generate astrocytes from human pluripotent stem cells (hPSCs) offers a promising cellular model to study the development and physiology of human astrocytes. The extant methods for generating functional astrocytes required long culture periods and there remained much ambiguityon whether such paradigms follow the innate developmental program. In this report, we provided an efficient and rapid method for generating physiologically functional astrocytes from hPSCs. Overexpressing the nuclear factor IB in hPSC-derived neural precursor cells induced a highly enriched astrocyte population in 2 weeks. RNA sequencing and functional analyses demonstrated progressive transcriptomic and physiological changes in the cells, resembling in vivo astrocyte development. Further analyses substantiated previous results and established the MAPK pathway necessary for astrocyte differentiation. Hence, this differentiation paradigm provides a prospective in vitro model for human astrogliogenesis studies and the pathophysiology of neurological diseases concerning astrocytes.

Can chronopharmacology improve the therapeutic management of neurological diseases?

The importance of circadian rhythm dysfunctions in the pathophysiology of neurological diseases has been highlighted recently. Chronopharmacology principles imply that tailoring the timing of treatments to the circadian rhythm of individual patients could optimize therapeutic management. According to these principles, chronopharmacology takes into account the individual differences in patients' clocks, the rhythmic changes in the organism sensitivity to therapeutic and side effects of drugs, and the predictable time variations of disease. This review examines the current literature on chronopharmacology of neurological diseases focusing its scope on epilepsy, Alzheimer and Parkinson diseases, and neuropathic pain, even if other neurological diseases could have been analyzed. While the results of the studies discussed in this review point to a potential therapeutic benefit of chronopharmacology in neurological diseases, the field is still in its infancy. Studies including a sufficiently large number of patients and measuring gold standard markers of the circadian rhythmicity are still needed to evaluate the beneficial effect of administration times over the 24-hour day but also of clock modulating drugs.

First evidence of altered microbiota and intestinal damage and their link to absence epilepsy in a genetic animal model, the WAG/Rij rat.

A large number of studies have highlighted the important role of the gut microbiota in the pathophysiology of neurological disorders, suggesting that its manipulation might serve as a treatment strategy. We hypothesized that the gut microbiota participates in absence seizure development and maintenance in the WAG/Rij rat model and tested this hypothesis by evaluating potential gut microbiota and intestinal alterations in the model, as well as measuring the impact of microbiota manipulation using fecal microbiota transplantation (FMT). Initially, gut microbiota composition and intestinal histology of WAG/Rij rats (a well-recognized genetic model of absence epilepsy) were studied at 1, 4, and 8 months of age in comparison to nonepileptic Wistar rats. Subsequently, in a second set of experiments, at 6 months of age, untreated Wistar or WAG/Rij rats treated with ethosuximide (ETH) were used as gut microbiota donors for FMT in WAG/Rij rats, and electroencephalographic (EEG) recordings were obtained over 4weeks. At the end of FMT, stool and gut samples were collected, absence seizures were measured on EEG recordings, and microbiota analysis and histopathological examinations were performed. Gut microbiota analysis showed differences in beta diversity and specific phylotypes at all ages considered and significant variances in the Bacteroidetes/Firmicutes ratio between Wistar and WAG/Rij rats. FMT, from both Wistar and ETH-treated WAG/Rij donors to WAG/Rij rats, significantly decreased the number and duration of seizures. Histological results indicated that WAG/Rij rats were characterized by intestinal villi disruption and inflammatory infiltrates already at 1 month of age, before seizure occurrence; FMT partially restored intestinal morphology while also significantly modifying gut microbiota and concomitantly reducing absence seizures. Our results demonstrate for the first time that the gut microbiota is modified and contributes to seizure occurrence in a genetic animal model of absence epilepsy and that its manipulation may be a suitable therapeutic target for absence seizure management.

GAMER MRI: Gated-attention mechanism ranking of multi-contrast MRI in brain pathology

IntroductionDuring the last decade, a multitude of novel quantitative and semiquantitative MRI techniques have provided new information about the pathophysiology of neurological diseases. Yet, selection of the most relevant contrasts for a given pathology remains challenging. In this work, we developed and validated a method, Gated-Attention MEchanism Ranking of multi-contrast MRI in brain pathology (GAMER MRI), to rank the relative importance of MR measures in the classification of well understood ischemic stroke lesions. Subsequently, we applied this method to the classification of multiple sclerosis (MS) lesions, where the relative importance of MR measures is less understood. MethodsGAMER MRI was developed based on the gated attention mechanism, which computes attention weights (AWs) as proxies of importance of hidden features in the classification. In the first two experiments, we used Trace-weighted (Trace), apparent diffusion coefficient (ADC), Fluid-Attenuated Inversion Recovery (FLAIR), and T1-weighted (T1w) images acquired in 904 acute/subacute ischemic stroke patients and in 6,230 healthy controls and patients with other brain pathologies to assess if GAMER MRI could produce clinically meaningful importance orders in two different classification scenarios. In the first experiment, GAMER MRI with a pretrained convolutional neural network (CNN) was used in conjunction with Trace, ADC, and FLAIR to distinguish patients with ischemic stroke from those with other pathologies and healthy controls. In the second experiment, GAMER MRI with a patch-based CNN used Trace, ADC and T1w to differentiate acute ischemic stroke lesions from healthy tissue. The last experiment explored the performance of patch-based CNN with GAMER MRI in ranking the importance of quantitative MRI measures to distinguish two groups of lesions with different pathological characteristics and unknown quantitative MR features. Specifically, GAMER MRI was applied to assess the relative importance of the myelin water fraction (MWF), quantitative susceptibility mapping (QSM), T1 relaxometry map (qT1), and neurite density index (NDI) in distinguishing 750 juxtacortical lesions from 242 periventricular lesions in 47 MS patients. Pair-wise permutation t-tests were used to evaluate the differences between the AWs obtained for each quantitative measure. ResultsIn the first experiment, we achieved a mean test AUC of 0.881 and the obtained AWs of FLAIR and the sum of AWs of Trace and ADC were 0.11 and 0.89, respectively, as expected based on previous knowledge. In the second experiment, we achieved a mean test F1 score of 0.895 and a mean AW of Trace = 0.49, of ADC = 0.28, and of T1w = 0.23, thereby confirming the findings of the first experiment. In the third experiment, MS lesion classification achieved test balanced accuracy = 0.777, sensitivity = 0.739, and specificity = 0.814. The mean AWs of T1map, MWF, NDI, and QSM were 0.29, 0.26, 0.24, and 0.22 (p < 0.001), respectively. ConclusionsThis work demonstrates that the proposed GAMER MRI might be a useful method to assess the relative importance of MRI measures in neurological diseases with focal pathology. Moreover, the obtained AWs may in fact help to choose the best combination of MR contrasts for a specific classification problem.

A Mendelian randomization approach to characterize overlap in the pathophysiology of neurological disorders

AbstractBackgroundNeurodegenerative diseases are characterized by progressive neuronal death, leading to loss of cognitive function. This process is thought to commence decades before symptom onset. Consequently, there is a dire need to characterize the pre‐clinical phase of neurodegenerative diseases to provide early intervention. We employed a Mendelian randomization approach to identify genetic overlap across neurological disorders and describe common disease mechanisms.MethodWe utilized our web‐based multi‐omics analytic tool ONTIME (Online Neurodegenerative Trait Integrative Multi‐Omics Explorer, http://ngi.pub/ONTIME/) to apply two‐sample Mendelian randomization to neurological disorders. We estimated the causal effect of 59 cerebrospinal fluid (CSF) analytes and 134 plasma analytes on the risk of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS), and stroke. Instrumental variables for CSF (N = 672) and plasma (N = 818) analytes were obtained from quantitative genome‐wide association studies we performed using the RBM Human DiscoveryMAP panel.ResultIn CSF, we identified seven analytes that have a causal effect on AD, two analytes that have a causal effect on ALS, and three analytes that have a causal effect on stroke after false discovery rate (FDR) adjustment (Table 1). In plasma, we identified eleven analytes that have a causal effect on AD, eight analytes that have a causal effect on ALS, and five analytes that have a causal effect on stroke after FDR adjustment (Table 2). Furthermore, we detected overlap in the pathogenesis of AD and ALS as well as AD and stroke.ConclusionOur results support a growing body of evidence that there is significant genetic and pathophysiological overlap across neurodegenerative diseases. Furthermore, our findings provide evidence that vascular factors contribute to neurodegenerative disease onset. Finally, these results highlight the utility of ONTIME and its Mendelian randomization tool. Users can upload disease summary statistics and test if any CSF or plasma analyte in our catalogue has a causal effect on their uploaded health outcomes.

Pathophysiology of Neuro-COVID

With interest we read the review article by Battaglini et al., 2020 about the pathophysiology of neurological disease in SARSCoV- 2 infected patients with COVID-19. The authors discuss three possible mechanisms, viral neurotropism, hypercoagulability and inflammation, and brain-lung crosstalk. We have the following comments and concerns.

Sodium, Potassium, Calcium, and Magnesium in the Scalp Hair and Blood Samples Related to the Clinical Stages of the Parkinson's Disease.

Neurodegeneration disorders are complex and multifaceted, leading to many chronic diseases, like Parkinson's disease (PD). Electrolytes imbalance has a significant role in the pathophysiology of neurological disorders, which might serve as a bio-indicator of these problems. In the present study, the disturbances of the electrolytes, calcium (Ca), magnesium (Mg), sodium (Na), and potassium (K), concentrations, and their correlation with biochemical parameters of PD patients at three different age groups (15 to 75 years) and stages were studied. The all resulted data of PD patients was compared with non-diseased/referents (PD) of same age groups. The biological samples (scalp hair, serum and plasma) were collected from Parkinson's disease (PD) patients, diagnosed at three stages, early (15 to 30 years), mild (30 to 60 years) and severe (61 to 75 years). The electrolyte concentrations were measured after acid digested biological samples using flame atomic absorption spectrometry. The precision of the digestion method was verified by matrices matched certified reference materials. The resulted data indicated that the contents of Ca and Mg were found to be higher in scalp hair samples of PD patients at early to severe stages as compared with those results obtained from referents. The concentrations of Na and K were found to be lower for all PD patients groups as compared with referents; however, the difference was not significant (p < 0.05). Electrolytes levels in blood serum and plasma were found to be lower in all patients than healthy groups (p < 0.01). These results suggest a disturbance in the electrolytes homeostasis during the different clinical stages of PD, whereas the higher disturbance was observed in patients at severe stage (61 to 75 years).

Visualization of activity-regulated BDNF expression in the living mouse brain using non-invasive near-infrared bioluminescence imaging

Altered levels of brain-derived neurotrophic factor (BDNF) have been reported in neurologically diseased human brains. Therefore, it is important to understand how the expression of BDNF is controlled under pathophysiological as well as physiological conditions. Here, we report a method to visualize changes in BDNF expression in the living mouse brain using bioluminescence imaging (BLI). We previously generated a novel transgenic mouse strain, Bdnf-Luciferase (Luc), to monitor changes in Bdnf expression; however, it was difficult to detect brain-derived signals in the strain using BLI with d-luciferin, probably because of incomplete substrate distribution and light penetration. We demonstrate that TokeOni, which uniformly distributes throughout the whole mouse body after systematic injection and produces a near-infrared bioluminescence light, was suitable for detecting signals from the brain of the Bdnf-Luc mouse. We clearly detected brain-derived bioluminescence signals that crossed the skin and skull after intraperitoneal injection of TokeOni. However, repeated BLI using TokeOni should be limited, because repeated injection of TokeOni on the same day reduced the bioluminescence signal, presumably by product inhibition. We successfully visualized kainic acid-induced Bdnf expression in the hippocampus and sensory stimulation-induced Bdnf expression in the visual cortex. Taken together, non-invasive near-infrared BLI using Bdnf-Luc mice with TokeOni allowed us to evaluate alterations in BDNF levels in the living mouse brain. This will enable better understanding of the involvement of BDNF expression in the pathogenesis and pathophysiology of neurological diseases.

Accumulation of Neurofascin at Nodes of Ranvier Is Regulated by a Paranodal Switch.

The paranodal junctions flank mature nodes of Ranvier and provide a barrier between ion channels at the nodes and juxtaparanodes. These junctions also promote node assembly and maintenance by mechanisms that are poorly understood. Here, we examine their role in the accumulation of NF186, a key adhesion molecule of PNS and CNS nodes. We previously showed that NF186 is initially targeted/accumulates via its ectodomain to forming PNS (hemi)nodes by diffusion trapping, whereas it is later targeted to mature nodes by a transport-dependent mechanism mediated by its cytoplasmic segment. To address the role of the paranodes in this switch, we compared accumulation of NF186 ectodomain and cytoplasmic domain constructs in WT versus paranode defective (i.e., Caspr-null) mice. Both pathways are affected in the paranodal mutants. In the PNS of Caspr-null mice, diffusion trapping mediated by the NF186 ectodomain aberrantly persists into adulthood, whereas the cytoplasmic domain/transport-dependent targeting is impaired. In contrast, accumulation of NF186 at CNS nodes does not undergo a switch; it is predominantly targeted to both forming and mature CNS nodes via its cytoplasmic domain and requires intact paranodes. Fluorescence recovery after photobleaching analysis indicates that the paranodes provide a membrane diffusion barrier that normally precludes diffusion of NF186 to nodes. Linkage of paranodal proteins to the underlying cytoskeleton likely contributes to this diffusion barrier based on 4.1B and βII spectrin expression in Caspr-null mice. Together, these results implicate the paranodes as membrane diffusion barriers that regulate targeting to nodes and highlight differences in the assembly of PNS and CNS nodes.SIGNIFICANCE STATEMENT Nodes of Ranvier are essential for effective saltatory conduction along myelinated axons. A major question is how the various axonal proteins that comprise the multimeric nodal complex accumulate at this site. Here we examine how targeting of NF186, a key nodal adhesion molecule, is regulated by the flanking paranodal junctions. We show that the transition from diffusion-trapping to transport-dependent accumulation of NF186 requires the paranodal junctions. We also demonstrate that these junctions are a barrier to diffusion of axonal proteins into the node and highlight differences in PNS and CNS node assembly. These results provide new insights into the mechanism of node assembly and the pathophysiology of neurologic disorders in which impaired paranodal function contributes to clinical disability.