Human genome studies have suggested that strawberry notch homologue 1 (SBNO1) is crucial for normal brain development, with mutations potentially contributing to neurodevelopmental disorders. In a previous study, we observed significant developmental abnormalities in the neocortex of Sbno1 as early as one week after birth. In the present study, we conducted an extensive analysis of Sbno1 postnatal expression in the brain of C57BL/6 mice using a newly developed in-house polyclonal antibody against Sbno1. We found that Sbno1 is expressed in all neurons, with certain neuronal populations exhibiting distinct dynamic changes (both temporal and spatial) in expression level. These findings suggest that the neuronal expression of Sbno1 is developmentally regulated after birth. They also indicate that while Sbno1 may play a general role across all neurons, it may also serve more specialized functions in certain neuronal types and/or for certain cellular activities related to particular neuronal pathways.

Many children suffer from neurodevelopmental aberrations that have long-term effects. To un-derstand the consequences of pathological processes during particular periods in neurodevelop-ment, one has to understand the differences in the developmental timelines of brain regions. The cerebellum is one of the first brain structures to differentiate during development, but one of the last to achieve maturity. This relatively long period of development underscores its vulnerability to detrimental environmental exposures throughout gestation. Moreover, as postnatal functional-ity of the cerebellum is multifaceted, enveloping sensorimotor, cognitive, and emotional domains, prenatal disruptions in cerebellar development can result in a large variety of neurological and mental health disorders. Here, we review major intrauterine insults that affect cerebellar devel-opment in both humans and rodents, ranging from abuse of toxic chemical agents such as alcohol, nicotine, cannabis and opioids, to stress, malnutrition as well as infections. Understanding these pathological mechanisms in the context of the different stages of cerebellar development in hu-mans and rodents can help us to identify critical and vulnerable periods and thereby to prevent the risk of associated prenatal and early postnatal damage that can lead to lifelong neurological and cognitive disabilities. The scope of the review is to raise awareness and to provide information for expecting parents, obstetricians, and other healthcare professionals to eventually de-sign strategies for preventing or rescuing related neurodevelopmental disorders.

The human microbiota constitutes a very complex ecosystem of microorganisms inhabiting both the inside and outside of our bodies, in which health maintenance and disease modification are the main regulatory features. The recent explosion of microbiome research has begun to detail its important role in neurological health, particularly concerning cerebral small vessel disease (CSVD), a disorder associated with cognitive decline and vascular dementia. This narrative review represents state-of-the-art knowledge of the intimate, complex interplay between microbiota and brain health through the gut-brain axis (GBA) and the emerging role of the glymphatic system dysfunction (glymphopathy) and circulating cell-derived microparticles (MPs) as mediators of these interactions. We discuss how microbial dysbiosis promotes neuroinflammation, vascular dysfunction, and impaired waste clearance in the brain which are critical factors in the pathogenesis of CSVD. Further, we discuss lifestyle factors that shape the microbiota composition and functionality, focusing on sleep as a modifiable risk factor in neurological disorders. This narrative review places recent microbiome research into a neuroscientific and vascular perspective to establish future therapeutic avenues in targeting the microbiota to improve brain health and reduce the burden of CSVD.

Background/Objectives: This study investigates the effectiveness of an herbal formulation, STRESSLESS (ST-65), which combines ashwagandha (Withania somnifera) and bacopa (Bacopa monnieri), on SH-SY5Y human neuroblastoma cells. Given the rising interest in natural compounds for neuroprotection and stress alleviation, we aimed to explore the cellular and molecular effects of this formulation. Methods: Utilizing a nuclear magnetic resonance (NMR) metabolomic approach and ultra-high-performance liquid chromatography-high-resolution mass spectrometry (UHPLC-HRMS), we identified key bioactive compounds in ST-65, including withanolides from ashwagandha and bacosides from bacopa. Results: Our findings indicate that ST-65 treatment significantly alters the metabolic profile of SH-SY5Y cells. Key changes included increased levels of metabolites linked to neuroprotection, energy metabolism, and antioxidant defense. Notable enhancements were observed in specific amino acids and neuroprotective compounds, suggesting activation of neuroprotective mechanisms and mitigation of stress-induced damage. Conclusions: The study reveals a complex phyto-chemical profile of ST-65 and underscores its potential as a natural active agent for addressing stress-related neurodegenerative conditions. These insights into neuronal mechanisms provide a foundation for further exploration of herbal formulations in neuroprotection.

The aim of the study was to evaluate two widely studied biomarkers: MMP-9 and S100B in blood serum in healthy people after physical exercise mimicking physical activity during bi-lateral tonic-clonic seizures. Both biomarkers have been shown to increase after seizures, and their serum levels tend to be higher in epilepsy patients compared to individuals without epi-lepsy. To achieve this goal, we have developed two sets of exercises, each consisting of a tonic contrac-tion phase and a phase of alternating muscle work, lasting a total of approximately 5 minutes. Both sets of motor exercises were performed in the same group of healthy volunteers 6 months apart. Serum samples were collected before exercise, 3 hours after exercise, and the next day (time points 0, 3 hours, and 24 hours). Our results demonstrated that both sets of motor exercises led to a similar increase in MMP-9 levels, while neither while neither affected S100B levels. No significant differences in MMP-9 levels were observed due to muscle failure. We propose that the increase in MMP-9 is primarily induced by muscle contraction and additional mechanisms observed during exercise, such as neutrophil degranulation. S100B appears to be a promising biomarker in epilepsy, as it is not induced by physical activity but does increase following seizures.

Volatile organic compounds, colloquially referred to as “terpenes”, are proposed to impact the therapeutic qualities that are traditionally ascribed to cannabis. However, the contribution of these terpenes in anxiety, at relevant levels and exposure methods common with cannabis use, is lacking empirical assessment. We tested the anxiolytic properties of two prominent cannabis terpenes, linalool and β-myrcene, in male and female mice using short duration vapor pulls to model human inhalation when combusting flower or vaping cannabis oil. We observed sex differences in the locomotor effects and anxiolytic properties of these terpenes that depended on their exposure characteristics. Both linalool and β-myrcene had anxiolytic effects in female mice when delivered in discrete vapor pulls over the course of 30 minutes. In male mice, only a single vapor hit containing linalool or β-myrcene had anxiolytic effects. The combination of sub-effective levels of linalool and the phytocannabinoid, cannabidiol (CBD), had synergistic anxiolytic effects in females, but these Entourage Effects between CBD and terpenes were absent with β-myrcene for females and for either terpene in males. Together, our findings reveal sex differences in the anxiolytic properties of common cannabis terpenes and highlight the benefits of unique combinations of CBD and terpenes in expanding the therapeutic dose window.

Essential Tremor (ET) is among the most common neurological movement disorders, with incidence rates increasing with age. The disorder is characterized by a bilateral action tremor of the upper limbs, enduring for a minimum of three years in duration, and shows early signs of onset with progression over time. Recent terminology has categorized a subcategory of ET, known as Essential-Tremor Plus (ET-Plus), which consists of a combination of symptoms that include tremors at rest and additional neurological signs. This includes memory impairment, gait disturbances, or various other neurological symptoms that do not have full clinical significance for diagnosis and suggest a more complex underlying neurological condition. Abnormalities located primarily in the cerebellum, including the loss and damage to Purkinje Cells (PC), were core pathological features of cerebellar damage in postmortem ET. Given the complexity and uncertainty of the pathophysiological aspects of tremor generation, treatment options are still limited, and current therapeutic measures lack the capacity to fully alleviate symptoms. In consideration, there are current pharmaceutical, stimulation, and genetic studies being conducted to characterize the etiology and pathophysiology of ET and aid in the reduction of progression and symptoms. In this review, we will discuss various aspects of ET including neurophysiology, pathophysiology, genetic factors and etiology, treatment options and future directions of advancements for ET management.

The biological function of rapid eye movement (or REM) sleep—one of the great mysteries of neuroscience and evolutionary biology—remains unknown. Here, I demonstrate that the biological function of REM sleep is to heighten brain alertness, significantly reducing the high vulnerability of deep sleep. Every organism with a nervous system must undergo deep sleep: a necessity that comes with substantial vulnerability. Deep sleep, by lowering alertness, compromises the organism's safety, putting its survival at risk. Therefore, REM sleep is a necessary adaptation for any organism that must sleep. My primary goal here is to present a comprehensive conceptual framework—supported by extensive empirical evidence—to connect numerous disparate empirical findings under a unified theory of the biological function of REM sleep. Additionally, I also provide a historical narrative to explain its origin and subsequent evolution. To test the theory, I drew on a substantial body of evidence and testable hypotheses. All hypotheses capable of empirical verification were corroborated, revealing that the theory is widely corroborated. Furthermore, it also resisted numerous attempts at refutation. All of this allows me to claim that I solved this great enigma of science. In addition to solving one of the biggest theoretical problems in neuroscience and evolutionary biology, my article will change the way REM sleep research is planned and carried out.

The claustrum, a small but densely interconnected brain structure, is innervated by axons containing neuromodulators such as serotonin (5-HT), a neuromodulator that has been implicated in control of sleep and in the actions of psychedelic drugs. However, little is known about how 5-HT influences the claustrum. We have combined whole-cell patch clamp measurements of ionic currents, flash photolysis and receptor pharmacology to characterize the 5-HT responses of individual claustral projection neurons (PNs) in mouse brain slices. Serotonin application elicited a long-lasting outward current in claustral PNs. This current was due to an increase in membrane permeability to K⁺ ions and was mediated mainly by the type 1A 5-HT receptor (5-HTR-1A). The 5-HT-induced K⁺ current hyperpolarized, and thereby inhibited, PNs by reducing action potential firing. Focal uncaging of 5-HT revealed that inhibitory 5-HTR-1As were located at both the soma and dendrites of PNs. We conclude that 5-HT creates a net inhibition in the claustrum, an action that should decrease claustrum sensitivity to excitatory input from other brain areas and thereby contribute to 5-HT action in the brain.

GNAO1 encephalopathies are a group of neglected genetic disorders primarily occurring due to de-novo point mutations in the Gαo protein-encoding gene in human GNAO1. This gene is reported to be highly conserved among Caenorhabditis elegans (C. elegans) and humans, with a sequence similarity of nearly 80%. Signaling pathways involved in various neurotransmitters, including GPCR pathways can be easily studied in the C. elegans model system. Therefore, using this model system to delineate downstream effectors and clinical targets to Gαo can be highly advantageous. Mutations that cause GNAO1 encephalopathy can be easily replicated in transgenic C. elegans and validated by rescuing phenotypic defects, primarily locomotion and egg-laying defects in worms. Although there are recent technical advancements in understanding the interacting proteins, there are unclear and uncertain hypotheses that explain the effect of Gαo mutations in humans. Coming to the clinical aspect of this disorder, there are no available approved diagnostic procedures to detect GNAO1 encephalopathy in the early stages of life. The present diagnostic procedures reiterate symptoms and overlap with other neurological symptoms that record neglected data of cases. Therefore, here we provide an overview of past research and a perspective of future work, with the primary objective of focusing on GNAO1 encephalopathy.

Psychosis in Alzheimer's disease (AD) is a prevalent phenomenon, marked by delusions and hallucinations, along with other neuropsychiatric symptoms such as agitation, depression, anxiety, and apathy. These neuropsychiatric symptoms, also known as behavioral and psychological symptoms of dementia (BPSD), affect up to 97% of Alzheimer's patients. The presence of psychosis in AD significantly impacts patients' daily lives and places a considerable burden on caregivers. The development of AD-related psychosis (ADP) is influenced by a range of factors, including genetic predispositions and life-acquired factors. AD affects cognitive function and various brain regions, resulting in widespread brain atrophy. In addition to its neurological impact, AD can induce pathological physiological changes that serve as biomarkers for ADP. Research efforts have focused on developing pharmacological treatments for psychosis in AD, aiming to minimize side effects. Brexpiprazole has emerged as a promising medication for ADP, alongside other antipsychotics. Treatment approaches for ADP extend beyond pharmacology, incorporating methods such as sensory stimulation and digital therapeutics. This review will explore the characteristics of psychosis in Alzheimer's disease, the pathological underpinnings of ADP, and the current therapeutic landscape, highlighting emerging opportunities for managing this challenging condition.

Background/Objectives : This study investigates the utility of vision transformers (ViTs) for predicting early responses to SRS using a minimal pre-processing approach on MRI images. Methods: We analyzed MRI scans from 19 patients with BM, focusing on axial fluid-attenuated inversion recovery (FLAIR) and high-resolution contrast-enhanced T1-weighted (CE T1w) sequences. Patients were classified as responders (complete or partial response) or non-responders (stable or progressive disease). Results: Our findings demonstrate that ViTs can effectively predict treatment responses, achieving an overall accuracy of 97%. The model exhibited high precision (96% for progression and 97% for regression) and strong recall rates (92% for progression and 99% for regression), distinguishing between treatment outcomes reliably. The confusion matrix analysis further supports its reliability, with minimal misclassifications. The model also achieved an almost perfect area under the ROC curve (AUC = 0.99), indicating accurate differentiation between responders and non-responders across various thresholds. Conclusions : These findings highlight the potential of the Vision Transformer model as a non-invasive predictive tool in clinical settings, significantly influencing clinical decision-making processes and enhancing patient management for brain metastases. By improving early response predictions, this model contributes to the development of personalized treatment strategies in oncology. Future research should focus on validating these results in larger, diverse cohorts, integrating additional data types, and refining the model to further enhance its utility in clinical practice.

Traumatic brain injury (TBI) causes multiple cerebrovascular disruptions and oxidative stress, resulting in pathophysiological mechanisms. These are often accompanied by serious impairment in cerebral blood flow autoregulation, as well as neuronal and glial degeneration. Most currently available early antioxidant therapies lack sufficient efficacy. However, the application of a newly developed class of biologically compatible carbon-based nanoclusters, namely poly-ethylene-glycol-functionalized hydrophilic carbon clusters (PEG-HCCs), mitigate secondary injury after a TBI in early studies. In the present pilot study, we explore the efficacy of PEG-HCCs in an open blast rat model of TBI. Here we report on the neuroprotective efficacy of PEG-HCCs.

Contrary to a prevailing dogma in twentieth-century neuroscience, emerging evidence suggests that the generation of new neurons continues throughout life, contributing significantly to crucial life functions owing to their robust ability to enhance neuroplasticity. Hippocampal neurogenesis occurs in the subgranular layer of the dentate gyrus, a region characterized by a specific microenvironment conducive to the proliferation of neuronal cells. A substantial body of evidence supports the belief that this phenomenon impacts various functions, including learning, emotional responses, and the formation of new memories. Diseases affecting these areas can significantly disrupt cognition and general behavior. For instance, in mesial temporal lobe epilepsy, aberrant neurogenesis has been observed, leading to increased cell proliferation, altered patterns of cellular integration, errors in information processing, and the formation of abnormal synaptic connections and transmissions. These abnormalities have the potential to generate epileptic seizures, underscoring the profound impact of these diseases on cognitive functions. Conversely, the chronic recurrence of seizures, can result in chronic recurrence of seizures, which can lead to a persistent reduction of neurogenesis in the epileptic brain. This reduction directly impacts various learning processes and the formation of hippocampus-dependent declarative memory. The mechanisms behind these processes remain fully elucidated and involve the delicate balance between neuronal excitation and inhibition, directly influencing brain performance and potentially leading to a decline in cognitive functions. In mesial temporal lobe epilepsy, this condition stands out as one of the most severe disorders affecting the well-being of epileptic patients. While memory is highlighted as one of the most affected functions, it is not the sole cognitive function compromised by this comorbidity. The alterations can extend from language to executive and spatial functions.

Hypofunction of the glutamate system in the brain is one of the pathophysiological hypotheses for schizophrenia. Accumulating animal and clinical studies show that sarcosine (N-methylglycine), a glycine transporter-1 inhibitor, is effective for ameliorating the negative and cognitive symptoms of schizophrenia. The aims of the present study were to observe the effects of sarcosine on neuronal activity in the dorsal CA1 (dCA1) hippocampal neurons within an NMDA receptor hypofunction model induced by MK801. We applied in vivo calcium imaging to observe the dynamics of fluorescence from the dCA1 hippocampal neurons when the mice were exploring in an open field. Using this tool, we directly measured and compared neuronal properties between sarcosine-treated and untreated mice. At the same time, the physiological function of the neurons was also quantified by measuring their place fields. Our data demonstrated that MK-801 (0.2 mg/kg) diminished the fluorescence intensity of dCA1 neurons that had been genetically modified with a calcium indicator. MK-801 also significantly increased the correlation coefficient between the fluorescence dynamics of pairs of cells, a feature that may be linked to the symptom of disorganization in human patients with schizophrenia. The spatial correlations of place fields in the mice were impaired by MK-801 as well. Injected sarcosine (500 mg or 1000 mg/kg) significantly alleviated the abovementioned abnormalities. Our data provide evidence to support the use of sarcosine to alleviate symptoms of schizophrenia, especially hippocampus-related functions.

Neurological disorders such as Autism Spectrum Disorder (ASD), Schizophrenia (SCH), Bipolar Disorder (BD), and Major Depressive Disorder (MDD) affect millions of people worldwide, yet their molecular mechanisms remain poorly understood. This study applied the Comparative Analysis of Shapley values (CASh) to transcriptomic data from nine datasets associated with these complex disorders, demonstrating its effectiveness in identifying differentially expressed genes (DEGs). CASh, which integrates Game Theory with Bootstrap resampling, offers a robust alternative to traditional statistical methods by evaluating the contribution of each gene within the broader context of the entire dataset. Unlike conventional approaches, CASh is highly effective at detecting subtle but meaningful molecular patterns that are often missed. These findings highlight the potential of CASh to enhance the precision of transcriptomic analysis, providing deeper insights into the molecular signatures of these disorders and establishing a solid basis for improving diagnostic techniques and developing more targeted therapeutic interventions.

In this article we focus on kynurenic acid metabolism, a biochemical part of L-tryptophan catabolism, in processes related to memory and cognitive impairment and its subsequent relevance to neuropsychiatric disorders and the ageing process. Kynurenic acid is synthesised from L-kynurenine by kynurenine aminotransferases. Experimental pharmacological studies have shown that elevated levels of kynurenic acid in the brain are associated with impaired learning and that lowering kynurenic acid levels can improve these symptoms. The discovery of new compounds with the ability to block kynurenine aminotransferase opens up new therapeutic avenues against memory impairment and dementia. The newly developed Helix pomatia snail model of memory is being used for this pharmacological approach. In conclusion, diet, exercise and physical activity have a significant impact on the endogenous pharmacology of kynurenic acid and significantly modulate steady-state conditions and delay the events of the ageing process.

Diabetic retinopathy is a prevalent complication of type 2 diabetes mellitus, characterized by progressive damage to retinal structure and function. Photobiomodulation therapy, using near-infrared light, has been proposed as a non-invasive intervention to mitigate retinal damage, but has been tested generally with short-term stimuli. This study aimed to evaluate the effects of prolonged photobiomodulation on retinal structure and function in a type 2 diabetes mouse model. Transgenic LepRdb/J (db/db) mice and their heterozygous controls were exposed to photobiomodulation therapy via LED devices emitting 654 nm light for 12 hours daily over ten weeks. Retinal function was evaluated by flash electro-retinography, while structural changes were assessed through histology and immuno-histochemistry to detect astro- and microgliosis. At 33 weeks of age, db/db mice were obese and severely diabetic, but exhibited only incipient indicators of retinal deterioration. Electroretinogram b-wave peak latencies were prolonged at intermediate flash intensities, while the outer plexiform layer displayed significantly elevated IBA1 expression. Photo-biomodulation therapy prevented these two markers of early retinal deterioration, but had no effect on other morphological and functional parameters. Photobiomodulation is well-tolerated and maintains potential as a complementary treatment option for diabetic retinopathy, but requires further optimization of therapeutic settings and combinatory treatment approaches.

Objectives: The Implicit Prosody Hypothesis (IPH) posits that individuals generate internal prosodic representations during silent reading, mirroring those produced in spoken language. While converging behavioral evidence supports the IPH, the underlying neurocognitive mechanisms remain largely unknown. Therefore, this study investigated the neurophysiological markers of sensitivity to speech rhythm cues during silent word reading. Methods: EEG was recorded while participants silently read four-word sequences, each composed of either trochaic words (stressed on the first syllable) or iambic words (stressed on the second syllable). Each sequence was followed by a target word that was either metrically congruent or incongruent with the preceding rhythmic pattern. Results: Single-trial event-related potentials (ERPs) and time-frequency representations (TFRs) triggered by the target words were examined using a hierarchical mass univariate general linear modeling approach to investigate the effects of metrical expectancy and stress type. ERP findings revealed significant differences based on expectancy, with words carrying unexpected stress eliciting larger negativities between 240-628 ms after word onset. TFRs further revealed that different frequency bands were sensitive to distinct aspects of rhythmic structure in language. Alpha activity, linked to attention, reflected expectations about the rhythmic pattern. Theta and beta activity, associated with processing rhythm and timing, were sensitive to both the expected rhythm and the specific location of stressed syllables within words. Conclusions: These findings highlight comparable neurophysiological responses to both implicit and explicit speech rhythm, further supporting the IPH and emphasizing the role of prosody in silent reading.

Fluctuations in kynurenic acid (KYNA) and brain-derived neurotrophic factor (BDNF) levels in the brain reflect its neurological status. The aim of the study was to investigate the effect of transiently elevated KYNA concentration in the cerebroventricular circulation on the expression of BDNF and its high-affinity tropomyosin-related kinase receptor B (TrkB) in specific structures of the sheep brain. Intracerebroventricularly cannulated anestrous sheep were subjected to a series of four 30-min infusions of KYNA: 4×5 μg/60 μL/30 min (KYNA20, n=6) and 4×25 μg/60 μL/30 min (KYNA100, n=6) or a control infusion (n=6), at 30-min intervals. Sections of the hippocampal CA3 field, amygdala (AMG), prefrontal cortex (PCx), and the hypothalamic medial-basal (MBH) and preoptic (POA) areas were dissected from the brain immediately after the experiment. The highest concentration of BDNF protein was found in the CA3 field (P<0.01), which was 8-fold higher than in the AMG and 12-fold higher than that in the PCx (MBH and POA were not analyzed). The most pronounced BDNF mRNA expression was observed in the MBH followed by the PCx, POA, AMG and CA3, while the highest abundance of TrkB mRNA was recorded in the AMG followed by the MBH, PCx, CA3 and POA. KYNA increased (P<0.05-P<0.01) BDNF protein levels and the expression of its gene in the brain structures examined, with the effect varying by dose and brain region. KYNA, particularly at the KYNA100 dose, also increased (P<0.01) TrkB gene expression, except for the AMG, where the lower KYNA20 dose was more effective (P<0.01). These findings suggest a positive relationships between KYNA levels in the cerebroventricular circulation and BDNF-TrkB expression in specific brain regions in a sheep model. This indicates that a transient increase in CSF KYNA concentration can potentially restore BDNF production, whose deficiency underlies numerous neurological disorders.

Febrile seizures (FSs) are defined as seizures occurring in children aged 6 months to 5 years with a background of elevated body temperature. It is one of the most common neurological disorders of childhood, emphasizing the importance of understanding the causes of FSs and their impact on the developing nervous system. However, there are significant limitations to the technologies currently available for studying the etiology and pathophysiology of seizures in humans. It is currently not possible to adequately capture the subtle molecular and structural rearrangements of the nervous system that can occur after seizures in humans. The use of animal models can be invaluable for these purposes. The most commonly used models in modern research are hyperthermic models in rats and mice aged 10-12 days. While these models can reproduce many of the characteristics of FSs, they have certain limitations. This review outlines the key considerations when working with models of FSs, provides an overview of current approaches to producing seizures in different model subjects, and presents a summary of key findings regarding morphological and functional changes in the brain, as well as behavioral alterations, that have been identified in studies using animal models of FSs.

Anxiety is a prevalent mental health disorder that significantly impairs daily functioning and social interactions. While pharmacological treatments can be effective, they are often limited by challenges such as treatment resistance, side effects, and relapse. Electroacupuncture (EA) has emerged as a promising non-pharmacological intervention for anxiety, though its mechanisms of action remain largely unexplored. This study investigates the role of microglial cells in anxiety and examines how EA influences microglial morphology and function in the basolateral amygdala (BLA) in a model of social isolation-induced anxiety. Using a socially isolated mouse model, we assessed anxiety-like behaviors through the Elevated Plus Maze (EPM) and Open Field Test (OFT), and conducted biochemical analyses and immunofluorescence imaging to evaluate NOX2 expression, microglial activation, and oxidative stress markers. Our results show that EA significantly alleviates anxiety-like behaviors, reduces NOX2 expression in BLA microglia, lowers reactive oxygen species (ROS) levels, and enhances microglial morphology. These findings suggest that EA exerts its anxiolytic effects by modulating oxidative stress and microglial activity in the BLA, offering new insights into the cellular mechanisms by which EA may aid in anxiety management.

Binaural beats are an acoustic-based form of brain stimulation that relies on engineering and neurophysiological principles. One important engineering factor in binaural beat stimulation is the carrier frequency Given the limited information available on the impact of carrier frequencies, our research aims to explore how carrier frequencies of 250 Hz and 400 Hz in binaural beats affect the theta, alpha, and gamma frequency bands in healthy individuals. The research involved 30 people between the ages of 20 and 30. It was conducted as a single-group comparative study. Prior to the test, brain maps were created for the participants. Based on these brain maps and the participants' resilience, various binaural beats with different carrier frequencies were played while the participants sat quietly in a chair and looked ahead. Their brain waves were then recorded. The results showed: 1- The relative power of the gamma frequency band changed significantly between the carrier frequencies of 250 and 400. However, there were no significant changes in the relative power of the alpha band, and no changes were observed in the theta frequency band. 2- Based on the principle of theta-gamma coupling in the theta frequency band, there have been positive changes in the gamma frequency band at the carrier frequency of 255 compared to 405. 3- The brain's topography map has shown changes at different carrier frequencies. The results indicate that as the carrier frequency increases, the energy also increases, but it must be proportional to the frequency band based on the energy equation between the carrier frequency and the frequency band. Based on the brain topography map, the carrier frequency mainly affects the intensity and extent of the involved areas.

Coronavirus disease 2019 (COVID-19) has been a global pandemic affecting millions of people’s lives, which has led to ‘post-COVID-19 fatigue’. Alarmingly, severe acute respiratory syn-drome-coronavirus 2 (SARS-CoV-2) not only infects the lungs but also influences the heart and brain. Endothelial cell dysfunction and hypercoagulation, which we know occur with this infection, lead to thrombo-inflammation that can manifest as many myriad cardio-cerebrovascular disorders, such as brain fog, fatigue cognitive dysfunction, etc. Additionally, SARS-CoV-2 has been associated with oxidative stress, protein aggregation, cytokine storm, and mitochondrial dysfunction in neurodegenerative diseases. Accordingly, the identification of molecular targets involved in these actions could provide strategies for preventing and treating this disease. In particular, the very common enzyme dipeptidyl peptidase IV (DPPIV) has recently been identified as a candidate co-receptor for the cell entry of the SARS-CoV-2 virus with its involvement in infection. In addition, DPPIV has been reported as a co-receptor for some viruses such as Middle East respiratory syn-drome-coronavirus (MERS-CoV). It mediates immunologic reactions and diseases such as type 2 diabetes mellitus, obesity, and hypertension, which have been considered the prime risk factors for stroke among other types of cardio-cerebrovascular diseases. Unlike angiotensin-converting enzyme 2 (ACE2), DPPIV has been implicated in aggravating the course of infection due to its disruptive effect on inflammatory signalling networks and the neuro–glia–vascular unit. Regarding the neurological, physiological, and molecular grounds governing post-COVID-19 fatigue, this review focuses on DPPIV as one of such reasons that progressively establishes cerebrovascular grievances following SARS-CoV infection.

Exergames (EG) are interactive video games that require physical activity and use gamification to make exercise more engaging. EG interventions have shown various benefits for older adults, such as improved mental health, quality of life, and reduced fall risk. Enhanced cognition is thought to drive these benefits. This review aimed to identify neural correlates underlying cognitive improvements in healthy older adults and those with neurocognitive disorders. We systematically searched major databases and included 13 studies from 2,095 records. Findings revealed that EG interventions led to structural brain changes and improved functional connectivity in healthy adults, Parkinson patients, and those with mild cognitive impairment (MCI). Increased activity in the frontal, temporal, and precuneus regions during rest was specific to adults with neurocognitive disorders. Neuroplastic changes, such as elevated BDNF levels and increased neurovascular coupling, were observed in both groups. However, methodological limitations in some studies highlight the need for further high-quality research.

Recent studies have indicated that hindbrain [fourth ventricle (4V)] administration of the neurohypophyseal hormone, oxytocin (OT), reduces body weight, energy intake and stimulates interscapular brown adipose tissue temperature (T_IBAT) in male diet-induced obese (DIO) rats. What remains unclear is whether chronic hindbrain (4V) OT can impact body weight in female high fat diet-fed (HFD) rodents and whether this involves activation of brown adipose tissue (BAT). We hypothesized that OT-elicited stimulation of sympathetic nervous system (SNS) activation of interscapular brown adipose tissue (IBAT) contributes to its ability to activate BAT and reduce body weight in female high HFD-fed rats. To test this hypothesis, we determined the effect of disrupting SNS activation of IBAT on OT-elicited stimulation of T_IBAT and reduction of body weight in DIO rats. We first measured the impact of bilateral surgical SNS denervation to IBAT on the ability of acute 4V OT (0.5, 1, and 5 µg ≈ 0.5, 0.99, and 4.96 nmol) to stimulate T_IBAT in female HFD-fed rats. We found that the high dose of 4V OT (5 µg ≈ 4.96 nmol) stimulated T_IBAT similarly between sham rats and denervated rats (P=NS). We subsequently measured the effect of bilateral surgical denervation of IBAT on the effect of chronic 4V OT (16 nmol/day ≈ 16.1 mg/day) or vehicle infusion to reduce body weight, adiposity and energy intake in female HFD-fed rats (N=7-8/group). Chronic 4V OT reduced body weight gain (sham: -18.0±4.9 g; denervation: -15.9±3.7 g) and adiposity (sham: -13.9±3.7 g; denervation: -13.6±2.4 g) relative to vehicle treatment (P<0.05) and these effects were similar between groups (P=NS). These effects were attributed, in part, to reduced energy intake evident during weeks 2 (P<0.05) and 3 (P<0.05). To test whether these results translate to other female rodent species, we also examined the effect of chronic 4V infusion of OT on body weight and adiposity in two strains of female HFD-fed mice. Similar to what we found in the HFD-fed rat model, we also found that chronic 4V OT (16 nmol/day) infusion resulted in reduced body weight gain, adiposity and energy intake in female DIO C57BL/6J and DBA/2J mice (P<0.05 vs vehicle). Together, these findings suggest that 1) sympathetic innervation of IBAT is not necessary for OT-elicited increases in BAT thermogenesis and weight loss in female HFD-fed rats and 2) the effects of OT to elicit weight loss translate to other mouse models of diet-induced obesity (DIO).

There are currently no effective treatments for retinal pigment epithelial (RPE) cell loss in atrophic AMD (aAMD). However, our research on Prom1, a known structural protein in photoreceptors (PRs), has revealed its distinct role in RPE and offers promising insights. While pathogenic Prom1 mutations have been linked to macular diseases with RPE atrophy, the broader physiological impact of dysfunctional Prom1 in RPE loss is unclear. We have shown that Prom1 plays a crucial role in regulating autophagy and cellular homeostasis in human and mouse RPE (mRPE) cells in vitro. Nevertheless, a comprehensive understanding of its in vivo expression and function in mRPE remains to be elucidated. To characterize Prom1 expression in RPE in situ, we used RNAscope assays and immunogold electron microscopy. Our use of chromogenic and fluorescent RNAscope assays in albino and C57BL/6J mice retinal sections has revealed Prom1 mRNA expression in perinuclear regions in mRPE in situ. Immunogold imaging showed Prom1 expression in RPE mitochondria. To confirm Prom1 expression in RPE, we interrogated human RPE single-cell RNA-sequencing datasets using an online resource, Spectacle. Our analysis showed Prom1 expression in human RPE. To investigate Prom1's function in RPE homeostasis, we performed RPE-specific Prom1-knockdown (KD) using subretinal injections of AAV2/1.CMV.saCas9.U6.Prom1gRNA in male and female mice. Our data show that RPE-specific Prom1-KD in vivo resulted in abnormal RPE morphology, sub-retinal fluid accumulation, and secondary PR loss. These changes were associated with patchy RPE cell death and reduced a-wave amplitude, indicating retinal degeneration. Our findings underscore the central role of Prom1 in cell-autonomous mRPE homeostasis. The implications of Prom1-KD in causing aAMD-like RPE defects and retinal degeneration in a mouse model are significant and could lead to novel treatments for aAMD.

Amyotrophic lateral sclerosis (ALS) is a devastating disease whose etiology is currently unknown. This paper presents a novel theory in which ALS is caused by an impairment of the alpha2de;ta subunit of voltage-gated calcium channels (VGCCs), most likely due to autoimmune targeting. I show how the impairment mechanistically induces chronic calcium, which in turn explains the major clinical, epidemiological, and pathological evidence known about the disease. The same theory explains the major variant of frontotemporal dementia (FTD) that greatly overlaps with ALS.

This article presents a mathematical model that captures the temporal dynamics of efficiencies in the responses to pleasure and pain, represented by $k_P(t)$ and $k_D(t)$, as well as the interaction factor $k_{PD}(t)$ between cortisol and dopamine. The model allows for the analysis of how these parameters evolve over time as a function of an individual's activities and physiological states, incorporating processes of tolerance, sensitization, and homeostasis. We present the updated differential equations, qualitative analyses, potential simulation scenarios, implications, and potential applications of the model.

N-methyl-D-aspartate receptors (NMDARs) are critical components of the mammalian central nervous system, involved in synaptic transmission, plasticity, and neurodevelopment. This review focuses on the structural and functional characteristics of NMDARs, with a particular emphasis on the GRIN2 subunits (GluN2A-D). The diversity of GRIN2 subunits, driven by alternative splicing and genetic variants, significantly impacts receptor function, synaptic localization, and disease manifestation. We explore the physiological properties and developmental regulation of these subunits, highlighting their roles in the pathophysiology of various NDDs, including ASD, epilepsy, and schizophrenia. By reviewing current knowledge and experimental models, including mouse models and human-induced pluripotent stem cells (hiPSCs), this article aims to elucidate different approaches through which the intricacies of NMDAR dysfunction in NDDs are currently being explored. The comprehensive understanding of NMDAR subunit composition and their mutations provides a foundation for developing targeted therapeutic strategies to address these complex disorders.

Mysticism has been an integral part of human society for ages. It involves both spirituality and religiosity. The former is associated with attaining higher states of consciousness without an essential belief in a supernatural power (or God), while the latter does. While there is plenty of speculative literature available on these topics, we instead focus on peer-reviewed scientific literature that is evidence-based. First, we briefly review technologies that can measure brain function. We make the case that concepts such as emotions and subjective experiences, which have long been considered outside the scope of objective scientific inquiry, are in fact amenable to objective scientific inquiry with technologies available today. To substantiate this point, we showcase scientific studies on spiritual aspects of mysticism such as meditation, mantra/chanting, and breath modulation. While we recognize that much of the research on these topics deals with their health benefits, we argue that associated brain changes are also conducive for attaining higher states of consciousness related to spirituality. Next, we present limited scientific literature on religiosity, dealing with its neural correlates, evolutionary biological origin, and usefulness for mental health. We close by arguing that the brain basis of mysticism cannot be seen in isolation from the body since these entities are intimately connected. We propose that future research should look at brain-body interactions and associated markers of mysticism using the latest technologies.

Emerging research into the human microbiome, an intricate ecosystem of microorganisms residing in and on our bodies, reveals that it plays a pivotal role in maintaining our health, highlighting the potential for microbiome-based interventions to prevent, diagnose, treat, and manage a myriad of diseases. The objective of this review is to highlight the importance of microbiome studies in enhancing our understanding of rare genetic epilepsy and related neurological disorders. Studies suggest that the gut microbiome, acting through the gut-brain axis, impacts the development and severity of epileptic conditions in children. Disruptions in microbial composition can affect neurotransmitter systems, inflammatory responses, and immune regulation, which are all critical factors in the pathogenesis of epilepsy. This growing body of evidence points to the potential of microbiome-targeted therapies, such as probiotics or dietary modifications, as innovative approaches to managing epilepsy. By harnessing the power of the microbiome, we stand to develop more effective and personalized treatment strategies for children affected by this and other rare neurological diseases.

In this article we focus on kynurenic acid metabolism, a biochemical part of L-tryptophan catabolism, in processes related to memory and cognitive impairment and its subsequent relevance to neuropsychiatric disorders and the ageing process. Kynurenic acid is synthesised from L-kynurenine by kynurenine aminotransferases.Experimental pharmacological studies have shown that elevated levels of kynurenic acid in the brain are associated with impaired learning and that lowering kynurenic acid levels can improve these symptoms. The discovery of new compounds with the ability to block kynurenine aminotransferase opens up new therapeutic avenues against memory impairment and dementia. The newly developed Helix pomatia snail model of memory is being used for this pharmacological approach. In conclusion, diet, exercise and physical activity have a significant impact on the endogenous pharmacology of kynurenic acid and significantly modulate steady-state conditions and delay the events of the ageing process.

Background/Objectives: Congenital Myasthenic Syndromes (CMS) are caused by variants in >30 genes with increasing numbers of variants of unknown significance (VUS) discovered by next generation sequencing. Establishing VUS pathogenicity requires in vitro studies that slow diagno-sis and treatment initiation. Recent protein structure prediction softwares, AlphaFold2/ColabFold, have revolutionised structural biology; such predictions have also been leveraged in AlphaM-issense which predicts ClinVar variant pathogenicity with 90% accuracy. Few reports, however, have tested these tools on rigorously-characterised clinical data. We therefore assessed ColabFold and AlphaMissense as diagnostic aids for CMS, using variants of the CHRN genes that encode the nicotinic acetylcholine receptor (nAChR). Methods: Utilising a dataset of 61 clinically-validated CHRN variants, (1) we evaluated the pos-sibility of a ColabFold metric (either predicted structural disruption, prediction confidence, and prediction quality), that distinguishes variant pathogenicity. (2) We assessed AlphaMissenses’ ability to differentiate variant pathogenicity. (3) We compared AlphaMissense to existing patho-genicity prediction programmes, AlamutVP and EVE. Results: Analysing variant effects on ColabFold CHRN structure prediction, prediction confi-dence, and prediction quality, doesn’t yield any pathogenicity-indicative metric. However, Al-phaMissense predicts variant pathogenicity with 63.93% accuracy on our dataset – a much greater proportion than AlamutVP (27.87%) and EVE (28.33%). Conclusions: Emerging in silico tools can revolutionise genetic disease diagnosis – however, im-provement, refinement, and clinical validation is imperative prior to practical acquisition.

In a systematic explorative study of genetic patterns on chromosome 19, we discovered a pattern comprised of 23 SNP alleles that is significantly associated with late-onset Alzheimer’s disease (AD). This association is validated using two independent data sets. The pattern includes THOP1, which has a long and disputatious relationship with AD. It also spans SLC39A3 and SGTA and is upstream from DIRAS1. We utilized population data to observe the frequencies of this genetic pattern for 11 different ancestries and note that it is highly common for Europeans and relatively infrequent for Africans. This research provides a distinct genetic signature for AD risk as well as insights into the complicated relationship between this disease and THOP1.

Substance abuse and psychiatric disorders are two prevalent and interrelated public health concerns that often coexist, leading to complex clinical scenarios. This comorbidity poses significant challenges in diagnosis, treatment, and understanding the causal relationships between the two conditions. Frequently, one disorder is neglected in favor of the other, and misconceptions abound regarding which condition precipitates the other. This article explores the common comorbidity of substance abuse and psychiatric disorders, delving into the prevalence, diagnostic challenges, treatment implications, and the bidirectional nature of causality. By examining current research and clinical practice, we aim to shed light on the misconceptions and emphasize the need for integrated approaches to effectively address both conditions concurrently.

Canine Multiple System Degeneration (CMSD) is an early onset, progressive movement disorder affecting Kerry Blue Terriers and Chinese Crested dogs. The associated pathologic lesions include degeneration of the cerebellum, caudate nucleus and substantia nigra. CMSD is inherited as an autosomal recessive trait in both dog breeds. Previous linkage mapping localized the CMSD locus to a 15 MB region on canine chromosome 1 (CFA1). Next generation sequencing was used to generate whole genome sequences from DNA of an affected dog from each breed. The resulting sequence reads were aligned to the NCBI canine reference genome (build 3.1). Among the homozygous sequence variants within the CFA1 target region, a nonsense variant in exon 15 of SERAC1 was identified in the affected Kerry Blue Terrier, while in the Chinese Crested dog, a 4 bp deletion in the SERAC1 exon 4 acceptor splice site was found. RT-PCR showed that this deletion resulted in exon 4 skipping. Genotyping of large cohorts of Kerry Blue Terriers and Chinese Crested dogs for the respective breed-specific SERAC1 variants showed complete concordance between genotype and disease phenotype. Genotype-phenotype concordance was also observed in offspring generated by cross breeding between SERAC1-heterozygous Kerry Blue Terrier and Chinese Crested dogs, with only the compound heterozygotes exhibiting the disease phenotype, further confirming the recessive inheritance of CMSD. Variants in human SERAC1 are associated with disorders with a range of ages of disease onset and patterns of clinical signs, but that are all characterized by movement abnormalities similar to those of the dogs with CMSD. Canine CMSD could serve as a valuable model to elucidate the mechanisms underlying SERAC1-deficiency disorders and to evaluate potential therapeutic interventions.

The precise localisation of epileptic foci with the help of EEG or ECoG signals is still a clinical challenge that is rarely successful, except in the case of foci that are very close to the surface and allow a clear assignment to a single electrode. On the research side, dipole reconstruction of instantaneous excitation fields via the lead-field matrix or the evaluation of time-dependent phase shifts in the measurements seem to be still possible and are under development. For the latter, we have investigated the necessary correlation of signals in the time range up to a few hundred milliseconds in an EEG of a healthy subject (self-experiment). We find periods of up to 190 msec in length in which a correlation over short latencies succeeds very well, alternating with periods in which long-range correlations occur while the short latencies come to a standstill. An automatic propagation time focus localisation to be developed therefore appears possible if an underlying state monitoring system independently recognises the suitable time periods and then successfully performs the comparatively shortest-range triangulation calculations over these.

Aging is a complex and inevitable biological process characterized by a gradual decline in physiological function, including increased oxidative stress, chronic inflammation, and mitochondrial dysfunction. While aging is a natural part of life, it is often accompanied by various disorders collectively known as age-related diseases (ARDs) or aging disorders. These include neurodegenerative diseases like Parkinson’s (PD), cardiovascular diseases, diabetes, osteoporosis, and frailty, among others. As the global population ages, the prevalence of ARDs such as PD and frailty is rising, necessitating innovative approaches to enhance healthy aging. Nutraceuticals are natural bioactive compounds in foods that offer health benefits beyond essential nutrition, which is pivotal in preventing and managing aging-related disorders. Nutraceuticals, with their antioxidant, anti-inflammatory, and neuroprotective properties, offer promising strategies to counteract these processes and promote healthy aging. This review highlights the potential of nutraceuticals as valuable adjuncts in managing PD and frailty, two conditions intricately linked to ARD. By examining the differential impacts of these bioactive compounds on the underlying mechanisms of each condition, this study underscores the promise of nutraceuticals in promoting healthy aging. The review aims to inform future research and clinical strategies by advocating for developing novel bioactive compounds, using advanced delivery technologies, and integrating personalized approaches based on genetic and epigenetic profiles. These efforts will pave the way for more precise, effective, and individualized interventions, ultimately extending health span and preventing ARD.

The associations among increased pain sensitivity, obesity, and systemic inflammation have not been described as a direct link between BBB dysfunctions. To analyze the metabolic, behavioral, and inflammatory effects of a HFD and ultrastructural modifications in brain regions, we used an experimental model. Adult male Wistar rats were randomly assigned to one of two conditions, an ad libitum control group, or a high-fat-diet (60%) group (HFD-fed), for eight weeks. At the end of the protocol, glucose, and insulin tolerance tests were performed. Additionally, we analyzed the response to a normally innocuous mechanical stimulus and changes in motor coordination. At the end of the protocol, HFD-fed individuals presented increased HOMA-IR and metabolic syndrome (MetS) prevalence. HFD-fed rats also developed an increased nociceptive response to mechanical stimuli and neurological injury, resulting in impaired motor function. Hypothalamus and cerebellum neurons from HFD-fed presented with nuclear swelling, an absence of nucleoli, and karyolysis. These results reveal that HFD consumption affecting vital brain structures such as the cerebellum, hippocampus, and hypothalamus. This, in turn, causes neuronal damage, impairs cellular communication, and alters motricity and pain sensitivity. Understanding the link between BBB impairment and sensory and motor changes could lead to targeted therapeutic strategies.

Botulinum toxin (BoNT) is recognized as one of the most potent neurotoxins, with a lethal dose as low as 2 ng/kg, but it has also demonstrated significant therapeutic potential in controlled doses. Produced by the gram-positive anaerobic bacterium Clostridium botulinum, BoNT exists in eight distinct serotypes (A, B, C1, C2, D, E, F, and G) that disrupt neuronal transmission by targeting the soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNARE) complex at the neuromuscular junction, inhibiting the release of acetylcholine and inducing flaccid paralysis. While BoNT is notorious for its toxicity, it has been repurposed for medical use across various clinical indications. Following their approval by the Food and Drug Administration (FDA), these toxins have been associated with significant improvements in patient outcomes, particularly for individuals with specific neuromuscular disorders such as spasticity, dystonia, and cerebral palsy, as well as non-neuromuscular conditions like hyperhidrosis and cosmetic concerns. This broad spectrum of therapeutic applications that botulinum neurotoxins offer has made them an integral part of contemporary healthcare. Considering their growing importance, a detailed evaluation of their pharmacological properties, available formulations, and clinical uses is crucial. This review provides a comprehensive analysis of BoNT's molecular structure, mechanism of action, and therapeutic applications, with a particular emphasis on the most widely used BoNT-A formulations: OnabotulinumtoxinA (Botox), AbobotulinumtoxinA (Dysport), and IncobotulinumtoxinA (Xeomin). We examine their clinical efficacy, safety profiles, and differences in pharmacological properties to guide healthcare providers in selecting the most appropriate treatment for various conditions. Additionally, the review explores the challenges of BoNT therapy, such as immunogenicity and dosing considerations, while highlighting its evolving role in neurorehabilitation and conservative treatment strategies.

Alzheimer’s disease (AD) is a progressive, degenerative brain disorder that impairs memory and thinking skills, leading to significant economic and humanistic burdens. It is associated with various neuropsychiatric symptoms (NPSs) such as anxiety, agitation, depression, aggression, apathy, and psychosis. NPSs are common in patients with AD, affecting up to 97% of individuals diagnosed with AD. The severity of NPS is linked to disease progression and cognitive decline. NPS in Alzheimer’s disease leads to increased morbidity, mortality, caregiver burden, earlier nursing home placement, and higher healthcare costs. Despite their significant impact, clinical research on NPS in AD is limited. In clinical settings, accurately distinguishing and diagnosing NPS related to AD remains a challenge. Additionally, conventional treatments for NPS in AD are often ineffective, highlighting the need for new therapies that target these specific symptoms. Understanding these comorbidities can aid in early diagnosis and better management of AD. In this review, we provide a summary of the various neurological and psychiatric symptoms (NPSs) associated with AD and new candidates under development for the treatment of NPSs based on their therapeutic targets and mechanisms. On top of the conventional NPSs studied far, this review adds recent advancements in the understanding of social functional impairment in AD. This review also provides information that can contribute to the advancement of studies and translational research in this field by emphasizing therapeutic targets and mechanism of action focused on AD-related NPS, rather than conventional mechanisms targeted in AD drug development. Above all, considering the relative lack of research in this new field despite the importance of clinical, medical, and translational research, it may increase interest in NPSs in AD, its pathophysiological mechanisms, and potential therapeutic candidates such as molecules with antioxidant potential.

This paper presents a new theory explaining the pathological mechanisms of multiple sclerosis (MS). MS is triggered by persistently activated immune cells, mainly B cells, as in reactivated Epstein-Barr virus infection. Activated immune cells release cytokines, the main one here being TNFa. A major role of TNFa is to support immune cell motility and tissue penetration, by promoting the breakdown of ceramide products that stabilize membranes (sphingomyelin (SPM) and galactosylceramide (GalCer)), by stimulating membrane breakdown via ceramide 1-phosphate-induced liberation of arachidonic acid, and by promoting the production of sphingosine 1-phosphate, a ceramide product that promotes immune motility. These ceramide products are expressed in endothelial cells, including the blood-brain barrier, and have a large presence in myelin. Thus, excessive cytokine release both allows immune penetration into the brain, and impairs existing myelin sheaths. SPM and GalCer are essential for myelin maintenance but not for its synthesis, explaining the dominant relapsing-remitting nature of the disease. The theory is supported by diverse evidence, and supports modern B cell-based treatment directions.

Traumatic brain injury (TBI) is a global healthcare concern affecting millions, with wide-ranging symptoms including sensory and behavioral changes that can persist long-term. Due to similarities with human brain cytoarchitecture and inflammation, minipig models are advantageous for translational TBI research. However, gaps in knowledge exist regarding their behavioral and sensory sequelae following injury. Therefore, in this study, we assessed changes in approachability using a forced human approach task (FHAT) and mechanical nociception using the von Frey Test in adult male and female Yucatan minipigs for up to one week following a sham or central fluid percussion injury (cFPI). Specifically, the FHAT assessed each animal’s response to a forced interaction with either a known or unknown experimenter. To evaluate changes in nociceptive sensory sensitivity, von Frey monofilaments ranging from 0.008 to 300 grams of force were applied to the pinna of the ear or base of the tail. We found that forced approachability was affected by experimenter familiarity as well as cFPI in a sex-specific manner at subacute timepoints. We also found reductions in sensitivity following cFPI on the ear in male minipigs and on the tail in female minipigs. Overall, the current study demonstrates that cFPI produces both behavioral and sensory changes in minipigs up to one-week post-injury.

Music has been proposed for a long time as a treatment for mental disorders. However, some special types of music or stimulating sounds might induce negative emotions. Herein, 8-week-old male mice were exposed to two specific genres of music, hip-hop (HH) and heavy metal (HM), and construction noise (CN), and a series of behavioral experiments were performed to evaluate the impact of these music or sounds on the emotion of mice. The experiment lasted 1 week in which 8-week-old male mice were used as animal models. We found that long term exposure HM, HH, and CN induced depressive symptoms with a decrease in dopamine receptor 1 and BDNF in the mixture of hippocampus and frontal cortex of mice. Our results have highly addressed that certain special types of sound or music might induce negative emotions and loss of dopaminergic neurons in mice, and it is necessary to intervene in adolescences who are exposed to these music or sounds for a long time.

Myalgic Encephalomyelitis (ME), sometimes called Chronic Fatigue Syndrome (CFS), is a complex, debilitating condition characterised by symptoms such as profound fatigue, autonomic dysfunction, gastrointestinal problems, unrefreshing sleep, cognitive problems, exercise intolerance and post-exertional malaise (PEM) (a worsening of symptoms after mild physical or mental effort). The pathophysiology of ME remains poorly understood. This paper proposes a novel hypothesis centred on norepinephrine dysregulation and insulin signaling as the underlying mechanisms contributing to distinct subtypes of ME. I hypothesise that ME can be categorised into three subtypes based on variations in norepinephrine transport and insulin signaling: ME1, ME2, and ME3. In ME1, a higher than normal rate of insulin secretion during the first phase insulin response and/or hypersensitive insulin receptors leads to reduced neuronal norepinephrine reuptake, resulting in elevated extracellular norepinephrine and subsequent down-regulation of beta-2 adrenergic receptors. ME2 is characterised by prolonged insulin release and insulin resistance, which may contribute to the development of postural orthostatic tachycardia syndrome (POTS) and microclot formation. ME3 is marked by reduced norepinephrine synthesis and a resultant deficiency of norepinephrine within neurons. All three subtypes involve a deficiency of norepinephrine inside the noradrenergic neuron which is worsened by physical and mental exertion. There are many similarities between ME and Long COVID. Both have their onset after a virus and have a similar symptom profile, as well as having the same co-occurring conditions such as mast cell activation and POTS. It is quite possible that a subset of Long COVID patients have ME, and so I will be referring to both ME and Long COVID research papers throughout this hypothesis paper. This hypothesis integrates genetic, metabolic, and neuroendocrine data to delineate these subtypes and suggests tailored diagnostic and therapeutic approaches for each. This hypothesis aims to guide future research into the distinct pathophysiological mechanisms of ME and enhance understanding and management of this debilitating condition.

The social fear conditioning (SFC) paradigm, which is an animal model of social anxiety disorder, has been extensively used to investigate the cellular and molecular mechanisms underlying the psychopathology of this disorder. Studies using the SFC paradigm have suggested that the lateral septum plays a pivotal role in regulating social fear. While several lines of evidence have indicated the involvement of various neuronal mechanisms within the LS in modulating social fear, the role played by LS astrocytes in the tripartite synapses in regulating social fear expression is not yet fully understood. Over the years, astrocytes have emerged as key players in regulating synaptic transmission and a plethora of animal behaviors. Given their dynamic morphological and molecular response to various stimuli, studying astrocyte morphology remains an excellent tool for understanding their role in brain function and disease. By applying immunofluorescent-immunohistochemical methods, here we describe a protocol to characterize changes in the morphology of astrocytes in response to social fear acquisition using confocal microscopy.

Astrocytes, the most abundant glial cells in the brain, are an integral part of the synaptic compartment and contribute to synaptic pruning, a key process for refining neural circuits during early postnatal development (PND). Dysregulations in this process are implicated in various neuropsychiatric disorders, including major depressive disorder (MDD). To investigate astrocyte functions in a physiologically relevant context, organotypic brain slice cultures (OBSCs) offer a powerful model, reproducing more closely in vivo conditions than traditional cell cultures and preserving complex brain architecture and interactions. Here, we present OBSCs as an ex vivo culturing method to provide a platform to explore astrocyte-mediated synaptic pruning dynamics in the rat prefrontal cortex (PFC) during PND. Our approach is based on assessing the role of MEGF10, a key protein involved in synaptic pruning, alongside the synaptic markers synaptophysin and PSD95, using Western blotting to analyse the expression levels of these markers in the cortex of developing rat pups. Additionally, we combine immunofluorescence staining with confocal imaging and IMARIS 9.8 software-assisted analysis to investigate the co-localization of the lysosomal marker LAMP1 with synaptic and astrocytic markers to evaluate the precise rate of synaptic engulfment. The methods presented here allow a deeper examination of an astrocyte-mediated synaptic remodelling in healthy and pathophysiological conditions.

Immunofluorescent methods in vitro have been widely used to characterize the distribution and extent of colocalization of molecules located in various intracellular compartments. These are key processes to better understand the role of those molecules in physiological and pathological conditions.In the brain, interactions of astrocytes with neurons are fundamental for the establishment and proper functioning of neuronal circuits. Among these, the phagocytosis of synapses that need to be removed is a process known as synaptic pruning. When this process is dysregulated, it might lead to the development of several brain disorders. Here, we describe the adaptation of a method to characterize the astrocyte-mediated synaptic phagocytosis and evaluate astrocytic (dys)functions in healthy cells and cells derived from an animal model of major depressive disorder (MDD).

People with aphantasia exhibit the inability to voluntarily generate or form mental imagery in their minds. Since the term “aphantasia” was proposed by Zeman et al. in 2015 to describe this, it has gained increasing attention from psychiatrists, neuroscientists, and clinicians. Previous studies have mainly focused on definition, prevalence, and measurement, its impacts on individuals’ cognitive and emotional processing, and theoretical frameworks synthesizing existing findings, which have contributed greatly to our understanding of aphantasia. However, there are still some debates regarding the conclusions derived from existing research and the theories that were constructed from various sources of evidence. Building upon existing endeavors, the current systematic review emphasizes that future research is much needed to refine definition and diagnosis of aphantasia, strengthen empirical investigations at behavioral and neural levels, and more importantly, develop or update theories. These multiple lines of efforts could lead to a deeper understanding of aphantasia and further guide researchers in future research directions.

Transactive response DNA-binding protein of 43 kDa (TDP-43) is a major component of pathological inclusions in various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The detection of TDP-43 in biofluids is crucial for the development of diagnostic and prognostic indicators of disease and therapeutic development for TDP-43 related proteinopathies. Despite its potential as a biomarker for numerous neurological disorders, the lack of a sensitive and reproducible TDP-43 assay hinders progress in TDP-43-based therapy development, underscoring the need for an effective and standardized method for accurate quantification. In this study, we developed and validated a sensitive immunoassay for the detection of TDP-43 in human biofluids using the Meso Scale Discovery (MSD) platform. We used this immunoassay to quantify TDP-43 levels in the plasma and serum of healthy controls and ALS patients. Our results indicate a reduction of total TDP-43 in the blood of ALS patients compared to healthy controls.

Alzheimer’s disease (AD), the leading cause of dementia (50-70%), is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and significant neuropathological changes, including β-amyloid plaques and neurofibrillary tangles. This review synthesizes current understanding of the complex interplays that contribute to the pathogenesis of AD, while exploring the mechanisms underlying the formation of β-amyloid plaques and neurofibrillary tangles, with a focus on the amyloidogenic and non-amyloidogenic pathways, Tau protein hyperphosphorylation, and the resultant neurotoxicity. Furthermore, the study delves into mitochondrial dysfunction and oxidative stress as critical contributors to neuronal degeneration, highlighting the mitochondrial cascade hypothesis and its implications in both early (EOAD) and late-onset AD (LOAD). The study emphasizes the irreversible nature of the disease’s progression, detailing the pathological transformations from the preclinical to the severe stage, where lesions disseminate throughout the entire cortex.

Although significant progress has been made in understanding the cortical correlates underlying balance control, these studies focused on a single task limiting the ability to generalize the find-ings. Different balance tasks may elicit cortical activations in the same regions but show different levels of activation because of distinct underlying mechanisms. In this study, we instructed twenty young, neurotypical adults to maintain standing balance while the standing support surface was either translated or rotated and investigated the differences in cortical activations between these two widely used tasks using whole head electroencephalography (EEG). Addi-tionally, we investigated whether transcranial magnetic stimulation could modulate these cortical activations. We found higher delta and lower alpha relative power over the fronto-central region during the platform translation task when compared to the platform rotation task suggesting greater engagement of attentional and sensory integration resources for the former. Continuous theta burst stimulation (cTBS) over the supplementary motor area (SMA) significantly reduced delta activity in the fronto-central region but did not alter alpha activity during the platform translation task. Our results provide a direct comparison of neural activations between two commonly used balance tasks and are expected to lay a strong foundation for designing neuro-interventions for balance improvements with effects generalizable across multiple balance scenarios.

Migraine is a neurological disorder characterized by severe disabling headaches with a substantial global burden and elevated morbidity rates. Extensive research has established a clear association between migraine and sex/gender, with a notably higher incidence reported in females, reaching up to 18%, which is three times greater compared to males. Additionally, women commonly experience more intense pain and greater frequency of migraine symptoms, both with and without aura, highlighting the differential impact of sex/gender on migraine presentation. This review comprehensively examines the pathophysiology of migraine, with a particular focus on the effects of sex hormones in migraine pathophysiology and the central nervous system. Furthermore, we explore various treatment modalities tailored to gender differences, including pharmacological interventions and emerging therapeutic approaches. Furthermore, we explored alternative treatment strategies such as nutraceuticals and behavioural techniques, including mindfulness and cognitive behavioural therapy. This review aims to provide a comprehensive overview of the multifaceted nature of migraine and the diverse therapeutic approaches available for their management.

Nonlinear single unit activity (SUA) characteristics are the useful measures to reveal the information processing and transfer features associated with Parkinson’s disease (PD) in the basal ganglia. Most of the state-of-the-art approaches to compute such parameters in continuous and discrete forms are strongly dependent on SUA recording length, noise level and input parameters. Due to the specificity of SUA data collection (mainly short recordings with relatively low signal-to-noise ratio) new techniques to evaluate neuronal nonlinear properties are needed. We have developed an encoding technique based on a mean interspike interval (ISI) value to calculate spike train discrete nonlinear features. The approach to compute mutual information (MI) of isolated neurons with its unstructured activity was also proposed. The proposed technique of SUA nonlinear features evaluation slightly depends on spike train length, has low correlations with other SUA characteristics (firing rate, coefficient of ISI variance and asymmetry index). The derived entropy measure in the subthalamic nucleus has significant positive correlation with PD severity. The proposed approach provides nonlinear features that are slightly dependent on investigated sample size and independent on input parameters. Also, the developed mean ISI based measures reflect the more complex nature of oscillatory activity in the basal ganglia, than it was thought previously. Moreover, MI, unlike entropy, takes into account the position of the spike train elements, which allows us to investigate the amount of information retained after the occurrence of temporary failures. The developed approach may be useful in describing nonlinear features of basal ganglia activity contributing to PD pathophysiology probably associated with impaired information transfer in movement disorders.

The authors propose a novel approach for a comprehensive evaluation of neuroprotective effects using both in vitro and in vivo methods. This approach allows for the initial screening of numerous newly synthesized chemical compounds and substances from plant and animal sources while preserving animal life. In vitro techniques, including mitochondrial suspensions and neuronal cell cultures, enable assessment of neuroprotective activity, which can be challenging in intact organisms. The preliminary methods help outline the neuroprotection mechanism depending on the neurodestruction agent. The authors have validated a model of acute cerebrovascular accident, which simulates key cerebrovascular phenomena such as reduced cerebral blood flow, energy deficit, glutamate-calcium excitotoxicity, oxidative stress, and early gene expression. A significant advantage of this model is its ability to reproduce the clinical picture of cerebral ischemia: impaired motor activity, signs of neurological deficits (paresis, paralysis, etc.), as well as disturbances in attention, learning, and memory. Crucial to this approach is the selection of biochemical, molecular, and cellular markers to evaluate nerve tissue damage and characterize potential neuroprotective agents. Additionally, a comprehensive set of molecular, biochemical, histological, and immunohistochemical methods is proposed for evaluating neuroprotective effects and underlying mechanisms of potential pharmaceutical compounds.

The human brain is highly dependent on oxygen, utilizing approximately 20% of the body’s oxygen at rest. Oxygen deprivation to the brain can lead to loss of consciousness within seconds and death within minutes. Recent studies have identified regions of the brain with spontaneous episodic hypoxia, referred to as "hypoxic pockets." Hypoxia can also result from impaired blood flow due to conditions such as heart disease, blood clots, stroke, or hemorrhage, as well as from reduced oxygen intake or excessive oxygen consumption caused by factors like low ambient oxygen, pulmonary diseases, infections, inflammation, and cancer. Severe hypoxia in the brain can manifest symptoms similar to Parkinson’s disease (PD), including cerebral edema, mood disturbances, and cognitive impairments. Additionally, the development of PD appears to be closely associated with hypoxia and hypoxic pathways. This review seeks to investigate the molecular interactions between hypoxia and PD, emphasizing the pathological role of hypoxic pathways in PD and exploring their potential as therapeutic targets.

The acoustic startle response (ASR) is an explosive motor response leaded by a sudden and intense acoustic stimulus. ASR has several clinically relevant forms of plasticity, including habituation and sensorimotor gating. Although ASR and its plasticity have been intensively studied in different animal models, including zebrafish (Danio rerio) larvae, information in adult zebrafish is still very scarce. In this manuscript we present Zebra_K, a new automated high-content kinematic analysis platform for assessing ASR, its habituation and prepulse inhibition (PPI), a quantitative measure of sensorimotor gating, in adult zebrafish. The analysis of the kinematic parameters in 1,875 ASR in adult zebrafish has shown a single response wave consistent with the short-latency C-bend described in zebrafish larvae. Moreover, protocols have been designed and validated in Zebra_K for the analysis of sensitivity, habituation and PPI of this response. Then, this platform has been used to determine the effect of pharmacological and physiological modulators of ASR plasticity. As described in other animal models, the NMDA-receptor antagonist ketamine increased the responsiveness to the acoustic stimuli, decreasing habituation and leading to complete abolition of PPI. Moreover, the effect of the gender on zebrafish ASR plasticity has been analyzed for the first time. Females exhibited higher responsiveness and a lower habituation and PPI than males, a result consistent with the gender effect described in other animal models and in humans. These results enhance the interest of using adult zebrafish to assess the potential effect of chemicals or genetic manipulations on ASR plasticity.

Sleep disturbances and chronic pain are prevalent and interrelated conditions that significantly impact individuals' quality of life. Understanding the intricate dynamics between sleep and pain is crucial for developing effective treatments that enhance the well-being of affected individuals and reduce the economic burden of these debilitating conditions. This narrative review examines the complex relationship between sleep disturbances and chronic pain. We describe the prevalence and types of sleep disturbances and sleep disorders in chronic pain patients. Posteriorly we critically review the clinical and experimental evidence investigating the relationship between sleep disturbances and chronic pain aiming to clarify the impact of chronic pain on sleep and, conversely, the impact of sleep disturbances on pain perception. We conclude that a bidirectional relationship between chronic pain and sleep disturbances is almost a consensus in the literature, however, the strength of each direction of the association is less clear. As of now, the literature suggests that sleep impairment is a stronger predictor of pain than pain is a predictor of sleep impairment. Additionally, addressing sleep disturbances in chronic pain patients is crucial, as poor sleep has been linked to higher levels of disability, depression, and pain-related catastrophizing.

Under physiological conditions the blood-brain barrier (BBB) is required for regulating the passage of substances between the bloodstream and the brain. To date, disruption of the BBB has been associated with nearly all neurological diseases. Dye and tracer experiments have been used to assess BBB integrity for decades, yet quantitative assessment of these experiments has only recently been implemented. Further, interpretation of these results requires the consideration of tracer-specific properties. Here, we describe a protocol for evaluating BBB leakage using the small molecule cadaverine in quantitative way. We also cover advantages/disadvantages of using some reagents and highlight limitations in data interpretations based on assays used to assess BBB permeability.

The traditional understanding of brain function has predominantly focused on chemical and electrical processes. However, new research in fruit fly (Drosophila) binocular vision reveals ultrafast photomechanical photoreceptor movements significantly enhance information processing, thereby impacting a fly's perception of its environment and behaviour. The coding advantages resulting from these mechanical processes suggest that similar physical motion-based coding strategies may affect neural communication ubiquitously. The theory of neural morphodynamics proposes that rapid biomechanical movements and microstructural changes at the level of neurons and synapses enhance the speed and efficiency of sensory information processing, intrinsic thoughts, and actions by regulating neural information in a phasic manner. We propose that morphodynamic information processing evolved to drive predictive coding, synchronising cognitive processes across neural networks to match the behavioural demands at hand effectively.

Proper blood-brain barrier (BBB) function is essential to maintain homeostasis keeping the central nervous system healthy. Disruption of the BBB has been described in nearly all neurological disease and injury contexts. Given the various physical and metabolic roles of the BBB and gliovascular unit (GVU), dysfunction should be assessed across multiple levels to pinpoint the exact nature of the impairment. Here we describe imaging techniques for evaluating various aspects of BBB and GVU integrity and function, tailored for use in mouse models with protocols for quantitative image analysis. These imaging techniques complement classical dye tracer experiments and reveal underlying molecular causes of BBB dysfunction.

The microvessel neurovascular unit with its brain endothelial cell (BEC) and blood-brain barrier remodeling is important in the development of impaired cognition in sporadic or late-onset Alzheimer’s disease (LOAD) and vascular dementia or vascular cognitive impairment and dementia including cerebral amyloid angiopathy in neurodegeneration. LOAD is considered to be the number one cause of dementia globally; however, when one considers the role of mixed dementia (MD) (the combination of both the amyloid cascade hypothesis and the vascular hypothesis of LOAD), it becomes apparent that MD is the number one cause. The microvessel BECs are the first cells in the brain to be exposed to the peripheral neurotoxins of the systemic circulation and are therefore the brain cells at the highest risk for early and chronic injury. Therefore, it is not surprising that microvessel BECs are the first cells to undergo injury and the response to injury wound healing mechanism and remodeling that is excessive and recurrent in the aging process plus other age-related diseases such as cerebro-cardiovascular disease, hypertension, type 2 diabetes mellitus, Parkinson’s disease, plus others. This narrative review explores the intricate relationship between microvessel remodeling, cerebral small vessel disease (SVD), and neurodegeneration as occurs in LOAD. Further, it discusses the current understanding of how microvessel dysfunction, disruption, and pathology contribute to the pathogenesis of LOAD and thus, highlights potential avenues for therapeutic interventions.

This study addresses the gap in methodological guidelines for Neuroergonomic attention assessment in safety-critical tasks, focusing on validating EEG indices including the Engagement Index (EI) and Beta/Alpha ratio alongside subjective ratings. A novel task-embedded reaction time paradigm was developed to evaluate the sensitivity of these metrics to dynamic attentional demands in a more naturalistic multitasking context. By manipulating attention levels through varying secondary tasks in the NASA MATB-II task while maintaining a consistent primary reaction-time task, the study successfully demonstrated the effectiveness of the paradigm. Results indicate that both Beta/Alpha ratio and EI are sensitive to changes in attentional demands, with Beta/Alpha being more responsive to dynamic variations in attention, and EI reflecting more the overall effort required to sustain performance, especially in conditions where maintaining attention is challenging. The potential for predicting the attention lapses through integration of performance metrics, EEG measures, and subjective assessments was demonstrated, providing a more nuanced understanding of dynamic fluctuations of attention in multitasking scenarios, mimicking those in real-world safety-critical tasks. These findings provide a foundation for advancing methods to accurately monitor attention fluctuations and mitigate risks in critical scenarios, such as train-driving or automated vehicle operation, where maintaining high attention level is crucial.

Objectives: Teachers’ intention understanding ability reflects their professional insight, which is the basis for effective classroom teaching activities. However, the cognitive process and brain mechanism of how teachers understand students' action intention in class are still unclear; Methods: This study used event-related potential (ERP) technology to explore the cognitive neural differences in intention understanding ability among teachers with different levels of knowledge and experience. The experiment used the comic strips paradigm to examine the ability of expert and novice teachers to understand students’ normative and non-normative classroom actions under different text prompts (“how” and “why”); Results: The results revealed that in the late time window, expert teachers induced larger P300 and LPC amplitudes when they understood students' classroom action intentions, while the N250 amplitudes induced by novice teachers in the early time window were significantly larger. In addition, for both types of teachers, when understanding the intentions behind students’ normative actions, the N250 amplitude was the most significant, while the P300 and LPC amplitudes were more significant for non-normative actions.; Conclusions: This study found that teachers at varying professional development stages had different time processing processes in intention understanding ability, which supported teachers' brain electrophysiological activities related to social ability.

Our previous study demonstrated that the acute high-dose rate (3.3 Gy/minute) gamma irradiation of postnatal day 3 (P3) mice with 5Gy induced depression and drastic neuropathological changes in the dentate gyrus of the hippocampus of the adult mice. The present study investigated the effects of chronic low-dose-rate (1.2mGy/h) gamma irradiation from P30 to P180 with a cumulative dose of 5Gy on animal behaviour, hippocampal cellular change, miRNA and mRNA expression in the hippocampus and blood in female mice. The radiation exposure did not significantly affect the animal's body weight and neuropsychiatric changes such as anxiety and depression examined by neurobehavioural tests including open field, light-dark box, elevated plus maze, tail suspension test and forced swim test. Immunohistochemical staining did not detect any obvious loss of mature and immature neurons (NeuN and DCX) or any inflammatory glial response (IBA1, GFAP, and PDGFR1). Nevertheless, r-H2AX foci in the stratum granulosum of the dentate gyrus were significantly increased, suggesting the chronic low dose rate irradiation induced persistent DNA damage foci in mice. miRNA sequencing and qRT-PCR indicated an increased expression of miR-448-3p and miR-361-5p, but decreased expression of miR-193a-3p in the mouse hippocampus. Meanwhile, mRNA sequencing and qRT-PCR showed a reduced expression of Ccn1, Fli1, Fosb, Ets1, Hs3st5, and Eif4ebp1, but enhanced expression of Cort, Foxh1, and Opalin. Database searching by miRDB and TargetScan predicted that FLI1 and HS3ST5 are the targets of miR-448-3p, and Eif4ebp2 is the target of miR-361-5p. miRNA/mRNA sequencing and qRT-PCR results in blood showed the increased expression of miR-6967-3p and the decreased expression of its target S1pr5. The interactions of these miRNAs and mRNAs may contribute to the chronic low dose rate radiation-induced persistent DNA damage.

Immersive virtual reality has the potential to motivate and challenge patients that need and want to relearn movements in the process of (neuro-)rehabilitation. The aims of this study were to evaluate the feasibility and users’ acceptance of an innovative immersive virtual reality system (head-mounted display) used in combination with robot assisted gait training in subjects suffering from neurological diseases. Fifteen participants tested a single session of immersive virtual reality by means of head-mounted display during a Lokomat gait session. Training parameters and safety indicators were collected and the acceptance was investigated among the participants and the therapists. The results suggest that the immersive virtual reality system is feasible with respect to safety and tolerance. Furthermore, the very positive overall acceptance of the system suggests that it has potential to be included in a robot assisted gait training session by means of Lokomat. Taken together, this study demonstrates the feasibility and acceptance of an innovative immersive virtual reality system in combination with a robot assisted gait training in subjects suffering from stroke and spinal cord injury, as well as their therapists.

The study of the pathogenesis of febrile seizures and their consequences frequently necessitates gene expression analysis. The primary methodology employed for such analysis is reverse transcription with quantitative polymerase chain reaction (RT-qPCR). To guarantee the accuracy of data obtained by RT-qPCR, it is crucial to utilize stably expressed reference genes. The objective of this study was to identify the most suitable reference genes for use in the analysis of mRNA production in various brain regions of rats following prolonged neonatal febrile seizures. The expression stability of eight housekeeping genes was evaluated using the online tool RefFinder in the dorsal and ventral hippocampal regions and in the temporal and medial prefrontal cortex of the brain. The Ppia gene exhibited the greatest stability of expression. Conversely, the genes with the least stable expression level are Actb and Ywhaz; thus, it is not recommended to use them for normalization in a febrile seizure model. Additionally, the majority of housekeeping genes demonstrate age-related, region-specific fluctuations. Therefore, it is crucial to employ the appropriate housekeeping genes for each brain structure under investigation when examining the expression dynamics of genes of interest in a febrile seizure model.

Glutamate transporter-1 (GLT-1) dynamics are implicated in excitotoxicity and Alzheimer's disease (AD) progression. Early stages of AD are often marked by hyperactivity and increased epileptiform activity preceding cognitive decline. Previously, we identified a direct interaction between GLT-1 and Presenilin 1 (PS1) in the brain, highlighting GLT-1 as a promising target in AD research. This study reports the significance of this interaction and uncovers a novel role of GLT-1 in modulating amyloid-beta (Aβ) production. Overexpression of GLT-1 in cells reduces the levels of Aβ40 and Aβ42 by decreasing γ-secretase activity pertinent to APP processing and induces a more "open" PS1 conformation, resulting in decreased Aβ42/40 ratio. Inhibition of the GLT-1/PS1 interaction using cell-permeable peptides produced an opposing effect on Aβ, highlighting the pivotal role of this interaction in regulating Aβ levels. These findings emphasize the potential of targeting GLT-1/PS1 interaction as a novel therapeutic strategy for AD.

Zebrafish (Danio rerio) is an important animal model for a wide range of neurodegenerative diseases. However, obtaining the cellular resolution that is essential for studying the zebrafish brain remains challenging as it requires high-spatial resolution and signal-to-noise ratios (SNR). In the current study, we present the first MRI results of the zebrafish brain at the state-of-the-art magnetic field strength of 28.2 T. The performance of MRI at 28.2 T was compared to 17.6 T. A 20% improvement in SNR was observed at 28.2 T as compared to 17.6 T. Excellent contrast, resolution, and SNR allowed the identification of several brain structures. The normative T1 and T2 relaxation values were established over different zebrafish brain structures at 28.2 T. To zoom into the white matter structures, we applied diffusion tensor imaging (DTI) and obtained axial, radial, and mean diffusivity, as well as fractional anisotropy at a very high spatial resolution. Visualization of white matter structures was achieved by short-track track-density imaging by applying the constrained spherical deconvolution method (stTDI CSD). For the first time, an algorithm for stTDI with multi-shell multi-tissue (msmt) CSD was tested on zebrafish brain data. A significant reduction of false-positive tracks from grey matter signals was observed compared to stTDI with single-shell single-tissue (ssst) CSD. This allowed the non-invasive identification of white matter structures at high resolution and contrast. Our results show that ultra-high field DTI and tractography provide reproducible and quantitative maps of fibre organization from tiny zebrafish brains, which can be implemented in the future for a mechanistic understanding of disease-related microstructural changes in zebrafish models of various brain diseases.

Background/Objectives: Determining the outcome of epilepsy is crucial for making proactive and timely treatment decisions, as well as for counseling patients. Recent research efforts have focused on using various imaging techniques and EEG for prognostication; however, there is insufficient evidence regarding the role of blood parameters. Our study aimed to investigate the additional prognostic value of routine blood parameters in predicting epilepsy outcomes. Methods: We analyzed data from 1,782 patients who underwent routine blood tests within 90 days of their first visit and had a minimum follow-up duration of three years. The etiological types were structural (35.1%), genetic (14.2%), immune (4.7%), infectious (2.9%), and unknown (42.6%). The outcome was defined as the presence of seizures in the last year. Results: Initially, a multivariate analysis was conducted based on clinical variables, MRI, and EEG data. This analysis revealed that sex, age of onset, epileptiform discharge, structural etiology, and the number of antiseizure medications were related to the outcome, with an area under curve (AUC) of 0.708. Among the blood parameters, fibrinogen, bilirubin, uric acid, and aPTT were significant, with AUCs of 0.602, 0.597, 0.455, and 0.549, respectively. Including these blood parameters in the analysis slightly improved the AUC to 0.713. Conclusions: Some blood parameters were found to be related to the final outcome, potentially paving the way to understanding the mechanisms of epileptogenesis and drug resistance.

In vivo proton (1H) magnetic resonance spectroscopy (MRS) is a powerful noninvasive method which can measure Alzheimer’s disease (AD) related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis, but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by 1H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of 1H MRS metabolites with biofluid, PET, and postmortem AD biomarkers, and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate to develop potential novel therapeutic approaches.

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (Fth-1), ferritin light-chain (Ftl), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCI were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher Ftl and Fth-1 associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% Confidence Interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher Ftl and Fth-1 associated with better NPZ-4 (Ftl: adjusted beta (β)=0.15, 95% CI 0.02-0.29; Ftl-by-sex βinteraction=0.32, p=0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (Ftl: rho=-0.47, p<0.001). Circulating Ftl and Fth-1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate underlying mechanisms.

Cognitive impairment is a core feature of schizophrenia, playing a pivotal role in understanding the causes, processes, and outcomes of the disorder. Cognitive impairments in schizophrenia encompass a wide range of domains, including processing speed, episodic memory, working memory, and executive function. These deficits persist throughout the course of the illness and significantly impact functional outcome and quality of life. Therefore, identifying the biological basis of cognitive deficits in schizophrenia and developing effective treatments are imperative. The role of N-methyl-D-aspartate (NMDA) receptors in synaptic transmission and plasticity has long been recognized, making them potential targets for schizophrenia treatment. This review will focus on emerging pharmacology targeting NMDA receptor, offering strategies for the prevention and treatment of cognitive deficits in schizophrenia.

Diabetic peripheral neuropathy (DPN) is a prevalent complication of type 2 diabetes that affects a significant proportion of diabetic patients worldwide. Although the pathogenesis of DPN involves axonal atrophy and demyelination, the exact mechanisms remain elusive. Current research has predominantly focused on neuronal damage, overlooking the potential contributions of Schwann cells, which are the predominant glial cells in the peripheral nervous system. Schwann cells play a critical role in neurodevelopment, neurophysiology, and nerve regeneration. This review highlights the emerging understanding of the involvement of Schwann cells in DPN pathogenesis. This review explores the potential role of Schwann cell plasticity as an underlying cellular and molecular mechanism in the development of DPN. Understanding the interplay between Schwann cell plasticity and diabetes could reveal novel strategies for the treatment and management of DPN.

Withania somnifera (WS), also known as ashwagandha, is a popular botanical supplement used to treat various conditions including memory loss, anxiety and depression. Previous studies from our group showed an aqueous extract of WS root (WSAq) enhances cognition and alleviates markers for depression in Drosophila. Here, we sought to confirm these effects in the 5xFAD mouse model of β-amyloid (Aβ) accumulation. Six- to seven-month-old male and female 5xFAD mice were treated with WSAq in their drinking water at 0 mg/mL, 0.5 mg/mL or 2.5 mg/mL for four weeks. In the fourth week of treatment, spatial memory, anxiety and depressive-like symptoms were evaluated. At the conclusion of behavioral testing, brain tissue was harvested, immunohistochemistry was performed, and the cortical expression of antioxidant response genes was evaluated. Both concentrations of WSAq improved spatial memory and reduced depressive and anxiety-related behavior. These improvements were accompanied by a reduction in Aβ plaque burden in the hippocampus and cortex and an attenuation of neuroinflammatory markers. Antioxidant response genes were upregulated in the cortex of WSAq treated mice. Oral WSAq treatment could be beneficial as a therapeutic option in AD for improving disease pathology and behavioral symptoms. Future studies focused on dose optimization of WSAq administration and further assessment of the mechanisms by which WSAq elicits its beneficial effects will help inform the clinical potential of this promising botanical therapy.

The role of astro- and microglial cells in the pathogenesis of epilepsy is currently under active in-vestigation. It is proposed that the activity of these cells may be regulated by agonists of peroxi-some proliferator-activated nuclear receptors (PPARs). The objective of this study was to investi-gate the effects of the PPAR β/δ agonist GW0742 (Fitorine) on the behavior and gene expression of astro- and microglial proteins involved in the regulation of epileptogenesis in rat brain in a lithi-um-pilocarpine model of temporal lobe epilepsy (TLE). A seven-day administration of GW0742 at a dose of 5 mg/kg/day has been shown to suppress TLE-related behavioral hyperactivity in the Open Field test and to attenuate the TLE-induced increase in gene expression and protein levels of astro- and microglial activation markers Gfap and Aif1 in the dorsal hippocampus and temporal cortex. Furthermore, GW0742 reversed the TLE-related increase in Lcn2 gene expression (a marker of the A1 phenotype of astrocytes) in the temporal cortex, the increase in the ratio of Nos2/Arg1 gene expression (markers of the M1/M2 phenotypes of microglia), and the decrease in Arg1 gene ex-pression in the dorsal hippocampus. The results suggest that GW0742 may mitigate behavioral and biochemical abnormalities in a lithium-pilocarpine model of TLE.

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a recognized treatment in Parkinson’s disease (PD), but knowledge is still limited regarding its possible impact on patients with behavioral addiction (BA) who undergo surgery. To assess this effect of STN-DBS, we prospectively studied the follow-up from 3-months pre-surgery to 12-months post-surgery of 12 PD patients with pre-existing BA (9 with pathological gambling disorder, 2 with hypersexual disorder, and 1 with compulsive shopping disorder) in a multicenter study. Patients were assessed for BA, for mental status with anxiety, depression, mania, emotional process and for PD, using the Unified Parkinson’s Disease Rating Scale motor examination (UPDRS3) and cumulative daily L-dopa equivalent daily dose (LEDD). Mean 6 and 12-month post-surgery scores were compared to baseline. After one year of STN-DBS, our results indicated that the treatment remained generally effective and stable. There was no effect on mania state or negative impact on motor signs. A significant improvement of the anxiety score was also observed. The STN is an interesting target for new therapeutic stimulation in BA and works to investigate the precise target in this neurobiological architecture should be performed in the future.

Mitochondria are dynamic organelles that can adjust and respond to different stimuli within a cell. This plastic ability allows them to effectively coordinate several cellular functions in cells and becomes particularly relevant in highly complex cells such as neurons. An imbalance in mitochondrial dynamics can disrupt mitochondrial function, leading to abnormal cellular function and ultimately to a range of diseases, including neurodegenerative disorders. Regulation of mRNA transport and local translation inside neurons is crucial for maintaining the proteome of distal mitochondria, which is vital for energy production and synaptic function. A significant portion of the axonal transcriptome is dedicated to mRNAs for mitochondrial proteins, emphasizing the importance of local translation in sustaining mitochondrial function in areas far from the cell body. In neurons, local translation and the regulation of mRNAs encoding mitochondrial-shaping proteins could be essential for synaptic plasticity and neuronal health. The dynamics of these mRNAs, including their transport and local translation, may influence the morphology and function of mitochondria, thereby affecting the overall energy status and responsiveness of synapses. Comprehending the mitochondria-related mRNAs regulation and local translation, as well as its influence on mitochondrial morphology near the synapses will help to better understand neuronal physiology and neurological diseases where mitochondrial dysfunction and impaired synaptic plasticity play a central role.

This review provides a comprehensive analysis of the pelvic plexus and its regulation across various mammalian species, including rats, cats, dogs, and pigs. The pelvic and hypogastric nerves play crucial roles in regulating pelvic functions such as micturition, defecation, and erection. The anatomical organization of these nerves varies, forming either well-defined ganglia or complex plexuses. Despite these variations, the neurons within these structures are consistently regulated by key neurotransmitters—norepinephrine and acetylcholine. These neurons also possess receptors for testosterone and prolactin, particularly in rats, indicating the significant role of these hormones in neuronal function and development. Moreover, neuropeptides such as vasoactive intestinal peptide (VIP), substance P, neuropeptide Y (NPY), somatostatin (SOM), galanin (GAL), and calcitonin gene-related peptide (CGRP) are co-released with neurotransmitters to modulate pelvic functions. This review highlights the complex interplay between neurotransmitters, neuropeptides, and hormones in regulating pelvic physiology and emphasizes the importance of hormonal regulation in maintaining the functionality and health of the pelvic plexus across different species.

Neurologic disorders such as traumatic brain injury, multiple sclerosis, Alzheimer’s disease, and drug-resistant epilepsy have a high socioeconomic impact around the world. Current therapies for these disorders are often not effective. This creates a demand for the development of new therapeutic approaches to treat these disorders. Recent data suggest that autoreactive naturally occurring immunoglobulins produced by subsets of B cells called B1 B cells combined with complement are actively involved in the processes of restoration of neuronal functions during pathological conditions and remyelination. The focus of this review is to discuss the possibility of creating specific therapeutic antibodies that can activate and fix complement to enhance neuronal survival and promote central nervous system repair after injuries associated with many types of neurodegenerative diseases.

White adipose tissue (WAT) and gut are involved as inducers of neuroinflammation when they detect injury and trigger inflammation. The autonomous nervous system innervates both tissues, although the roles of the sympathetic, parasympathetic and enteric nervous systems have not been fully elucidated. Here, we revisited the participation of both types of inflamed peripheral tissue in neuroinflammation. We first analyzed how inflamed peripheral WAT plays a key role in neuroinflammation once metainflammation is installed. Second, we described the impact of insulin resistance (IR) on hypothalamic dysfunction, T2DM and neurodegenerative diseases. Finally, we analyzed the gut-brain axis, examining cell interactions, soluble factors, the sensing of microbes and the role of the intestinal microbiota and mucosal barriers in neuroinflammation. Since intestinal mucosa and secondary lymphoid organs are densely innervated by the sympathetic, parasympathetic, and enteric nervous systems, we analyzed bidirectional crosstalk between different tissues, neurons, and immune systems in healthy and pathological circumstances to restore normal tissues functions, and consequently homeostasis.

A unique nucleus, the cerebrospinal fluid-contacting nucleus (CsfR), has been identified in the brain parenchyma. This nucleus features neurons with somas located within the parenchyma and processes extending into the cerebrospinal fluid (CSF). This anatomical configuration suggests that the CsfR may serve as a crucial interface between the nervous and body fluid regulatory systems, potentially playing a significant role in overall physiological modulation. Despite its importance, the precise biological significance of the CsfR remains to be fully elucidated. Previous research has characterized the CsfR in rats, detailing its position, adjacency, neuron distribution, size reconstruction, and stereotaxic coordinates in rats and non-human primates. Given the relevance of mice as a model organism, especially the C57BL/6J strain, this study aims to explore the existence and morphology of the CsfR in mice. Our findings confirm the presence of the CsfR, consistently located in the ventral gray area of the lower part of the aqueduct and the upper part of the fourth ventricle floor. It is bilaterally symmetrical and heart-shaped, which is slightly different from the Y-shape observed in rats. This study provides significant references for researchers investigating this specialized nucleus.

The use of pesticides such as rotenone can lead to toxicity, dysfunction and neuronal death in humans. The Copaifera Reticulata Ducke Oil-Resin (CPOR) is widely used by the natives of the Amazon, however, studies on its potential neuroprotective effect are lacking. This study investigated the cytoprotective effect of CPOR on total cell cultures of the ventral midbrain (VMC), hippocampus (HC) and cerebral cortex (CCC) exposed to rotenone at different concentrations. The total cell cultures of VMC, HC and CCC were exposed for 72 or 24 hours to rotenone, CPOR and rotenone + CPOR. Cell viability was measured using the MTT test and compared using one-way ANOVA. Exposure to rotenone reduced the cell viability of CMV, HC and CCC. Exposure to CPOR reduced the cell viability of CMV. The cell viability of CMV exposed simultaneously to rotenone and CPOR was higher compared to rotenone alone. The cell viability of HC exposed simultaneously to rotenone and CPOR was higher than that exposed to rotenone. CMVs are more vulnerable to rotenone toxicity and more sensitive to CPOR. Considering simultaneous exposure, CPOR revealed a possible neuroprotective effect against rotenone damage only for VMC and HC.

Dendritic spines are protruding membrane organelles from neuronal dendrites. The quantity of dendritic spines formed seems to be regulated with the -BAR family proteins, as they would initiate the membrane curvature to form the spines; however it is unclear whether the positions of these spines are selected based on spatial information due to the location of pre-existing spines or are selected via random molecular interactions. Through measuring the distance between dendritic spines from the images of Prada et. al (6), a distribution graph was created to determine whether the spine formations followed a random distribution pattern. Two groups of images were measured: dendritic spines when extracellular vesicles (EV) neuron contact was normal (control) and when EV-neuron contact was inhibited (experimental), preventing the transfer of MicroRNA (miRNA). Two randomly generated simulation groups were then created with the same spine density as the control and experimental conditions. Distribution graphs were created for the two randomly generated simulation groups as well. It was found that the randomly generated control simulation and the control group had significantly similar distribution; however, the randomly generated experimental simulation and the experimental simulation showed less of a similar distribution. These findings show that an element of randomness was removed when EV-neuron contact was inhibited.

Attention Deficit Hyperactivity Disorder (ADHD) diagnosis poses significant challenges due to its heterogeneous nature and reliance on subjective assessments. This study leverages deep learning to develop a robust diagnostic model by integrating a comprehensive set of EEG biomarkers. We incorporate parameters such as theta/beta ratio, coherency measures, delta power, event-related potentials (ERPs), power spectral density (PSD), microstates, entropy measures, fractal dimension, and source localization. Our convolutional neural network (CNN) model, designed to process these diverse features, demonstrates high accuracy and stability in distinguishing ADHD patients from controls, from all ages. The model's architecture includes convolutional layers for spatial feature extraction, followed by dense layers that integrate additional EEG parameters. The results indicate that deep learning, coupled with a rich feature set, can significantly enhance the predictive accuracy of ADHD diagnosis, offering a promising tool for clinical application.

Neurodevelopmental disorders are characterised by an amalgam of genetic and epigenetic faults implicating neuronal protein-related loss-of-function and gain-of-function respectively, hence their inclusion into the category of complex diseases. Neurodevelopmental disorders are regarded as autism spectrum disorder due to this reason; that the risk factors and phenotype constitute a spectrum of faults and protein overactivity. One example of an epigenetic factor leading to the onset of neurodevelopmental delays constitutes a set of immune response-based dysregulations, as well as the excessive growth of the adaptive immune memory of the foetus or the baby following significant infectious disease during pregnancy, as well as in babies aged 0-2, given the existence of profound links between developmental immunity and developmental neurology. Given that genetic information very likely represents a form of energy, the intake of excessive pathogen-related information may transiently overload the adaptive immune memory similarly to the manner functional pathogens do whilst inducing significant illness, and if events as such occur during important stages of neuro-immunological development, then there could often be irreversible effects upon the rate of development in neurological networks that normally have a major importance in the modulation of the related cognitive and behavioural phenotype. The full extent of evidence may only be obtained via a thorough study of the applications of physical laws into biology and medicine, given the foundational role of the physical matter in the development and maintenance of life. A common misconception is that neurodevelopmental delays are characterised solely by an accumulation of protein loss-of-function incidences in the central nervous system area, rather than a disruption of neuronal region developmental rates. For example, an overexpression of neuronal proteins related to cognition factors that is accompanied by an underexpression of proteins related to social behaviour is phenotypically manifested in people with sharper rational thinking and poorer communication skills, with an impact on the abilities of decision-making as well, and this tends to be regarded as a classical example of the clinical manifestation of neurodevelopmental delays. More severe forms of autism spectrum disorder tend to implicate a more generalistic impact upon the developmental rates of key human behaviours, including those related with the development and maintenance of social and intimate relationships. Likewise, more severe implications upon regular developmental rates tend to bring a major impact upon the healthy function of related functions. As a result, lower functioning forms of neurodevelopmental delays bring fresh concerns with regards to a possible uncanny increase of incidences of deviated sexuality during years of adulthood, and in the worst cases, such deviations may lead to the planning and development of criminal activity, particularly in individuals who are or become prone to breaking the moral code that established the civilised society. What holds the concerns valid is the exponential increase in the number of lower functioning autism cases throughout the world and the major signs that such an increase will continue with a full force. One major solution to this potential future problem would be a much higher investment into awareness of the exact genetic and environmental factors that directly or indirectly result in the onset of lower-functioning autism and of the current research efforts to develop the matching support for people found in situations as such. The most important aim of future research with regards to such a scenario would be a separation of disease and disability with choices made to step into more severe forms of disease and into areas that are outside of the established moral circle.

Some of neurodegenerative diseases may be characterized by continuing behavioral and cognitive dysfunction that contains memory loss and/or apathy. Alzheimer's disease is the most typical type of such neurodegenerative disease characterized by deficit of cognition and alteration of behavior. Despite the huge efforts against Alzheimer's disease, there has been yet no successful treatment for this disease. Interestingly, several possible risk genes to cognitive dysfunction are frequently expressed within brain cells, which may also be linked to cholesterol metabolism, lipid transport, exosomes and/or caveolae formation, suggesting that caveolae may be a therapeutic target to consider cognitive dysfunctions. Interestingly, modulation of autophagy/mitophagy with the alteration of glucagon-like peptide-1 (GLP-1) and N-methyl-d-aspartate (NMDA) receptors signaling may offer a novel approach to prevent and alleviate the cognitive dysfunction. A paradigm that both GLP-1 and NMDA receptors at caveolae sites is promising and crucial for the treatment of cognitive dysfunctions has been presented here, which might also be able to modify the progression of Alzheimer's disease. This research direction may open the potential to move a clinical care toward disease-modifying treatment strategies with maximal benefits for patients without detrimental adverse events for neurodegenerative diseases.

Epigenetic mechanisms, including histone post-translational modifications (PTMs), play a critical role in regulating pain perception and the pathophysiology of burn injury. However, the epigenetic regulation and molecular mechanisms underlying burn injury-induced pain remain insufficiently explored. Spinal dynorphinergic (Pdyn) neurons contribute to heat hyperalgesia induced by severe scalding-type burn injury through p-S10H3-dependent signaling. Beyond p-S10H3, burn injury may impact various other histone H3 PTMs. Double immunofluorescent staining and histone H3 protein analyses demonstrated significant hypermethylation at H3K4me1 and H3K4me3 sites and hyperphosphorylation at S10H3 within the spinal cord. By analyzing Pdyn neurons in the spinal dorsal horn, we found evidence of chromatin activation with a significant elevation in p-S10H3 immunoreactivity. We used RNA-seq analysis to compare the effects of burn injury and forma-lin-induced inflammatory pain on spinal cord transcriptomic profiles. We identified 98 DEGs for burn injury and 86 DEGs for formalin-induced inflammatory pain. A limited number of shared differentially expressed genes (DEGs) suggest distinct central pain processing mechanisms between burn injury and formalin models. KEGG pathway analysis supported this divergence, with burn injury activating Wnt signaling. This study enhances our understanding of burn injury mechanisms and uncovers converging and diverging pathways in pain models with different origins.

The agonist-antagonist myoneural interface (AMI), a surgical method to reinnervate physiologically-relevant proprioceptive feedback for control of limb prostheses, has demonstrated the ability to provide natural afferent sensations for limb amputees when actuating their prostheses. Following an AMI surgery, one potential challenge is atrophy of the disused muscles, which would weaken the reinnervation efficacy of AMI. It is well known that electrical muscle stimulus (EMS) can reduce the muscle atrophy. In this study, we conducted an animal investigation to explore whether the EMS can significantly improve the electrophysiological performance of AMI. The AMI surgery was performed in 14 rats, in which the distal tendons of bilateral solei donors were connected and positioned on the surface of the left biceps femoris. Subsequently, the left tibial nerve and the common peroneus nerve were sutured onto the ends of the connected donor solei. Two stimulation electrodes were affixed onto the ends of the donor solei for EMS delivery. The AMI rats were randomly divided into two groups. One group regularly received the EMS treatment (designated as EMS_on) for eight weeks and another was no EMS (designated as EMS_off). Two physiological parameters, nerve conduction velocity (NCV) and motor unit number, were derived from the electrically evoked compound action potential (CAP) signals to assess the electrophysiological performance of AMI. Our experimental results demonstrated that the reinnervated muscles of the EMS_on group generated higher CAP signals in comparison to the EMS_off group. Both NCV and motor unit number were significantly elevated in the EMS_on group. Moreover, the EMS_on group displayed statistically higher CAP signals on the indirectly activated proprioceptive afferents than the EMS_off group. These findings may suggested that the EMS treatment would be promise in enhancing the electrophysiological performance and facilitating the reinnervation process of AMI.

Transcranial magnetic stimulation, TMS, has been an innovative method of demure neuromodulation. This paper aims to delve into the different forms of its existence and to evaluate the use of TMS in five psychiatric disorders; Parkinson’s disease, schizophrenia, obsessive-compulsive disorder, major depressive disorder, and major anxiety disorder. Literature pertaining to the use of TMS in treating these specific diseases will be analyzed, and its efficacy and mechanisms will be explored. The literature will be evaluated through sources with established facts and research studies demonstrating function, potency, or inefficacy. TMS poses a method to have a more explicit effect on the regions of the brain, and the exploration of its use in the treatment of psychiatric diseases poses new possibilities in the treatment of psychiatric disorders. Venturing into the options it could have in a sole or combinatorial setting could provide penetrating insight into innovative forms of treatment and research.

Mutations in the lipoyltransferase 1 (LIPT1) gene are rare inborn errors of metabolism leading to a fatal condition characterized by lipoylation defects of the 2-ketoacid dehydrogenase complexes causing early-onset seizures, psychomotor retardation, abnormal muscle tone, severe lactic aci-dosis and increased urine lactate, ketoglutarate, and 2-oxoacids levels. In this article, we characterized the disease pathophysiology using fibroblasts and induced neurons derived from a patient bearing a compound heterozygous mutation in LIPT1. Western blot analysis revealed reduced expression of LIPT1 and absent expression of lipoylated pyruvate dehydrogenase E2 (PDH E2) and alpha-ketoglutarate dehydrogenase E2 (α-KGDH E2) subunits. Accordingly, activities of PDH and α-KGDH were markedly reduced, associated with cell bioenergetics failure, iron accumulation and lipid peroxidation. In addition, using a pharmacological screening, we identified a cocktail of antioxidants and mitochondrial boosting agents consisting of pantothenate, nicotinamide, vitamin E, thiamine, biotin, and alpha-lipoic acid, which is capable of rescuing LIPT1 patho-physiology, increasing LIPT1 expression and lipoylation of mitochondrial proteins, improving cell bioenergetics, and eliminating iron overload and lipid peroxidation. Furthermore, our data suggest that the beneficial effect of the treatment is mainly mediated by SIRT3 activation. In conclusion, we have identified a promising therapeutic approach for correcting LIPT1 mutations.

Glioblastoma is a highly aggressive brain tumor and is considered to be the most common primary one. Recurrence after treatment is a major problem. The recurrence of GBM is related to different cellular mechanisms and molecular signaling. Therapies to prolong survival are not completely effective. Epigenetics and non-coding genetic elements play a crucial role in gliomagenesis. Non-coding RNAs are novel regulatory RNAs that play key roles in different physiological processes such as gene regulation, cell differentiation, and proliferation. Interestingly, some LncRNAs have a tumor suppressor role while others are oncogenic. In this review article, we are going to illustrate the role of a well-known lncRNA HOX transcript antisense intergenic RNA (HOTAIR) in glioma and highlight the possible functions in glioma in both pre-clinical and clinically evident studies.

This study aimed to compare the effects of a permanent ischemic stroke model (focal ischemia by thermocoagulation of pial vessels) on sensorimotor function (cylinder test and adhesive removal test), behavioral tasks (novelty habituation memory-open field task), and cerebral infarct size in adult male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats over 42 days after the occurrence of stroke. We observed that the stroke caused asymmetry in the front paws and delayed adhesive removal. These effects were spontaneously reduced in WKY rats, but not in SHR. Short- and long-term novelty habituation memories were abolished by stroke in WYK and SHR. On the 3rd day after stroke, the size of the focal cerebral infarct was the same in WKY and SHR. However, on the 7th day, the infarct size decreased in WKY rats, but not SHR. These results suggested that SAH impairment of sensorimotor recovery in rats subjected to cerebral ischemia could be related to augmented focal cerebral infarct size. Moreover, the behavioral tasks used in this study were unaffected by Systemic Arterial Hypertension. Our results highlight the need for animal models of comorbidities in stroke research.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder, with a highly variable expression of phenotypes (restricted interest or activity and repetitive behavior in communication and social interactions), genes (mutation), markers (alteration of transcription) and pathways. Loss of function of the CC2D1A gene appears to primarily affect the brain, leading to a range of behavioral problems in humans. In our study published in 2020; we found that the expressions of miR-19a-3p, miR-361-5p, miR-150-5p, miR-3613-3p, miR-126-3p and miR-499a-5p were downregulated in the serum samples of autistic patients and their families. Here, acquired non-Mendelian hereditary character in a genetically defined mouse model of autism (Cc2d1a +/-) correlates with the transcriptional alteration of five miRNAs. We seek to test the hypothesis that miRNA levels are varying by changes in RNA/DNA structure during development, thereby creating transcription alteration. Behavioral tests were conducted on the offspring of Cc2d1a +/- mutant and control mice, such as novel object, social interaction, marble burying and tail suspension behavior. Two RNA fractions were isolated from mouse hippocampal tissues and sperm cells by standard TRIzol extraction: total RNA and fraction of RNA bound to DNA in the form of a DNA/RNA hybrid (R-loop). The expression levels of miR-19a-3p, miR-361-5p, miR-150-5p, miR-126-3p and miR-499a-5p were investigated by quantitative real-time RT-PCR. We report differences in the distribution of five miRNAs in the hippocampus between male and female mice in RNA fractions, particularly in colonies of Cc2d1a +/- mice. Furthermore, the number of miRNAs engaged in the DNA/RNA hybrid fraction is generally higher in the mutant pedigree than in the control group. On the other hand, in sperm both fractions are at lower levels than in controls. R-loops contribute to the physiology and pathology of organisms including human disease. Here we report a variation in five miRNA levels between gender and tissue. Our results suggest that the transcription levels of these five miRNAs are directly regulated by their RNA.

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by cognitive decline and neuronal loss, representing a most challenging health issue. We present a computational analysis of transcriptomic data of AD tissues vs. healthy controls, focused on elucidation of functional roles played by long non-coding RNAs (lncRNAs) throughout the AD progression. We first assembled our own lncRNA transcripts from the raw RNA-Seq data generated from 527 samples of dorsolateral prefrontal cortex, resulting in the identification of 31,574 novel lncRNA genes. Based on co-expression analyses between mRNAs and lncRNAs, a co-expression network is constructed. Maximal subnetworks with dense connections are identified as functional clusters. Pathway enrichment analyses are conducted over mRNAs and lncRNAs in each cluster, which serve as the basis for the inference of functional roles played by lncRNAs involved in each of the key steps in an AD development model that we have previously build based on transcriptomic data of protein-encoding genes. Detailed information is presented about the functional roles by lncRNAs in activities related to stress response, reprogrammed metabolism, cell-polarity, and development. Our analyses have also revealed that lncRNAs have discerning power in distinguishing between AD samples of each stage and healthy controls. This study represents the first of its kind.

Autism spectrum disorder (ASD) is a neurodevelopmental condition marked by re-stricted and repetitive behaviors as well as difficulties with social interaction. Nu-merous studies have revealed aberrant lipid mediators and autoimmunity as a recog-nized etiological cause of ASD that is amenable to therapeutic intervention. Methods: In this study, the relationship between the relative cyclooxygenase-2, / pros-taglandin E2 ratio (COX-2/PGE2) as lipid mediator marker and anti-nucleosome au-toantibodies as autoimmunity marker of ASD was investigated using multiple regres-sion and combined receiver operating characteristic (ROC) curve analyses. The study also sought to identify the linear combination of these variables that optimizes the partial area under the ROC curves. There were forty ASD children and forty age- and sex-matched controls included in the current study. Results: Using combined ROC curve analysis, a notable increase in the area under the curve was seen. Additionally, it was reported that the combined markers had improved specificity and sensitivity. Conclusions: This study shows that using a ROC curve analysis to measure the predictive value of specific biomarkers linked to lipid metabolism and autoimmunity in children with ASD should improve our understanding of the etiological mechanism of ASD and how it is related to metabolism. Early diagnosis and intervention may be facilitated by this knowledge.

Attention-Deficit/Hyperactivity Disorder (ADHD) is traditionally conceptualized within a framework emphasizing deficits in attention regulation and executive function. However, emerging evidence from the fields of predictive coding and active inference offers a novel lens through which to understand ADHD not merely as a disorder of attention but as a distinctive mode of neurodevelopmental variation. This article synthesizes current research and theoretical models to propose a redefined understanding of ADHD. By integrating insights from Ryan Smith, Paul B. Badcock, and Karl J. Friston (2020), we explore the premise that individuals with ADHD exhibit unique differences in how their brains generate and update predictions about the environment, leading to the characteristic behavioral patterns observed in ADHD. We argue that ADHD involves a divergence in the brain's predictive models and its ability to minimize prediction error, impacting sensory processing, attention allocation, and motor control. This perspective illuminates the adaptive aspects of ADHD, suggesting that what are often labeled as deficits could also reflect an adaptive fit to certain environmental contexts, underscoring the role of neurodiversity in human evolution. Furthermore, we discuss the implications of this reconceptualization for clinical practice, including diagnosis, treatment, and support for individuals with ADHD, emphasizing approaches that align with their unique neurocognitive profiles. This article calls for a shift in the narrative surrounding ADHD, advocating for a model that appreciates the complexity and adaptiveness of neurodevelopmental diversity.

Kynurenic acid (KYNA), a tryptophan metabolite, is believed to exert neuromodulatory and neuroprotective effects in the brain. The study aimed to examine the KYNA’s capacity to modify gene expression and the activity of cellular antioxidant enzymes in specific structures of the sheep brain. Anestrous sheep were infused intracerebroventricularly with two KYNA doses: lower (4×5 μg/60 μL/30 min, KYNA20) and higher (4×25 μg/60 μL/30 min, KYNA100) at 30min intervals. The abundance of superoxide dismutase (SOD2), catalase (CAT) and glutathione peroxidase (GPx1) mRNA, as well as enzyme activities (µM/µg of protein), were determined in the hypothalamic medial-basal (MBH) and preoptic (POA) areas, and in the hippocampal CA1 field. Both doses of KYNA caused a decrease (P&lt;0.01) in the expression of SOD2 and CAT mRNA in all structures examined compared to the control group (except for CAT in the POA at the KYNA100 dose). Furthermore, lower levels of SOD2 mRNA (P&lt;0.05) and CAT mRNA (P&lt;0.01) were found in the MBH and POA and in the POA and CA, respectively, in sheep administered with the KYNA20 dose. Different stimulatory effects on GPx1 mRNA expression were observed for both doses (P&lt;0.05-P&lt;0.01). KYNA exerted stimulatory, but dose-dependent effects on SOD2, CAT and GPx1 activities (P&lt;0.05-P&lt;0.01) in all brain tissues examined. The results indicate that KYNA may influence the level of oxidative stress in individual brain structures in sheep by modulating the expression of genes and activity of at least SOD2, CAT and GPx1. The present findings also expand the general knowledge about the potential neuroprotective properties of KYNA in the central nervous system.

The inclusion of various chemical substances in personal care products (PCPs) and cosmetic formulations can be associated with disruption and damage to the nervous system. Microplastics, benzophenones, parabens, phthalates and metals are among the most common chemical substances found in cosmetics that have been shown to induce neurotoxic mechanisms. Although cosmetic neurotoxin exposure is believed to be minimal, different exposure scenarios of cosmetics suggest that these neurotoxins remain a threat. Special attention should be paid to early exposure in the first gestation weeks, when critical processes, like the migration and proliferation of the neural crest derived cells start to form the ENS. Importantly, cosmetic’s neurotoxins can cross the placenta barrier and so affect the future embryo, but are also secreted in the breast milk, so that babies remain exposed for longer periods, even after birth. In this review we explore how neurotoxins contained in cosmetic and PCPs may have a role in the pathogenesis of various neurodevelopment disorders and neurodegenerative diseases, and therefore also in congenital enteric aganglionosis as well as in postnatal motility disorders. Understanding the mechanisms of these chemicals used in cosmetic formulations and their role in neurotoxicity is crucial to determining the safety of use for cosmetic products during pregnancy.