Neurotransmitter Research Articles

Application of Optogenetics in the Regulation of Neural Circuits in Parkinson’s Disease

This paper reviews the application of optogenetics in the study of Parkinson’s disease and discuss how optogenetics stimulates specific neural circuits to regulate the symptoms and behaviors of Parkinson’s disease. Optogenetics technology has a higher spatial resolution than traditional electrical stimulation, and optogenetics can accurately control specific neuron populations, providing a new perspective for studying PD and exploring potential treatments. The researchers found that selective optogenetic stimulation of the dorsal striatum was sufficient to induce levodopalike dyskinesia in 6-hydroxydopamine (6-OHDA)-induced PD rat models. In addition, the researchers found that transplanted dopamine neurons can correct some of the motor deficits through their neural activity, including dopamine release and synaptic transmission. Although the utility of optogenetic techniques in human patients is unclear, the precise control of neural circuits in animal models provides an important way to understand the mechanisms and side effects of DBS therapy. The study also suggests that optogenetic stimulation of glutamatergic neurons in the mesocerebellar nucleus may improve motor function in PD mouse models, providing a new potential target for PD treatment. Finally, the article discusses how optogenetic technology can be transformed from a research tool into a treatment for PD, and how to repair damaged neural circuits through optogenetic technology to provide a more durable and effective treatment.

SARS-CoV-2 variants mediated tissue-specific metabolic reprogramming determines the disease pathophysiology in a hamster model

Despite significant effort, a clear understanding of host tissue-specific responses and their implications for immunopathogenicity against the severe acute respiratory syndrome coronavirus2 (SARS-CoV-2) variant infection has remained poorly defined. To shed light on the interaction between tissues and SARS-CoV-2 variants, we sought to characterize the complex relationship among acute multisystem manifestations, dysbiosis of the gut microbiota, and the resulting implications for SARS-CoV-2 variant-specific immunopathogenesis in the Golden Syrian Hamster (GSH) model using multi-omics approaches. Our investigation revealed the presence of increased SARS-CoV-2 genomic RNA in diverse tissues of delta-infected GSH compared to the omicron variant. Multi-omics analyses uncovered distinctive metabolic responses between the delta and omicron variants, with the former demonstrating dysregulation in synaptic transmission proteins associated with neurocognitive disorders. Additionally, delta-infected GSH exhibited an altered fecal microbiota composition, marked by increased inflammation-associated taxa and reduced commensal bacteria compared to the omicron variant. These findings underscore the SARS-CoV-2-mediated tissue insult, characterized by modified host metabolites, neurological protein dysregulation, and gut dysbiosis, highlighting the compromised gut-lung-brain axis during acute infection.

Oxytocin alleviates high-fat diet-induced anxiety by decreasing glutamatergic synaptic transmission in the ventral dentate gyrus in adolescent mice

A high-fat diet (HFD)-induced obesity is associated with mental disorders in adolescence. However, the mechanisms underlying these associations remain unclear. In this study, we hypothesized that synaptic remodeling occurs in the ventral hippocampus (vHP) of obese mice. To investigate this, we established a postnatal model of HFD-induced obesity in mice and observed increased body weight, elevated plasma luteinizing hormone and testosterone levels, premature puberty, and enhanced anxiety-like behavior in male subjects. We also examined the effect of HFD on the c-Fos protein expression in the ventral dentate gyrus (vDG) and explored the influence of intracerebroventricular (i.c.v) oxytocin injections on HFD-induced anxiety. Our results indicated an increase in c-Fos-positive cells in the vDG following HFD consumption. Additionally, we recorded the spontaneous synaptic activity of miniature excitatory postsynaptic currents (mEPSCs) in the vDG. Notably, HFD resulted in an elevated mEPSC frequency without affecting mEPSC amplitude. Subsequently, investigations demonstrated that i.c.v oxytocin injections reversed anxiety-like behavior induced by HFD. Moreover, the application of oxytocin in a bath solution reduced the mEPSC frequency in the vDG. These findings suggest that postnatal HFD intake induces synaptic dysfunction in the vDG, associated with the hyperactivity of vDG neurons, potentially contributing to the anxiety-like behavior in juvenile obesity.

Molecular landscape of the overlap between Alzheimer’s disease and somatic insulin-related diseases

Alzheimer’s disease (AD) is a multifactorial disease with both genetic and environmental factors contributing to its etiology. Previous evidence has implicated disturbed insulin signaling as a key mechanism that plays a role in both neurodegenerative diseases such as AD and comorbid somatic diseases such as diabetes mellitus type 2 (DM2). In this study, we analysed available genome-wide association studies (GWASs) of AD and somatic insulin-related diseases and conditions (SID), i.e., DM2, metabolic syndrome and obesity, to identify genes associated with both AD and SID that could increase our insights into their molecular underpinnings. We then performed functional enrichment analyses of these genes. Subsequently, using (additional) GWAS data, we conducted shared genetic etiology analyses between AD and SID, on the one hand, and blood and cerebrospinal fluid (CSF) metabolite levels on the other hand. Further, integrating all these analysis results with elaborate literature searches, we built a molecular landscape of the overlap between AD and SID. From the landscape, multiple functional themes emerged, including insulin signaling, estrogen signaling, synaptic transmission, lipid metabolism and tau signaling. We also found shared genetic etiologies between AD/SID and the blood/CSF levels of multiple metabolites, pointing towards “energy metabolism” as a key metabolic pathway that is affected in both AD and SID. Lastly, the landscape provided leads for putative novel drug targets for AD (including MARK4, TMEM219, FKBP5, NDUFS3 and IL34) that could be further developed into new AD treatments.

Mixed representations of choice direction and outcome by GABA/glutamate cotransmitting neurons in the entopeduncular nucleus.

The basal ganglia (BG) are an evolutionarily conserved and phylogenetically old set of sub-cortical nuclei that guide action selection, evaluation, and reinforcement. The entopeduncular nucleus (EP) is a major BG output nucleus that contains a population of GABA/glutamate cotransmitting neurons (EP Sst+ ) that specifically target the lateral habenula (LHb) and whose function in behavior remains mysterious. Here we use a probabilistic switching task that requires an animal to maintain flexible relationships between action selection and evaluation to examine when and how GABA/glutamate cotransmitting neurons contribute to behavior. We find that EP Sst+ neurons are strongly engaged during this task and show bidirectional changes in activity during the choice and outcome periods of a trial. We then tested the effects of either permanently blocking cotransmission or modifying the GABA/glutamate ratio on behavior in well-trained animals. Neither manipulation produced detectable changes in behavior despite significant changes in synaptic transmission in the LHb, demonstrating that the outputs of these neurons are not required for on-going action-outcome updating in a probabilistic switching task.

MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination.

Muscleblind-like proteins (MBNLs) are a family of RNA-binding proteins that play essential roles in the regulation of RNA metabolism. Beyond their canonical role in RNA regulation, MBNL proteins have emerged as key players in the pathogenesis of Myotonic Dystrophy type 1 (DM1). In DM1, sequestration of MBNL proteins by expansion of the CUG repeat RNA leads to functional depletion of MBNL, resulting in deregulated alternative splicing and aberrant RNA processing, which underlie the clinical features of the disease. While attention to MBNL proteins has focused on their functions in skeletal muscle, new evidence suggests that their importance extends to motor neurons (MNs), pivotal cellular components in the control of motor skills and movement. To address this question, we generated conditional double knockout mice in which Mbnl1 and Mbnl2 were specifically deleted in motor neurons (MN-dKO). Adult MN-dKO mice develop gait coordination deficits associated with structural and ultrastructural defects in the neuromuscular junction, indicating that MBNL activity in MNs is crucial for the maintenance of the neuromuscular junction. In addition, transcriptome analysis performed on the spinal cord of MN-dKO mice identified mis-splicing events in genes associated with synaptic transmission and neuromuscular junction homeostasis. In summary, our results highlight the complex roles and regulatory mechanisms of MBNL proteins in MNs for muscle function and locomotion. This work provides valuable insights into fundamental aspects of RNA biology and offers promising avenues for therapeutic intervention in DM1 as well as a range of diseases associated with RNA dysregulation.

Mechanism of Gastrodin against neurotoxicity based on network pharmacology, molecular docking and experimental verification

BackgroundDisorders of glutamate metabolism and excessive release participat in multiple neuronal pathologies including ischemic stroke (IS), Alzheimer's disease (AD), or Parkinson's disease (PD). Recently, herbal medicines have been widely used and have shown satisfactory results in the treatment of neurological disorders. Gastrodin is a traditional Chinese medicine (TCM) used for the treatment of nerve injuries, spinal cord injuries, and some central nervous system diseases as well. This research examines the neuroprotective effects of Gastrodin against glutamate-induced neurotoxicity in neuronal cells. MethodsThe HERB database was used to explore the active ingredients and target genes of Gastrodia Elata. The STRING database and Cytoscape software were used to screen and construct the Protein-Protein Interaction (PPI). Furthermore, we used molecular docking to predict the potential targets of Gastrodin. The effects of Gastrodin were revealed by western blot, calcium imaging, membrane clamp, CCK8 and flow cytometry. Neuronal oxidative stress and damage were assessed by measuring malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. Neuronal morphology was examined using Golgi-Cox staining. Finally, animal behavior was examined using novel object recognition and fear conditioning tests. ResultsWe have obtained 22 components such as TM10, TM17, TM25 (Gastrodin), and 281 targets such as AKT, EGFR, and CDK1 through network pharmacology. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed these genes were significantly enriched in protein phosphorylation, protein serine/threonine/tyrosine kinase activity, apoptosis and HIF-1 signaling pathways, etc. A higher affinity between Gastrodin and AKT was revealed by PPI analysis and molecular docking. Further, Gastrodin significantly inhibited Ca2+ influxes and excitatory synaptic transmission in cortical neurons. In addition, Gastrodin effectively alleviated neuron apoptosis, oxidative stress and damage. ConclusionGastrodin has neuroprotective effects against glutamate-induced neurotoxicity.

Synaptic and extrasynaptic distribution of NMDA receptors in the cortex of Alzheimer's disease patients.

Synaptic and extrasynaptic distribution of N-methyl-D-aspartate receptors (NMDARs) has not been addressed in the brain from Alzheimer´s disease (AD) subjects, despite theircontribution to neurodegeneration. We have developed a protocol to isolate synaptic and extrasynaptic membranes from controls and AD frontal cortex. We characterized the distribution of the NMDAR subunits GluN2B, GluN2A, GluN1, and GluN3A, as well aspost-translational modifications, such as phosphorylation and glycosylation. Lower levels of synaptic GluN2B and GluN2A were found in AD fractions, while extrasynaptic GluN2B and GluN1 levels were significantly higher; GluN3A distribution remained unaffected in AD. We also identified different glycoforms of GluN2B and GluN2A in extrasynaptic membranes. Synaptic Tyr1472 GluN2B phosphorylation was significantly lower in AD fractions. Reduction of synaptic NMDAR subunits, particularly for GluN2B, is likely to contribute to synaptic transmission failure in AD. Additionally, the increment of extrasynaptic NMDAR subunits could favor the activation of excitotoxicity in AD. New protocol to isolate synaptic and extrasynaptic membranes from the human cortex. Low GluN2B and GluN2A levels in Alzheimer´s disease (AD) synaptic membranes. High GluN2B and GluN1 levels in AD extrasynaptic membranes. Specific glycoforms of extrasynaptic GluN2B and GluN2A. Low phosphorylation at Tyr1472 in synaptic GluN2B in AD.

Mice lacking acid-sensing ion channel 2 in the medial prefrontal cortex exhibit social dominance.

Social dominance is essential for maintaining a stable society and has both positive and negative impacts on social animals, including humans. However, the regulatory mechanisms governing social dominance, as well as the crucial regulators and biomarkers involved, remain poorly understood. We discover that mice lacking acid-sensing ion channel 2 (ASIC2) exhibit persistently higher social dominance than their wild-type cagemates. Conversely, overexpression of ASIC2 in the medial prefrontal cortex reverses the dominance hierarchy observed in ASIC2 knockout (Asic2-/-) mice. Asic2-/- neurons exhibit increased synaptic transmission and plasticity, potentially mediated by protein kinase A signaling pathway. Furthermore, ASIC2 plays distinct functional roles in excitatory and inhibitory neurons, thereby modulating the balance of neuronal activities underlying social dominance behaviors-a phenomenon suggestive of a cell subtype-specific mechanism. This research lays the groundwork for understanding the mechanisms of social dominance, offering potential insights for managing social disorders, such as depression and anxiety.

Mefloquine-induced conformational shift in Cx36 N-terminal helix leading to channel closure mediated by lipid bilayer

Connexin 36 (Cx36) forms interneuronal gap junctions, establishing electrical synapses for rapid synaptic transmission. In disease conditions, inhibiting Cx36 gap junction channels (GJCs) is beneficial, as it prevents abnormal synchronous neuronal firing and apoptotic signal propagation, mitigating seizures and progressive cell death. Here, we present cryo-electron microscopy structures of human Cx36 GJC in complex with known channel inhibitors, such as mefloquine, arachidonic acid, and 1-hexanol. Notably, these inhibitors competitively bind to the binding pocket of the N-terminal helices (NTH), inducing a conformational shift from the pore-lining NTH (PLN) state to the flexible NTH (FN) state. This leads to the obstruction of the channel pore by flat double-layer densities of lipids. These studies elucidate the molecular mechanisms of how Cx36 GJC can be modulated by inhibitors, providing valuable insights into potential therapeutic applications.

Dopamine internalization via Uptake2 and stimulation of intracellular D5-receptor-dependent calcium mobilization and CDP-diacylglycerol signaling

Dopamine stimulates CDP-diacylglycerol biosynthesis through D1-like receptors, particularly the D5 subtype most of which is intracellularly localized. CDP-diacylglycerol regulates phosphatidylinositol-4,5-bisphosphate-dependent signaling cascades by serving as obligatory substrate for phosphatidylinositol biosynthesis. Here, we used acute and organotypic brain tissues and cultured cells to explore the mechanism by which extracellular dopamine acts to modulate intracellular CDP-diacylglycerol. Dopamine stimulated CDP-diacylglycerol in organotypic and neural cells lacking the presynaptic dopamine transporter, and this action was selectively mimicked by D1-like receptor agonists SKF38393 and SKF83959. Dopaminergic CDP-diacylglycerol stimulation was blocked by decynium-22 which blocks Uptake2-like transporters and by anti-microtubule disrupters of cytoskeletal transport, suggesting transmembrane uptake and guided transport of the ligands to intracellular sites of CDP-diacylglycerol regulation. Fluorescent or radiolabeled dopamine was saturably transported into primary neurons or B35 neuroblastoma cells expressing the plasmamembrane monoamine transporter, PMAT. Microinjection of 10-nM final concentration of dopamine into human D5-receptor-transfected U2-OS cells rapidly and transiently increased cytosolic calcium concentrations by 316%, whereas non-D5-receptor-expressing U2-OS cells showed no response. Given that U2-OS cells natively express PMAT, bath application of 10 μM dopamine slowly increased cytosolic calcium in D5-expressing cells. These observations indicate that dopamine is actively transported by a PMAT-implicated Uptake2-like mechanism into postsynaptic-type dopaminoceptive cells where the monoamine stimulates its intracellular D5-type receptors to mobilize cytosolic calcium and promote CDP-diacylglycerol biosynthesis. This is probably the first demonstration of functional intracellular dopamine receptor coupling in neural tissue, thus challenging the conventional paradigm that postsynaptic dopamine uptake serves merely as a mechanism for deactivating spent or excessive synaptic transmitter.

Hippocampal Leptin Resistance and Cognitive Decline: Mechanisms, Therapeutic Strategies and Clinical Implications

Background: Leptin, an adipokine essential for regulating energy balance, exerts important effects on brain function, notably within the hippocampus, a region integral to learning and memory. Leptin resistance, characterized by diminished responsiveness to elevated leptin levels, disrupts hippocampal function and exacerbates both obesity and cognitive impairments. Scope: This review critically examines how leptin resistance impairs hippocampal synaptic plasticity processes, specifically affecting long-term potentiation (LTP) and long-term depression (LTD), which are crucial for cognitive performance. Findings: Recent research highlights that leptin resistance disrupts N-methyl-D-aspartate (NMDA) receptor dynamics and hippocampal structure, leading to deficits in spatial learning and memory. Additionally, high-fat diets (HFDs), which contribute to leptin resistance, further deteriorate hippocampal function. Potential therapeutic strategies, including leptin sensitizers, show promise in mitigating brain disorders associated with leptin resistance. Complementary interventions such as caloric restriction and physical exercise also enhance leptin sensitivity and offer potential benefits to alleviating cognitive impairments. Aims of the review: This review synthesizes recent findings on the molecular pathways underlying leptin resistance and its impact on synaptic transmission and plasticity in the hippocampus. By identifying potential therapeutic targets, this work aims to provide an integrated approach for addressing cognitive deficits in obesity, ultimately improving the quality of life for affected individuals.

What Is the Role of Cytokines in Synaptic Transmission?

What Is the Role of Cytokines in Synaptic Transmission?

A Non-Invasive and DNA-free Approach to Upregulate Mammalian Voltage-Gated Calcium Channels and Neuronal Calcium Signaling via Terahertz Stimulation.

Mammalian voltage-gated calcium channels (CaV) play critical roles in cardiac excitability, synaptic transmission, and gene transcription. Dysfunctions in CaV are implicated in a variety of cardiac and neurodevelopmental disorders. Current pharmacological approaches to enhance CaV activity are limited by off-target effects, drug metabolism issues, cytotoxicity, and imprecise modulation. Additionally, genetically-encoded channel activators and optogenetic tools are restricted by gene delivery challenges and biosafety concerns. Here a novel terahertz (THz) wave-based method to upregulate CaV1.2, a key subtype of CaV, and boost CaV1-mediated Ca2+ signaling in neurons without introducing exogenous DNA is presented. Using molecular dynamics simulations, it is shown that 42.5 THz (7.05µm, 1418cm-1) waves enhance Ca2+ conductance in CaV1.2 by resonating with the stretching mode of the -COO- group in the selectivity filter. Electrophysiological recordings and Ca2+ imaging confirm that these waves rapidly, reversibly, and non-thermally increase calcium influx of CaV1.2 in HEK293 cells and induce acute Ca2+ signals in neurons. Furthermore, this irradiation upregulates critical CaV1 signals, including CREB phosphorylation and c-Fos expression, in vitro and in vivo, without raising significant biosafety risks. This DNA-free, non-invasive approach offers a promising approach for modulating CaV gating and Ca2+ signaling and treating diseases characterized by deficits in CaV functions.

Parvalbumin interneuron impairment causes synaptic transmission deficits and seizures in SCN8A developmental and epileptic encephalopathy.

SCN8A developmental and epileptic encephalopathy (DEE) is a severe epilepsy syndrome resulting from mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.6 is expressed in excitatory and inhibitory neurons, yet previous studies primarily focus on how SCN8A mutations affect excitatory neurons, with limited studies on the importance of inhibitory interneurons. Parvalbumin (PV) interneurons are a prominent inhibitory interneuron subtype that expresses Nav1.6. To assess PV interneuron function within SCN8A DEE, we used 2 mouse models harboring patient-derived SCN8A gain-of-function variants, Scn8aD/+, where the SCN8A variant N1768D is expressed globally, and Scn8aW/+-PV, where the SCN8A variant R1872W is selectively expressed in PV interneurons. Expression of the R1872W SCN8A variant selectively in PV interneurons led to development of spontaneous seizures and seizure-induced death. Electrophysiology studies showed that Scn8aD/+ and Scn8aW/+-PV interneurons were susceptible to depolarization block and exhibited increased persistent sodium current. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed synaptic transmission deficits in Scn8aD/+ and Scn8aW/+-PV interneurons. Together, our findings indicate that PV interneuron failure via depolarization block along with inhibitory synaptic impairment likely elicits an overall inhibitory reduction in SCN8A DEE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.

The Trigeminal Sensory System and Orofacial Pain

The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area travel into the trigeminal sensory system, where they are processed into integrated sensory information that is relayed to higher sensory brain areas. Thus, knowledge of the trigeminal sensory system is essential for comprehending orofacial pain. This review elucidates the individual nuclei that comprise the trigeminal sensory system and their synaptic transmission. Additionally, it discusses four types of orofacial pain and their relationship to the system. Consequently, this review aims to enhance the understanding of the mechanisms underlying orofacial pain.

Suppressing DUSP16 overexpression induced by ELK1 promotes neural progenitor cell differentiation in mouse models of Alzheimer's disease.

Emerged evidence indicated that stimulating hippocampal neurogenesis is a potential strategy for restoring cognition in AD. Mitogen-activated protein kinases (MAPKs) play an essential role in neurogenesis. Meanwhile, the enzymatic power of the phosphatases is much greater than that of kinases. Dual-specificity phosphatase 16 (DUSP16), known to as a phosphatase negatively regulate MAPKs, may be implicated in neural differentiation. Nevertheless, the effect of DUSP16 on cognitive disorders by stimulating neural progenitor cell (NPC) differentiation in AD mice remains unclear. Our study demonstrates an association between DUSP16 SNPs and clinical progression in individuals with mild cognitive impairment (MCI). Besides, increased DUSP16 expression was detected in both 3xTg and SAMP8 mouse models of AD, accompanied by NPC neural differentiation impairments. By silencing DUSP16, the induction of neural differentiation, synaptic transmission, and cognitive benefits were observed in both AD mice. Furthermore, DUSP16 was involved in the process of NPC differentiation through regulating c-Jun N-terminal kinase (JNK) phosphorylation and SOX2 expression. Moreover, ETS transcription factor (ELK1) was involved in the DUSP16 transcription, which resulted in the upregulation of DUSP16 at the state of AD. Our data uncovers a potential regulatory role for DUSP16 in adult hippocampal neurogenesis (AHN) and provides a possibility to find a novel strategy for AD intervention.

Manipulation of radixin phosphorylation in the nucleus accumbens core modulates risky choice behavior

Ezrin-Radixin-Moesin (ERM) proteins are actin-binding proteins that contribute to morphological changes in dendritic spines. Despite their significant role in regulating spine structure, the role of ERM proteins in the nucleus accumbnes (NAcc) is not well known, especially in in the context of risk-reward decision-making. Here, we measured the relationship between synaptic excitation and inhibition (E/I ratio) from medium spiny neurons in the NAcc core obtained in the rat after a rat gambling task (rGT). Then, after surgery of a phosphomimetic pseudo-active mutant form of radixin (Rdx-T564D) in the NAcc core, we examined its role in synaptic plasticity and the accompanying risk-choice behavior in rGT. We found that basal E/I ratio in the NAcc core was higher in risk-averse rats than risk-seeking rats. However, it was significantly reduced in risk-averse rats similar to that in risk-seeking rats in the presence of Rdx-T564D in the NAcc core. Furthermore, the head sizes of spines were shifted in risk-averse rats expressing Rdx-T564D in the NAcc core, similar to those observed in risk-seeking rats. The effects of Rdx-T564D in risk-averse rats were again manifested as behavioral changes, with reduced selection of optimal choices and increased selection of disadvantageous ones. In this study, we demonstrated that manipulation of radixin phosphorylation status in the NAcc core can alter glutamatergic synaptic transmission and spine structure at this site, as well as risk choice behaviors in the rGT. These novel findings illustrate that radixin in the NAcc core plays a significant role in determining risk preference during the rGT.

The corticospinal tract in multiple sclerosis: correlation between cortical excitability and magnetic resonance imaging measures.

Multiple sclerosis (MS) is a central nervous system disease involving gray and white matters. Transcranial magnetic stimulation (TMS) and magnetic resonance imaging (MRI) could help identify potential markers of disease evolution, disability, and treatment response. This work evaluates the relationship between intracortical inhibition and facilitation, motor cortex lesions, and corticospinal tract (CST) integrity. Consecutive adult patients with progressive MS were included. Sociodemographic and clinical data were collected. MRI was acquired to assess primary motor cortex lesions (double inversion and phase-sensitive inversion recovery) and CST integrity (diffusion tensor imaging). TMS outcomes were obtained: motor evoked potentials (MEP) latency, resting motor threshold, short-interval intracortical facilitation (ICF) and inhibition. Correlation analysis was performed. Twenty-five patients completed the study (13 females, age: 55.60 ± 11.49 years, Expanded Disability Status Score: 6.00 ± 1.25). Inverse correlations were found between ICF mean and each of CST radial diffusivity (RD) (ρ =-0.56; p < 0.01), CST apparent diffusion coefficient (ADC) (ρ=-0.44; p = 0.03), and disease duration (ρ=-0.46; p = 0.02). MEP latencies were directly correlated with disability scores (ρ = 0.55; p < 0.01). High ADC/RD and low ICF have been previously reported in patients with MS. While the former could reflect structural damage of the CST, the latter could hint towards an aberrant synaptic transmission as well as a depletion of facilitatory compensatory mechanisms that helps overcoming functional decline. The findings suggest concomitant structural and functional abnormalities at later disease stages that would be accompanied with a heightened disability. The results should be interpreted with caution mainly because of the small sample size that precludes further comparisons (e.g., treated vs. untreated patients, primary vs. secondary progressive MS). The role of these outcomes as potential MS biomarkers merit to be further explored.

Correlations between alterations in global brain functional connectivity in patients with major depressive disorder and their genetic characteristics

This study aims to elucidate the neuroimaging changes associated with major depressive disorder (MDD) and their relationship with genetic characteristics. We conducted a global-brain functional connectivity (GFC) and genetic-neuroimaging correlation analysis on 42 MDD patients and 42 healthy controls (HCs), exploring the correlation between GFC abnormalities and clinical variables. Results showed that compared to HCs, MDD patients had significantly decreased GFC values in the bilateral posterior cingulate cortex/precuneus and increased GFC values in the left and right cerebellum Crus I/II. Additionally, a negative correlation was observed between the GFC values of the left cerebellum Crus I/II and subjective support scores, as well as social support revalued scale total scores. We identified genes associated with GFC changes in MDD, which are enriched in biological processes such as synaptic transmission and ion transport. Our findings indicate the presence of abnormal GFC values in severe depression, complementing the pathological research on the condition. Furthermore, this study provides preliminary evidence for the correlation between social support levels and brain functional connectivity, offering insights into the potential association between GFC changes and gene expression in MDD patients.