Neuronal Function Research Articles

Growth Factor Gene Therapy for Alzheimer's Disease.

Nervous system growth factors are natural proteins of the brain that influence neuronal survival and function throughout life, from embryonic development to old age. In animal models of Alzheimer's disease (AD), the growth factor brain derived neurotrophic factor (BDNF) prevents neuronal death, activates neuronal function, builds new synapses and improves learning and memory. Accordingly, we are determining whether gene delivery of BDNF in patients with AD will slow disease progression and improve memory. In a previous clinical trial of nerve growth factor (NGF) gene therapy in AD patients (NCT00017940, June 2001), we learned that growth factors can unequivocally elicit classic trophic responses from degenerating neurons in AD. Experience gained from the earlier NGF gene therapy trial is guiding our effort to optimize gene delivery of BDNF in our present clinical program (NCT05040217, June 2021).

MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector in Caenorhabditis elegans.

The muscleblind family of mRNA splicing regulators is conserved across species and regulates the development of muscles and the nervous system. However, how Muscleblind proteins regulate neuronal fate specification and neurite morphogenesis at the single-neuron level is not well understood. In this study, we found that the C. elegans Muscleblind/MBL-1 promotes axonal growth in the touch receptor neurons (TRNs) by regulating microtubule stability and polarity. Transcriptomic analysis identified dozens of MBL-1-controlled splicing events in genes related to neuronal differentiation or microtubule functions. Among the MBL-1 targets, the LIM-domain transcription factor mec-3 is the terminal selector for the TRN fate and induces the expression of many TRN terminal differentiation genes. MBL-1 promotes the splicing of the mec-3 long isoform, which is essential for TRN fate specification, and inhibits the short isoforms that have much weaker activities in activating downstream genes. MBL-1 promotes mec-3 splicing through three "YGCU(U/G)Y" motifs located in or downstream of the included exon, which is similar to the mechanisms used by mammalian Muscleblind and suggests a deeply conserved context-dependency of the splicing regulation. Interestingly, the expression of mbl-1 in the TRNs is dependent on the mec-3 long isoform, indicating a positive feedback loop between the splicing regulator and the terminal selector. Finally, through a forward genetic screen, we found that MBL-1 promotes neurite growth partly by inhibiting the DLK-1/p38 MAPK pathway. In summary, our study provides mechanistic understanding of the role of Muscleblind in regulating cell fate specification and neuronal morphogenesis.

The Emerging Role of Immunoglobulins and Complement in the Stimulation of Neuronal Activity and Repair: Not as Simple as We Thought

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.

Toll-Like Receptor 4 (TLR4) Promotes DRG Regeneration and Repair after Sciatic Nerve Injury via the ERK-NF-kB Pathway.

Previously, we found that the expression of Toll-like receptor 4 (TLR4) is altered after sciatic nerve injury, and its differential expression plays a key role in recovery. However, the mechanisms by which TLR4 affects neuronal function in the dorsal root ganglion (DRG) have not been completely evaluated. The objective is to determine TLR4 expression in DRG tissues after sciatic neural injury and exploring the effects of TLR4 knockdown and overexpression in the DRG on neuronal function and nerve regeneration in rats in vivo and in vitro. We established a model of nerve injury and utilized molecular biology and cell biology experiments to explore the molecular mechanisms by which TLR4 in the DRG affects sciatic nerve restoration and regeneration after injury. Verified the localization of TLR4 in DRG neurons. Investigated pathways that related to apoptosis or nerve regeneration by which TLR4 regulates the function of DRG neurons. TLR4 expression was upregulated in the DRG tissues of rats after sciatic nerve injury. TLR4 overexpression promoted axon regeneration and inhibited apoptosis in DRG neurons. TLR4 promoted the regeneration of axons and the recovery of motor and sensory functions in the sciatic nerve after injury in vivo, and the data showed that TLR4 may regulate the function of DRG neurons and promote nerve repair and regeneration through the ERK and NF-κB signaling pathways in vivo and ex vivo. The study suggests that TLR4 may regulate the function of DRG neurons and promote nerve regeneration by affecting the ERK and NF-κB signaling pathways.

Reconfigurable Selector-Free All-Optical Controlled Neuromorphic Memristor for In-Memory Sensing and Reservoir Computing.

Recently, the rising demand for data-based applications has driven the convergence of image sensing, memory, and computing unit interfaces. While specialized electronic hardware has spurred advancements in the in-memory and in-sensor computing, integrating the entire signal-processing chain into a single device still faces significant challenges. Here, a reconfigurable all-optical controlled memristor with the selector-free feature is demonstrated. The conductance of the device can be controlled within the pure light domain, which enables it to integrate sensing, memory, and computing together. The integrate-and-fire behavior is also realized through electrical stimuli. Furthermore, the device exhibits an excellent rectifying ratio and nonlinearity to overcome the sneak current. Finally, an in-memory sensing and computing architecture is realized through reservoir computing based on neuron and synaptic functions mimicked by the proposed device. Such an all-in-one paradigm facilitates the computing architecture with low energy consumption, low latency, and reduced hardware complexity.

Viruses and Mitochondrial Dysfunction in Neurodegeneration and Cognition: An Evolutionary Perspective

Mitochondria, the cellular powerhouses with bacterial evolutionary origins, play a pivotal role in maintaining neuronal function and cognitive health. Several viruses have developed sophisticated mechanisms to target and disrupt mitochondrial function which contribute to cognitive decline and neurodegeneration. The interplay between viruses and mitochondria might be traced to their co-evolutionary history with bacteria and may reflect ancient interactions that have shaped modern mitochondrial biology.

DNA methylation profiles of transgenerational rat hyperactivity primed by silver nanoparticles: Comparison with valproate model rats of autism

There is an increasing body of evidence suggesting that a single exposure to certain chemicals can have transgenerational effects, with the underlying mechanism believed to be epigenetic. However, it remains largely unknown whether psychiatric conditions like ADHD or autism, induced by environmental chemicals, can be inherited across generations. Pregnant rats were purchased from a commercial breeder. On the 7th day of gestation (E7), they were divided into two groups: one group was orally exposed to silver nanoparticles (AgNP; 4 mg/kg), while the control group received vehicle alone. The subsequent generation (F1) underwent spontaneous motor activity (SMA) measurements at 8–11 weeks of age. For breeding at 26 weeks of age, rats with higher SMA were selected from hyperactive litters, while untreated rats were randomly selected. This process was continued for four generations in both groups. The AgNP-primed rats at 4th generation displayed significantly higher SMA, 1.8 times greater than that of untreated rats. Intraperitoneal injection of valproic acid (150 mg/kg), an epigenetic modifier to 5-day-old rats causes adult hyperactivity (1.4-fold), suggesting that epigenetic modification contributes to rat hyperactivity. Global DNA methylation profiles in the mesencephalon were positively correlated in both groups of hyperactive rats. Furthermore, there were 7–8 common genes showing both hypermethylation and hypomethylation, which are involved in neuronal development, neuronal function, transcriptional activity, DNA binding activity, cell differentiation, ubiquitination processes, or histone modification, including Pax 6 and Mecp 2. Thus, it is most likely that rats retain hyperactivity through mesencephalic DNA methylation status across transgeneration.

Altered tubulin detyrosination due to SVBP malfunction induces cytokinesis failure and senescence, underlying a complex hereditary spastic paraplegia.

Senescence, marked by permanent cell cycle arrest may contribute to the decline in regenerative potential and neuronal function, thereby promoting neurodegenerative disorders. In this study, we employed whole exome sequencing to identify a previously unreported biallelic missense variant in SVBP (p.Leu49Pro) in six patients from three unrelated families. These affected individuals present with a complex hereditary spastic paraplegia (HSP), peripheral neuropathy, verbal apraxia, and intellectual disability, exhibiting a milder phenotype compared to patients with nonsense SVBP mutations described previously. Consistent with SVBP's primary role as a chaperone necessary for VASH-mediated tubulin detyrosination, both patient fibroblasts with the p.Leu49Pro mutation, and HeLa cells harboring an SVBP knockdown exhibit microtubule dynamic instability and alterations in pericentriolar material (PCM) component trafficking and centrosome cohesion. In patient fibroblasts, structural abnormalities in the centrosome trigger mitotic errors and cellular senescence. Notably, premature senescence characterized by elevated levels of p16INK4, was also observed in patient peripheral blood mononuclear cells (PBMCs). Taken together, our findings underscore the critical role of SVBP in the development and maintenance of the central nervous system, providing novel insights associating cytokinesis failure with cortical motor neuron disease and intellectual disability.

Compact Physical Implementation of Spiking Neural Network Using Ambipolar WSe2 n-Type/p-Type Ferroelectric Field-Effect Transistor.

Spiking neural networks (SNNs) are attracting increasing interests for their ability to emulate biological processes, offering energy-efficient computation and event-driven processing. Currently, no devices are known to combine both neuronal and synaptic functions. This study presents an experimental demonstration of an ambipolar WSe2 n-type/p-type ferroelectric field-effect transistor (n/p-FeFET) integrated with ferroelectric Hf0.5Zr0.5O2 (HZO) to achieve both volatile and nonvolatile properties in a single device. The nonvolatile n-FeFET, driven by the stable ferroelectric properties of HZO, exhibits highly linear synaptic behavior. In contrast, the volatile p-FeFET, influenced by electron self-compensation in the ambipolar WSe2, enables self-resetting leaky-integrate-and-fire neurons. Integrating neuronal and synaptic functions in the same device allows for compact neuromorphic computing applications. Additionally, simulations of SNNs using experimentally calibrated synaptic and neuronal models achieved a 93.8% accuracy in MNIST digit recognition. This innovative approach advances the development of SNNs with high biomimetic fidelity and reduced hardware costs.

Constitutive sodium permeability in a C. elegans two-pore domain potassium channel

Two-pore domain potassium (K2P) channels play a central role in modulating cellular excitability and neuronal function. The unique structure of the selectivity filter in K2P and other potassium channels determines their ability to allow the selective passage of potassium ions across cell membranes. The nematode C. elegans has one of the largest K2P families, with 47 subunit-coding genes. This remarkable expansion has been accompanied by the evolution of atypical selectivity filter sequences that diverge from the canonical TxGYG motif. Whether and how this sequence variation may impact the function of K2P channels has not been investigated so far. Here, we show that the UNC-58 K2P channel is constitutively permeable to sodium ions and that a cysteine residue in its selectivity filter is responsible for this atypical behavior. Indeed, by performing in vivo electrophysiological recordings and Ca2+ imaging experiments, we demonstrate that UNC-58 has a depolarizing effect in muscles and sensory neurons. Consistently, unc-58 gain-of-function mutants are hypercontracted, unlike the relaxed phenotype observed in hyperactive mutants of many neuromuscular K2P channels. Finally, by combining molecular dynamics simulations with functional studies in Xenopus laevis oocytes, we show that the atypical cysteine residue plays a key role in the unconventional sodium permeability of UNC-58. As predicting the consequences of selectivity filter sequence variations in silico remains a major challenge, our study illustrates how functional experiments are essential to determine the contribution of such unusual potassium channels to the electrical profile of excitable cells.

Gut Analysis Toolbox - automating quantitative analysis of enteric neurons.

The enteric nervous system (ENS) consists of an extensive network of neurons and glial cells embedded within the wall of the gastrointestinal (GI) tract. Alterations in neuronal distribution and function are strongly associated with GI dysfunction. Current methods for assessing neuronal distribution suffer from undersampling, partly due to challenges associated with imaging and analyzing large tissue areas, and operator bias due to manual analysis. We present the Gut Analysis Toolbox (GAT), an image analysis tool designed for characterization of enteric neurons and their neurochemical coding using two-dimensional images of GI wholemount preparations. GAT is developed in Fiji, has a user-friendly interface, and offers rapid and accurate segmentation via custom deep learning (DL)-based cell segmentation models developed using StarDist, as well as a ganglia segmentation model in deepImageJ. We apply proximal neighbor-based spatial analysis to reveal differences in cellular distribution across gut regions using a public dataset. In summary, GAT provides an easy-to-use toolbox to streamline routine image analysis tasks in ENS research. GAT enhances throughput, allowing rapid unbiased analysis of larger tissue areas, multiple neuronal markers and numerous samples.

Electrophysiological Changes in Median Nerve among Young Male Cigarette Smokers

Background: Cigarette smoking has been associated with numerous cardiovascular and respiratory disorders. Chronic smoking may also disrupt neuronal function and damage neurons in the peripheral nervous system. Median nerve conduction study is an important electrodiagnostic test for the detection of peripheral nerve dysfunction. Objectives: To observe the impact of cigarette smoking on the electrophysiological status of median motor and sensory nerves in apparently healthy male cigarette smokers. Materials and Methods: This case-control study was carried out in the Department of Physiology, Sir Salimullah Medical College, Dhaka, from July 2017 to June 2018 on thirty male cigarette smokers aged 25 to 40 years. For comparison, thirty age and BMI matched non-smoker healthy male subjects were selected as controls. Motor and sensory nerve conduction parameters (latency, amplitude and nerve conduction velocity) of right median nerve were evaluated by standard methods, using standard nerve conduction study and electromyography machines in the Department of Neurology, Dhaka Medical College Hospital. For statistical analysis, unpaired t test was performed. Results: In this study, median sensory nerve latency was significantly prolonged (p ˂ 0.001) and sensory nerve conduction velocity was significantly slower (p ˂ 0.001) in cigarette smokers. The mean amplitude was also slightly reduced in smokers, but statistically, it was insignificant. However, the distal latency of median motor nerve was slightly prolonged whereas, the amplitude and motor nerve conduction velocity were slightly reduced in cigarette smokers in comparison to those of non-smokers. But the differences were not statistically significant. In addition, 10% of cigarette smokers had subclinical impairment in median sensory nerve function. Conclusion: Chronic cigarette smoking induces significant electrophysiological changes in median sensory nerve fibers and causes sensory nerve dysfunction, while it does not markedly affect median motor nerve fibers in young individuals. KYAMC Journal Volume: 15, No: 01, April 2024: 03-07.

Mitigating sTNF/TNFR1 activation on VGluT2 + spinal cord interneurons improves immune function after mid-thoracic spinal cord injury

Spinal cord injury (SCI) is a devastating condition with 250,000 to 500,000 new cases globally each year. Respiratory infections, e.g., pneumonia and influenza are the leading cause of death after SCI. Unfortunately, there is a poor understanding of how altered neuro-immune communication impacts an individual’s outcome to infection. In humans and rodents, SCI leads to maladaptive changes in the spinal-sympathetic reflex (SSR) circuit which is crucial to sympathetic function. The cause of the impaired immune function may be related to harmful neuroinflammation which is detrimental to homeostatic neuronal function, aberrant plasticity, and hyperexcitable circuits. Soluble tumor necrosis factor (sTNF) is a pro-inflammatory cytokine that is elevated in the CNS after SCI and remains elevated for several months after injury. By pharmacologically attenuating sTNF in the CNS after SCI we were able to demonstrate improved immune function. Furthermore, when we investigated the specific cellular population which may be involved in altered neuro-immune communication we reported that excessive TNFR1 activity on excitatory INs promotes immune dysfunction. Furthermore, this observation is NF-kβ dependent in VGluT2 + INs. Our data is the first report of a target within the CNS, TNFR1, that contributes to SCI-induced immune dysfunction after T9-SCI and is a potential avenue for future therapeutics.

Author Correction: Fractional order memcapacitive neuromorphic elements reproduce and predict neuronal function

Author Correction: Fractional order memcapacitive neuromorphic elements reproduce and predict neuronal function

Shared and unique consequences of Joubert Syndrome gene dysfunction on the zebrafish central nervous system.

Joubert Syndrome (JBTS) is a neurodevelopmental ciliopathy defined by a highly specific midbrain-hindbrain malformation, variably associated with additional neurological features. JBTS displays prominent genetic heterogeneity with >40 causative genes that encode proteins localising to the primary cilium, a sensory organelle that is essential for transduction of signalling pathways during neurodevelopment, among other vital functions. JBTS proteins localise to distinct ciliary subcompartments, suggesting diverse functions in cilium biology. Currently, there is no unifying pathomechanism to explain how dysfunction of such diverse primary cilia-related proteins results in such a highly specific brain abnormality. In order to identify the shared consequence of JBTS gene dysfunction, we carried out transcriptomic analysis using zebrafish mutants for the JBTS-causative genes cc2d2aw38, cep290fh297, inpp5ezh506, talpid3i264 and togaram1zh510and the Bardet-Biedl syndrome-causative gene bbs1k742. We identified no commonly dysregulated signalling pathways in these mutants and yet all mutants displayed an enrichment of altered gene sets related to central nervous system function. We found that JBTS mutants have altered primary cilia throughout the brain, however do not display abnormal brain morphology. Nonetheless, behavioural analyses revealed reduced locomotion and loss of postural control which, together with the transcriptomic results, hint at underlying abnormalities in neuronal activity and/or neuronal circuit function. These zebrafish models therefore offer the unique opportunity to study the role of primary cilia in neuronal function beyond early patterning, proliferation and differentiation.

One Nervous System: Critical Links Between Central and Peripheral Nervous System Health and Implications for Obesity and Diabetes.

There are key differences between the central nervous system (CNS) (brain and spinal cord) and peripheral nervous system (PNS), such as glial cell types, whether there is protection by the blood-brain barrier, modes of synaptic connections, etc. However, there are many more similarities between these two arms of the nervous system, including neuronal structure and function, neuroimmune and neurovascular interactions, and, perhaps most essentially, the balance between neural plasticity (including processes like neuron survival, neurite outgrowth, synapse formation, gliogenesis) and neurodegeneration (neuronal death, peripheral neuropathies like axonopathy and demyelination). This article brings together current research evidence on shared mechanisms of nervous system health and disease between the CNS and PNS, particularly with metabolic diseases like obesity and diabetes. This evidence supports the claim that the two arms of the nervous system are critically linked and that previously understudied conditions of central neurodegeneration or peripheral neurodegeneration may actually be manifesting across the entire nervous system at the same time, through shared genetic and cellular mechanisms. This topic has been critically underexplored due to the research silos between studies of the brain and studies of peripheral nerves and an overemphasis on the brain in neuroscience as a field of study. There are likely shared and linked mechanisms for how neurons stay healthy versus undergo damage and disease among this one nervous system in the body—providing new opportunities for understanding neurological disease etiology and future development of neuroprotective therapeutics.

NMDA Receptors in POMC Neurons Connect Exercise With Insulin Sensitivity.

Increased arcuate proopiomelanocortin (POMC) neuron activity improves glucose metabolism and reduces appetite, facilitating weight loss. We recently showed that arcuate POMC neurons are activated by exercise. However, the role of excitatory glutamatergic input in these neurons and the metabolic outcomes of exercise remains undefined. To investigate this, we developed a mouse model with NMDA receptors (NMDARs) selectively deleted from POMC neurons of adult mice. We performed metabolic assessments, including the monitoring of body weight, body composition analysis, and glucometabolic tolerance tests. We also examined the metabolic outcomes of these mice in response to exercise, including changes in arcuate POMC neuronal activity and insulin sensitivity. Loss of NMDARs in POMC neurons failed to alter body weight or body composition. Notably, however, we did observe a marked impairment in glucose tolerance and insulin sensitivity. Additionally, exercise resulted in activation of arcuate POMC neurons and a sustained improvement in insulin sensitivity, an effect that was abrogated in mice deficient for NMDARs in POMC neurons when compared with their respective sedentary controls. This underscores an important link among exercise, hypothalamic neuron function, and metabolic health. Moreover, this highlights an underappreciated role of hypothalamic POMC neurons in mediating beneficial effects of exercise on glucose metabolism.

Unique Glycans in Synaptic Glycoproteins in Mouse Brain.

The synapse is an essential connection between neuronal cells in which the membrane and secreted glycoproteins regulate neurotransmission. The post-translational modifications of glycoproteins with carbohydrates, although essential for their functions as well as their specific localization, are not well understood. Oddly, whereas galactose addition to glycoproteins is required for neuronal functions, galactosylation is severely restricted for Asn-linked on N-glycans in the brain, and genetic evidence highlights the important roles of galactose in brain functions and development. To explore this novel glycosylation, we exploited an orthogonal technology in which a biotinylated sialic acid derivative (CMP-biotin-Sia) is transferred to terminally galactosylated proteins by a recombinant sialyltransferase (rST6Gal1). This approach allowed us to identify the carrier proteins as well as their localization on brain sections. Immunohistochemical analysis of the biotinylated glycoproteins in brain sections demonstrates that they are largely positioned in the pre- and postsynaptic membranes. Consistent with this positioning, glycoproteomic analyses of the labeled glycoproteins identified a number of them that are involved in synaptic function, cell adhesion, and extracellular matrix interactions. The discovery of these galactosylated N-glycoproteins and their relative confinement to synapses provide novel insights into the unusual and specific nature of protein glycosylation in the brain.

In vivo imaging in mouse spinal cord reveals that microglia prevent degeneration of injured axons

Microglia, the primary immune cells in the central nervous system, play a critical role in regulating neuronal function and fate through their interaction with neurons. Despite extensive research, the specific functions and mechanisms of microglia-neuron interactions remain incompletely understood. In this study, we demonstrate that microglia establish direct contact with myelinated axons at Nodes of Ranvier in the spinal cord of mice. The contact associated with neuronal activity occurs in a random scanning pattern. In response to axonal injury, microglia rapidly transform their contact into a robust wrapping form, preventing acute axonal degeneration from extending beyond the nodes. This wrapping behavior is dependent on the function of microglial P2Y12 receptors, which may be activated by ATP released through axonal volume-activated anion channels at the nodes. Additionally, voltage-gated sodium channels (NaV) and two-pore-domain potassium (K2P) channels contribute to the interaction between nodes and glial cells following injury, and inhibition of NaV delays axonal degeneration. Through in vivo imaging, our findings reveal a neuroprotective role of microglia during the acute phase of single spinal cord axon injury, achieved through neuron-glia interaction.

A multilayer network analysis of Alzheimer's disease pathogenesis: Roles for p-tau, synaptic peptides, and physical activity.

In the aging brain, cognitive abilities emerge from the coordination of complex pathways arising from a balance between protective lifestyle and environmental factors and accumulation of neuropathologies. As part of the Rush Memory and Aging Project (n=440), we measured accelerometer-based actigraphy, cognitive performance, and after brain autopsy, selected reaction monitoring mass spectrometry. Multilevel network analysis was used to examine the relationships among the molecular machinery of vesicular neurotransmission, Alzheimer's disease (AD) neuropathology, cognition, and late-life physical activity. Synaptic peptides involved in neuronal secretory function were the most influential contributors to the multilayer network, reflecting the complex interdependencies among AD pathology, synaptic processes, and late-life cognition. Older adults with lower physical activity evidenced stronger adverse relationships among phosphorylated tau peptides, markers of synaptic integrity, and tangle pathology. Network-based approaches simultaneously model interdependent biological processes and advance understanding of the role of physical activity in age-associated cognitive impairment. Network-based approaches simultaneously model interdependent biological processes. Secretory synaptic peptides were influential contributors to the multilayer network. Older adults with lower physical activity had adverse relationships among pathology. There was interdependence among phosphorylated tau, synaptic integrity, and tangles. Network methods elucidate the role of physical activity in cognitive impairment.