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Morphological changes of various peripheral nervous system components of rats, rabbits, and guinea pigs under influence of cobalt 60 irradiation
Hypomyelination, a neurological disorder characterized by a decrease in the production of myelin sheets by glial cells, often has no known etiology. Elucidating the genetic causes of hypomyelination provides a better understanding of myelination, as well as means to diagnose, council, and treat patients. Here, we present evidence that YIPPEE LIKE 3 (YPEL3), a gene whose developmental role was previously unknown, is required for central and peripheral glial cell development. We identified a child with a constellation of clinical features including cerebral hypomyelination, abnormal peripheral nerve conduction, hypotonia, areflexia, and hypertrophic peripheral nerves. Exome and genome sequencing revealed a de novo mutation that creates a frameshift in the open reading frame of YPEL3 , leading to an early stop codon. We used zebrafish as a model system to validate that YPEL3 mutations are causative of neuropathy. We found that ypel3 isexpressed in the zebrafish central and peripheral nervous system. Using CRISPR/Cas9 technology, we created zebrafish mutants carrying a genomic lesion similar to that of the patient. Our analysis revealed that Ypel3 is required for specification and migration of myelinating oligodendrocytes, timely exit of the perineurial glial precursors from the central nervous system (CNS), formation of the perineurium, and Schwann cell maturation. Consistent with these observations, zebrafish ypel3 mutants have metabolomic signatures characteristic of oligodendrocyte and Schwann cell differentiation defects, show decreased levels of Myelin basic protein in the central and peripheral nervous system, and develop defasciculated peripheral nerves. Locomotion defects were observed in adult zebrafish ypel3 mutants. These studies demonstrate that Ypel3 is a novel gene required for perineurial cell differentiation and glial myelination.
The overarching objective of this project was to identify changes in neural and biochemical systems of the central and peripheral nervous systems (the CNS and PNS) that are related to disruptions of functional motor responses, or motor control. The identification of neural and biochemical changes that are related to sensory-motor adaptation elicited as animals react to changes in the gravitational field was of particular interest. Thus, the major objective of this work was to study disruptions of motor responses that arise after (sic. due to) chronic exposure to altered gravity (G). To do this, parallel studies investigating changes in neural, sensory, and neuromuscular systems were conducted after animals (rats) experienced chronic exposure to conditions of altered-G. Conditions of altered-G included hyper-G produced by centrifugation, micro-G produced by orbital flight, and simulated micro-G produced by hind limb suspension. A second major interest was to examine the contribution of putative changes in sensory systems to disruptions of motor responses. To do this, motor responses and reflexes of rats were studied following chronic treatment with streptomycin sulfate (STP, an ototoxic chemical) to damage the vestibular hair cells.
The senseless (sens) gene is required for proper development of most cell types of the embryonic and adult peripheral nervous system (PNS) of Drosophila. Sens is a nuclear protein with four Zn fingers that is expressed and required in the sensory organ precursors (SOP) for proper proneural gene expression. Ectopic expression of Sens in many ectodermal cells causes induction of PNS external sensory organ formation and is able to recreate an ectopic proneural field. Hence, sens is both necessary and sufficient for PNS development. Our data indicate that proneural genes activate sens expression. Sens is then in turn required to further activate and maintain proneural gene expression. This feedback mechanism is essential for selective enhancement and maintenance of proneural gene expression in the SOPs.
Neuromodulation devices are rapidly evolving for the treatment of neurological diseases and conditions. Injury from implantation or long-term use without obvious functional losses is often only detectable through terminal histology. New technologies are needed that assess the peripheral nervous system (PNS) under normal and diseased or injured conditions. We aim to demonstrate an imaging and stimulation platform that can elucidate the biological mechanisms and impacts of neurostimulation in the PNS and apply it to the sciatic nerve to extract imaging metrics indicating electrical overstimulation. A sciatic nerve injury model in a 15-rat cohort was observed using a newly developed imaging and stimulation platform that can detect electrical overstimulation effects with polarization-sensitive optical coherence tomography. The sciatic nerve was electrically stimulated using a custom-developed nerve holder with embedded electrodes for 1 h, followed by a 1-h recovery period, delivered at above-threshold Shannon model k-values in experimental groups: sham control (SC, n = 5, 0.0 mA / 0 Hz), stimulation level 1 (SL1, n = 5, 3.4 mA / 50 Hz, and k = 2.57), and stimulation level 2 (SL2, n = 5, 6.8 mA / 100 Hz, and k = 3.17). The stimulation and imaging system successfully captured study data across the cohort. When compared to a SC after a 1-week recovery, the fascicle closest to the stimulation lead showed an average change of +4 % / – 309 % (SL1/SL2) in phase retardation and –79 % / – 148 % in optical attenuation relative to SC. Analysis of immunohistochemistry (IHC) shows a +1 % / – 36 % difference in myelin pixel counts and –13 % / + 29 % difference in axon pixel counts, and an overall increase in cell nuclei pixel count of +20 % / + 35 % . These metrics were consistent with IHC and hematoxylin/eosin tissue section analysis. The poststimulation changes observed in our study are manifestations of nerve injury and repair, specifically degeneration and angiogenesis. Optical imaging metrics quantify these processes and may help evaluate the safety and efficacy of neuromodulation devices.
Nerve agents have experienced a resurgence in recent times with their use against civilian targets during the attacks in Syria (2012), the poisoning of Sergei and Yulia Skripal in the United Kingdom (2018) and Alexei Navalny in Russia (2020), strongly renewing the importance of antidote development against these lethal substances. The current standard treatment against their effects relies on the use of small molecule-based oximes that can efficiently restore acetylcholinesterase (AChE) activity. Despite their efficacy in reactivating AChE, the action of drugs like 2-pralidoxime (2-PAM) is primarily limited to the peripheral nervous system (PNS) and, thus, provides no significant protection to the central nervous system (CNS). This lack of action in the CNS stems from their ionic nature that, on one end makes them very powerful reactivators and on the other renders them ineffective at crossing the Blood Brain Barrier (BBB) to reach the CNS. In this report, we describe the use of an iterative approach composed of parallel chemical and in silico syntheses, computational modeling, and a battery of detailed in vitro and in vivo assays that resulted in the identification of a promising, novel CNS-permeable oxime reactivator. Additional experiments to determine acute and chronic toxicity are ongoing.
Abstract Parkinson’s disease (PD) is a multifactorial neurodegenerative disease that is characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta and by the anomalous accumulation of α-synuclein aggregates into Lewy bodies and Lewy neurites. Research suggests 2 distinct subtypes of PD: the brain-first subtype if the pathology arises from the brain and then spreads to the peripheral nervous system (PNS) and the body-first subtype, where the pathological process begins in the PNS and then spreads to the central nervous system. This review primarily focuses on the body-first subtype. The influence of the gut microbiota on the development of PD has been the subject of growing interest among researchers. It has been suggested that gut inflammation may be closely associated with pathogenesis in PD, therefore leading to the hypothesis that gut microbiota modulation could play a significant role in this process. Nutrition can influence gut health and alter the risk and progression of PD by altering inflammatory markers. This review provides an overview of recent research that correlates variations in gut microbiota composition between patients with PD and healthy individuals with the impact of certain nutrients and dietary patterns, including the Mediterranean diet, the Western diet, and the ketogenic diet. It explores how these diets influence gut microbiota composition and, consequently, the risk of PD. Last, it examines fecal transplantation and the use of prebiotics, probiotics, or synbiotics as potential therapeutic strategies to balance the gut microbiome, aiming to reduce the risk or delay the progression of PD.
This is the final report for the DOE ASCR grant SC-0022260, Data Summarization and Inference at Scale, PI: Alex Pothen, Purdue University. The goal of the project was to solve data-intensive and compute-intensive problems in the physical sciences, engineering, information science, data science, etc. by designing and implementing new algorithms that could work with a subset of the data. The four subgoals were: (a) The solution of problems where the data is too large to be stored in the memory of a computer. In this streaming model of computation, the data arrives as a stream of elements to the computer, each element is processed as it arrives, and a decision is made to discard the data or to store it; only a small subset of the data proportional to the size of the output solution is stored, and when all the data has been streamed, a solution to the problem is computed from the stored subset. (b) The use of machine learning methods to compute solutions to data-intensive problems. The use of GPUs is critical to obtain high performance on machine learning tasks, but their memory sizes are smaller relative to that of CPUs. For large-scale problems, the data is sampled many times, and small samples are used with repetition, for robustness, to compute solutions to inference tasks. This sampling reduces the memory required to solve the problem, but attention is needed to avoid slow convergence to the solutions, and reduced accuracy of inference. We propose submodular optimization, Large Language Models, and physics-informed neural networks to enable GPU computations here. (c) Modeling and visualization of high-dimensional data using interpretable features. Clinical proteomic data sets from immunology for the detection of cancer and other diseases are temporal and high-dimensional, and algorithms for visualizing these data sets using clinically interpretable features are lacking. We propose methods that compute distances based on the optimal transportation problem and graph edit distances to address this problem. We also propose the use of optimal transport-based distances, spatial statistics, and network structure to classify image data sets, We apply these algorithms to electron micrographs of the peripheral nervous system in the digestive tract. (d) The design of data-intensive algorithms on emerging architectures, specifically, noisy, intermediate-scale quantum (NISQ) devices. Quantum computers offer the possibility of exploring large solution spaces due to the principle of superposition, but current quantum computers are limited by few qubits, short coherence times due to noise, poor interconections among the qubits, etc. We propose the use of the divide and conquer paradigm to solve large-scale problems, wherein collections of small subproblems are solved on the quantum devices, and the solutions to the subproblems are integrated into a solution for the original problem on a classical computer.
A 10-year cumulative bibliography of publications resulting from research supported by the neuroscience discipline of the space physiology and countermeasures program of NASA's Life Sciences Division is provided. Primary subjects included in this bibliography are space motion sickness; vestibular performance, posture, and motor coordination; vestibular physiology; central and peripheral nervous system physiology; and general performance and methodologies. General physiology references are also included.
Neuromodulation denotes controlled electrical stimulation of the central or peripheral nervous system. The three forms of neuromodulation described in this paper-deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation-were chosen primarily for their demonstrated or potential clinical usefulness. Deep brain stimulation is a completely implanted technique for improving movement disorders, such as Parkinson's disease, by very focal electrical stimulation of the brain-a technique that employs well-established hardware (electrode and pulse generator/battery). Vagus nerve stimulation is similar to deep brain stimulation in being well-established (for the treatment of refractory epilepsy), completely implanted, and having hardware that can be considered standard at the present time. Vagus nerve stimulation differs from deep brain stimulation, however, in that afferent stimulation of the vagus nerve results in diffuse effects on many regions throughout the brain. Although use of deep brain stimulation for applications beyond movement disorders will no doubt involve placing the stimulating electrode(s) in regions other than the thalamus, subthalamus, or globus pallidus, the use of vagus nerve stimulation for applications beyond epilepsy-for example, depression and eating disorders-is unlikely to require altering the hardware significantly (although stimulation protocols may differ). Transcranial magnetic stimulation is an example of an external or non-implanted, intermittent (at least given the current state of the hardware) stimulation technique, the clinical value of which for neuromodulation and neuroprotection remains to be determined.
Norepinephrine (NE), a key neurotransmitter of the central and peripheral nervous systems, is synthesized by dopamine beta-hydroxylase (DBH) that catalyzes oxidation of dopamine (DA) to NE. NE deficiency is a congenital disorder of unknown etiology, in which affected patients suffer profound autonomic failure. Biochemical features of the syndrome include undetectable tissue and circulating levels of NE and epinephrine, elevated levels of DA, and undetectable levels of DBH. Here, we report identification of seven novel variants including four potentially pathogenic mutations in the human DBH gene (OMIM 223360) from analysis of two unrelated patients and their families. Both patients are compound heterozygotes for variants affecting expression of DBH protein. Each carries one copy of a T-->C transversion in the splice donor site of DBH intron 1, creating a premature stop codon. In patient 1, there is a missense mutation in DBH exon 2. Patient 2 carries missense mutations in exons 1 and 6 residing in cis. We propose that NE deficiency is an autosomal recessive disorder resulting from heterogeneous molecular lesions at DBH. Copyright 2002 Wiley-Liss, Inc.
As the number of new transgenic mouse models of human neuromuscular disease continues to increase, the development of sophisticated electrophysiologic techniques for assessing the peripheral nervous system in these models has become important. Neuromuscular junction (NMJ) dysfunction, in particular, is often not detectable by morphologic or other techniques. To enable sensitive testing of murine NMJ function, we developed and tested a method for stimulated single fiber electromyography (S-SFEMG) in the gastrocnemius muscles of anesthetized mice. Jitter was assessed by measuring the mean consecutive latency difference (MCD) of single fiber responses to sciatic nerve stimulation at 2 HZ. Mean MCD values in normothermic mice were in the range of 6-8 micros for different strains, with no MCD values exceeding 25 micros. Reduced core temperature (to 29 degrees--30 degrees C) resulted in increased jitter, whereas intubation and mechanical ventilation of mice did not alter these values. Intraperitoneal and intravenous injection of vecuronium, however, resulted in progressively increased jitter followed by blocking in continuously monitored fibers. These observations validate the utility of S-SFEMG in mice as an index of NMJ function under a variety of physiologic conditions, and suggest that a high safety factor for neuromuscular transmission exists at mouse NMJs. Copyright 2001 John Wiley & Sons, Inc.
The Lyra mutation was first described by Jerry Coyne in 1935. Lyra causes recessive pupal lethality and adult heterozygous Lyra mutants exhibit a dominant loss of the anterior and posterior wing margins. Unlike many mutations that cause loss of wing tissue (e.g., scalloped, Beadex, cut, and apterous-Xasta), Lyra wing discs do not exhibit increased necrotic or apoptotic cell death, nor do they show altered BrdU incorporation. However, during wing disc eversion, loss of the anterior and posterior wing margins is apparent. We have previously shown that senseless, a gene that is necessary and sufficient for peripheral nervous system (PNS) development, is allelic to Lyra. Here we show by several genetic criteria that Lyra alleles are neomorphic alleles of senseless that cause ectopic expression of SENSELESS in the wing pouch. Similarly, overexpression of SENSELESS in the wing disc causes loss of wing margin tissue, thereby mimicking the Lyra phenotype. Lyra mutants display aberrant expression of DELTA, VESTIGIAL, WINGLESS, and CUT. As in Lyra mutants, overexpression of SENSELESS in some areas of the wing pouch also leads to loss of WINGLESS and CUT. In summary, our data indicate that overexpression of SENSELESS causes a severe reduction in NOTCH signaling that in turn may lead to decreased transcription of several key genes required for wing development, leading to a failure in cell proliferation and loss of wing margin tissue.
Drosophila atonal (ato) is the proneural gene of the chordotonal organs (CHOs) in the peripheral nervous system (PNS) and the larval and adult photoreceptor organs. Here, we show that ato is expressed at multiple stages during the development of a lineage of central brain neurons that innervate the optic lobes and are required for eclosion. A novel fate mapping approach shows that ato is expressed in the embryonic precursors of these neurons and that its expression is reactivated in third instar larvae (L3). In contrast to its function in the PNS, ato does not act as a proneural gene in the embryonic brain. Instead, ato performs a novel function, regulating arborization during larval and pupal development by interacting with Notch.
Model of peripheral auditory system - case study in neural modeling
Effect of local and total, single and chronic vibration on state of peripheral and central nervous systems
Long-term conditioning of orienting responses in electrodermal and peripheral vasomotor systems of humans
Peripheral auditory system model relating all-or- none activity of nerve fibers to acoustic stimulation