Anatomy and Neuroscience - Research Publications
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ItemNo Preview AvailableNeural pathways for colorectal control, relevance to spinal cord injury and treatment: a narrative review(NATURE PUBLISHING GROUP, 2018-03)STUDY DESIGN: Narrative review. OBJECTIVES: The purpose is to review the organisation of the nerve pathways that control defecation and to relate this knowledge to the deficits in colorectal function after SCI. METHODS: A literature review was conducted to identify salient features of defecation control pathways and the functional consequences of damage to these pathways in SCI. RESULTS: The control pathways for defecation have separate pontine centres under cortical control that influence defecation. The pontine centres connect, separately, with autonomic preganglionic neurons of the spinal defecation centres and somatic motor neurons of Onuf's nucleus in the sacral spinal cord. Organised propulsive motor patterns can be generated by stimulation of the spinal defecation centres. Activation of the somatic neurons contracts the external sphincter. The analysis aids in interpreting the consequences of SCI and predicts therapeutic strategies. CONCLUSIONS: Analysis of the bowel control circuits identifies sites at which bowel function may be modulated after SCI. Colokinetic drugs that elicit propulsive contractions of the colorectum may provide valuable augmentation of non-pharmacological bowel management procedures.
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ItemA novel statistical methodology for quantifying the spatial arrangements of axons in peripheral nerves(FRONTIERS MEDIA SA, 2023-03-09)A thorough understanding of the neuroanatomy of peripheral nerves is required for a better insight into their function and the development of neuromodulation tools and strategies. In biophysical modeling, it is commonly assumed that the complex spatial arrangement of myelinated and unmyelinated axons in peripheral nerves is random, however, in reality the axonal organization is inhomogeneous and anisotropic. Present quantitative neuroanatomy methods analyze peripheral nerves in terms of the number of axons and the morphometric characteristics of the axons, such as area and diameter. In this study, we employed spatial statistics and point process models to describe the spatial arrangement of axons and Sinkhorn distances to compute the similarities between these arrangements (in terms of first- and second-order statistics) in various vagus and pelvic nerve cross-sections. We utilized high-resolution transmission electron microscopy (TEM) images that have been segmented using a custom-built high-throughput deep learning system based on a highly modified U-Net architecture. Our findings show a novel and innovative approach to quantifying similarities between spatial point patterns using metrics derived from the solution to the optimal transport problem. We also present a generalizable pipeline for quantitative analysis of peripheral nerve architecture. Our data demonstrate differences between male- and female-originating samples and similarities between the pelvic and abdominal vagus nerves.
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ItemEditorial: Multiscale anatomy and biophysics of the autonomic nervous system: implications for neuromodulation(FRONTIERS MEDIA SA, 2023-11-01)
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ItemGLA-modified RNA treatment lowers GB3 levels in iPSC-derived cardiomyocytes from Fabry-affected individuals(Cell Press, 2023-09-07)Recent studies in non-human model systems have shown therapeutic potential of nucleoside-modified messenger RNA (modRNA) treatments for lysosomal storage diseases. Here, we assessed the efficacy of a modRNA treatment to restore the expression of the galactosidase alpha (GLA), which codes for α-Galactosidase A (α-GAL) enzyme, in a human cardiac model generated from induced pluripotent stem cells (iPSCs) derived from two individuals with Fabry disease. Consistent with the clinical phenotype, cardiomyocytes from iPSCs derived from Fabry-affected individuals showed accumulation of the glycosphingolipid Globotriaosylceramide (GB3), which is an α-galactosidase substrate. Furthermore, the Fabry cardiomyocytes displayed significant upregulation of lysosomal-associated proteins. Upon GLA modRNA treatment, a subset of lysosomal proteins were partially restored to wild-type levels, implying the rescue of the molecular phenotype associated with the Fabry genotype. Importantly, a significant reduction of GB3 levels was observed in GLA modRNA-treated cardiomyocytes, demonstrating that α-GAL enzymatic activity was restored. Together, our results validate the utility of iPSC-derived cardiomyocytes from affected individuals as a model to study disease processes in Fabry disease and the therapeutic potential of GLA modRNA treatment to reduce GB3 accumulation in the heart.
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ItemNo Preview AvailableSelective recording of physiologically evoked neural activity in a mixed autonomic nerve using a minimally invasive array(AIP Publishing LLC, 2023-12-01)Real-time closed-loop control of neuromodulation devices requires long-term monitoring of neural activity in the peripheral nervous system. Although many signal extraction methods exist, few are both clinically viable and designed for extracting small signals from fragile peripheral visceral nerves. Here, we report that our minimally invasive recording and analysis technology extracts low to negative signal to noise ratio (SNR) neural activity from a visceral nerve with a high degree of specificity for fiber type and class. Complex activity was recorded from the rat pelvic nerve that was physiologically evoked during controlled bladder filling and voiding, in an extensively characterized in vivo model that provided an excellent test bed to validate our technology. Urethane-anesthetized male rats (n = 12) were implanted with a four-electrode planar array and the bladder instrumented for continuous-flow cystometry, which measures urodynamic function by recording bladder pressure changes during constant infusion of saline. We demonstrated that differential bipolar recordings and cross-correlation analyses extracts afferent and efferent activity, and discriminated between subpopulations of fibers based on conduction velocity. Integrated Aδ afferent fiber activity correlated with bladder pressure during voiding (r2: 0.66 ± 0.06) and was not affected by activating nociceptive afferents with intravesical capsaicin (r2: 0.59 ± 0.14, P = 0.54, and n = 3). Collectively, these results demonstrate our minimally invasive recording and analysis technology is selective in extracting mixed neural activity with low/negative SNR. Furthermore, integrated afferent activity reliably correlates with bladder pressure and is a promising first step in developing closed-loop technology for bladder control.
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ItemEarly Depletion of Neutrophils Reduces Retinal Inflammation and Neovascularization in Mice with Oxygen-Induced Retinopathy(MDPI, 2023-11)Retinal inflammation is a central feature of ocular neovascular diseases such as diabetic retinopathy and retinopathy of prematurity, but the contribution of neutrophils to this process is not fully understood. We studied oxygen-induced retinopathy (OIR) which develops in two phases, featuring hyperoxia-induced retinal vaso-obliteration in phase I, followed by retinal neovascularization in phase II. As neutrophils are acute responders to tissue damage, we evaluated whether neutrophil depletion with an anti-Ly6G mAb administered in phase I OIR influenced retinal inflammation and vascular injury. Neutrophils were measured in blood and spleen via flow cytometry, and myeloperoxidase, an indicator of neutrophil activity, was evaluated in the retina using Western blotting. Retinal vasculopathy was assessed by quantitating vaso-obliteration, neovascularization, vascular leakage, and VEGF levels. The inflammatory factors, TNF, MCP-1, and ICAM-1 were measured in retina. In the OIR controls, neutrophils were increased in the blood and spleen in phase I but not phase II OIR. In OIR, the anti-Ly6G mAb reduced neutrophils in the blood and spleen, and myeloperoxidase, inflammation, and vasculopathy in the retina. Our findings revealed that the early rise in neutrophils in OIR primes the retina for an inflammatory and angiogenic response that promotes severe damage to the retinal vasculature.
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ItemAAV capsid bioengineering in primary human retina models(NATURE PORTFOLIO, 2023-12-11)Adeno-associated viral (AAV) vector-mediated retinal gene therapy is an active field of both pre-clinical as well as clinical research. As with other gene therapy clinical targets, novel bioengineered AAV variants developed by directed evolution or rational design to possess unique desirable properties, are entering retinal gene therapy translational programs. However, it is becoming increasingly evident that predictive preclinical models are required to develop and functionally validate these novel AAVs prior to clinical studies. To investigate if, and to what extent, primary retinal explant culture could be used for AAV capsid development, this study performed a large high-throughput screen of 51 existing AAV capsids in primary human retina explants and other models of the human retina. Furthermore, we applied transgene expression-based directed evolution to develop novel capsids for more efficient transduction of primary human retina cells and compared the top variants to the strongest existing benchmarks identified in the screening described above. A direct side-by-side comparison of the newly developed capsids in four different in vitro and ex vivo model systems of the human retina allowed us to identify novel AAV variants capable of high transgene expression in primary human retina cells.
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ItemNo Preview AvailableA critical discussion on the relationship between E3 ubiquitin ligases, protein degradation, and skeletal muscle wasting: it's not that simple(AMER PHYSIOLOGICAL SOC, 2023-12-13)Ubiquitination is an important post-translational modification (PTM) for protein substrates, whereby ubiquitin is added to proteins through the coordinated activity of activating (E1), ubiquitin-conjugating (E2), and ubiquitin ligase (E3) enzymes. The E3s provide key functions in the recognition of specific protein substrates to be ubiquitinated and aid in determining their proteolytic or nonproteolytic fates, which has led to their study as indicators of altered cellular processes. MuRF1 and MAFbx/Atrogin-1 were two of the first E3 ubiquitin ligases identified as being upregulated in a range of different skeletal muscle atrophy models. Since their discovery, the expression of these E3 ubiquitin ligases has often been studied as a surrogate measure of changes to bulk protein degradation rates. However, emerging evidence has highlighted the dynamic and complex regulation of the ubiquitin proteasome system (UPS) in skeletal muscle and demonstrated that protein ubiquitination is not necessarily equivalent to protein degradation. These observations highlight the potential challenges of quantifying E3 ubiquitin ligases as markers of protein degradation rates or ubiquitin proteasome system (UPS) activation. This perspective examines the usefulness of monitoring E3 ubiquitin ligases for determining specific or bulk protein degradation rates in the settings of skeletal muscle atrophy. Specific questions that remain unanswered within the skeletal muscle atrophy field are also identified, to encourage the pursuit of new research that will be critical in moving forward our understanding of the molecular mechanisms that govern protein function and degradation in muscle.
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ItemNo Preview AvailableVasculature is getting Hip(po): Hippo in vascular development and disease(CELL PRESS, 2023-12-04)The Hippo signaling pathway regulates developmental organ growth, regeneration, and cell fate decisions. Although the role of the Hippo pathway, and its transcriptional effectors YAP and TAZ, has been well documented in many cell types and species, only recently have the roles for this pathway come to light in vascular development and disease. Experiments in mice, zebrafish, and in vitro have uncovered roles for the Hippo pathway, YAP, and TAZ in vasculogenesis, angiogenesis, and lymphangiogenesis. In addition, the Hippo pathway has been implicated in vascular cancers and cardiovascular diseases, thus identifying it as a potential therapeutic target for the treatment of these conditions. However, despite recent advances, Hippo's role in the vasculature is still underappreciated compared with its role in epithelial tissues. In this review, we appraise our current understanding of the Hippo pathway in blood and lymphatic vessel development and highlight the current knowledge gaps and opportunities for further research.
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ItemTopographical organization and morphology of substance P (SP)-immunoreactive axons in the whole stomach of mice(WILEY, 2023-02)Nociceptive afferents innervate the stomach and send signals centrally to the brain and locally to stomach tissues. Nociceptive afferents can be detected with a variety of different markers. In particular, substance P (SP) is a neuropeptide and is one of the most commonly used markers for nociceptive nerves in the somatic and visceral organs. However, the topographical distribution and morphological structure of SP-immunoreactive (SP-IR) axons and terminals in the whole stomach have not yet been fully determined. In this study, we labeled SP-IR axons and terminals in flat mounts of the ventral and dorsal halves of the stomach of mice. Flat-mount stomachs, including the longitudinal and circular muscular layers and the myenteric ganglionic plexus, were processed with SP primary antibody followed by fluorescent secondary antibody and then scanned using confocal microscopy. We found that (1) SP-IR axons and terminals formed an extensive network of fibers in the muscular layers and within the ganglia of the myenteric plexus of the whole stomach. (2) Many axons that ran in parallel with the long axes of the longitudinal and circular muscles were also immunoreactive for the vesicular acetylcholine transporter (VAChT). (3) SP-IR axons formed very dense terminal varicosities encircling individual neurons in the myenteric plexus; many of these were VAChT immunoreactive. (4) The regional density of SP-IR axons and terminals in the muscle and myenteric plexus varied in the following order from high to low: antrum-pylorus, corpus, fundus, and cardia. (5) In only the longitudinal and circular muscles, the regional density of SP-IR axon innervation from high to low were: antrum-pylorus, corpus, cardia, and fundus. (6) The innervation patterns of SP-IR axons and terminals in the ventral and dorsal stomach were comparable. Collectively, our data provide for the first time a map of the distribution and morphology of SP-IR axons and terminals in the whole stomach with single-cell/axon/synapse resolution. This work will establish an anatomical foundation for functional mapping of the SP-IR axon innervation of the stomach and its pathological remodeling in gastrointestinal diseases.