Biology subjects

Shah, S.

Publications and source records attributed to Shah, S..

At least 109 records · Page 6Linked to original sources

bioRxiv2022

Web-based Tool Validation for Antimicrobial Resistance Prediction: An Empirical Comparative Analysis

Global public health is seriously threatened by Antimicrobial Resistance (AMR), and there is an urgent need for quick and precise AMR diagnostic tools. The prevalence of novel Antibiotic Resistance Genes (ARGs) has increased substantially during the last decade, owing to the recent burden of microbial sequencing. The major problem is extracting vital information from the massive amounts of generated data. Even though there are many tools available to predict AMR, very few of them are accurate and can keep up with the unstoppable growth of data in the present. Here, we briefly examine a variety of AMR prediction tools that are available. We highlighted three potential tools from the perspective of the user experience that is preferable web-based AMR prediction analysis, as a web-based tool offers users accessibility across devices, device customization, system integration, eliminating the maintenance hassles, and provides enhanced flexibility and scalability. By using the Pseudomonas aeruginosa Complete Plasmid Sequence (CPS), we conducted a case study in which we identified the strengths and shortcomings of the system and empirically discussed its prediction efficacy of AMR sequences, ARGs, amount of information produced and visualisation. We discovered that ResFinder delivers a great amount of information regarding the ARGS along with improved visualisation. KmerResistance is useful for identifying resistance plasmids, obtaining information about related species and the template gene, as well as predicting ARGs. ResFinderFG does not provide any information about ARGs, but it predicts AMR determinants and has a better visualisation than KmerResistance. Author summaryAMR is the capacity of microorganisms to survive or grow in the presence of drugs intended to stop them or kill them. Consequently, there is an increase in the Burden of disease, death rates, and the cost of healthcare, making it a serious global threat to both human and animal health. Next-Generation Sequencing (NGS) based molecular monitoring can be a real boon to phenotypic monitoring of AMR. Researchers face difficult challenges in terms of producing, managing, analysing, and interpreting massive amounts of sequence data. There are many tools available to predict AMR, but only a small number of them are reliable and able to keep up with the current rate of unstoppable data growth. Each tool has specific benefits and drawbacks of its own. Our research offers a comprehensive overview of the outcomes produced by three different tools, enabling users to choose the tool that best suits their requirements.

bioinformatics↗

bioRxiv2022

A Biologically Plausible Spiking Neural Network for Decoding Kinematics in the Hippocampus and Premotor Cortex

This work presents a spiking neural network for predicting kinematics from neural data towards accurate and energy-efficient brain machine interface. A brain machine interface is a technological system that interprets neural signals to allow motor impaired patients to control prosthetic devices. Spiking neural networks have the potential to improve brain machine interface technology due to their low power cost and close similarity to biological neural structures. The SNN in this study uses the leaky integrate-and-fire model to simulate the behavior of neurons, and learns using a local learning method that uses surrogate gradient to learn the parameters of the network. The network implements a novel continuous time output encoding scheme that allows for regression-based learning. The SNN is trained and tested offline on neural and kinematic data recorded from the premotor cortex of a primate and the hippocampus of a rat. The model is evaluated by finding the correlation between the predicted kinematic data and true kinematic data, and achieves peak Pearson Correlation Coefficients of 0.77 for the premotor cortex recordings and 0.80 for the hippocampus recordings. The accuracy of the model is benchmarked against a Kalman filter decoder and a LSTM network, as well as a spiking neural network trained with backpropagation to compare the effects of local learning.

bioengineering↗

bioRxiv2022

Understanding and leveraging phenotypic plasticity during metastasis formation

Cancer metastasis is the process of detrimental systemic spread and the primary cause of cancer-related fatalities. Successful metastasis formation requires tumor cells to be proliferative and invasive; however, cells cannot be effective at both tasks simultaneously. Tumor cells compensate for this trade-off by changing their phenotype during metastasis formation through phenotypic plasticity. Given the changing selection pressures and competitive interactions that tumor cells face, it is poorly understood how plasticity shapes the process of metastasis formation. Here, we develop an ecology-inspired mathematical model with phenotypic plasticity and resource competition between phenotypes to address this knowledge gap. We find that phenotypically plastic tumor cell populations attain a stable phenotype equilibrium that maintains tumor cell heterogeneity. Considering treatment types inspired by chemo- and immunotherapy, we highlight that plasticity can protect tumors against interventions. Turning this strength into a weakness, we corroborate current clinical practices to use plasticity as a target for adjuvant therapy. We present a parsimonious view of tumor plasticity-driven metastasis that is quantitative and experimentally testable, and thus potentially improving the mechanistic understanding of metastasis and its treatment consequences.

cancer biology↗

bioRxiv2022

Development and validation of PainFace, a software platform that simplifies and standardizes mouse grimace analyses

Facial grimaces are now commonly used to quantify spontaneous pain in mice and other mammalian species, but scoring remains subjective and relies on humans with very different levels of proficiency. Here, we developed a Mouse Grimace Scale (MGS) for black-coated (C57BL/6) mice consisting of four facial action units (orbitals, nose, ears, whiskers). We used this scale to generate ground truth data from over 70,000 images of black mice in different settings. With this large data set, we developed a deep neural network and cloud-based software platform called PainFace (http://painface.net) that accurately scores facial grimaces of black mice on a 0-8 scale. PainFace generates over two orders of magnitude more MGS data than humans can realistically achieve, and at superhuman speed. By analyzing the frequency distribution of grimace scores, we found that mice spent >7x more time in a high grimace state following laparotomy surgery relative to sham surgery controls. The analgesic carprofen reduced the amount of time animals spent in this high grimace state after surgery. Specific facial action unit score combinations were overrepresented following laparotomy surgery, suggesting that characteristic facial expressions are associated with a high grimace state. We performed validation experiments in two labs located in different countries to demonstrate reproducibility of the PainFace platform. To further enhance rigor and reproducibility, we will invite pain researchers to beta test PainFace and then incorporate their feedback into the software and manuscript prior to peer review. While this study is focused on mice, PainFace was designed to simplify, standardize, and scale up grimace analyses with many other mammalian species, including humans.

neuroscience↗

bioRxiv2022

Data-Independent Acquisition and Quantification of Extracellular Matrix from Human Lung in Chronic Inflammation-Associated Carcinomas

Early events associated with chronic inflammation and cancer involve significant remodeling of the extracellular matrix (ECM), which greatly affects its composition and functional properties. Using lung squamous cell carcinoma (LSCC), a chronic inflammation-associated cancer (CIAC), we optimized a robust proteomic pipeline to discover potential biomarker signatures and protein changes specifically in the stroma. We combined ECM enrichment from fresh human tissues, data-independent acquisition strategies, and stringent statistical processing to analyze Tumor and matched adjacent histologically normal ( Matched Normal) tissues from patients with LSCC. Overall, 1,802 protein groups were quantified with at least two unique peptides, and 56% of those proteins were annotated as extracellular. Confirming dramatic ECM remodeling during CIAC progression, 529 proteins were significantly altered in the Tumor compared to Matched Normal tissues. The signature was typified by a coordinated loss of basement membrane proteins and small leucine-rich proteins. The dramatic increase in the stromal levels of SERPINH1/heat shock protein 47, that was discovered using our ECM proteomic pipeline, was validated by immunohistochemistry (IHC) of Tumor and Matched Normal tissues, obtained from an independent cohort of LSCC patients. This integrated workflow provided novel insights into ECM remodeling during CIAC progression, and identified potential biomarker signatures and future therapeutic targets. Statement of significance of the studyThe extracellular matrix (ECM) is a complex scaffolding network composed of glycoproteins, proteoglycans and collagens, which binds soluble factors and, most importantly, significantly impacts cell fate and function. Alterations of ECM homeostasis create a microenvironment promoting tumor formation and progression, therefore deciphering molecular details of aberrant ECM remodeling is essential. Here, we present a multi-laboratory and refined proteomic workflow, featuring i) the prospective collection of tumor and matched histologically normal tissues from patients with lung squamous cell carcinoma, ii) the enrichment for ECM proteins, and iii) subsequent label-free data-independent acquisition (DIA)-based quantification. DIA is a powerful strategy to comprehensively profile and quantify all detectable precursor ions contained in the biological samples, with high quantification accuracy and reproducibility. When combined with very stringent statistical cutoffs, this unbiased strategy succeeded in capturing robust and highly confident proteins changes associated with cancer, despite biological variability between individuals. This label-free quantification workflow provided the flexibility required for ongoing prospective studies. Discussions with clinicians, surgeons, pathologists, and cancer biologists represent an opportunity to interrogate the DIA digitalized maps of the samples for newly formulated questions and hypotheses, thus gaining insights into the continuum of the disease and opening the path to novel ECM-targeted therapies.

cancer biology↗

bioRxiv2022

FMRP-Regulated RNA Splicing is Mediated by Multiple Splicing Factors and Translational Control of Mbnl1 RNA

Fragile X Syndrome (FXS) is a neurodevelopmental disorder that is often modeled in Fmr1 knockout mice where the RNA binding protein FMRP is absent. Here we show that in Fmr1-deficient mice, RNA mis-splicing occurs in several brain regions and peripheral tissues. To assess molecular mechanisms of splicing mis-regulation, we employed N2A cells depleted of Fmr1. In the absence of FMRP, RNA-specific exon skipping events are linked to the splicing factors hnRNPF, PTBP1, and MBNL1. FMRP regulates the translation of Mbnl1 mRNA as well as Mbnl1 RNA auto-splicing. Elevated Mbnl1 auto-splicing in FMRP-deficient cells results in the loss of a nuclear localization signal (NLS)-containing exon. This in turn alters the nucleus-to-cytoplasm ratio of MBNL1. This re-distribution of MBNL1 isoforms in Fmr1-deficient cells could result in downstream splicing changes in other RNAs. Indeed, further investigation revealed that splicing distruptions resulting from Fmr1 depletion could be rescued by overexpression of nuclear MBNL1. Altered Mbnl1 auto-splicing also occurs in human FXS post-mortem brain. These data suggest that FMRP-controlled translation and RNA processing may cascade into a general dys-regulation of splicing in Fmr1-deficient cells.

cell biology↗

bioRxiv2022

Evolution of resilience against heat stress in a red-tide dinoflagellate

"Red tides" are harmful algal blooms (HABs) caused by dinoflagellate microalgae that accumulate toxins lethal to other organisms, including humans via consumption of contaminated seafood. Increasingly frequent, HABs are driven by a combination of environmental factors including nutrient enrichment, particularly in warm waters. Here, we present the de novo assembled genome (~4.75 Gbp), transcriptome, proteome, and metabolome from Prorocentrum cordatum, a globally abundant, bloom-forming dinoflagellate. Using axenic algal cultures, we studied the molecular mechanisms that underpin response to temperature stress, which is relevant to current ocean warming trends. We discovered a complementary interplay between RNA editing and exon usage that regulates the expression and functional diversity of biomolecules, reflected by reduction in photosynthesis, central metabolism, and protein synthesis. Our multi-omics analyses uncover the molecular response to heat stress in an important HAB species, which is driven by complex gene structures in a large, high-G+C genome, combined with multi-level transcriptional regulation.

genomics↗

bioRxiv2022

Improved Cladocopium goreaui genome assembly reveals features of a facultative coral symbiont and the complex evolutionary history of dinoflagellate genes

Dinoflagellates of the family Symbiodiniaceae are crucial photosymbionts in corals and other marine organisms. Of these algae, Cladocopium goreaui is one of the most dominant symbiont species in the Indo-Pacific. Here, we present an improved genome assembly of C. goreaui combining new long-read sequence data with earlier generated short-read data. Incorporating new full-length transcripts to guide gene prediction, the C. goreaui genome (1.2 Gb) exhibits a high extent of completeness (82.4% based on BUSCO protein recovery) and better resolution of repetitive sequence regions; 45,322 gene models were predicted, and 327 putative, topologically associated domains of the chromosomes were identified. Comparison with other Symbiodiniaceae genomes revealed a prevalence of repeats and duplicated genes in C. goreaui, and lineage-specific genes indicating functional innovation. Incorporating 2,841,408 protein sequences from 96 broadly sampled eukaryotes and representative prokaryotes in a phylogenomic approach, we assessed the evolutionary history of C. goreaui genes. Of the 5,246 phylogenetic trees inferred from homologous protein sets containing two or more phyla, 35-36% have putatively originated via horizontal gene transfer (HGT), predominantly (19-23%) via an ancestral Archaeplastida lineage implicated in the endosymbiotic origin of plastids: 10-11% are of green algal origin, including genes encoding photosynthetic functions. Our results demonstrate the utility of long-read sequence data in resolving structural features of a dinoflagellate genome and highlight how genetic transfer has shaped genome evolution of a facultative symbiont, and more broadly of dinoflagellates.

genomics↗

bioRxiv2022

Coenzyme A binding sites induce proximal acylation across protein families

Lysine N{varepsilon}-acylations, such as acetylation or succinylation, are post-translational modifications that regulate protein function. In mitochondria, lysine acylation is predominantly non-enzymatic, and only a specific subset of the proteome is acylated. Coenzyme A (CoA) can act as an acyl group carrier via a thioester bond, but what controls the acylation of mitochondrial lysines remains poorly understood. Using published datasets, here we found that proteins with a CoA-binding site are more likely to be acetylated, succinylated, and glutarylated. Using computational modeling, we show that lysine residues near the CoA-binding pocket are highly acylated compared to those farther away. We hypothesized that acyl-CoA binding enhances acylation of nearby lysine residues. To test this hypothesis, we co-incubated enoyl-CoA hydratase short chain 1 (ECHS1), a CoA-binding mitochondrial protein, with succinyl-CoA and CoA. Using mass spectrometry, we found that succinyl-CoA induced widespread lysine succinylation and that CoA competitively inhibited ECHS1 succinylation. CoA-induced inhibition at a particular lysine site correlated inversely with the distance between that lysine and the CoA-binding pocket. Our study indicated that CoA acts as a competitive inhibitor of ECHS1 succinylation by binding to the CoA-binding pocket. Together, this suggests that proximal acylation at CoA-binding sites is a primary mechanism for lysine acylation in the mitochondria.

biochemistry↗

bioRxiv2022

Whole-genome duplication in an algal symbiont serendipitously confers thermal tolerance to corals

The algal endosymbiont Durusdinium trenchii enhances the resilience of coral reefs under thermal stress1,2. As an endosymbiont, D. trenchii is generally expected to have a reduced genome compared to its free-living relatives, due in part to the lack of selective pressure for maintaining redundant gene functions in a stable intracellular environment within the host3. However, D. trenchii can live freely or in endosymbiosis, and the analysis of genetic markers4 suggests that this species has undergone whole-genome duplication (WGD). Here we present genome assemblies for two D. trenchii isolates, confirm WGD in these taxa, and examine how selection has shaped the duplicated genome regions. We assess how the competing free-living versus endosymbiotic lifestyles of D. trenchii have contributed to the retention and divergence of duplicated genes, and how these processes have enhanced thermotolerance of corals hosting these symbionts. We find that lifestyle is the driver of post-WGD evolution in D. trenchii, with the free-living phase being most important, followed by endosymbiosis. Adaptations to both lifestyles collectively result in increased cellular fitness for D. trenchii, which provides enhanced thermal stress protection to the host coral. Beyond corals, this polyploid alga is a valuable model for understanding how genome-wide selective forces act to balance the often, divergent constraints imposed by competing lifestyles.

genomics↗

bioRxiv2022

Human Elp3/Kat9 is a mitochondrial tRNA modifying enzyme

Post-translational modifications, such as lysine acetylation, regulate the activity of diverse proteins across many cellular compartments. Protein deacetylation in mitochondria is catalyzed by the enzymatic activity of the NAD+-dependent deacetylase sirtuin 3 (SIRT3), however it remains unclear whether corresponding mitochondrial acetyltransferases exist. We used a bioinformatics approach to search for mitochondrial proteins with an acetyltransferase catalytic domain, and identified a novel splice variant of ELP3 (mt-ELP3) of the elongator complex, which localizes to the mitochondrial matrix in mammalian cells. Unexpectedly, mt-ELP3 does not mediate mitochondrial protein acetylation but instead induces a post-transcriptional modification of mitochondrial-transfer RNAs (mt-tRNAs). Overexpression of mt-ELP3 leads to the protection of mt-tRNAs against the tRNA-specific RNase angiogenin, increases mitochondrial translation, and furthermore increases expression of OXPHOS complexes. This study thus identifies mt-ELP3 as a non-canonical mt-tRNA modifying enzyme.

molecular biology↗

bioRxiv2022

Targeted photothrombotic stroke leads to disruptions in neurovascular coupling

Functional neuroimaging, which measures hemodynamic responses to brain activity, has great potential for monitoring stroke patients. However, the neurophysiological interpretations of these hemodynamic signals remain a challenge as the stroke is likely to alter both neural activity and neurovascular coupling. To address this challenge, we simultaneously captured neural activity, through fluorescence calcium imaging, and hemodynamics, through intrinsic optical signal imaging, during longitudinal stroke recovery. We found that photothrombotic stroke to somatosensory forelimb region altered neurovascular coupling in the acute phase (2 days and 1 week post-stroke) within the affected forelimb and peri-infarct regions. Neurovascular coupling was reestablished in the chronic phase (4 weeks post-stroke), and acute recovery of neurovascular coupling predicted sensorimotor function. Stroke also resulted in increases in the power of global brain oscillations, which showed distinct patterns between calcium and hemodynamics. Increased calcium excitability in the contralesional hemisphere was associated with increased intrahemispheric connectivity. Additionally, acute increases in hemodynamic oscillations were associated with improved sensorimotor outcomes. TeaserAcute ischemic stroke leads to neurovascular uncoupling and the extent of early recoupling predicts sensorimotor recovery.

physiology↗

bioRxiv2022

Epigenetic dysregulation from chromosomal transit in micronuclei

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers [1-4], yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei [5, 6], and subsequent micronuclear envelope rupture [7] profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and non-transformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer.

cancer biology↗

bioRxiv2022

SIRT5 is a proviral factor that interacts with SARS-CoV-2 Nsp14 protein

SARS-CoV-2 non-structural protein Nsp14 is a highly conserved enzyme necessary for viral replication. Nsp14 forms a stable complex with non-structural protein Nsp10 and exhibits exoribonuclease and N7-methyltransferase activities. Protein-interactome studies identified human sirtuin 5 (SIRT5) as a putative binding partner of Nsp14. SIRT5 is an NAD-dependent protein deacylase critical for cellular metabolism that removes succinyl and malonyl groups from lysine residues. Here we investigated the nature of this interaction and the role of SIRT5 during SARS-CoV-2 infection. We showed that SIRT5 stably interacts with Nsp14, but not with Nsp10, suggesting that SIRT5 and Nsp10 are parts of separate complexes. We found that SIRT5 catalytic domain is necessary for the interaction with Nsp14, but that Nsp14 does not appear to be directly deacylated by SIRT5. Furthermore, knock-out of SIRT5 or treatment with specific SIRT5 inhibitors reduced SARS-CoV-2 viral levels in cell-culture experiments. SIRT5 knock-out cells expressed higher basal levels of innate immunity markers and mounted a stronger antiviral response. Our results indicate that SIRT5 is a proviral factor necessary for efficient viral replication, which opens novel avenues for therapeutic interventions.

microbiology↗

bioRxiv2021

Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways

The S209F variant of Abelson Interactor Protein 3 (ABI3) increases risk for Alzheimers disease (AD), but little is known about ABI3 function. RNAscope showed Abi3 is expressed in microglial and non-microglial cells, though its increased expression appears to be driven in plaque-associated microglia. Here, we evaluated Abi3-/- mice and document that both Abi3 and its overlapping gene, Gngt2, are disrupted in these mice. Expression of Abi3 and Gngt2 are tightly correlated, and elevated, in rodent models of AD. RNA-seq of the Abi3-Gngt2-/- mice revealed robust induction of an AD-associated neurodegenerative signature, including upregulation of Trem2, Plcg2 and Tyrobp. In APP mice, loss of Abi3-Gngt2 resulted in a gene dose- and age-dependent reduction in A{beta} deposition. Additionally, in Abi3-Gngt2-/- mice, expression of a pro-aggregant form of human tau exacerbated tauopathy and astrocytosis. Further, the AD-associated S209F mutation alters the extent of ABI3 phosphorylation. These data provide an important experimental framework for understanding the role of Abi3-Gngt2 function in AD. Our studies also demonstrate that manipulation of glial function could have opposing effects on amyloid and tau pathology, highlighting the unpredictability of targeting such pathways in AD.

neuroscience↗

bioRxiv2021

Microglia-specific promoter activities of human HexB gene

Adeno-associated virus (AAV)-mediated genetic targeting of microglia remains challenging. Overcoming this hurdle is essential for gene editing in the central nervous system (CNS). Here, we characterized the minimal/native promoter of the HexB gene, which is known to be specifically and stably expressed in the microglia during homeostatic and pathological conditions. Dual reporter and serial deletion assays identified the critical role of the natural 5 untranslated region (-97 bp related to the first ATG) in driving transcriptional activity of the mouse HexB gene. The native promoter region of mouse, human and monkey HexB located at -135, -134 and -170 bp to the first ATG, respectively. These promoters were highly active and specific in microglia with strong cross-species transcriptional activities, but had no activities in primary astrocytes. In addition, we identified a 135 bp promoter of CD68 gene was also highly active in microglia but not in astrocytes. Considering that HexB is specifically expressed in microglia, not in monocytes/macrophages or other neuronal cells, these data suggest that the newly characterized 134 bp microglia-specific HexB promoter can be an ideal candidate for microglia-targeting AAV gene therapy, which could be developed for HIV eradication in the brain wherein microglia harbor the main HIV reservoirs in the CNS. SummaryIt is hard to overstate the importance of gene therapy that can remove viral genes from human cells. A cure for HIV would mean a lifetime free of treatment for patients who now must maintain a strict regimen of ART indefinitely. In order to develop a cure using AAV delivery, payload DNA must meet the AAV vector size limitations, and the payload genes must be expressed appropriately. Previous studies have identified microglia-specific HexB gene that shows stable expression during neural homeostasis and pathogenesis. Our study identified the essential HexB gene promoter (134 bp) as a strong candidate for AAV gene therapy to specifically target the brain microglia, the main cellular reservoirs of HIV in the central nervous system. Our studies continue to move us closer to identifying target-specific gene therapy for NeuroAIDS.

neuroscience↗

bioRxiv2021

The Mismatch Between Neuroscience Graduate Training and Professional Skill Sets

Understanding the skill sets required for career paths is a prerequisite for preparing students for those careers. Neuroscience career paths are rapidly changing as the field expands and increasingly overlaps with computational and data-heavy job sectors. With the steady growth in neuroscience trainees and the diversification of jobs for those trainees, it is important to assess whether or not our training is matching the skill sets required in the workforce. Here, we surveyed hundreds of neuroscience professionals and graduate students to assess their use and valuation of a range of skills, from bench skills to communication and management. We find that professionals with neuroscience degrees can be clustered into three main groups based on their skill sets: academic research, industry research and technical work, and non-research. Further, we find that while graduate students do not use or highly value management and communication skills, almost all neuroscience professionals report strongly needing those skills. Finally, coding and data analysis skills are widely used in academic and industry research and predict higher salaries. Our findings can help trainees assess their own skill sets as well as encourage educational leaders to offer training in management and communication-skills which may help catapult trainees into the next stages of their careers.

scientific communication and education↗

bioRxiv2021

Spinal ganglia control nociceptive input to the central nervous system

Accumulating observations suggest that peripheral somatosensory ganglia may regulate nociceptive transmission, yet direct evidence is sparse. Here we show that the peripheral afferent nociceptive information undergoes dynamic filtering within the dorsal root ganglion (DRG) and suggest that this filtering occurs at the axonal bifurcations (t-junctions). Using synchronous in vivo electrophysiological recordings from the peripheral and central processes of sensory neurons (in the spinal nerve and dorsal root), ganglionic transplantation of GABAergic progenitor cells, and optogenetics we demonstrate existence of tonic and dynamic filtering of action potentials traveling through the DRG. Filtering induced by focal application of GABA or optogenetic GABA release from the DRG-transplanted GABAergic progenitor cells was specific to nociceptive fibers. Light-sheet imaging and computer modeling demonstrated that, compared to other somatosensory fiber types, nociceptors have shorter stem axons, making somatic control over t-junctional filtering more efficient. Optogenetically-induced GABA release within DRG from the transplanted GABAergic cells enhanced filtering and alleviated hypersensitivity to noxious stimulation produced by chronic inflammation and neuropathic injury in vivo. These findings support gating of pain information by DRGs and suggest new therapeutic approaches for pain relief.

neuroscience↗