A harmonized atlas of mouse spinal cord cell types and their spatial organization

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Сен. 29, 2021

Abstract Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases mouse spinal cord have been published in recent years but not integrated together. Here, we generate an atlas types based on single-cell transcriptomic data, unifying available datasets into a common reference framework. We report hierarchical structure postnatal relationships, with location providing highest level organization, then neurotransmitter status, family, and finally, dozens refined populations. validate combinatorial marker code for each neuronal map their spatial distributions adult cord. also show complex lineage relationships among Additionally, develop open-source classifier, SeqSeek, to facilitate standardization identification. This work provides view types, gene expression signatures, organization.

Язык: Английский

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Brain circuits for pain and its treatment

Science Translational Medicine, Год журнала: 2021, Номер 13(619)

Опубликована: Ноя. 10, 2021

Understanding the organization of brain’s pain circuits is critical for developing effective treatments patients suffering from chronic pain.

Язык: Английский

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A functional subdivision within the somatosensory system and its implications for pain research

Neuron, Год журнала: 2022, Номер 110(5), С. 749 - 769

Опубликована: Янв. 10, 2022

Язык: Английский

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Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β

Frontiers in Pain Research, Год журнала: 2021, Номер 2

Опубликована: Авг. 25, 2021

Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast fibroblasts, keratinocytes and epithelial cells activated leading to the generation an "inflammatory soup" containing cytokines, chemokines growth factors. These primary mediators sensitize sensory endings, attract macrophages, neutrophils lymphocytes, alter gene expression, promote post-translational modification proteins, ion channel function in afferent neurons. This leads increased excitability spontaneous activity secondary including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, Wnt5a. Release these from neurons alters properties spinal microglial causing them release tertiary mediators, many situations

Язык: Английский

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Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets

Frontiers in Pain Research, Год журнала: 2021, Номер 2

Опубликована: Дек. 13, 2021

The persistence of increased excitability and spontaneous activity in injured peripheral neurons is imperative for the development many forms neuropathic pain. This aberrant involves and/or expression voltage-gated Na

Язык: Английский

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Neuroplasticity related to chronic pain and its modulation by microglia

Inflammation and Regeneration, Год журнала: 2022, Номер 42(1)

Опубликована: Май 3, 2022

Neuropathic pain is often chronic and can persist after overt tissue damage heals, suggesting that its underlying mechanism involves the alteration of neuronal function. Such an be a direct consequence nerve or result neuroplasticity secondary to tissues neurons. Recent studies have shown linked causing neuropathic in response damage, which may occur adjacent remotely from site injury. Furthermore, revealed relevant modulated by microglia, resident immune cells central nervous system (CNS). Microglia directly contribute synaptic remodeling altering circuits, indirectly through property changes, including secretion growth factors. We herein highlight mechanisms somatosensory circuit spinal dorsal horn, thalamus, cortex associated with following injury peripheral (PNS) CNS. also discuss dynamic functions microglia shaping related pain. suggest further understanding post-injury ectopic plasticity circuits shed light on differential nociceptive, neuropathic, nociplastic-type While one prominent roles played appears modulation neuroplasticity. Therefore, future molecular- genetics-based address microglia-mediated development novel therapies for

Язык: Английский

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scRNA-sequencing reveals subtype-specific transcriptomic perturbations in DRG neurons of PirtEGFPf mice in neuropathic pain condition

eLife, Год журнала: 2022, Номер 11

Опубликована: Окт. 20, 2022

Functionally distinct subtypes/clusters of dorsal root ganglion (DRG) neurons may play different roles in nerve regeneration and pain. However, details about their transcriptomic changes under neuropathic pain conditions remain unclear. Chronic constriction injury (CCI) the sciatic represents a well-established model pain, we conducted single-cell RNA-sequencing (scRNA-seq) to characterize subtype-specific perturbations transcriptomes lumbar DRG on day 7 post-CCI. By using PirtEGFPf mice that selectively express an enhanced green fluorescent protein neurons, established highly efficient purification process enrich for scRNA-seq. We observed emergence four prominent CCI-induced clusters loss marker genes injured neurons. Importantly, portion from several were spared injury-induced identity loss, suggesting Moreover, uninjured which are necessary mediating evoked also demonstrated cell-type-specific these clusters, but not others. Notably, male female showed differential multiple neuronal after CCI, sexual dimorphism injury. Using Fgf3 as proof-of-principle, RNAscope study provided further evidence increased supporting scRNA-seq analysis, calcium imaging unraveled functional role excitability. These findings contribute identification new target development neuron therapies optimizing treatment regeneration.

Язык: Английский

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Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn

eLife, Год журнала: 2023, Номер 12

Опубликована: Фев. 7, 2023

Spinally projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how mediate these opposing effects. Utilizing virus-based strategies Tph2-Cre transgenic mice, we identified two anatomically separated populations of hindbrain located the lateral paragigantocellularis (LPGi) medial hindbrain, which respectively innervate superficial deep spinal dorsal horn have contrasting effects sensory perception. Our tracing experiments revealed that LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than neurons. Taking advantage this difference, employed intersectional chemogenetic approaches demonstrate activation projections decreases thermal sensitivity, whereas increases mechanical von Frey stimulation. Together results suggest there are functionally distinct classes differ their anatomical location postsynaptic targets cord, impact nociceptive sensitivity. The give rise rather global bilateral throughout rostrocaudal extent cord appear be ideally poised contribute widespread systemic control.

Язык: Английский

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Electroacupuncture alleviates mechanical allodynia and anxiety‐like behaviors induced by chronic neuropathic pain via regulating rostral anterior cingulate cortex‐dorsal raphe nucleus neural circuit

CNS Neuroscience & Therapeutics, Год журнала: 2023, Номер 29(12), С. 4043 - 4058

Опубликована: Июль 3, 2023

Abstract Aims Epidemiological studies in patients with neuropathic pain have demonstrated a strong association between and psychiatric conditions such as anxiety. Preclinical clinical work has that electroacupuncture (EA) effectively alleviates anxiety‐like behaviors induced by chronic pain. In this study, potential neural circuitry underlying the therapeutic action of EA was investigated. Methods The effects stimulation on mechanical allodynia animal models spared nerve injury (SNI) were examined. plus chemogenetic manipulation glutamatergic (Glu) neurons projecting from rostral anterior cingulate cortex (rACC Glu ) to dorsal raphe nucleus (DRN) used explore changes SNI mice. Results Electroacupuncture significantly alleviated both increased activities rACC serotoninergic DRN. Chemogenetic activation ‐DRN projections attenuated mice at day 14 after SNI. inhibition pathway did not induce under physiological conditions, but inhibiting produced 7 SNI; effect reversed EA. circuit produce synergistic behaviors. analgesic anxiolytic could be blocked pathway. Conclusions role may different during progression these related These findings describe novel through which exerts exhibiting

Язык: Английский

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Neuropathic pain; what we know and what we should do about it

Frontiers in Pain Research, Год журнала: 2023, Номер 4

Опубликована: Сен. 22, 2023

Neuropathic pain can result from injury to, or disease of the nervous system. It is notoriously difficult to treat. Peripheral nerve promotes Schwann cell activation and invasion immunocompetent cells into site injury, spinal cord higher sensory structures such as thalamus cingulate cortices. Various cytokines, chemokines, growth factors, monoamines neuropeptides effect two-way signalling between neurons, glia immune cells. This sustained hyperexcitability spontaneous activity in primary afferents that crucial for onset persistence well misprocessing information supraspinal structures. Much current understanding aetiology identification drug targets derives studies consequences peripheral rodent models. Although a vast amount has been forthcoming, translation this clinical arena minimal. Few, if any, major therapeutic approaches have appeared since mid 1990's. may reflect failure recognise differences processing males vs. females, cellular responses different types humans animals. Basic science which seek bridge knowledge gap include better assessment animal models, use models emulate human disease, stratification phenotypes according quantitative signs symptoms disease. lead more personalized effective treatments individual patients. Significance statement: There an urgent need find new neuropathic pain. classical revealed essential features central sensitization some molecular mechanisms involved, they do not adequately model multiplicity states injuries bring forth clinic. review seeks integrate disciplines understand pain; including immunology, biology, electrophysiology biophysics, anatomy, neurology, pharmacology behavioral science. Beyond this, it underlines ongoing refinements basic practice will engender improved management.

Язык: Английский

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