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1.
Proc Natl Acad Sci U S A ; 120(31): e2217033120, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37487063

RESUMO

Type I spiral ganglion neurons (SGNs) are the auditory afferents that transmit sound information from cochlear inner hair cells (IHCs) to the brainstem. These afferents consist of physiological subtypes that differ in their spontaneous firing rate (SR), activation threshold, and dynamic range and have been described as low, medium, and high SR fibers. Lately, single-cell RNA sequencing experiments have revealed three molecularly defined type I SGN subtypes. The extent to which physiological type I SGN subtypes correspond to molecularly defined subtypes is unclear. To address this question, we have generated mouse lines expressing CreERT2 in SGN subtypes that allow for a physiological assessment of molecular subtypes. We show that Lypd1-CreERT2 expressing SGNs represent a well-defined group of neurons that preferentially innervate the IHC modiolar side and exhibit a narrow range of low SRs. In contrast, Calb2-CreERT2 expressing SGNs preferentially innervate the IHC pillar side and exhibit a wider range of SRs, thus suggesting that a strict stratification of all SGNs into three molecular subclasses is not obvious, at least not with the CreERT2 tools used here. Genetically marked neuronal subtypes refine their innervation specificity onto IHCs postnatally during the time when activity is required to refine their molecular phenotype. Type I SGNs thus consist of genetically defined subtypes with distinct physiological properties and innervation patterns. The molecular subtype-specific lines characterized here will provide important tools for investigating the role of the physiologically distinct type I SGNs in encoding sound signals.


Assuntos
Tronco Encefálico , Células Ciliadas Vestibulares , Animais , Camundongos , Cóclea , Células Ciliadas Auditivas Internas , Neurônios
2.
Curr Opin Otolaryngol Head Neck Surg ; 29(5): 391-399, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34412064

RESUMO

PURPOSE OF REVIEW: We review recent progress in the characterization of spiral ganglion neurons (SGNs), the afferent neurons that transmit sound information from mechanosensory hair cells in the inner ear to the central nervous system. RECENT FINDINGS: Single-cell ribonucleic acid sequencing studies of murine SGNs have demonstrated that SGNs consist of molecularly distinct subtypes. The molecularly defined SGN subtypes likely correspond to SGN subtypes previously identified on the basis of physiological properties, although this has not been experimentally demonstrated. Subtype maturation is completed postnatally in an activity-dependent manner and is impaired in several models of hearing loss. SUMMARY: The recent molecular studies open new avenues to rigorously test whether SGN subtypes are important for the encoding of different sound features and if they show differential vulnerability to genetic factors and environmental insults. This could have important implications for the development of therapeutic strategies to treat hearing loss.


Assuntos
Surdez , Orelha Interna , Perda Auditiva , Animais , Humanos , Camundongos , Neurônios , Gânglio Espiral da Cóclea
3.
Cell ; 174(5): 1247-1263.e15, 2018 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-30078710

RESUMO

Type I spiral ganglion neurons (SGNs) transmit sound information from cochlear hair cells to the CNS. Using transcriptome analysis of thousands of single neurons, we demonstrate that murine type I SGNs consist of subclasses that are defined by the expression of subsets of transcription factors, cell adhesion molecules, ion channels, and neurotransmitter receptors. Subtype specification is initiated prior to the onset of hearing during the time period when auditory circuits mature. Gene mutations linked to deafness that disrupt hair cell mechanotransduction or glutamatergic signaling perturb the firing behavior of SGNs prior to hearing onset and disrupt SGN subtype specification. We thus conclude that an intact hair cell mechanotransduction machinery is critical during the pre-hearing period to regulate the firing behavior of SGNs and their segregation into subtypes. Because deafness is frequently caused by defects in hair cells, our findings have significant ramifications for the etiology of hearing loss and its treatment.


Assuntos
Células Ciliadas Auditivas/fisiologia , Audição/fisiologia , Mecanotransdução Celular , Neurônios/fisiologia , Transdução de Sinais , Gânglio Espiral da Cóclea/fisiologia , Animais , Análise por Conglomerados , Marcadores Genéticos , Masculino , Camundongos , Camundongos Endogâmicos CBA , Camundongos Knockout , Mutação , Neuroglia/fisiologia , Análise de Sequência de RNA
4.
Proc Natl Acad Sci U S A ; 114(10): E1996-E2005, 2017 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-28223516

RESUMO

Human Mas-related G protein-coupled receptor X1 (MRGPRX1) is a promising target for pain inhibition, mainly because of its restricted expression in nociceptors within the peripheral nervous system. However, constrained by species differences across Mrgprs, drug candidates that activate MRGPRX1 do not activate rodent receptors, leaving no responsive animal model to test the effect on pain in vivo. Here, we generated a transgenic mouse line in which we replaced mouse Mrgprs with human MrgprX1 This humanized mouse allowed us to characterize an agonist [bovine adrenal medulla 8-22 (BAM8-22)] and a positive allosteric modulator (PAM), ML382, of MRGPRX1. Cellular studies suggested that ML382 enhances the ability of BAM8-22 to inhibit high-voltage-activated Ca2+ channels and attenuate spinal nociceptive transmission. Importantly, both BAM8-22 and ML382 effectively attenuated evoked, persistent, and spontaneous pain without causing obvious side effects. Notably, ML382 by itself attenuated both evoked pain hypersensitivity and spontaneous pain in MrgprX1 mice after nerve injury without acquiring coadministration of an exogenous agonist. Our findings suggest that humanized MrgprX1 mice provide a promising preclinical model and that activating MRGPRX1 is an effective way to treat persistent pain.


Assuntos
Analgésicos/farmacologia , Benzamidas/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Modelos Animais de Doenças , Fragmentos de Peptídeos/farmacologia , Receptores Acoplados a Proteínas G/genética , Sulfonamidas/farmacologia , Regulação Alostérica , Animais , Canais de Cálcio/genética , Canais de Cálcio/metabolismo , Bovinos , Dor Crônica , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Nociceptividade/efeitos dos fármacos , Traumatismos dos Nervos Periféricos/tratamento farmacológico , Traumatismos dos Nervos Periféricos/patologia , Traumatismos dos Nervos Periféricos/fisiopatologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/metabolismo , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/lesões , Nervo Isquiático/fisiopatologia , Transgenes
5.
Neuron ; 93(4): 840-853.e5, 2017 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-28231466

RESUMO

Coding of itch versus pain has been heatedly debated for decades. However, the current coding theories (labeled line, intensity, and selectivity theory) cannot accommodate all experimental observations. Here we identified a subset of spinal interneurons, labeled by gastrin-releasing peptide (Grp), that receive direct synaptic input from both pain and itch primary sensory neurons. When activated, these Grp+ neurons generated rarely seen, simultaneous robust pain and itch responses that were intensity dependent. Accordingly, we propose a "leaky gate" model in which Grp+ neurons transmit both itch and weak pain signals; however, upon strong painful stimuli, the recruitment of endogenous opioids works to close this gate, reducing overwhelming pain generated by parallel pathways. Consistent with our model, loss of these Grp+ neurons increased pain responses while itch was decreased. Our new model serves as an example of non-monotonic coding in the spinal cord and better explains observations in human psychophysical studies.


Assuntos
Gânglios Espinais/fisiopatologia , Interneurônios/metabolismo , Neurônios Aferentes/metabolismo , Dor/fisiopatologia , Prurido/metabolismo , Medula Espinal/fisiopatologia , Animais , Gânglios Espinais/metabolismo , Peptídeo Liberador de Gastrina/metabolismo , Camundongos , Modelos Animais , Dor/metabolismo , Receptores da Bombesina/metabolismo , Medula Espinal/metabolismo
6.
Semin Immunopathol ; 38(3): 293-307, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26385480

RESUMO

Itch is a unique sensation associated with the scratch reflex. Although the scratch reflex plays a protective role in daily life by removing irritants, chronic itch remains a clinical challenge. Despite urgent clinical need, itch has received relatively little research attention and its mechanisms have remained poorly understood until recently. The goal of the present review is to summarize our current understanding of the mechanisms of acute as well as chronic itch and classifications of the primary itch populations in relationship to transient receptor potential (Trp) channels, which play pivotal roles in multiple somatosensations. The convergent involvement of Trp channels in diverse itch signaling pathways suggests that Trp channels may serve as promising targets for chronic itch treatments.


Assuntos
Prurido/etiologia , Prurido/metabolismo , Canais de Potencial de Receptor Transitório/genética , Canais de Potencial de Receptor Transitório/metabolismo , Animais , Antipruriginosos/farmacologia , Antipruriginosos/uso terapêutico , Modelos Animais de Doenças , Humanos , Terapia de Alvo Molecular , Prurido/tratamento farmacológico , Receptores de Citocinas/genética , Receptores de Citocinas/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/metabolismo , Canais de Potencial de Receptor Transitório/agonistas , Canais de Potencial de Receptor Transitório/antagonistas & inibidores
7.
Nat Commun ; 6: 7864, 2015 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-26216096

RESUMO

Sensory neurons expressing Mas-related G-protein-coupled receptors (Mrgprs) mediate histamine-independent itch. We show that the cysteine protease cathepsin S activates MrgprC11 and evokes receptor-dependent scratching in mice. In contrast to its activation of conventional protease-activated receptors, cathepsin S-mediated activation of MrgprC11 did not involve the generation of a tethered ligand. We demonstrate further that different cysteine proteases selectively activate specific mouse and human Mrgpr family members. This expansion of our understanding by which proteases interact with G-protein-coupled receptors (GPCRs) redefines the concept of what constitutes a protease-activated receptor. The findings also implicate proteases as ligands to members of this orphan receptor family while providing new insights into how cysteine proteases contribute to itch.


Assuntos
Catepsinas/metabolismo , Prurido/metabolismo , RNA Mensageiro/metabolismo , Receptores Acoplados a Proteínas G/genética , Animais , Western Blotting , Células HeLa , Humanos , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Receptores Acoplados a Proteínas G/metabolismo , Receptores Ativados por Proteinase , Reação em Cadeia da Polimerase Via Transcriptase Reversa
8.
Neuron ; 81(4): 873-887, 2014 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-24462040

RESUMO

The peripheral terminals of primary nociceptive neurons play an essential role in pain detection mediated by membrane receptors like TRPV1, a molecular sensor of heat and capsaicin. However, the contribution of central terminal TRPV1 in the dorsal horn to chronic pain has not been investigated directly. Combining primary sensory neuron-specific GCaMP3 imaging with a trigeminal neuropathic pain model, we detected robust neuronal hyperactivity in injured and uninjured nerves in the skin, soma in trigeminal ganglion, and central terminals in the spinal trigeminal nucleus. Extensive TRPV1 hyperactivity was observed in central terminals innervating all dorsal horn laminae. The central terminal TRPV1 sensitization was maintained by descending serotonergic (5-HT) input from the brainstem. Central blockade of TRPV1 or 5-HT/5-HT3A receptors attenuated central terminal sensitization, excitatory primary afferent inputs, and mechanical hyperalgesia in the territories of injured and uninjured nerves. Our results reveal central mechanisms facilitating central terminal sensitization underlying chronic pain.


Assuntos
Dor Crônica/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Nociceptores/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Capsaicina/farmacologia , Dor Crônica/tratamento farmacológico , Dor Crônica/genética , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Nociceptores/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Gânglio Trigeminal/efeitos dos fármacos
9.
J Neurosci ; 32(42): 14532-7, 2012 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-23077038

RESUMO

ß-Alanine, a popular supplement for muscle building, induces itch and tingling after consumption, but the underlying molecular and neural mechanisms are obscure. Here we show that, in mice, ß-alanine elicited itch-associated behavior that requires MrgprD, a G-protein-coupled receptor expressed by a subpopulation of primary sensory neurons. These neurons exclusively innervate the skin, respond to ß-alanine, heat, and mechanical noxious stimuli but do not respond to histamine. In humans, intradermally injected ß-alanine induced itch but neither wheal nor flare, suggesting that the itch was not mediated by histamine. Thus, the primary sensory neurons responsive to ß-alanine are likely part of a histamine-independent itch neural circuit and a target for treating clinical itch that is unrelieved by anti-histamines.


Assuntos
Prurido/etiologia , Prurido/metabolismo , Receptores Acoplados a Proteínas G/biossíntese , beta-Alanina/toxicidade , Adulto , Animais , Feminino , Gânglios Espinais/metabolismo , Gânglios Espinais/fisiologia , Técnicas de Introdução de Genes , Humanos , Injeções Intradérmicas/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Prurido/genética , Receptores Acoplados a Proteínas G/deficiência , Receptores Acoplados a Proteínas G/fisiologia , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/patologia , Adulto Jovem
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