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1.
Genes (Basel) ; 10(10)2019 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-31615056

RESUMO

A single male domestic shorthair cat that did not complete puberty was reported. At four years of age, it still had primary dentition, testicular hypoplasia, and was relatively small for its age. We hypothesized that the phenotype might have been due to an inherited form of hypogonadotropic hypogonadism (HH). We sequenced the genome of the affected cat and compared the data to 38 genomes from control cats. A search for private variants in 40 candidate genes associated with human HH revealed a single protein-changing variant in the affected cat. It was located in the TAC3 gene encoding tachykinin 3, a precursor protein of the signaling molecule neurokinin B, which is known to play a role in sexual development. TAC3 variants have been reported in human patients with HH. The identified feline variant, TAC3:c.220G>A or p.(Val74Met), affects a moderately conserved region of the precursor protein, 11 residues away from the mature neurokinin B sequence. The affected cat was homozygous for the mutant allele. In a cohort of 171 randomly sampled cats, 169 were homozygous for the wildtype allele and 2 were heterozygous. These data tentatively suggest that the identified TAC3 variant might have caused the suppression of puberty in the affected cat.


Assuntos
Doenças do Gato/genética , Hipogonadismo/veterinária , Mutação de Sentido Incorreto , Taquicininas/genética , Dente Decíduo/metabolismo , Animais , Doenças do Gato/metabolismo , Gatos/genética , Hipogonadismo/genética , Hipogonadismo/patologia , Masculino , Neurocinina B/genética , Receptores da Neurocinina-3/genética , Maturidade Sexual/genética , Taquicininas/metabolismo , Testículo/patologia , Anormalidades Dentárias/genética , Anormalidades Dentárias/veterinária , Dente Decíduo/anormalidades
2.
Nat Immunol ; 20(11): 1435-1443, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591569

RESUMO

Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor-MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.


Assuntos
Alérgenos/imunologia , Dermatite Atópica/imunologia , Mastócitos/imunologia , Nociceptores/imunologia , Pyroglyphidae/imunologia , Animais , Comunicação Celular/imunologia , Dermatite Atópica/patologia , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Mastócitos/metabolismo , Camundongos Knockout , Nociceptores/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Pele/citologia , Pele/imunologia , Canais de Cátion TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismo
3.
Transl Psychiatry ; 9(1): 232, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31530797

RESUMO

In susceptible individuals, exposure to intensely traumatic life events can lead to the development of posttraumatic stress disorder (PTSD), including long-term dysregulation of the contextual processing of aversive stimuli, the overgeneralization of learned fear, and impairments in the ability to learn or respond to safety signals. The neuropathophysiological changes that underlie PTSD remain incompletely understood. Attention has focused on forebrain structures associated with fear processing. Here we consider evidence from human and animal studies that long-lasting changes in functional connectivity between the midbrain periaqueductal gray (dPAG) and amygdala may be one of the precipitating events that contribute to PTSD. Long-lasting neuroplastic changes in the dPAG can persist after a single aversive stimulation and are pharmacologically labile. The early stage (at least up to 24 h post-stimulation) involves neurokinin-1 receptor-mediated events in the PAG and amygdala and is also regulated by dopamine, both of which are mainly involved in transferring ascending aversive information from the dPAG to higher brain structures, mainly the amygdala. Changes in the functional connectivity within the dPAG-amygdala circuit have been reported in PTSD patients. We suggest that further investigations of plasticity and pharmacology of the PAG-amygdala network provide a promising target for understanding pathophysiological circuitry that underlies PTSD in humans and that dopaminergic and neurokininergic drugs may have a potential for the treatment of psychiatric disorders that are associated with a dysfunctional dPAG.


Assuntos
Dopamina/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Taquicininas/metabolismo , Animais , Humanos
4.
Endocrinology ; 160(10): 2453-2463, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504389

RESUMO

The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.


Assuntos
Gonadotropinas/metabolismo , Neurocinina A/metabolismo , Animais , Feminino , Kisspeptinas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurocinina A/genética , Neurocinina B/genética , Neurocinina B/metabolismo , Precursores de Proteínas , Receptores da Neurocinina-2/genética , Receptores da Neurocinina-2/metabolismo , Maturidade Sexual , Substância P/genética , Substância P/metabolismo , Taquicininas
5.
Am J Physiol Renal Physiol ; 317(5): F1154-F1163, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31461351

RESUMO

Tachykinins (TKs) are involved in both the physiological regulation of urinary bladder functions and development of overactive bladder syndrome. The aim of the present study was to investigate the signal transduction pathways of TKs in the detrusor muscle to provide potential pharmacological targets for the treatment of bladder dysfunctions related to enhanced TK production. Contraction force, intracellular Ca2+ concentration, and RhoA activity were measured in the mouse urinary bladder smooth muscle (UBSM). TKs and the NK2 receptor (NK2R)-specific agonist [ß-Ala8]-NKA(4-10) evoked contraction, which was inhibited by the NKR2 antagonist MEN10376. In Gαq/11-deficient mice, [ß-Ala8]-NKA(4-10)-induced contraction and the intracellular Ca2+ concentration increase were abolished. Although Gq/11 proteins are linked principally to phospholipase Cß and inositol trisphosphate-mediated Ca2+ release from intracellular stores, we found that phospholipase Cß inhibition and sarcoplasmic reticulum Ca2+ depletion failed to have any effect on contraction induced by [ß-Ala8]-NKA(4-10). In contrast, lack of extracellular Ca2+ or blockade of voltage-dependent Ca2+ channels (VDCCs) suppressed contraction. Furthermore, [ß-Ala8]-NKA(4-10) increased RhoA activity in the UBSM in a Gq/11-dependent manner and inhibition of Rho kinase with Y-27632 decreased contraction force, whereas the combination of Y-27632 with either VDCC blockade or depletion of extracellular Ca2+ resulted in complete inhibition of [ß-Ala8]-NKA(4-10)-induced contractions. In summary, our results indicate that NK2Rs are linked exclusively to Gq/11 proteins in the UBSM and that the intracellular signaling involves the simultaneous activation of VDCC and the RhoA-Rho kinase pathway. These findings may help to identify potential therapeutic targets of bladder dysfunctions related to upregulation of TKs.


Assuntos
Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Músculo Liso/fisiologia , Receptores da Neurocinina-2/fisiologia , Bexiga Urinária/fisiologia , Quinases Associadas a rho/metabolismo , Animais , Cálcio/metabolismo , Antagonistas de Estrogênios/farmacologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Contração Muscular/efeitos dos fármacos , Taquicininas/metabolismo , Tamoxifeno/farmacologia , Quinases Associadas a rho/genética
6.
J Physiol Pharmacol ; 70(1)2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31019119

RESUMO

Tachykinins act as neurotransmitters and neuromodulators in the central and peripheral nervous system. Preclinical studies and clinical trials showed that inhibition of the tachykinin receptors, mainly NK2 may constitute a novel attractive option in the treatment of irritable bowel syndrome (IBS). In this review, we focused on the role of tachykinins in physiology and pathophysiology of gastrointestinal (GI) tract. Moreover, we summed up recent data on tachykinin receptor antagonists in the therapy of IBS. Ibodutant is a novel drug with an interesting pharmacological profile, which exerted efficacy in women with diarrhea-predominant IBS (IBS-D) in phase II clinical trials. The promising results were not replicable and confirmed in phase III of clinical trials. Ibodutant is not ready to be introduced in the pharmaceutical market and further studies on alternative NK2 antagonist are needed to make NK2 antagonists useful tools in IBS-D treatment.


Assuntos
Diarreia/tratamento farmacológico , Síndrome do Intestino Irritável/tratamento farmacológico , Receptores da Neurocinina-2/antagonistas & inibidores , Animais , Trato Gastrointestinal/metabolismo , Humanos , Receptores da Neurocinina-2/metabolismo , Taquicininas/metabolismo
7.
Neuroreport ; 30(8): 533-537, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-30896676

RESUMO

Vagal capsaicin-sensitive afferent C-fibers play an important role in the maintenance of visceral homeostasis and contribute to symptoms in visceral diseases. Based on their developmental origin two functionally distinct types of vagal C-fibers are recognized: those with neurons in the vagal nodose ganglia (derived from epibranchial placodes) and in the vagal jugular ganglia (from neural crest). Studies in nonprimate species demonstrated that the vagal nodose and jugular C-fibers differ in activation profile, neurotrophic regulation, and expression of neurotransmitters. We hypothesized that the expression of selected markers related to key phenotypic properties of vagal C-fibers in the cynomolgus monkey is similar to that reported in nonprimate species. We performed single-cell RT-PCR on nodose and jugular putative C-fiber (TRPV1-positive) neurons isolated from the cynomolgus monkey. We found that the expression of purinergic P2X receptors that underlie selective responsiveness of nodose C-fiber terminals to ATP was conserved in that P2X2 and P2X3 subunits were expressed in nodose, but only P2X3 subunit was expressed in jugular TRPV1-positive neurons. Also conserved was the preferential expression of neurotrophic receptor TrkB in the nodose and preprotachykinin-A in the jugular TRPV1-positive neurons. Several key distinctions in gene expression between nodose and jugular TRPV1-positive (C-fiber) neurons that have been noted in mice, rats, and guinea pigs, are conserved in the cynomolgus monkey. Our results support the translatability of distinct vagal C-fiber phenotypes to primates.


Assuntos
Gânglio Nodoso/metabolismo , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/metabolismo , Animais , Macaca fascicularis , Fibras Nervosas Amielínicas/metabolismo , Fenótipo , Precursores de Proteínas/metabolismo , Receptores Purinérgicos P2X2/metabolismo , Receptores Purinérgicos P2X3/metabolismo , Especificidade da Espécie , Taquicininas/metabolismo
8.
Gene ; 696: 176-185, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30769143

RESUMO

Tachykinin 2 (Tac2) is expressed in a number of areas throughout the brain, including the hippocampus. However, knowledge about its function has been only well explored in the hypothalamus in the context of reproductive health. In this study, we identified and validated increased hippocampal Tac2 mRNA expression in response to chronic mild stress in mice. Expression quantitative trait locus (eQTL) analysis showed Tac2 is cis-regulated in the hippocampus. Using a systems genetics approach, we constructed a Tac2 co-expression network to better understand the relationship between Tac2 and the hippocampal stress response. Our network identified 69 total genes associated with Tac2, several of which encode major neuropeptides involved in hippocampal stress signaling as well as critical genes for producing neural plasticity, indicating that Tac2 is involved in these processes. Pathway analysis for the member of Tac2 gene network revealed a strong connection between Tac2 and neuroactive ligand-receptor interaction, calcium signaling pathway, as well as cardiac muscle contraction. In addition, we also identified 46 stress-related phenotypes, specifically fear conditioning response, that were significantly correlated with Tac2 expression. Our results provide evidence for Tac2 as a strong candidate gene who likely plays a role in hippocampal stress processing and neural plasticity.


Assuntos
Regulação da Expressão Gênica/fisiologia , Redes Reguladoras de Genes/fisiologia , Hipocampo/fisiologia , Precursores de Proteínas/fisiologia , Estresse Psicológico/fisiopatologia , Taquicininas/fisiologia , Animais , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Plasticidade Neuronal/fisiologia , RNA Mensageiro/metabolismo , Estresse Psicológico/genética
9.
Brain Res Bull ; 147: 165-173, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30664920

RESUMO

The Tac4 gene-derived hemokinin-1 (HK-1) is present in pain-related regions and activates the tachykinin NK1 receptor, but with binding site and signaling pathways different from Substance P (SP). NK1 receptor is involved in nociception, but our earlier data showed that it has no role in chronic neuropathic hyperalgesia, similarly to SP. Furthermore, NK1 antagonists failed in clinical trials as analgesics due to still unknown reasons. Therefore, we investigated the role of HK-1 in pain conditions of distinct mechanisms using genetically modified mice. Chronic neuropathic mechanical and cold hyperalgesia after partial sciatic nerve ligation (PSL) were determined by dynamic plantar aesthesiometry and withdrawal latency from icy water, motor coordination on the accelerating Rotarod. Peripheral nerve growth factor (NGF) production was measured by ELISA, neuronal and glia cell activation by immunohistochemistry in pain-related regions. Acute somatic and visceral chemonocifensive behaviors were assessed after intraplantar formalin or intraperitoneal acetic-acid injection, respectively. Resiniferatoxin-induced inflammatory mechanical and thermal hyperalgesia by aesthesiometry and increasing temperature hot plate. Chronic neuropathic mechanical and cold hypersensitivity were significantly decreased in HK-1 deficient mice. NGF level in the paw homogenates of intact mice were significantly lower in case of HK-1 deletion. However, it significantly increased under neuropathic condition in contrast to wildtype mice, where the higher basal concentration did not show any changes. Microglia, but not astrocyte activation was observed 14 days after PSL in the ipsilateral spinal dorsal horn of wildtype, but not HK-1-deficient mice. However, under neuropathic conditions, the number of GFAP-positive astrocytes was significantly smaller in case of HK-1 deletion. Acute visceral, but not somatic nocifensive behavior, as well as neurogenic inflammatory mechanical and thermal hypersensitivity were significantly reduced by HK-1 deficiency similarly to NK1, but not to SP deletion. We provide evidence for pro-nociceptive role of HK-1, via NK1 receptor activation in acute inflammation models, but differently from SP-mediated actions. Identification of its targets and signaling can open new directions in pain research.


Assuntos
Dor/metabolismo , Taquicininas/genética , Taquicininas/metabolismo , Analgésicos/farmacologia , Animais , Modelos Animais de Doenças , Feminino , Hiperalgesia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nociceptividade/efeitos dos fármacos , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores da Neurocinina-1/metabolismo , Nervo Isquiático/metabolismo , Corno Dorsal da Medula Espinal/metabolismo , Substância P/metabolismo , Taquicininas/fisiologia
10.
PLoS One ; 14(1): e0203980, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30695038

RESUMO

Despite the conserved function of aggression across taxa in obtaining critical resources such as food and mates, serotonin's (5-HT) modulatory role on aggressive behavior appears to be largely inhibitory for vertebrates but stimulatory for invertebrates. However, critical gaps exist in our knowledge of invertebrates that need to be addressed before definitively stating opposing roles for 5-HT and aggression. Specifically, the role of 5-HT receptor subtypes are largely unknown, as is the potential interactive role of 5-HT with other neurochemical systems known to play a critical role in aggression. Similarly, the influence of these systems in driving sex differences in aggressive behavior of invertebrates is not well understood. Here, we investigated these questions by employing complementary approaches in a novel invertebrate model of aggression, the stalk-eyed fly. A combination of altered social conditions, pharmacological manipulation and 5-HT2 receptor knockdown by siRNA revealed an inhibitory role of this receptor subtype on aggression. Additionally, we provide evidence for 5-HT2's involvement in regulating neuropeptide F activity, a suspected inhibitor of aggression. However, this function appears to be stage-specific, altering only the initiation stage of aggressive conflicts. Alternatively, pharmacologically increasing systemic concentrations of 5-HT significantly elevated the expression of the neuropeptide tachykinin, which did not affect contest initiation but instead promoted escalation via production of high intensity aggressive behaviors. Notably, these effects were limited solely to males, with female aggression and neuropeptide expression remaining unaltered by any manipulation that affected 5-HT. Together, these results demonstrate a more nuanced role for 5-HT in modulating aggression in invertebrates, revealing an important interactive role with neuropeptides that is more reminiscent of vertebrates. The sex-differences described here also provide valuable insight into the evolutionary contexts of this complex behavior.


Assuntos
Agressão/fisiologia , Comportamento Animal/fisiologia , Dípteros/fisiologia , Caracteres Sexuais , 5-Hidroxitriptofano/administração & dosagem , 5-Hidroxitriptofano/farmacologia , Agressão/efeitos dos fármacos , Animais , Técnicas de Observação do Comportamento/métodos , Comportamento Animal/efeitos dos fármacos , Feminino , Técnicas de Silenciamento de Genes , Masculino , Modelos Animais , Neuropeptídeos/metabolismo , RNA Interferente Pequeno/metabolismo , Receptores 5-HT2 de Serotonina/genética , Receptores 5-HT2 de Serotonina/metabolismo , Serotonina/metabolismo , Taquicininas/metabolismo
11.
Neuron ; 101(1): 45-59.e9, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30554781

RESUMO

Uncontrollable itch-scratching cycles lead to serious skin damage in patients with chronic itch. However, the neural mechanism promoting the itch-scratching cycle remains elusive. Here, we report that tachykinin 1 (Tac1)-expressing glutamatergic neurons in the lateral and ventrolateral periaqueductal gray (l/vlPAG) facilitate the itch-scratching cycle. We found that l/vlPAG neurons exhibited scratching-behavior-related neural activity and that itch-evoked scratching behavior was impaired after suppressing the activity of l/vlPAG neurons. Furthermore, we showed that the activity of Tac1-expressing glutamatergic neurons in the l/vlPAG was elevated during itch-induced scratching behavior and that ablating or suppressing the activity of these neurons decreased itch-induced scratching behavior. Importantly, activation of Tac1-expressing neurons induced robust spontaneous scratching and grooming behaviors. The scratching behavior evoked by Tac1-expressing neuron activation was suppressed by ablation of spinal neurons expressing gastrin-releasing peptide receptor (GRPR), the key relay neurons for itch. These results suggest that Tac1-expressing neurons in the l/vlPAG promote itch-scratching cycles.


Assuntos
Neurocinina A/biossíntese , Neurônios/metabolismo , Substância Cinzenta Periaquedutal/metabolismo , Prurido/metabolismo , Tratos Piramidais/metabolismo , Receptores da Neurocinina-1/biossíntese , Animais , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurocinina A/genética , Neurônios/química , Substância Cinzenta Periaquedutal/química , Prurido/patologia , Tratos Piramidais/química , Distribuição Aleatória , Receptores da Neurocinina-1/genética , Taquicininas/biossíntese , Taquicininas/genética
12.
Nature ; 565(7737): 86-90, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30532001

RESUMO

Animals and humans display two types of response to noxious stimuli. The first includes reflexive defensive responses that prevent or limit injury; a well-known example of these responses is the quick withdrawal of one's hand upon touching a hot object. When the first-line response fails to prevent tissue damage (for example, a finger is burnt), the resulting pain invokes a second-line coping response-such as licking the injured area to soothe suffering. However, the underlying neural circuits that drive these two strings of behaviour remain poorly understood. Here we show in mice that spinal neurons marked by coexpression of TAC1Cre and LBX1Flpo drive coping responses associated with pain. Ablation of these spinal neurons led to the loss of both persistent licking and conditioned aversion evoked by stimuli (including skin pinching and burn injury) that-in humans-produce sustained pain, without affecting any of the reflexive defensive reactions that we tested. This selective indifference to sustained pain resembles the phenotype seen in humans with lesions of medial thalamic nuclei1-3. Consistently, spinal TAC1-lineage neurons are connected to medial thalamic nuclei by direct projections and via indirect routes through the superior lateral parabrachial nuclei. Furthermore, the anatomical and functional segregation observed at the spinal level also applies to primary sensory neurons. For example, in response to noxious mechanical stimuli, MRGPRD- and TRPV1-positive nociceptors are required to elicit reflexive and coping responses, respectively. Our study therefore reveals a fundamental subdivision within the cutaneous somatosensory system, and challenges the validity of using reflexive defensive responses to measure sustained pain.


Assuntos
Adaptação Psicológica/fisiologia , Dor Crônica/fisiopatologia , Dor Crônica/psicologia , Vias Neurais/fisiologia , Animais , Aprendizagem da Esquiva , Condicionamento Clássico , Feminino , Humanos , Masculino , Núcleo Mediodorsal do Tálamo/citologia , Núcleo Mediodorsal do Tálamo/fisiologia , Camundongos , Neurônios Aferentes/fisiologia , Núcleos Parabraquiais/citologia , Núcleos Parabraquiais/fisiologia , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Canais de Cátion TRPV/metabolismo , Taquicininas/genética , Taquicininas/metabolismo
13.
Pain ; 160(2): 442-462, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30247267

RESUMO

Excitatory interneurons account for the majority of neurons in the superficial dorsal horn, but despite their presumed contribution to pain and itch, there is still limited information about their organisation and function. We recently identified 2 populations of excitatory interneuron defined by expression of gastrin-releasing peptide (GRP) or substance P (SP). Here, we demonstrate that these cells show major differences in their morphological, electrophysiological, and pharmacological properties. Based on their somatodendritic morphology and firing patterns, we propose that the SP cells correspond to radial cells, which generally show delayed firing. By contrast, most GRP cells show transient or single-spike firing, and many are likely to correspond to the so-called transient central cells. Unlike the SP cells, few of the GRP cells had long propriospinal projections, suggesting that they are involved primarily in local processing. The 2 populations also differed in responses to neuromodulators, with most SP cells, but few GRP cells, responding to noradrenaline and 5-HT; the converse was true for responses to the µ-opioid agonist DAMGO. Although a recent study suggested that GRP cells are innervated by nociceptors and are strongly activated by noxious stimuli, we found that very few GRP cells receive direct synaptic input from TRPV1-expressing afferents, and that they seldom phosphorylate extracellular signal-regulated kinases in response to noxious stimuli. These findings indicate that the SP and GRP cells differentially process somatosensory information.


Assuntos
Peptídeo Liberador de Gastrina/metabolismo , Interneurônios/fisiologia , Corno Dorsal da Medula Espinal/citologia , Substância P/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/genética , Analgésicos/farmacologia , Animais , Capsaicina/farmacologia , Toxina da Cólera/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Peptídeo Liberador de Gastrina/genética , Técnicas In Vitro , Interneurônios/efeitos dos fármacos , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurotransmissores/farmacologia , Técnicas de Patch-Clamp , Estimulação Física , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , RNA Mensageiro/metabolismo , Fármacos do Sistema Sensorial/farmacologia , Estatísticas não Paramétricas , Substância P/genética , Taquicininas/genética , Taquicininas/metabolismo , Transdução Genética
14.
J Endocrinol ; 239(3): 339-350, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382693

RESUMO

Restraint stress is a psychosocial stressor that suppresses reproductive status, including LH pulsatile secretion, but the neuroendocrine mechanisms underlying this inhibition remains unclear. Reproductive neural populations upstream of gonadotropin-releasing hormone (GnRH) neurons, such as kisspeptin, neurokinin B and RFRP-3 (GnIH) neurons, are possible targets for psychosocial stress to inhibit LH pulses, but this has not been well examined, especially in mice in which prior technical limitations prevented assessment of in vivo LH pulse secretion dynamics. Here, we examined whether one-time acute restraint stress alters in vivo LH pulsatility and reproductive neural populations in male mice, and what the time-course is for such alterations. We found that endogenous LH pulses in castrated male mice are robustly and rapidly suppressed by one-time, acute restraint stress, with suppression observed as quickly as 12­18 min. This rapid LH suppression parallels with increased in vivo corticosterone levels within 15 min of restraint stress. Although Kiss1, Tac2 and Rfrp gene expression in the hypothalamus did not significantly change after 90 or 180 min restraint stress, arcuate Kiss1 neural activation was significantly decreased after 180 min. Interestingly, hypothalamic Rfrp neuronal activation was strongly increased at early times after restraint stress initiation, but was attenuated to levels lower than controls by 180 min of restraint stress. Thus, the male neuroendocrine reproductive axis is quite sensitive to short-term stress exposure, with significantly decreased pulsatile LH secretion and increased hypothalamic Rfrp neuronal activation occurring rapidly, within minutes, and decreased Kiss1 neuronal activation also occurring after longer stress durations.


Assuntos
Kisspeptinas/metabolismo , Hormônio Luteinizante/metabolismo , Neuropeptídeos/metabolismo , Precursores de Proteínas/metabolismo , Estresse Psicológico/metabolismo , Taquicininas/metabolismo , Animais , Corticosterona/sangue , Masculino , Camundongos Endogâmicos C57BL , Sistemas Neurossecretores/metabolismo
15.
Aging (Albany NY) ; 10(11): 3353-3370, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30485833

RESUMO

To investigate possible mechanism of abnormal methylation of long non-coding RNA (lncRNA) on endometrial carcinoma (EC) progression, we detected the genome methylation profiling of endometrial carcinoma by bioinformatic analysis. Accordingly, gene LOC134466 was chosen for the further research. We also found that TAC1 was the target gene of LOC134466 and miRNA, hsa-miR-196a-5p, might form a connection between LOC134466 and TAC1. The relationship was further proved by dual-luciferase reporter assay. In vitro studies, DNA methylation and expression were determined by MSP and qRT-PCR respectively. Cell proliferation, apoptosis and cell cycle were demonstrated by colony formation assay, Annexin V/PI double staining and flow cytometry. Besides, the function of LOC134466 and TAC1 in EC was further confirmed by Tumor Xenograft. Our results indicated that EC progression was promoted by hypermethylated LOC134466 and TAC1. Moreover, TAC1 transcription was regulated by LOC134466 via hsa-miR-196a-5p binding. LOC134466 and TAC1 demethylation by 5-Aza-2-Deoxycytidine inhibited EC cells proliferation and accelerated cell apoptosis. Furthermore, the expression of TACR1, TACR2 and TACR3 was remarkably decreased through LOC134466 and TAC1 treatments. Our findings establish a novel regulatory axis, LOC134466/hsa-miR-196a-5p/TAC1. Downregulation of the axis promoted EC development through TACR3, which further activated neuroactive ligand-receptor interaction.


Assuntos
Carcinogênese , Carcinoma/metabolismo , Neoplasias do Endométrio/metabolismo , MicroRNAs/genética , Proteínas Repressoras/metabolismo , Taquicininas/metabolismo , Carcinoma/genética , Proliferação de Células , Transformação Celular Neoplásica , Neoplasias do Endométrio/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Proteínas Repressoras/genética , Taquicininas/genética
16.
Neuron ; 100(6): 1491-1503.e3, 2018 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-30449655

RESUMO

Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord circuits for simple reflexive responses, but the mechanisms underlying more complex behaviors remain poorly understood. We now describe a brainstem circuit that controls escape responses to select noxious stimuli. Tracing experiments characterized a highly interconnected excitatory circuit involving the dorsal spinal cord, parabrachial nucleus (PBNl), and reticular formation (MdD). A combination of chemogenetic, optogenetic, and genetic ablation approaches revealed that PBNlTac1 neurons are activated by noxious stimuli and trigger robust escape responses to heat through connections to the MdD. Remarkably, MdDTac1 neurons receive excitatory input from the PBN and target both the spinal cord and PBN; activation of these neurons phenocopies the behavioral effects of PBNlTac1 neuron stimulation. These findings identify a substrate for controlling appropriate behavioral responses to painful stimuli.


Assuntos
Tronco Encefálico/fisiologia , Vias Neurais/fisiologia , Nociceptores/fisiologia , Dor/patologia , Medula Espinal/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Peptídeo Relacionado com Gene de Calcitonina/genética , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Estado de Descerebração , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Optogenética , Dor/fisiopatologia , Percepção da Dor/fisiologia , Taquicininas/genética , Taquicininas/metabolismo , Transdução Genética
17.
eNeuro ; 5(5)2018.
Artigo em Inglês | MEDLINE | ID: mdl-30294668

RESUMO

Broad neuronal classes are surprisingly heterogeneous across many parameters, and subclasses often exhibit partially overlapping traits including transmitter coexpression. However, the extent to which transmitter coexpression occurs in predictable, consistent patterns is unknown. Here, we demonstrate that pairwise coexpression of GABA and multiple neuropeptide families by olfactory local interneurons (LNs) of the moth Manduca sexta is highly heterogeneous, with a single LN capable of expressing neuropeptides from at least four peptide families and few instances in which neuropeptides are consistently coexpressed. Using computational modeling, we demonstrate that observed coexpression patterns cannot be explained by independent probabilities of expression of each neuropeptide. Our analyses point to three organizing principles that, once taken into consideration, allow replication of overall coexpression structure: (1) peptidergic neurons are highly likely to coexpress GABA; (2) expression probability of allatotropin depends on myoinhibitory peptide expression; and (3) the all-or-none coexpression patterns of tachykinin neurons with several other neuropeptides. For other peptide pairs, the presence of one peptide was not predictive of the presence of the other, and coexpression probability could be replicated by independent probabilities. The stochastic nature of these coexpression patterns highlights the heterogeneity of transmitter content among LNs and argues against clear-cut definition of subpopulation types based on the presence of single neuropeptides. Furthermore, the receptors for all neuropeptides and GABA were expressed within each population of principal neuron type in the antennal lobe (AL). Thus, activation of any given LN results in a dynamic cocktail of modulators that have the potential to influence every level of olfactory processing within the AL.


Assuntos
Encéfalo/metabolismo , Hormônios de Inseto/metabolismo , Interneurônios/metabolismo , Neuropeptídeos/metabolismo , Condutos Olfatórios/metabolismo , Animais , Feminino , Masculino , Mariposas , Neurônios/metabolismo , Taquicininas/metabolismo , Ácido gama-Aminobutírico/metabolismo
19.
Mol Biol Rep ; 45(6): 2257-2262, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30225581

RESUMO

Substance P (SP), a neuropeptide belonging to the tachykinin family, exerts different biological activities mainly through neurokinin-1 receptor (NK1R). The role of SP/NK1R system in tumoral growth and spread is reported in several cancers. We aimed to evaluate the serum SP concentration and NK1R tissue distribution in endometrial cancer, and to study the relationship between these factors with tumor size, lymph node involvement, disease stage and cancer grade. Recruiting 22 patients with endometrial cancer and 21 patients with leiomyoma as the control group, serum SP concentration was measured using an ELISA method, and NK1R tissue distributions were immunohistochemically analyzed. Serum SP concentration in patients was significantly higher than the control group (p-value = 0.005). The expression level of NK1R in tumoral tissue was more than normal tissue (p-value < 0.001). The NK1R expression had a significant relationship with lymph node involvement (p-value = 0.005) and disease stage (p-value = 0.017). The NK1R expression was higher in more advanced and less-differentiated tumors. SP/NK1R system seems to play a role in tumor growth and development in endometrial cancer. As well, the NK1R expression increased in endometrial cancer, and may be considered as a prognostic factor; but further studies are needed in this field.


Assuntos
Neoplasias do Endométrio/metabolismo , Receptores da Neurocinina-1/análise , Substância P/análise , Adulto , Neoplasias do Endométrio/fisiopatologia , Feminino , Humanos , Imuno-Histoquímica/métodos , Irã (Geográfico) , Substância P/sangue , Taquicininas/metabolismo , Distribuição Tecidual/genética
20.
Elife ; 72018 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-30079889

RESUMO

The neuropeptides tachykinin2 (Tac2) and kisspeptin (Kiss1) in hypothalamic arcuate nucleus Kiss1 (Kiss1ARH) neurons are essential for pulsatile release of GnRH and reproduction. Since 17ß-estradiol (E2) decreases Kiss1 and Tac2 mRNA expression in Kiss1ARH neurons, the role of Kiss1ARH neurons during E2-driven anorexigenic states and their coordination of POMC and NPY/AgRP feeding circuits have been largely ignored. Presently, we show that E2 augmented the excitability of Kiss1ARH neurons by amplifying Cacna1g, Hcn1 and Hcn2 mRNA expression and T-type calcium and h-currents. E2 increased Slc17a6 mRNA expression and glutamatergic synaptic input to arcuate neurons, which excited POMC and inhibited NPY/AgRP neurons via metabotropic receptors. Deleting Slc17a6 in Kiss1 neurons eliminated glutamate release and led to conditioned place preference for sucrose in E2-treated KO female mice. Therefore, the E2-driven increase in Kiss1 neuronal excitability and glutamate neurotransmission may play a key role in governing the motivational drive for palatable food in females.


Assuntos
Kisspeptinas/genética , Neurônios/metabolismo , Precursores de Proteínas/genética , Taquicininas/genética , Proteína Vesicular 2 de Transporte de Glutamato/genética , Animais , Núcleo Arqueado do Hipotálamo/efeitos dos fármacos , Núcleo Arqueado do Hipotálamo/metabolismo , Cálcio/metabolismo , Canais de Cálcio Tipo T/genética , Estradiol/administração & dosagem , Estradiol/metabolismo , Feminino , Humanos , Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização/genética , Camundongos , Neurônios/patologia , Canais de Potássio/genética , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética
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