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1.
Proc Natl Acad Sci U S A ; 120(42): e2308204120, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37812728

RESUMO

Migration is essential for the laminar stratification and connectivity of neurons in the central nervous system. In the retina, photoreceptors (PRs) migrate to positions according to birthdate, with early-born cells localizing to the basal-most side of the outer nuclear layer. It was proposed that apical progenitor mitoses physically drive these basal translocations non-cell autonomously, but direct evidence is lacking, and whether other mechanisms participate is unknown. Here, combining loss- or gain-of-function assays to manipulate cell cycle regulators (Sonic hedgehog, Cdkn1a/p21) with an in vivo lentiviral labelling strategy, we demonstrate that progenitor division is one of two forces driving basal translocation of rod soma. Indeed, replacing Shh activity rescues abnormal rod translocation in retinal explants. Unexpectedly, we show that rod differentiation also promotes rod soma translocation. While outer segment function or formation is dispensable, Crx and SNARE-dependent synaptic function are essential. Thus, both non-cell and cell autonomous mechanisms underpin PR soma sublaminar positioning in the mammalian retina.


Assuntos
Neurossecreção , Células Fotorreceptoras Retinianas Bastonetes , Animais , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Proteínas Hedgehog/metabolismo , Retina/metabolismo , Diferenciação Celular , Mamíferos
2.
Int J Mol Sci ; 22(9)2021 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919253

RESUMO

Mutations in the X-linked MECP2 gene are responsible for Rett syndrome (RTT), a severe neurological disorder. MECP2 is a transcriptional modulator that finely regulates the expression of many genes, specifically in the central nervous system. Several studies have functionally linked the loss of MECP2 in astrocytes to the appearance and progression of the RTT phenotype in a non-cell autonomous manner and mechanisms are still unknown. Here, we used primary astroglial cells from Mecp2-deficient (KO) pups to identify deregulated secreted proteins. Using a differential quantitative proteomic analysis, twenty-nine proteins have been identified and four were confirmed by Western blotting with new samples as significantly deregulated. To further verify the functional relevance of these proteins in RTT, we tested their effects on the dendritic morphology of primary cortical neurons from Mecp2 KO mice that are known to display shorter dendritic processes. Using Sholl analysis, we found that incubation with Lcn2 or Lgals3 for 48 h was able to significantly increase the dendritic arborization of Mecp2 KO neurons. To our knowledge, this study, through secretomic analysis, is the first to identify astroglial secreted proteins involved in the neuronal RTT phenotype in vitro, which could open new therapeutic avenues for the treatment of Rett syndrome.


Assuntos
Astrócitos/metabolismo , Proteína 2 de Ligação a Metil-CpG/genética , Proteínas do Tecido Nervoso/metabolismo , Neurossecreção , Síndrome de Rett/metabolismo , Animais , Astrócitos/fisiologia , Modelos Animais de Doenças , Deleção de Genes , Regulação da Expressão Gênica , Masculino , Camundongos , Proteômica , Síndrome de Rett/genética , Síndrome de Rett/fisiopatologia
3.
J Neurosci ; 40(37): 7080-7090, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32801151

RESUMO

Many clinical and preclinical studies report higher prevalence and severity of chronic pain in females. We used hyperalgesic priming with interleukin 6 (IL-6) priming and PGE2 as a second stimulus as a model for pain chronicity. Intraplantar IL-6 induced hypersensitivity was similar in magnitude and duration in both males and females, while both paw and intrathecal PGE2 hypersensitivity was more persistent in females. This difference in PGE2 response was dependent on both circulating estrogen and translation regulation signaling in the spinal cord. In males, the duration of hypersensitivity was regulated by testosterone. Since the prolactin receptor (Prlr) is regulated by reproductive hormones and is female-selectively activated in sensory neurons, we evaluated whether Prlr signaling contributes to hyperalgesic priming. Using ΔPRL, a competitive Prlr antagonist, and a mouse line with ablated Prlr in the Nav1.8 sensory neuronal population, we show that Prlr in sensory neurons is necessary for the development of hyperalgesic priming in female, but not male, mice. Overall, sex-specific mechanisms in the initiation and maintenance of chronic pain are regulated by the neuroendocrine system and, specifically, sensory neuronal Prlr signaling.SIGNIFICANCE STATEMENT Females are more likely to experience chronic pain than males, but the mechanisms that underlie this sex difference are not completely understood. Here, we demonstrate that the duration of mechanical hypersensitivity is dependent on circulating sex hormones in mice, where estrogen caused an extension of sensitivity and testosterone was responsible for a decrease in the duration of the hyperalgesic priming model of chronic pain. Additionally, we demonstrated that prolactin receptor expression in Nav1.8+ neurons was necessary for hyperalgesic priming in female, but not male, mice. Our work demonstrates a female-specific mechanism for the promotion of chronic pain involving the neuroendrocrine system and mediated by sensory neuronal prolactin receptor.


Assuntos
Hiperalgesia/metabolismo , Neurossecreção , Receptores da Prolactina/metabolismo , Células Receptoras Sensoriais/metabolismo , Caracteres Sexuais , Animais , Dinoprostona/metabolismo , Estrogênios/sangue , Feminino , Humanos , Hiperalgesia/fisiopatologia , Interleucina-6/metabolismo , Masculino , Camundongos , Canal de Sódio Disparado por Voltagem NAV1.8/metabolismo , Nociceptividade , Receptores da Prolactina/genética , Células Receptoras Sensoriais/fisiologia , Medula Espinal/citologia , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia
4.
Dev Comp Immunol ; 113: 103782, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32679114

RESUMO

The transcription factor glial cell missing, Gcm, is known to be an important protein in the determination of glial cell fate as well as embryonic plasmatocyte differentiation in Drosophila melanogaster. So far, no function for Gcm in crustaceans has been reported. In this study, we show the cDNA sequence of a Gcm homologue in the freshwater crayfish Pacifastacus leniusculus. The P. leniusculus Gcm transcript is expressed exclusively in brain and nervous tissue, and by in situ hybridization we show that the expression is restricted to a small number of large cells with morphology similar to neurosecretory cells. Furthermore, we show that the expression of Gcm coincides with the expression of a Repo homologue, that is induced in expression by Gcm in Drosophila. Moreover, the Gcm transcript is increased shortly and transiently after injection of cystamine, a substance that inhibits transglutaminase and also strongly affects the movement behavior of crayfish. This finding of Gcm transcripts in a subpopulation of brain cells in very low numbers may enable more detailed studies about Gcm in adult crustaceans.


Assuntos
Proteínas de Artrópodes/genética , Astacoidea/genética , Encéfalo/metabolismo , Neuroglia/fisiologia , Animais , Comportamento Animal , Diferenciação Celular , Cistamina/administração & dosagem , Cistamina/farmacologia , Proteínas de Ligação a DNA/genética , Drosophila/genética , Proteínas de Drosophila/genética , Desenvolvimento Embrionário/genética , Água Doce , Proteínas de Homeodomínio/genética , Atividade Motora , Neurossecreção/genética , Especificidade de Órgãos , Homologia de Sequência , Fatores de Transcrição/genética , Transcriptoma , Transglutaminases/antagonistas & inibidores
5.
Acta Neuropathol Commun ; 8(1): 35, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-32192527

RESUMO

The choroid plexus (CP) is a key regulator of the central nervous system (CNS) homeostasis through its secretory, immunological and barrier properties. Accumulating evidence suggests that the CP plays a pivotal role in the pathogenesis of multiple sclerosis (MS), but the underlying mechanisms remain largely elusive. To get a comprehensive view on the role of the CP in MS, we studied transcriptomic alterations of the human CP in progressive MS and non-neurological disease controls using RNA sequencing. We identified 17 genes with significantly higher expression in progressive MS patients relative to that in controls. Among them is the newly described long non-coding RNA HIF1A-AS3. Next to that, we uncovered disease-affected pathways related to hypoxia, secretion and neuroprotection, while only subtle immunological and no barrier alterations were observed. In an ex vivo CP explant model, a subset of the upregulated genes responded in a similar way to hypoxic conditions. Our results suggest a deregulation of the Hypoxia-Inducible Factor (HIF)-1 pathway in progressive MS CP. Importantly, cerebrospinal fluid levels of the hypoxia-responsive secreted peptide PAI-1 were higher in MS patients with high disability relative to those with low disability. These findings provide for the first time a complete overview of the CP transcriptome in health and disease, and suggest that the CP environment becomes hypoxic in progressive MS patients, highlighting the altered secretory and neuroprotective properties of the CP under neuropathological conditions. Together, these findings provide novel insights to target the CP and promote the secretion of neuroprotective factors into the CNS of progressive MS patients.


Assuntos
Plexo Corióideo/metabolismo , Hipóxia/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Neuroproteção/genética , Neurossecreção/genética , Adrenomedulina/líquido cefalorraquidiano , Adrenomedulina/genética , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Glicoproteínas/líquido cefalorraquidiano , Glicoproteínas/genética , Humanos , Fator 1 Induzível por Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Peptídeos e Proteínas de Sinalização Intercelular/líquido cefalorraquidiano , Peptídeos e Proteínas de Sinalização Intercelular/genética , Ventrículos Laterais , Masculino , Metalotioneína/genética , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/líquido cefalorraquidiano , Esclerose Múltipla Recidivante-Remitente/líquido cefalorraquidiano , Inibidor 1 de Ativador de Plasminogênio/líquido cefalorraquidiano , Inibidor 1 de Ativador de Plasminogênio/genética , RNA Antissenso/genética , RNA Longo não Codificante , RNA-Seq
6.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31650157

RESUMO

CONTEXT: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition. OBJECTIVE: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function. PATIENTS, DESIGN, AND SETTING: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting. MAIN OUTCOME MEASURES: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates. RESULTS: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels. CONCLUSIONS: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure.


Assuntos
Imunoglobulinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Proteínas de Membrana/fisiologia , Neurossecreção/fisiologia , Somatotrofos/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Hormônio do Crescimento/biossíntese , Humanos , Imunoglobulinas/deficiência , Fator de Crescimento Insulin-Like I/análise , Peptídeos e Proteínas de Sinalização Intercelular/deficiência , Masculino , Proteínas de Membrana/deficiência , Camundongos , Pessoa de Meia-Idade
7.
Int J Mol Sci ; 19(10)2018 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-30297647

RESUMO

Significant growth hormone (GH) reductions have been reported in diabetic animal models with disturbed metabolic balance coinciding with GH deficiency. Therefore, enhanced GH secretion may have beneficial effects in controlling diabetes. Thus, we aim to investigate the effect of hexarelin, a synthetic GH secretagogue (GHS), on GH secretion in streptozotocin (STZ, 65 mg/kg)-induced diabetic rats. Daily hexarelin (100 µg/kg) treatment was performed for two weeks in four-week-long STZ-diabetic and vehicle control rats. Pulsatile GH secretion in STZ-rats was significantly reduced in total, pulsatile, basal, and mass of GH secretion per burst. In addition, impaired GH secretion was followed by an increase in fasting-level free fatty acids (FFAs) and a decrease in insulin-like growth factor 1 (IGF-1) compared to control rats. After hexarelin treatment, pulsatile GH secretion in STZ-rats was significantly increased in total, pulsatile, and basal, but not in the mass GH secretion per burst, compared to STZ-rats without hexarelin treatment. However, there was no significant elevation in GH secretion in the hexarelin-treated control group. In addition, hexarelin-treated STZ-rats showed a significant decrease in fasting level FFAs, whereas suppression of fasting level for IGF-1 was maintained. These results suggest that STZ-induced diabetic rats have impaired pulsatile GH secretion, causing increased FFAs and decreased IGF-1 levels in circulation. Hexarelin injections for two weeks is able to normalize impaired pulsatile GH secretion with normal fasting levels of FFAs, but fails to recover IGF-1 levels.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Hormônio do Crescimento/sangue , Substâncias de Crescimento/farmacologia , Oligopeptídeos/farmacologia , Secretagogos/farmacologia , Animais , Ácidos Graxos/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Neurossecreção/efeitos dos fármacos , Ratos , Ratos Wistar
8.
NeuroRehabilitation ; 43(3): 327-345, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30347624

RESUMO

BACKGROUND: Sleep and endocrine disruptions are prevalent after traumatic brain injury (TBI) and are likely to contribute to morbidity. OBJECTIVE: To describe the interaction between sleep and hormonal regulation following TBI and elucidate the impact that alterations of these systems have on cognitive responses during the posttraumatic chronic period. METHODS: Review of preclinical and clinical literature describing long-lasting endocrine dysregulation and sleep alterations following TBI. The bidirectional relationship between sleep and hormones is described. Literature describing co-occurrence between sleep-wake disturbances and hormonal dysregulation will be presented. Review of literature describing cognitive effects of seep and hormones. The cognitive and functional impact of sleep disturbances and hormonal dysregulation is discussed within the context of TBI. RESULTS/CONCLUSIONS: Sleep and hormonal alterations impact cognitive and functional outcome after TBI. Diagnosis and treatment of these disturbances will impact recovery following TBI and should be considered in the post-acute rehabilitative setting.


Assuntos
Lesões Encefálicas Traumáticas/metabolismo , Hormônios/metabolismo , Neurossecreção/fisiologia , Transtornos do Sono-Vigília/metabolismo , Sono/fisiologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/fisiopatologia , Humanos , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/fisiopatologia
9.
Biochim Biophys Acta Gen Subj ; 1862(12): 2701-2713, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30251660

RESUMO

BACKGROUND: Neurosecretion is the multistep process occurring in separate spatial and temporal cellular boundaries which complicates its comprehensive analysis. Most of the research are focused on one distinct stage of synaptic vesicle recycling. Here, we describe approaches for complex analysis of synaptic vesicle (SV) endocytosis and separate steps of exocytosis at the level of presynaptic bouton and highly purified SVs. METHODS: Proposed fluorescence-based strategies and analysis of neurotransmitter transport provided the advantages in studies of exocytosis steps. We evaluated SV docking/tethering, their Ca2+-dependent fusion and release of neurotransmitters gamma-aminobutyric acid (GABA) and glutamate in two animal models. RESULTS: Approaches enabled us to study: 1) endocytosis/Ca2+-dependent release of fluorescent carbon nanodots (CNDs) during stimulation of nerve terminals; 2) the action of levetiracetam, modulator of SV glycoprotein SV2, on fusion competence of SVs and stimulated release of GABA and glutamate; 3) impairments of several steps of neurosecretion under vitamin D3 deficiency. CONCLUSIONS: Our algorithm enabled us to verify the method validity for multidimensional analysis of SV turnover. By increasing SV docking and the size of readily releasable pool (RRP), levetiracetam is able to selectively enhance the stimulated GABA secretion in hippocampal neurons. Findings suggest that SV2 regulates RRP through impact on the number of docked/primed SVs. GENERAL SIGNIFICANCE: Methodology can be widely applied to study the stimulated neurosecretion in presynapse, regulation of SV docking, their Ca2+-dependent fusion with target membranes, quantitative analysis of expression of neuron-specific proteins, as well as for testing the efficiency of pre-selected designed neuroactive substances.


Assuntos
Levetiracetam/farmacologia , Neurossecreção/efeitos dos fármacos , Animais , Anticonvulsivantes/farmacologia , Colecalciferol/deficiência , Endocitose , Exocitose , Fluorescência , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Modelos Animais , Terminações Pré-Sinápticas/efeitos dos fármacos , Terminações Pré-Sinápticas/metabolismo , Ratos , Transmissão Sináptica/fisiologia , Vesículas Sinápticas/metabolismo , Deficiência de Vitamina D/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
10.
Math Biosci ; 305: 29-41, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30075152

RESUMO

The neuroendocrine systems of the hypothalamus are critical for survival and reproduction, and are highly conserved throughout vertebrate evolution. Their roles in controlling body metabolism, growth and body composition, stress, electrolyte balance and reproduction have been intensively studied, and have yielded a rich crop of original and challenging insights into neuronal function, insights that circumscribe a vision of the brain that is quite different from conventional views. Despite the diverse physiological roles of pituitary hormones, most are secreted in a pulsatile pattern, but arising through a variety of mechanisms. An important exception is vasopressin which uses bursting neural activity, but produces a graded secretion response to osmotic pressure, a sustained robust linear response constructed from noisy, nonlinear components. Neuroendocrine systems have many features such as multiple temporal scales and nonlinearity that make their underlying mechanisms hard to understand without mathematical modelling. The models presented here cover the wide range of temporal scales involved in these systems, including models of single cell electrical activity and calcium dynamics, receptor signalling, gene expression, coordinated activity of neuronal networks, whole-organism hormone dynamics and feedback loops, and the menstrual cycle. Many interesting theoretical approaches have been applied to these systems, but important problems remain, at the core the question of what is the true advantage of pulsatility.


Assuntos
Modelos Neurológicos , Neuroendocrinologia , Sistemas Neurossecretores/fisiologia , Hormônio Adrenocorticotrópico/fisiologia , Animais , Feminino , Gonadotropinas Hipofisárias/fisiologia , Hormônio do Crescimento/fisiologia , Humanos , Hipotálamo/fisiologia , Masculino , Conceitos Matemáticos , Ejeção Láctea/fisiologia , Neurossecreção/fisiologia , Ocitocina/fisiologia , Hipófise/fisiologia , Gravidez , Prolactina/fisiologia , Tireotropina/fisiologia , Vasopressinas/fisiologia
11.
G3 (Bethesda) ; 8(9): 2979-2990, 2018 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-30006413

RESUMO

CORL proteins (known as SKOR in mice, Fussel in humans and fussel in Flybase) are a family of CNS specific proteins related to Sno/Ski oncogenes. Their developmental and adult roles are largely unknown. A Drosophila CORL (dCORL) reporter gene is expressed in all Drosophila insulin-like peptide 2 (dILP2) neurons of the pars intercerebralis (PI) of the larval and adult brain. The transcription factor Drifter is also expressed in the PI in a subset of dCORL and dILP2 expressing neurons and in several non-dILP2 neurons. dCORL mutant virgin adult brains are missing all dILP2 neurons that do not also express Drifter. This phenotype is also seen when expressing dCORL-RNAi in neurosecretory cells of the PI. dCORL mutant virgin adults of both sexes have a significantly shorter lifespan than their parental strain. This longevity defect is completely reversed by mating (lifespan increases over 50% for males and females). Analyses of dCORL mutant mated adult brains revealed a complete rescue of dILP2 neurons without Drifter. Taken together, the data suggest that dCORL participates in a neural network connecting the insulin signaling pathway, longevity and mating. The conserved sequence and CNS specificity of all CORL proteins imply that this network may be operating in mammals.


Assuntos
Proteínas de Drosophila/biossíntese , Regulação da Expressão Gênica/fisiologia , Insulina/metabolismo , Longevidade/fisiologia , Neurônios/metabolismo , Neurossecreção/fisiologia , Animais , Drosophila melanogaster , Feminino , Masculino , Rede Nervosa/citologia , Rede Nervosa/metabolismo , Neurônios/citologia
12.
Pflugers Arch ; 470(1): 7-11, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-28801866

RESUMO

Many of the molecular players in the stimulus-secretion chain are similarly active in neurosecretion and catecholamine release. Therefore, studying chromaffin cells uncovered many details of the processes of docking, priming, and exocytosis of vesicles. However, morphological specializations at synapses, called active zones (AZs), confer extra speed of response and another layer of control to the fast release of vesicles by action potentials. Work at the Calyx of Held, a glutamatergic nerve terminal, has shown that in addition to such rapidly released vesicles, there is a pool of "Slow Vesicles," which are held to be perfectly release-competent, but lack a final step of tight interaction with the AZ. It is argued here that such "Slow Vesicles" have many properties in common with chromaffin granules. The added complexity in the AZ-dependent regulation of "Fast Vesicles" can lead to misinterpretation of data on neurosecretion. Therefore, the study of Slow Vesicles and of chromaffin granules may provide a clearer picture of the early steps in the highly regulated process of neurosecretion.


Assuntos
Grânulos Cromafim/fisiologia , Neurossecreção , Animais , Grânulos Cromafim/metabolismo , Humanos , Transmissão Sináptica
13.
Network ; 28(2-4): 53-73, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29120672

RESUMO

A hybrid simulation model (macro-molecular dynamics and Monte Carlo method) is proposed to reproduce neurosecretion and exocytosis. A theory has been developed for vesicular dynamics based on quasi-static electric interactions and a simple transition-state model for the vesicular fusion. Under the non-equilibrium electric conditions in an electrolytic fluid, it is considered that the motion of each synaptic vesicle is influenced by electrostatic forces exerted by the membranes of the synaptic bouton, other vesicles, the intracellular and intravesicular fluids, and external elements to the neuron. In addition, friction between each vesicle and its surrounding intracellular fluid is included in the theory, resulting in a drift type movement. To validate the vesicle equations of motion, a molecular dynamics method has been implemented, where the synaptic pool was replaced by a straight angle parallelepiped, the vesicles were represented by spheres and the fusion between each vesicle and the presynaptic membrane was simulated by a Monte Carlo type probabilistic change of state. Density profiles showing clusters of preferential activity as well as fusion distributions similar to the Poisson distributions associated with miniature end-plate potentials were obtained in the simulations.


Assuntos
Modelos Estatísticos , Neurossecreção , Eletricidade Estática , Vesículas Sinápticas , Animais , Exocitose/fisiologia , Método de Monte Carlo , Neurossecreção/fisiologia , Vesículas Sinápticas/fisiologia
14.
Dev Biol ; 431(2): 226-238, 2017 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-28916169

RESUMO

Split ends (SPEN) is the founding member of a well conserved family of nuclear proteins with critical functions in transcriptional regulation and the post-transcriptional processing and nuclear export of transcripts. In animals, the SPEN proteins fall into two size classes that perform either complementary or antagonistic functions in different cellular contexts. Here, we show that the two Drosophila representatives of this family, SPEN and Spenito (NITO), regulate metamorphic remodeling of the CCAP/bursicon neurosecretory cells. CCAP/bursicon cell-targeted overexpression of SPEN had no effect on the larval morphology or the pruning back of the CCAP/bursicon cell axons at the onset of metamorphosis. During the subsequent outgrowth phase of metamorphic remodeling, overexpression of either SPEN or NITO strongly inhibited axon extension, axon branching, peripheral neuropeptide accumulation, and soma growth. Cell-targeted loss-of-function alleles for both spen and nito caused similar reductions in axon outgrowth, indicating that the absolute levels of SPEN and NITO activity are critical to support the developmental plasticity of these neurons. Although nito RNAi did not affect SPEN protein levels, the phenotypes produced by SPEN overexpression were suppressed by nito RNAi. We propose that SPEN and NITO function additively or synergistically in the CCAP/bursicon neurons to regulate multiple aspects of neurite outgrowth during metamorphic remodeling.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Família Multigênica , Crescimento Neuronal , Sistemas Neurossecretores/citologia , Sistemas Neurossecretores/metabolismo , Animais , Larva/metabolismo , Neurônios/metabolismo , Neurossecreção , Terminações Pré-Sinápticas/metabolismo , Interferência de RNA , Asas de Animais/metabolismo
15.
Prostate ; 77(13): 1373-1380, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28804908

RESUMO

BACKGROUND: To determine the influence of abiraterone Acetate (AA) on neuroendocrine differentiation (NED) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC). METHODS: We conducted an analysis in 115 chemotherapy-naïve mCRPC patients who would be treated with chemotherapy. The serum levels of chromogranin A (CgA), neurone-specific enolase (NSE) were measured in 67 mCRPC patients without AA treatment and 48 patients after the failure of AA treatment, in which these markers were also measured in 34 patients before and after 6 months of AA treatment. Comparative t-test was used to evaluate the serial changes of serum NED markers during AA treatment and univariate and multivariate analyses were performed to test the influence of AA treatment on NED. RESULTS: Serum CgA were NSE were evaluated to be above the upper limit of normal (ULN) in 56 (48.7%) and 29 (25.2%) patients before chemotherapy. In 34 patients with serial evaluation, serum CgA level of 14 patients and NSE of 14 patients increased after the failure of AA treatment. There was no significant difference of NED markers (CgA or NSE variation (P = 0.243) between at baseline and after the failure of AA treatment. Compared with the CgA elevation group in the first 6 months of AA treatment and baseline supranormal CgA group, the CgA decline group, and baseline normal CgA group has a much longer median PSA PFS (14.34 vs 10.00 months, P < 0.001, and 14.23 vs 10.30 months, P = 0.02) and rPFS, respectively (18.33 vs 11.37 months, P < 0.001, and 17.10 vs 12.07 months, P = 0.03). In logistic univariate analysis, AA treatment and its duration were not independent factors influencing NED. CONCLUSIONS: We hypothesized that AA might not significantly lead to progression of NED of mCRPC in general. Furthermore, we found there was heterogeneity in changes of NED markers in different mCRPC patients during AA treatment. Serial CgA and NSE evaluation might help clinicians guide clinical treatment of mCRPC patients.


Assuntos
Acetato de Abiraterona , Adenocarcinoma , Biomarcadores , Cromogranina A , Neurossecreção , Próstata , Neoplasias de Próstata Resistentes à Castração , Acetato de Abiraterona/administração & dosagem , Acetato de Abiraterona/farmacocinética , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Biomarcadores/sangue , Biomarcadores/metabolismo , China , Cromogranina A/sangue , Cromogranina A/metabolismo , Monitoramento de Medicamentos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Neurossecreção/efeitos dos fármacos , Neurossecreção/fisiologia , Próstata/metabolismo , Próstata/patologia , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos
16.
Am J Physiol Heart Circ Physiol ; 313(3): H548-H557, 2017 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-28626074

RESUMO

Recent studies have supported an important contribution of prorenin (PR) and its receptor (PRR) to the regulation of hypothalamic, sympathetic, and neurosecretory outflows to the cardiovascular system, including systemic release of vasopressin (VP), both under physiological and cardiovascular disease conditions. Still, the identification of precise cellular mechanisms and neuronal/molecular targets remain unknown. We have recently shown that PRR is expressed in VP neurons and that their activation increases neuronal activity. However, the underlying ionic channel mechanisms are undefined. Here, we performed patch-clamp electrophysiology from identified VP neurons in acute hypothalamic slices obtained from enhanced green fluorescent protein-VP transgenic rats. Voltage-clamp recordings showed that PR inhibited the magnitude of A-type K+ current (IA; ~50% at -25 mV), a subthreshold voltage-dependent current that restrains VP firing activity. PR also increased the inactivation rate of IA and shifted the steady-state voltage-dependent inactivation function toward more hyperpolarized membrane potential (~7 mV shift), thus resulting in less channel availability to be activated at any given membrane potential. PR also inhibited a sustained component of IA ("window" current). PR-mediated changes in action potential waveform and increased firing activity were occluded when IA was blocked by 4-aminopyridine. Finally, PR failed to increase superoxide production within the supraoptic nucleus/paraventricular nucleus, and PR excitatory effects persisted in slices treated with the SOD mimetic tempol. Taken together, these experiments indicated that PR excitatory effects on vasopressin neurons involve inhibition of IA, due, in part, to increases in its voltage-dependent inactivation properties. Moreover, our results indicate that PR effects did not involve an increase in oxidative stress.NEW & NOTEWORTHY Here, we demonstrate that prorenin/the prorenin receptor is an important signaling unit for the regulation of vasopressin firing activity and, thus, systemic hormonal release. We identified A-type K+ channels as key molecular targets mediating prorenin stimulation of vasopressin neuronal activity, thus standing as a potential therapeutic target for neurohumoral activation in cardiovascular disease.


Assuntos
Precursores Enzimáticos/farmacologia , Hipotálamo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/antagonistas & inibidores , Renina/farmacologia , Vasopressinas/metabolismo , Potenciais de Ação , Animais , Genótipo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hipotálamo/citologia , Hipotálamo/metabolismo , Técnicas In Vitro , Ativação do Canal Iônico/efeitos dos fármacos , Masculino , Neurônios/metabolismo , Neurossecreção , Técnicas de Patch-Clamp , Fenótipo , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Ratos Transgênicos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Tempo , Vasopressinas/genética
17.
PLoS Genet ; 13(4): e1006697, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28384151

RESUMO

Animal behaviors are often composed of distinct alternating behavioral states. Neuromodulatory signals are thought to be critical for establishing stable behavioral states and for orchestrating transitions between them. However, we have only a limited understanding of how neuromodulatory systems act in vivo to alter circuit performance and shape behavior. To address these questions, we have investigated neuromodulatory signaling in the context of Caenorhabditis elegans egg-laying. Egg-laying activity cycles between discrete states-short bursts of egg deposition (active phases) that alternate with prolonged quiescent periods (inactive phases). Here using genetic, pharmacological and optogenetic approaches for cell-specific activation and inhibition, we show that a group of neurosecretory cells (uv1) located in close spatial proximity to the egg-laying neuromusculature direct the temporal organization of egg-laying by prolonging the duration of inactive phases. We demonstrate that the modulatory effects of the uv1 cells are mediated by peptides encoded by the nlp-7 and flp-11 genes that act locally to inhibit circuit activity, primarily by inhibiting vesicular release of serotonin from HSN motor neurons. This peptidergic inhibition is achieved, at least in part, by reducing synaptic vesicle abundance in the HSN motor neurons. By linking the in vivo actions of specific neuropeptide signaling systems with the generation of stable behavioral outcomes, our study reveals how cycles of neuromodulation emanating from non-neuronal cells can fundamentally shape the organization of a behavioral program.


Assuntos
Proteínas de Caenorhabditis elegans/genética , Neuropeptídeos/genética , Oviposição/genética , Acetilcolina/metabolismo , Animais , Comportamento Animal , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Neurônios Motores/metabolismo , Neuropeptídeos/metabolismo , Neurossecreção/genética , Neurônios Serotoninérgicos/metabolismo , Serotonina/metabolismo , Transdução de Sinais/genética
18.
Crit Rev Immunol ; 37(2-6): 213-248, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29773021

RESUMO

The discovery of the ability of the nervous system to communicate through "public" circuits with other systems of the body is attributed to Ernst and Berta Scharrer, who described the neurosecretory process in 1928. Indeed, the immune system has been identified as another important neuroendocrine target tissue. Opioid peptides are involved in this communication (i.e., neuroimmune) and with that of autoimmunoregulation (communication between immunocytes). The significance of opioid neuropeptide involvement with the immune system is ascertained from the presence of novel δ, µ., and κ receptors on inflammatory cells that result in modulation of cellular activity after activation, as well as the presence of specific enzymatic degradation and regulation processes. In contrast to the relatively uniform antinociceptive action of opiate and opioid signal molecules in neural tissues, the presence of naturally occurring morphine in plasma and a novel µ3 opiate-specific receptor on inflammatory cells adds to the growing knowledge that opioid and opiate signal molecules may have antagonistic actions in select tissues. In examining various disorders (e.g., human immunodeficiency virus, substance abuse, parasitism, and the diffuse inflammatory response associated with surgery) evidence has also been found for the involvement of opiate/opioid signaling in prominent mechanisms. In addition, the presence of similar mechanisms in man and organisms 500 million years divergent in evolution bespeaks the importance of this family of signal molecules. The present review provides an overview of recent advances in the field of opiate and opioid immunoregulatory processes and speculates as to their significance in diverse biological systems.


Assuntos
Sistema Imunitário/imunologia , Inflamação/imunologia , Sistemas Neurossecretores/imunologia , Peptídeos Opioides/imunologia , Receptores Opioides/imunologia , Síndrome de Imunodeficiência Adquirida/imunologia , Síndrome de Imunodeficiência Adquirida/metabolismo , Animais , Autoimunidade , Evolução Biológica , Regulação da Expressão Gênica/imunologia , Interações Hospedeiro-Parasita/imunologia , Humanos , Inflamação/metabolismo , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Neurossecreção/imunologia , Peptídeos Opioides/metabolismo , Infecções por Protozoários/imunologia , Infecções por Protozoários/metabolismo , Infecções por Protozoários/parasitologia , Receptores Opioides/metabolismo , Transdução de Sinais/imunologia , Transtornos Relacionados ao Uso de Substâncias/imunologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo
19.
Biol Psychol ; 119: 200-9, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27377789

RESUMO

Shyness and sociability are orthogonal personality dimensions, but little is known about how the two traits are instantiated in the brain and body. Using a 3-stimulus auditory oddball task, we examined whether shyness and sociability were distinguishable on P300 event-related potentials (ERPs) in processing task-relevant, novel, and standard auditory tones in 48 young adults. ERP amplitudes were measured at four midline scalp sites (Fz, FCz, Cz, Pz). We found that shyness, but not sociability, was related to reduced frontal novelty P300 amplitudes and to high emotionality. We also found that low baseline salivary cortisol levels mediated the relation between: (a) high shyness and reduced frontal P300 amplitudes to novel tones, and (b) high shyness and high scores of emotionality. We speculate that low baseline cortisol may serve as a putative mechanism influencing central attentional states of avoidance to threat and novelty and emotional arousal in adults who are shy.


Assuntos
Nível de Alerta/fisiologia , Emoções/fisiologia , Potenciais Evocados P300/fisiologia , Timidez , Habilidades Sociais , Adulto , Atenção/fisiologia , Aprendizagem da Esquiva/fisiologia , Metabolismo Basal/fisiologia , Encéfalo/fisiologia , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/metabolismo , Masculino , Neurossecreção/fisiologia , Comportamento Social , Adulto Jovem
20.
Cell Rep ; 15(4): 681-682, 2016 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-27119847

RESUMO

In this issue of Cell Reports, Stagkourakis et al. (2016) report that oscillating hypothalamic TIDA neurons, previously thought to be simple neurosecretory neurons controlling pituitary prolactin secretion, control dopamine output via autoregulatory mechanisms and thus could potentially regulate other physiologically important hypothalamic neuronal circuits.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Neurossecreção , Animais , Hipotálamo/metabolismo , Modelos Biológicos , Rede Nervosa/metabolismo , Neurônios/metabolismo
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