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1.
Nat Commun ; 11(1): 471, 2020 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980655

RESUMO

Astrocytes may function as mediators of the impact of noradrenaline on neuronal function. Activation of glial α1-adrenergic receptors triggers rapid astrocytic Ca2+ elevation and facilitates synaptic plasticity, while activation of ß-adrenergic receptors elevates cAMP levels and modulates memory consolidation. However, the dynamics of these processes in behaving mice remain unexplored, as do the interactions between the distinct second messenger pathways. Here we simultaneously monitored astrocytic Ca2+ and cAMP and demonstrate that astrocytic second messengers are regulated in a temporally distinct manner. In behaving mice, we found that while an abrupt facial air puff triggered transient increases in noradrenaline release and large cytosolic astrocytic Ca2+ elevations, cAMP changes were not detectable. By contrast, repeated aversive stimuli that lead to prolonged periods of vigilance were accompanied by robust noradrenergic axonal activity and gradual sustained cAMP increases. Our findings suggest distinct astrocytic signaling pathways can integrate noradrenergic activity during vigilance states to mediate distinct functions supporting memory.


Assuntos
Nível de Alerta/fisiologia , Astrócitos/fisiologia , Norepinefrina/fisiologia , Sistemas do Segundo Mensageiro/fisiologia , Animais , Sinalização do Cálcio/fisiologia , Condicionamento Clássico/fisiologia , AMP Cíclico/metabolismo , Medo/fisiologia , Corantes Fluorescentes , Locus Cerúleo/citologia , Locus Cerúleo/fisiologia , Memória/fisiologia , Camundongos , Plasticidade Neuronal/fisiologia , Lobo Parietal/citologia , Lobo Parietal/fisiologia , Receptores Adrenérgicos/fisiologia
2.
Nat Neurosci ; 22(11): 1771-1781, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636449

RESUMO

Microglia dynamically survey the brain parenchyma. Microglial processes interact with neuronal elements; however, what role neuronal network activity plays in regulating microglial dynamics is not entirely clear. Most studies of microglial dynamics use either slice preparations or in vivo imaging in anesthetized mice. Here we demonstrate that microglia in awake mice have a relatively reduced process area and surveillance territory and that reduced neuronal activity under general anesthesia increases microglial process velocity, extension and territory surveillance. Similarly, reductions in local neuronal activity through sensory deprivation or optogenetic inhibition increase microglial process surveillance. Using pharmacological and chemogenetic approaches, we demonstrate that reduced norepinephrine signaling is necessary for these increases in microglial process surveillance. These findings indicate that under basal physiological conditions, noradrenergic tone in awake mice suppresses microglial process surveillance. Our results emphasize the importance of awake imaging for studying microglia-neuron interactions and demonstrate how neuronal activity influences microglial process dynamics.


Assuntos
Microglia/fisiologia , Neurônios/fisiologia , Norepinefrina/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Encéfalo/efeitos dos fármacos , Receptor 1 de Quimiocina CX3C/genética , Clozapina/análogos & derivados , Clozapina/farmacologia , Isoflurano/farmacologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microinjeções , Muscimol/farmacologia , Norepinefrina/farmacologia , Optogenética , Propanolaminas/farmacologia , Propranolol/farmacologia , Receptores Purinérgicos P2Y12/genética , Privação Sensorial/fisiologia , Córtex Somatossensorial/efeitos dos fármacos , Tetrodotoxina/farmacologia , Vigília
3.
Nat Neurosci ; 22(11): 1782-1792, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636451

RESUMO

Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of ß2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of ß2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.


Assuntos
Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Norepinefrina/fisiologia , Córtex Visual/fisiologia , Animais , Benzilaminas/farmacologia , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Ritmo Circadiano/fisiologia , Clembuterol/farmacologia , Dexmedetomidina/farmacologia , Dominância Ocular , Feminino , Fentanila/farmacologia , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Nadolol/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Norepinefrina/metabolismo , Propanolaminas/farmacologia , Restrição Física/fisiologia , Terbutalina/farmacologia , Vigília , Ferimentos e Lesões/fisiopatologia
4.
PLoS Comput Biol ; 15(7): e1007126, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31276488

RESUMO

Living creatures must accurately infer the nature of their environments. They do this despite being confronted by stochastic and context sensitive contingencies-and so must constantly update their beliefs regarding their uncertainty about what might come next. In this work, we examine how we deal with uncertainty that evolves over time. This prospective uncertainty (or imprecision) is referred to as volatility and has previously been linked to noradrenergic signals that originate in the locus coeruleus. Using pupillary dilatation as a measure of central noradrenergic signalling, we tested the hypothesis that changes in pupil diameter reflect inferences humans make about environmental volatility. To do so, we collected pupillometry data from participants presented with a stream of numbers. We generated these numbers from a process with varying degrees of volatility. By measuring pupillary dilatation in response to these stimuli-and simulating the inferences made by an ideal Bayesian observer of the same stimuli-we demonstrate that humans update their beliefs about environmental contingencies in a Bayes optimal way. We show this by comparing general linear (convolution) models that formalised competing hypotheses about the causes of pupillary changes. We found greater evidence for models that included Bayes optimal estimates of volatility than those without. We additionally explore the interaction between different causes of pupil dilation and suggest a quantitative approach to characterising a person's prior beliefs about volatility.


Assuntos
Modelos Biológicos , Pupila/fisiologia , Acetilcolina/fisiologia , Adolescente , Adulto , Teorema de Bayes , Biologia Computacional , Simulação por Computador , Tomada de Decisões , Meio Ambiente , Humanos , Locus Cerúleo/fisiologia , Cadeias de Markov , Modelos Neurológicos , Norepinefrina/fisiologia , Transdução de Sinais , Incerteza , Adulto Jovem
5.
Endocrinology ; 160(9): 2074-2084, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31150047

RESUMO

Stress decreases milk components such as milk protein and milk yield. The objective of this study was to investigate whether noradrenaline (NA) in milk constituted a factor associated with stress-induced changes in milk proteins such as ß-casein. Breast milk obtained from eight healthy, nursing women contained NA at concentrations ranging from 12.7 to 115.5 nM. The expression of tyrosine hydroxylase (TH), a rate-limiting enzyme of NA synthesis, was observed in primary normal human mammary epithelial cells (HMECs), and in MCF-12A and MCF-10A cell lines. The mean NA concentration in culture medium used by MCF-12A transfected with TH small interfering RNA (siRNA) was significantly lower than that of cells transfected with control siRNA. NA concentration in milk in restraint-stressed nursing mice was significantly higher than that in nonstressed nursing mice, owing to elevated TH expression in the mammary epithelium. The mean ß-casein concentration in milk in restraint-stressed mice was significantly lower than that in nonstressed mice. NA treatment resulted in a concentration-dependent decrease in ß-casein expression in HMECs. ß2 adrenergic receptor (ADRB2) expression was observed in HMECs, MCF-12A, and MCF-10A, and immunohistochemical analysis of ADRB2 using mammary epithelium sections obtained from mice at day 10 of lactation showed that ADRB2 was expressed at the apical membrane of mammary epithelium. Treatment with salbutamol, an ADRB2 stimulant, decreased ß-casein expression in a concentration-dependent manner in MCF-12A. Our results showed that endogenous NA derived from mammary epithelial cells likely comprises one of the factors involved in stress-induced changes in milk proteins such as ß-casein.


Assuntos
Caseínas/análise , Leite/química , Norepinefrina/fisiologia , Estresse Psicológico/metabolismo , Adulto , Animais , Mama/metabolismo , Células Cultivadas , Feminino , Humanos , Camundongos , Gravidez , Receptores Adrenérgicos beta 2/análise , Tirosina 3-Mono-Oxigenase/genética
6.
Neurobiol Learn Mem ; 161: 72-82, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30930287

RESUMO

Beta-adrenergic receptor (b-AR) activation by noradrenaline (NA) enhances memory formation and long-term potentiation (LTP), a form of synaptic plasticity characterized by an activity-dependent increase in synaptic strength. LTP is believed to be a cellular mechanism for contextual learning and memory. In the mammalian hippocampus, LTP can be observed at multiple synaptic pathways after strong stimulation of a single synaptic pathway. This heterosynaptic LTP is believed to involve synaptic tagging of active synapses and capture of plasticity-related proteins that enable heterosynaptic transfer of persistent potentiation. These processes may permit distinct neural pathways to associate information transmitted by separate, but convergent, synaptic inputs. We had previously shown that transcription and epigenetic modifications were necessary for stabilization of homosynaptic LTP. However, it is unclear whether transfer of LTP to a second, heterosynaptic pathway involves b-ARs signalling to the nucleus. Using electrophysiologic recordings in area CA1 of murine hippocampal slices, we show here that pharmacologically inhibiting b-AR activation, transcription, DNA methyltransferase or histone acetyltransferase activation, prevents stabilization of heterosynaptic LTP. Our data suggest that noradrenergic stabilization of heterosynaptic ("tagged") LTP requires not only transcription, but specifically, DNA methylation and histone acetylation. NA promotes stable heterosynaptic plasticity through engagement of nuclear processes that may contribute to prompt consolidation of short-term memories into resilient long-term memories under conditions when the brain's noradrenergic system is recruited.


Assuntos
Região CA1 Hipocampal/fisiologia , Epigênese Genética/fisiologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Potenciação de Longa Duração/fisiologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Transdução de Sinais/fisiologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Citidina/análogos & derivados , Citidina/farmacologia , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Histona Acetiltransferases/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Propranolol/farmacologia , Receptores Adrenérgicos beta/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
7.
Rev Esp Med Nucl Imagen Mol ; 38(4): 262-271, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-31031167

RESUMO

Imaging of cardiac sympathetic innervation is only possible by nuclear cardiology techniques and its assessment is key in the evaluation of and decision-making for patients with cardiac sympathetic impairment. This review includes the basis of cardiac sympathetic scintigraphy with 123I-meta-iodobenzylguanidine (123I-MIBG), recommended protocols, patient preparation, image acquisition and quantification, reproducibility, dosimetry, etc., and also the clinical indications for cardiac patients, mainly with regard to heart failure, arrhythmia, coronary artery disease, cardiotoxicity, including its contribution to establishing the indication for and monitoring the response to implantable cardiac devices, pharmacological treatment, heart transplantation and other.


Assuntos
3-Iodobenzilguanidina , Sistema de Condução Cardíaco/diagnóstico por imagem , Cardiopatias/diagnóstico por imagem , Coração/inervação , Radioisótopos do Iodo , Compostos Radiofarmacêuticos , Sistema Nervoso Simpático/diagnóstico por imagem , 3-Iodobenzilguanidina/administração & dosagem , 3-Iodobenzilguanidina/farmacocinética , Dispositivos de Terapia de Ressincronização Cardíaca , Pré-Escolar , Tomada de Decisão Clínica , Desfibriladores Implantáveis , Coração/diagnóstico por imagem , Sistema de Condução Cardíaco/fisiopatologia , Cardiopatias/induzido quimicamente , Cardiopatias/fisiopatologia , Transplante de Coração , Humanos , Processamento de Imagem Assistida por Computador , Infusões Intravenosas , Radioisótopos do Iodo/administração & dosagem , Radioisótopos do Iodo/farmacocinética , Norepinefrina/fisiologia , Percloratos/administração & dosagem , Compostos de Potássio/administração & dosagem , Prognóstico , Radiometria , Compostos Radiofarmacêuticos/administração & dosagem , Compostos Radiofarmacêuticos/farmacocinética , Receptores Adrenérgicos/fisiologia , Reprodutibilidade dos Testes , Sistema Nervoso Simpático/fisiopatologia , Glândula Tireoide/efeitos dos fármacos , Resultado do Tratamento
8.
Psychopharmacology (Berl) ; 236(6): 1807-1816, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30706097

RESUMO

RATIONALE: Trust is a key component of social interactions. In order to assess the trustworthiness of others, people rely on both information learned from previous encounters, as well as on implicit biases associated with specific facial features. OBJECTIVE: Here, we investigated the role of catecholamine (dopamine and noradrenaline) transmission on trust decisions as a function of both experienced behavior and facial features. METHODS: To increase catecholamine levels, methylphenidate (MPH, i.e., Ritalin®, 20 mg) was administered to participants (N = 24) prior to their playing a well-studied economic task, namely the Trust Game (Berg et al. 1995). We measured the amount of money invested with a variety of game partners. Across game partners, we manipulated two aspects of trust: the facial trust level (high facial trust, low facial trust, and non-social) and the likelihood of reciprocation (high, low). RESULTS: Results demonstrated no main effect of MPH on investments, but rather a selective lowering of investments under MPH as compared with placebo with the game partners who were low on facial trustworthiness and were low reciprocators. CONCLUSION: These results provide evidence that MPH administration impacts social trust decision-making, but does so in a context-specific manner.


Assuntos
Dopamina/fisiologia , Expressão Facial , Relações Interpessoais , Metilfenidato/farmacologia , Norepinefrina/fisiologia , Confiança/psicologia , Adolescente , Estudos Cross-Over , Tomada de Decisões/efeitos dos fármacos , Tomada de Decisões/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Método Duplo-Cego , Feminino , Jogos Experimentais , Humanos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Adulto Jovem
9.
Cell Immunol ; 336: 48-57, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30600100

RESUMO

Males exhibit stronger sympathetic nervous system (SNS) activity, but weaker primary CD4+ T-cell (auto)immune responses. To test the role of catecholamines, major end-point SNS mediators, in this dimorphism, influence of propranolol (ß-adrenoceptor blocker) on mitogen/neuroantigen-stimulated CD4+ T cells from female and male EAE rat draining lymph node (dLN) cell cultures was examined. Male rat dLNs exhibited higher noradrenaline concentration and frequency of ß2-adrenoceptor-expressing CD4+ T lymphocytes and antigen presenting cells. Propranolol, irrespective of exogenous noradrenaline presence, more prominently augmented IL-2 production and proliferation of CD4+ lymphocytes in male than female rat dLN cell cultures. In neuroantigen-stimulated dLN cells of both sexes propranolol increased IL-1ß and IL-23/p19 expression and IL-17+ CD4+ cell frequency, but enhanced IL-17 production only in male rat CD4+ lymphocytes, thereby abrogating sexual dimorphism in IL-17 concentration observed in propranolol-free cultures. Thus, ß-adrenoceptor-mediated signalling may contribute to sex bias in rat IL-17-producing cell secretory capacity.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Encefalomielite Autoimune Experimental/imunologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/fisiologia , Caracteres Sexuais , Antagonistas Adrenérgicos beta/farmacologia , Animais , Feminino , Interleucina-17/análise , Ativação Linfocitária , Masculino , Proteína Básica da Mielina/farmacologia , Ratos
10.
Psychoneuroendocrinology ; 99: 191-195, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30253326

RESUMO

Signaling through ß-adrenergic receptors drives cancer progression and ß-blockers are being evaluated as a novel therapeutic strategy to prevent metastasis. Orthotopic mouse models of breast cancer show that ß-adrenergic signaling induced by chronic stress accelerates metastasis, and that ß2-adrenergic receptors on tumor cells are critical for this. Endogenous catecholamines are released during chronic stress: norepinephrine from the adrenal medulla and sympathetic nerves, and epinephrine from the adrenal medulla. ß2-adrenergic receptors are much more sensitive to epinephrine than to norepinephrine. To determine if epinephrine is necessary in the effects of stress on cancer progression, we used a denervation strategy to eliminate circulating epinephrine, and quantified the effect on metastasis. Using both human xenograft and immune-intact murine models of breast cancer, we show that circulating epinephrine is dispensable for the effects of chronic stress on cancer progression. Measured levels of circulating norepinephrine were sufficiently low that they were unlikely to influence ß2-adrenergic signaling, suggesting a possible role for norepinephrine release from sympathetic nerve terminals.


Assuntos
Epinefrina/fisiologia , Metástase Neoplásica/fisiopatologia , Estresse Psicológico/metabolismo , Medula Suprarrenal/fisiopatologia , Antagonistas Adrenérgicos beta/farmacologia , Animais , Neoplasias da Mama/fisiopatologia , Modelos Animais de Doenças , Epinefrina/sangue , Epinefrina/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/fisiopatologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta , Transdução de Sinais/efeitos dos fármacos , Circulação Esplâncnica , Nervos Esplâncnicos/metabolismo , Sistema Nervoso Simpático
11.
Eur J Pharmacol ; 843: 121-125, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30395850

RESUMO

We have investigated the mode of cardiovascular action of the stimulant methylhexaneamine (MHA) in terms of direct or indirect adrenergic actions in anaesthetised rats. Male and female rats were anaesthetised with pentobarbitone and pressor (changes in diastolic blood pressure) and cardioaccelerator responses to MHA were examined in vehicle treated or chemically sympathectomised rats. MHA produced pressor and cardioaccelerator responses over the same dose range in vehicle treated animals, with significant cardioaccelerator and pressor responses occurring at MHA (0.1 mg/kg). However, tachycardia was more marked than pressor responses. In sympathectomised rats, cardiac and pressor actions of MHA were greatly attenuated. MHA was also studied in isolated tissues. In rat vas deferens, MHA produced small tonic contractions, but these were virtually abolished by sympathectomy In rat aorta, MHA produced almost no contractions. These results are also consistent with largely indirect actions. There were no differences between male and female rats. It is concluded that MHA acts predominantly indirectly in both male and female rats causing noradrenaline release to produce cardiovascular actions and that as a result pressor and cardiac responses occur at similar doses. This propensity for MHA to cause tachycardia and rises in blood pressure at similar doses range may have implications for adverse cardiovascular actions.


Assuntos
Aminas/farmacologia , Norepinefrina/fisiologia , Taquicardia/induzido quimicamente , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Feminino , Frequência Cardíaca/efeitos dos fármacos , Técnicas In Vitro , Masculino , Ratos , Ratos Wistar , Taquicardia/metabolismo , Taquicardia/fisiopatologia , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologia
12.
Gigascience ; 8(2)2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544133

RESUMO

Background: Monitoring the activity and morphology of neuron-astrocyte networks in culture is a powerful tool for studying dynamics, structure, and communication in neuron-astrocyte networks independently or as a model of the sub-brain network. These cultures are known to produce stereotypical patterns of activity, e.g., highly synchronized network bursts resembling sleep or seizure states, thus it enables the exploration of behaviors that can relate to brain function and disease. High-resolution microscopy of calcium imaging combined with simultaneous electrical recording provides a comprehensive overview on the network's dynamics. This setup makes it possible to apply global perturbations of electrical and chemical stimulation on the cultures during the recording task and to record the effects on network activity on-line. Morphological changes in the cultures can be obtained to have a complete dataset for structure-function study of neuron-astrocyte networks in vitro. Findings: The 4 TB of data presented here was recorded and imaged as part of an accompanying study looking at in vitro structure-function of neuron-astrocyte networks. Simultaneous optical (calcium imaging) and electrical (micro-electrode array) recordings lasted 5-12 minutes and included spontaneous activity recording, electrical and chemical stimulation of neuron-astrocyte, and isolated astrocyte cultures. The data include activity recordings of 58 different cultures, with 1-2 regions of interest recorded for each culture. Production procedures, experimental protocols, and reuse options are included. The data have been suitable to reveal changes in the activity and morphology of the cultures and enabled observation and analysis of neuron-astrocyte and isolated astrocyte culture behaviors under the applied perturbations. Conclusions: Our dataset is sufficient to show significant changes in activity and morphology of neuron-astrocyte networks in culture under the applied stimulations. More than 100 recordings of 58 different cultures give insight of the observation's significance and led to conclusions about astrocyte activity and neuron-astrocyte network communication. Making it available here will allow others to test new tools for calcium imaging analysis and extracellular neuronal voltage recordings.


Assuntos
Astrócitos/fisiologia , Cálcio/metabolismo , Comunicação Celular , Imagem Molecular/métodos , Neurônios/fisiologia , Norepinefrina/fisiologia , Animais , Astrócitos/metabolismo , Humanos , Neurônios/metabolismo , Norepinefrina/metabolismo
13.
Pharmacol Res ; 140: 43-49, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30189295

RESUMO

Perivascular adipose tissue (PVAT) modulates vascular tone and altered PVAT function is observed in vascular diseases such as hypertension and atherosclerosis. We discovered that the PVAT surrounding rat thoracic aorta (RA) and the superior mesenteric artery (SMA) contain significant amounts of 5-hydroxytryptamine (5-HT). We hypothesized that the 5-HT contained within the PVAT is functional and vasoactive. Isolated tissue baths were used for isometric contractility studies and high performance liquid chromatography was used to quantitatively measure amines in the PVAT and release studies. The 5-HT releaser fenfluramine (10 nM-100 µM) was tested for its ability to contract arteries with and without PVAT. Contraction was reported as a percentage of the initial contraction to 10 µM phenylephrine. The RA with PVAT contracted to fenfluramine to a greater maximum (98 ± 10%) than RA without PVAT (24 ± 4%), while no difference in contraction of SMA to maximum fenfluramine with (78 ± 2%) and without (75 ± 6%) PVAT was observed. Contradicting our hypothesis, the maximum contraction of RA with PVAT to fenfluramine was diminished by the alpha-1 adrenoreceptor antagonist prazosin (100 nM; vehicle: 71 ± 4%, prazosin: 24 ± 2%) and the norepinephrine transporter (NET) inhibitor nisoxetine (1 µM; vehicle: 71 ± 4%, nisoxetine: 25 ± 4%) but not the 5-HT2A/2C receptor antagonist ketanserin (10 nM) or serotonin specific reuptake inhibitor fluoxetine (10 µM). To test if fenfluramine caused release of 5-HT or NE from PVAT, PVAT from RA was incubated with vehicle or fenfluramine (10 µM-10 mM), and amines released into the incubating buffer were quantified. A pronounced concentration-dependent NE-release (more than 5-HT) was observed. Collectively, this research illustrates the pharmacology of fenfluramine to primarily stimulate NE release (better than 5-HT) in a NET-dependent manner, leading to vasoconstriction. This adds additional support to PVAT as being an important reservoir of amines.


Assuntos
Tecido Adiposo/fisiologia , Aorta Torácica/efeitos dos fármacos , Fenfluramina/farmacologia , Norepinefrina/fisiologia , Inibidores de Captação de Serotonina/farmacologia , Animais , Aorta Torácica/fisiologia , Masculino , Ratos Sprague-Dawley , Serotonina/fisiologia , Vasoconstrição/efeitos dos fármacos
14.
Trends Neurosci ; 42(2): 102-114, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30455050

RESUMO

Adaptation to the ever-changing world is critical for survival, and our brains are particularly tuned to remember events that differ from previous experiences. Novel experiences induce dopamine release in the hippocampus, a process which promotes memory persistence. While axons from the ventral tegmental area (VTA) were generally thought to be the exclusive source of hippocampal dopamine, recent studies have demonstrated that noradrenergic neurons in the locus coeruleus (LC) corelease noradrenaline and dopamine in the hippocampus and that their dopamine release boosts memory retention as well. In this opinion article, we propose that the projections originating from the VTA and the LC belong to two distinct systems that enhance memory of novel events. Novel experiences that share some commonality with past ones ('common novelty') activate the VTA and promote semantic memory formation via systems memory consolidation. By contrast, experiences that bear only a minimal relationship to past experiences ('distinct novelty') activate the LC to trigger strong initial memory consolidation in the hippocampus, resulting in vivid and long-lasting episodic memories.


Assuntos
Dopamina/fisiologia , Comportamento Exploratório , Hipocampo/fisiologia , Locus Cerúleo/fisiologia , Consolidação da Memória/fisiologia , Área Tegmentar Ventral/fisiologia , Neurônios Adrenérgicos/fisiologia , Animais , Neurônios Dopaminérgicos/fisiologia , Humanos , Vias Neurais/fisiologia , Norepinefrina/fisiologia
15.
Brain Res ; 1702: 3-11, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29102776

RESUMO

Building upon the knowledge that a number of important brain circuits undergo significant degeneration in Alzheimer's disease, numerous recent studies suggest that the norepinephrine-ergic system in the brainstem undergoes significant alterations early in the course of both Alzheimer's disease and Down syndrome. Massive projections from locus coeruleus neurons to almost the entire brain, extensive innervation of brain capillaries, and widespread distribution of noradrenergic receptors enable the norepinephrine-ergic system to play a crucial role in neural processes, including cognitive function. These anatomical and functional characteristics support the role of the norepinephrine-ergic system as an important target for developing new therapies for cognitive dysfunction. Careful neuropathological examinations using postmortem samples from individuals with Alzheimer's disease have implicated the role of the norepinephrine-ergic system in the etiopathogenesis of Alzheimer's disease. Furthermore, numerous studies have supported the existence of a strong interaction between norepinephrine-ergic and neuroimmune systems. We explore the interaction between the two systems that could play a role in the disease-modifying effects of norepinephrine in Alzheimer's disease and Down syndrome.


Assuntos
Doença de Alzheimer/metabolismo , Síndrome de Down/metabolismo , Norepinefrina/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/patologia , Síndrome de Down/patologia , Humanos , Locus Cerúleo/metabolismo , Locus Cerúleo/patologia , Microglia/metabolismo , Microglia/patologia , Neurônios/patologia , Norepinefrina/fisiologia , Receptores Adrenérgicos beta/metabolismo
16.
Brain Res ; 1702: 46-53, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29577889

RESUMO

The evolution of peptidergic signaling systems in the central nervous system serves a distinct and crucial role in brain processes and function. The diversity of physiological peptides and the complexity of their regulation and secretion from the dense core vesicles (DCV) throughout the brain is a topic greatly in need of investigation, though recent years have shed light on cellular and molecular mechanisms that are summarized in this review. Here, we focus on the convergence of peptidergic systems onto the Locus Coeruleus (LC), the sole provider of norepinephrine (NE) to the cortex and hippocampus, via large DCV. As the LC-NE system is one of the first regions of the brain to undergo degeneration in Alzheimer's Disease (AD), and markers of DCV have consistently been demonstrated to have biomarker potential for AD progression, here we summarize the current literature linking the LC-NE system with DCV dysregulation and Aß peptides. We also include neuroanatomical data suggesting that the building blocks of senile plaques, Aß monomers, may be localized to DCV of the LC and noradrenergic axon terminals of the prefrontal cortex. Finally, we explore the putative consequences of chronic stress on Aß production and the role that DCV may play in LC degeneration. Clinical data of immunological markers of DCV in AD patients are discussed.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Locus Cerúleo/fisiologia , Vesículas Secretórias/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Encéfalo/metabolismo , Córtex Cerebral/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Humanos , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Norepinefrina/metabolismo , Norepinefrina/fisiologia , Vesículas Secretórias/patologia
17.
Brain Res ; 1702: 12-16, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29307592

RESUMO

The locus coeruleus-noradrenergic (LC-NA) system supplies the cerebral cortex with norepinephrine, a key modulator of cognition. Neurodegeneration of the LC is an early hallmark of Alzheimer's disease (AD). In this article, we analyze current literature to understand whether NA degeneration in AD simply leads to a loss of norepinephrine input to the cortex. With reported adaptive changes in the LC-NA system at the anatomical, cellular, and molecular levels in AD, existing evidence support a seemingly sustained level of extracellular NE in the cortex, at least at early stages of the long course of AD. We postulate that loss of the integrity of the NA system, rather than mere loss of NE input, is a key contributor to AD pathogenesis. A thorough understanding of NA dysfunction in AD has a large impact on both our comprehension and treatment of this devastating disease.


Assuntos
Neurônios Adrenérgicos/fisiologia , Doença de Alzheimer/metabolismo , Norepinefrina/metabolismo , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/patologia , Humanos , Locus Cerúleo/patologia , Microglia/metabolismo , Microglia/patologia , Neurônios/patologia , Norepinefrina/fisiologia
18.
Neurobiol Learn Mem ; 156: 68-79, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30395938

RESUMO

When consolidated long-term memories are reactivated they can destabilize, rendering the memory labile and vulnerable to modification. This period of lability is followed by reconsolidation, a process that restabilizes the memory trace. Reactivation-induced memory destabilization is the gateway process to reconsolidation, but research in this area has focused primarily on the mechanisms underlying post-reactivation restabilization. As a result, our understanding of processes subserving destabilization have lagged behind those responsible for reconsolidation. Here we review the literature investigating the neural basis of reactivation-induced memory destabilization. We begin by reviewing memory destabilization broadly and the boundary conditions that influence the likelihood of reactivated memories to destabilize. We then discuss the fact that boundary conditions can be overcome in the presence of novelty, providing evidence for the theory that reconsolidation is a mechanism for memory updating. From here, we delve into a detailed review of the role of classical neurotransmitter systems, including dopamine, serotonin, noradrenaline, glutamate, GABA and acetylcholine, in reconsolidation, with a focus on their involvement in destabilization. Many of these neurotransmitters appear capable of promoting memory destabilization, and research investigating the cellular pathways through which they influence destabilization is a growing area. However, gaps remain in our understanding of how these neurotransmitters work in conjunction with one another to support destabilization across different types of memory and in different brain regions. Advances in the coming years within this research field should greatly contribute to our understanding of the neural mechanisms that influence the dynamic process of long-term memory storage and modification, information crucial to the development of potential treatments for disorders characterized by strong, maladaptive memories.


Assuntos
Acetilcolina/fisiologia , Dopamina/fisiologia , Ácido Glutâmico/fisiologia , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologia , Norepinefrina/fisiologia , Serotonina/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais
19.
Adv Exp Med Biol ; 1099: 93-100, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30306517

RESUMO

Gabapentinoids are effective in a wide range of animal pain models and in patients with neuropathic pain and has become one of first-line treatments for neuropathic pain. Because spinal plasticity and sensitization have been intensely studied in neuropathic pain, most laboratory studies have focused on actions of gabapentinoids in the spinal cord, where they reduce primary afferent traffic and excitation of spinal nociceptive neurons, via interaction with α2δ subunits of voltage-gated Ca2+ channels. However, a recent clinical study questioned the relevance of this in vitro and in vivo rodent studies by demonstrating a complete lack of clinical efficacy of intrathecal gabapentin in patients with chronic pain. Curiously, preclinical studies continue to focus on spinal cord actions of gabapentinoids despite this lack of translation to humans.We and others demonstrated that gabapentin inhibits presynaptic GABA release and induces glutamate release from astrocytes in the locus coeruleus (LC), thereby increasing LC neuron activity and spinal noradrenaline release, and that gabapentin relies on this action in the LC for its analgesia. We also recently discovered that, with prolonged time after neuropathic injury, noradrenergic neurons in the LC become less responsive to gabapentin, leading to impaired gabapentin analgesia, and that astroglial glutamate dysregulation is critical to this impaired LC response. The clinically available drug valproate increases glutamate transporter-1 (GLT-1) expression in the LC to restore this impaired gabapentin analgesia.


Assuntos
Analgesia , Gabapentina/farmacologia , Locus Cerúleo/fisiologia , Neuralgia/tratamento farmacológico , Norepinefrina/fisiologia , Animais , Transportador 2 de Aminoácido Excitatório/fisiologia , Ácido Glutâmico/fisiologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico
20.
Perspect Psychol Sci ; 13(6): 655-677, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30304640

RESUMO

Neuroeconomics is the study of the neurobiological bases of subjective preferences and choices. We present a novel framework that synthesizes findings from the literatures on neuroeconomics and creativity to provide a neurobiological description of creative cognition. We propose that value-based decision-making processes and activity in the locus ceruleus-norepinephrine (LC-NE) neuromodulatory system underlie creative cognition, as well as the large-scale brain network dynamics shown to be associated with creativity. This reconceptualization leads to several falsifiable hypotheses that can further understanding of creativity, decision making, and brain network dynamics.


Assuntos
Cognição/fisiologia , Criatividade , Encéfalo/fisiologia , Comportamento de Escolha/fisiologia , Tomada de Decisões/fisiologia , Humanos , Locus Cerúleo/fisiologia , Norepinefrina/fisiologia , Satisfação Pessoal , Receptores Adrenérgicos/fisiologia
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