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1.
Am J Physiol Regul Integr Comp Physiol ; 319(1): R123-R131, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32491938

RESUMO

Fetal heart rate (FHR) variability (FHRV) and ST segment morphology are potential clinical indices of fetal well-being during labor. ß-Adrenergic stimulation by circulating catecholamines has been hypothesized to contribute to both FHRV and ST segment morphology during labor, but this has not been tested during brief repeated fetal hypoxemia that is characteristic of labor. Near-term fetal sheep (0.85 gestation) received propranolol (ß-adrenergic blockade; n = 10) or saline (n = 7) 30 min before being exposed to three 2-min complete umbilical cord occlusions (UCOs) separated by 3-min reperfusions. T/QRS ratio was calculated throughout UCOs and reperfusion periods, and measures of FHRV (RMSSD, SDNN, and STV) were calculated between UCOs. During the baseline period, before the start of UCOs, propranolol was associated with reduced FHR, SDNN, and STV but did not affect RMSSD or T/QRS ratio. UCOs were associated with rapid FHR decelerations and increased T/QRS ratio; propranolol significantly reduced FHR during UCOs and was associated with a slower rise in T/QRS ratio during the first UCOs, without affecting the maximal rise or T/QRS ratio during the second and third UCO. Between UCOs propranolol reduced FHR and T/QRS ratio but did not affect any measure of FHRV. These data demonstrate that circulating catecholamines do not contribute to FHRV during labor-like hypoxemia. Furthermore, circulating catecholamines did not contribute to the major rise in T/QRS ratio during labor-like hypoxemia but may regulate T/QRS ratio between brief hypoxemia.


Assuntos
Catecolaminas/fisiologia , Frequência Cardíaca Fetal/fisiologia , Carneiro Doméstico/fisiologia , Cordão Umbilical/fisiologia , Agonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Adulto , Animais , Catecolaminas/sangue , Eletrocardiografia , Feminino , Hipóxia Fetal/fisiopatologia , Humanos , Hipóxia/fisiopatologia , Trabalho de Parto , Gravidez , Propranolol/farmacologia
2.
Curr Hypertens Rep ; 21(11): 90, 2019 10 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599352

RESUMO

PURPOSE OF REVIEW: The present paper will review the results of experimental and clinical studies aimed at defining the functional behavior of the central and peripheral nervous system in adrenal pheochromocytoma. RECENT FINDINGS: The contribution of sympathetic neural influences to the development of high blood pressure values in pheochromocytoma is complex. Studies performed in experimental animal models have shown that hypertension and the concomitant high circulating levels of catecholamines can lead to inhibition of central sympathetic neural outflow by reflex mechanisms and direct stimulation of central adrenergic receptors, respectively. However, these studies have also shown that high circulating levels of catecholamines favor a downregulation of alpha- and beta-adrenergic receptors, lessening their response to endogenous and exogenous adrenergic stimulation. The present paper reviews results of human studies performed by our group and others on the behavior of the central and peripheral nervous system in human pheochromocytoma. We discuss data collected in patients with different levels of peripheral sympathetic drive, i.e., before and after surgical removal of the adrenal pheochromocytoma. In the presence of elevated plasma catecholamine level, such as that characterizing adrenal pheochromocytoma, microneurography shows that central sympathetic neural activity is normal or even inhibited. At the peripheral vascular level, pheochromocytoma is characterized by a reduced vascular reactivity to exogenous sympathetic stimulation but a normal response by the vessels to endogenous adrenergic stimulation.


Assuntos
Neoplasias das Glândulas Suprarrenais/fisiopatologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Hipertensão/fisiopatologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Feocromocitoma/fisiopatologia , Sistema Nervoso Simpático/fisiopatologia , Neoplasias das Glândulas Suprarrenais/sangue , Neoplasias das Glândulas Suprarrenais/cirurgia , Animais , Doenças do Sistema Nervoso Autônomo/sangue , Catecolaminas/sangue , Catecolaminas/fisiologia , Sistema Nervoso Central/fisiopatologia , Humanos , Hipertensão/sangue , Hipertensão/etiologia , Doenças do Sistema Nervoso Periférico/sangue , Feocromocitoma/sangue , Feocromocitoma/cirurgia
3.
Dis Model Mech ; 12(11)2019 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-31615832

RESUMO

N-glycanase 1 (NGLY1) deficiency is an ultra-rare and complex monogenic glycosylation disorder that affects fewer than 40 patients globally. NGLY1 deficiency has been studied in model organisms such as yeast, worms, flies and mice. Proteasomal and mitochondrial homeostasis gene networks are controlled by the evolutionarily conserved transcriptional regulator NRF1, whose activity requires deglycosylation by NGLY1. Hypersensitivity to the proteasome inhibitor bortezomib is a common phenotype observed in whole-animal and cellular models of NGLY1 deficiency. Here, we describe unbiased phenotypic drug screens to identify FDA-approved drugs that are generally recognized as safe natural products, and novel chemical entities, that rescue growth and development of NGLY1-deficient worm and fly larvae treated with a toxic dose of bortezomib. We used image-based larval size and number assays for use in screens of a 2560-member drug-repurposing library and a 20,240-member lead-discovery library. A total of 91 validated hit compounds from primary invertebrate screens were tested in a human cell line in an NRF2 activity assay. NRF2 is a transcriptional regulator that regulates cellular redox homeostasis, and it can compensate for loss of NRF1. Plant-based polyphenols make up the largest class of hit compounds and NRF2 inducers. Catecholamines and catecholamine receptor activators make up the second largest class of hits. Steroidal and non-steroidal anti-inflammatory drugs make up the third largest class. Only one compound was active in all assays and species: the atypical antipsychotic and dopamine receptor agonist aripiprazole. Worm and fly models of NGLY1 deficiency validate therapeutic rationales for activation of NRF2 and anti-inflammatory pathways based on results in mice and human cell models, and suggest a novel therapeutic rationale for boosting catecholamine levels and/or signaling in the brain.


Assuntos
Catecolaminas/fisiologia , Defeitos Congênitos da Glicosilação/etiologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Inflamação/prevenção & controle , Fator 2 Relacionado a NF-E2/fisiologia , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/deficiência , Animais , Bortezomib/farmacologia , Dípteros , Descoberta de Drogas , Humanos , Proteína 1 Associada a ECH Semelhante a Kelch/fisiologia , Nematoides , Transdução de Sinais/fisiologia
4.
Brain Behav Immun ; 81: 111-121, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31176001

RESUMO

PURPOSE: Elevated catecholamines in the tumor microenvironment often correlate with tumor development. However, the mechanisms by which catecholamines modulate lung cancer growth are still poorly understood. This study is aimed at examining the functions and mechanisms of catecholamine-induced macrophage polarization in angiogenesis and tumor development. EXPERIMENTAL DESIGN: We established in vitro and in vivo models to investigate the relationship between catecholamines and macrophages in lung cancer. Flow cytometry, cytokine detection, tube formation assay, immunofluorescence, and western blot analysis were performed, and animal models were also used to explore the underlying mechanism of catecholamine-induced macrophage polarization and host immunological response. RESULTS: Catecholamines were shown to be secreted into tumor under the control of the sympathetic nerve system to maintain the pro-tumoral microenvironment. In vivo, the chemical depletion of the natural catecholamine stock with 6OHDA could reduce the release of catecholamines within tumor tissues, restrain the function of alternatively activated M2 macrophage, attenuate tumor neovascularization, and inhibit tumor growth. In vitro, catecholamine treatment triggered the M2 polarization of macrophages, enhanced the expression of VEGF, promoted tumor angiogenesis, and these catecholamine-stimulated effects could be reversed by the adrenergic receptor antagonist propranolol. In addition to regulating tumor-associated macrophages (TAM) recruitment, decreasing catecholamine levels could also shift the immunosuppressive microenvironment by decreasing myeloid-derived suppressor cells' (MDSCs) recruitment and facilitating dendritic cells' (DCs) activation, potentially resulting in a positive antitumor immune response. CONCLUSION: Our study demonstrates the potential of adrenergic stress and catecholamine-driven adrenergic signaling of TAMs to regulate the immune status of a tumor microenvironment and provides promising targets for anticancer therapies.


Assuntos
Catecolaminas/metabolismo , Neoplasias Pulmonares/metabolismo , Neovascularização Patológica/fisiopatologia , Animais , Catecolaminas/fisiologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Citocinas/metabolismo , Humanos , Ativação de Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Transdução de Sinais , Microambiente Tumoral
5.
Artigo em Inglês | MEDLINE | ID: mdl-31096708

RESUMO

Hormones are secreted in a circadian rhythm, but also follow larger-scale timetables, such as monthly (hormones of the menstrual cycle), seasonal (i.e., winter, summer), and, ultimately, lifespan-related patterns. Several contexts modulate their secretion, such as genetics, lifestyle, environment, diet, and exercise. They play significant roles in human physiology, influencing growth of muscle, bone, and regulating metabolism. Exercise training alters hormone secretion, depending on the frequency, duration, intensity, and mode of training which has an impact on the magnitude of the secretion. However, there remains ambiguity over the effects of exercise training on certain hormones such as glucoregulatory hormones in aging adults. With advancing age, there are many alterations with the endocrine system, which may ultimately alter human physiology. Some recent studies have reported an anti-aging effect of exercise training on the endocrine system and especially cortisol, growth hormone and insulin. As such, this review examines the effects of endurance, interval, resistance and combined training on hormones (i.e., at rest and after) exercise in older individuals. We summarize the influence of age on glucoregulatory hormones, the influence of exercise training, and where possible, examine masters' athletes' endocrinological profile.


Assuntos
Envelhecimento/fisiologia , Exercício Físico/fisiologia , Catecolaminas/fisiologia , Glucagon/fisiologia , Humanos , Hidrocortisona/fisiologia , Insulina/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia
6.
J Cogn Neurosci ; 31(7): 1044-1053, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30883291

RESUMO

Recent behavioral modeling and pupillometry studies suggest that neuromodulatory arousal systems play a role in regulating decision formation but neurophysiological support for these observations is lacking. We employed a randomized, double-blinded, placebo-controlled, crossover design to probe the impact of pharmacological enhancement of catecholamine levels on perceptual decision-making. Catecholamine levels were manipulated using the clinically relevant drugs methylphenidate and atomoxetine, and their effects were compared with those of citalopram and placebo. Participants performed a classic EEG oddball paradigm that elicits the P3b, a centro-parietal potential that has been shown to trace evidence accumulation, under each of the four drug conditions. We found that methylphenidate and atomoxetine administration shortened RTs to the oddball targets. The neural basis of this behavioral effect was an earlier P3b peak latency, driven specifically by an increase in its buildup rate without any change in its time of onset or peak amplitude. This study provides neurophysiological evidence for the catecholaminergic enhancement of a discrete aspect of human decision-making, that is, evidence accumulation. Our results also support theoretical accounts suggesting that catecholamines may enhance cognition via increases in neural gain.


Assuntos
Encéfalo/fisiologia , Catecolaminas/fisiologia , Tomada de Decisões/fisiologia , Percepção Visual/fisiologia , Adolescente , Inibidores da Captação Adrenérgica/administração & dosagem , Adulto , Cloridrato de Atomoxetina/administração & dosagem , Encéfalo/efeitos dos fármacos , Citalopram/administração & dosagem , Estudos Cross-Over , Tomada de Decisões/efeitos dos fármacos , Inibidores da Captação de Dopamina/administração & dosagem , Método Duplo-Cego , Eletroencefalografia , Potenciais Evocados Visuais/efeitos dos fármacos , Humanos , Masculino , Metilfenidato/administração & dosagem , Pessoa de Meia-Idade , Inibidores de Captação de Serotonina/administração & dosagem , Percepção Visual/efeitos dos fármacos , Adulto Jovem
7.
J Med Biogr ; 27(3): 179-183, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30848165

RESUMO

Hermann (Hugh) Blaschko was a biochemical pharmacologist best known for discovering how adrenaline (epinephrine), noradrenaline (norepinephrine), and dopamine were synthesized, stored, and metabolized in adrenomedullary cells and sympathetic nerves. Blaschko's work not only supported the validity of the concept of neurochemical synaptic transmission but he also made fundamental contributions to the development of drugs used in clinical medicine to treat diseases such as depression, hypertension, and Parkinson's Disease.


Assuntos
Bioquímica/história , Medicina Clínica/história , Farmacologia/história , Catecolaminas/história , Catecolaminas/fisiologia , Inglaterra , Alemanha , História do Século XX , Transmissão Sináptica/fisiologia
8.
Eur Heart J ; 40(15): 1183-1187, 2019 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-30831580

RESUMO

AIMS: Takotsubo syndrome (TTS) is characterized by acute left ventricular dysfunction often triggered by emotional or physical stress. Severe activation of the sympathetic nervous system with catecholamine release caused by a dysfunctional limbic system has been proposed as a potential mechanism. We hypothesize that brain regions responsible for autonomic integration and/or limbic processing might be involved in the development of TTS. Here, we investigated alterations in resting state functional connectivity in TTS patients compared with healthy controls. METHODS AND RESULTS: Using brain functional magnetic resonance imaging (fMRI), resting state functional connectivity has been assessed in 15 subjects with TTS and 39 healthy controls. Network-based statistical analyses were conducted to identify subnetworks with altered resting state functional connectivity. Sympathetic and parasympathetic networks have been constructed in addition to the default mode network and whole-brain network. We found parasympathetic- and sympathetic-associated subnetworks both showing reduced resting state functional connectivity in TTS patients compared with controls. Important brain regions constituting parasympathetic- and sympathetic-associated subnetworks included the amygdala, hippocampus, and insula as well as cingulate, parietal, temporal, and cerebellar regions. Additionally, the default mode network as well as limbic regions in the whole-brain analysis demonstrated reduced resting state functional connectivity in TTS, including the hippocampus, parahippocampal, and medial prefrontal regions. CONCLUSION: For the first time, we demonstrate hypoconnectivity of central brain regions associated with autonomic functions and regulation of the limbic system in patients with TTS. These findings suggest that autonomic-limbic integration might play an important role in the pathophysiology and contribute to the understanding of TTS.


Assuntos
Encéfalo/fisiopatologia , Sistema Límbico/fisiopatologia , Cardiomiopatia de Takotsubo/fisiopatologia , Adulto , Sistema Nervoso Autônomo/fisiopatologia , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Catecolaminas/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Redes Neurais de Computação , Disfunção Ventricular Esquerda/fisiopatologia
10.
Brain Res ; 1702: 54-73, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29705605

RESUMO

The success of anti-retroviral therapy has improved the quality of life and lifespan of HIV + individuals, transforming HIV infection into a chronic condition. These improvements have come with a cost, as chronic HIV infection and long-term therapy have resulted in the emergence of a number of new pathologies. This includes a variety of the neuropathological and neurocognitive effects collectively known as HIVassociated neurocognitive disorders (HAND) or NeuroHIV. These effects persist even in the absence of viral replication, suggesting that they are mediated the long-term changes in the CNS induced by HIV infection rather than by active replication. Among these effects are significant changes in catecholaminergic neurotransmission, especially in dopaminergic brain regions. In HIV-infected individuals not treated with ARV show prominent neuropathology is common in dopamine-rich brain regions and altered autonomic nervous system activity. Even infected individuals on therapy, there is significant dopaminergic neuropathology, and elevated stress and norepinephrine levels correlate with a decreased effectiveness of antiretroviral drugs. As catecholamines function as immunomodulatory factors, the resultant dysregulation of catecholaminergic tone could substantially alter the development of HIVassociated neuroinflammation and neuropathology. In this review, we discuss the role of catecholamines in the etiology of HIV neuropathogenesis. Providing a comprehensive examination of what is known about these molecules in the context of HIV-associated disease demonstrates the importance of further studies in this area, and may open the door to new therapeutic strategies that specifically ameliorate the effects of catecholaminergic dysregulation on NeuroHIV.


Assuntos
Catecolaminas/metabolismo , Infecções por HIV/metabolismo , Doenças do Sistema Nervoso/metabolismo , Catecolaminas/fisiologia , Dopamina/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Humanos , Macrófagos/efeitos dos fármacos , Monócitos/efeitos dos fármacos , Receptores Adrenérgicos beta/metabolismo
12.
Adv Exp Med Biol ; 1090: 199-210, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30390292

RESUMO

Lipolysis is a critical process to hydrolyze triglyceride in adipose tissue, thereby breaking down the stored lipid and maintaining energy homeostasis. Recent studies have made significant progress in understanding the steps of lipolysis. This chapter discusses the major pathways that regulate lipolysis in adipose tissue. Specifically we focus on the mechanisms by which the activities of critical lipolytic enzymes are regulated. We further discuss how the lipolysis is regulated by other factors, including insulin and neurotransmitters, in particular catecholamines and the role of sympathetic nervous system in the whole process. Finally we provide clinical perspectives about the novel therapeutic strategies to target or promote adipose tissue lipolysis for treatment/prevention of obesity and type 2 diabetes.


Assuntos
Tecido Adiposo/fisiologia , Lipólise , Catecolaminas/fisiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Metabolismo Energético , Homeostase , Humanos , Lipase/metabolismo , Obesidade/prevenção & controle , Sistema Nervoso Simpático/fisiologia , Triglicerídeos/metabolismo
13.
J Comp Neurol ; 526(14): 2319-2338, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30325514

RESUMO

The nucleus of the solitary tract is a potential site for taste-visceral interactions. Connections from the caudal, visceral area of the nucleus (cNST) to the rostral, gustatory zone (rNST) have been described, but the phenotype of cells giving rise to the projection(s) and their distribution among rNST subdivisions are unknown. To determine these characteristics of the intrasolitary pathway, we injected pan-neuronal and floxed AAV viruses into the cNST of mice expressing cre in glutamatergic, GABAergic, or catecholaminergic neurons. Particular attention was paid to the terminal field distribution in rNST subdivisions by simultaneously visualizing P2X2 localized to gustatory afferent terminals. All three phenotypically identified pathways terminated in rNST, with the density greatest for glutamatergic and sparsest for catecholaminergic projections, observations supported by retrograde tracing. Interestingly, cNST neurons had more prominent projections to rNST regions medial and ventral to P2X2 staining, i.e., the medial and ventral subdivisions. In addition, GABAergic neurons projected robustly to the lateral subdivision and adjacent parts of the reticular formation and spinal trigeminal nucleus. Although cNST neurons also projected to the P2X2-rich central subdivision, such projections were sparser. These findings suggest that cNST visceral signals exert stronger excitatory and inhibitory influences on local autonomic and reflex pathways associated with the medial and ventral subdivisions compared to weaker modulation of ascending pathways arising from the central subdivision and ultimately destined for the forebrain.


Assuntos
Neurônios/fisiologia , Núcleo Solitário/citologia , Animais , Catecolaminas/fisiologia , Feminino , Ácido Glutâmico/fisiologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Neurônios Aferentes/fisiologia , Prosencéfalo/citologia , Prosencéfalo/fisiologia , Receptores Purinérgicos P2X2/metabolismo , Paladar/fisiologia , Ácido gama-Aminobutírico/fisiologia
14.
Brain Res ; 1701: 177-188, 2018 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30217439

RESUMO

Vocal species use acoustic signals to facilitate diverse behaviors such as mate attraction and territorial defense. However, little is known regarding the neural substrates that interpret such divergent conspecific signals. Using the plainfin midshipman fish model, we tested whether specific catecholaminergic (i.e., dopaminergic and noradrenergic) nuclei and nodes of the social behavior network (SBN) are differentially responsive following exposure to playbacks of divergent social signals in sneaker males. We chose sneaker (type II) males since they attempt to steal fertilizations from territorial type I males who use an advertisement call (hum) to attract females yet are also subjected to vocal agonistic behavior (grunts) by type I males. We demonstrate that induction of cFos (an immediate early gene product and proxy for neural activation) in two forebrain dopaminergic nuclei is greater in sneaker males exposed to hums but not grunts compared to ambient noise, suggesting hums preferentially activate these nuclei, further asserting dopamine as an important regulator of social-acoustic behaviors. Moreover, acoustic exposure to social signals with divergent salience engendered contrasting shifts in functional connectivity between dopaminergic nuclei and nodes of the SBN, supporting the idea that interactions between these two circuits may underlie adaptive decision-making related to intraspecific male competition.


Assuntos
Batracoidiformes/fisiologia , Neurônios Dopaminérgicos/fisiologia , Comportamento Sexual Animal/fisiologia , Estimulação Acústica/métodos , Neurônios Adrenérgicos/fisiologia , Animais , Percepção Auditiva/fisiologia , Batracoidiformes/metabolismo , Catecolaminas/fisiologia , Núcleo Celular , Audição/fisiologia , Masculino , Reprodução/fisiologia , Comportamento Social , Vocalização Animal/fisiologia
15.
Arq Bras Cir Dig ; 31(3): e1383, 2018 Aug 16.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30133675

RESUMO

BACKGROUND: The role of autonomic nervous system in the development and maintenance of portal hypertension is not fully elucidated. It is known that the gene expression of norepinephrine in the superior mesenteric artery varies with time, and it may contribute for splanchnic vasodilation and its consequent hemodynamic repercussions. It is still not known exactly how the adrenergic expression behaves at the heart level in the initial stages of this process. AIM: To evaluate the immunohistochemical expression of the enzyme tyrosine hydroxylase (tyrosine 3-monooxygenase), involved in the synthesis of norepinephrine, in the myocardium of rats submitted to partial ligation of the portal vein. METHODS: Twenty-four Wistar rats were divided into two groups: Sham Operated and Portal Hypertension. The partial ligation was performed in the Portal Hypertension group, and after 1/6/24 h and 3/5/14 days the animals were euthanized. Immunohistochemical analysis was performed to quantify the expression of the stained enzyme using the ImageJ program. RESULTS: The Portal Hypertension group expressed percentages between 4.6-6% of the marked area, while the Sham Operated group varied between 4-5%. Although there was no statistical significance, the percentage stained in the Portal Hypertension group followed an increasing pattern in the first 6 h and a decreasing pattern after 24 h, which was not observed in the Sham Operated group. CONCLUSION: The expression of noradrenaline in rat myocardium during the first two weeks after partial ligation of the portal vein, with tyrosine hydroxylase as marker, did not show differences between groups over time.


Assuntos
Hipertensão Portal/etiologia , Miocárdio/metabolismo , Norepinefrina/biossíntese , Animais , Catecolaminas/fisiologia , Modelos Animais de Doenças , Masculino , Norepinefrina/fisiologia , Ratos , Ratos Wistar , Tirosina 3-Mono-Oxigenase/biossíntese
16.
ISME J ; 12(11): 2736-2747, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29995838

RESUMO

The microorganisms in the gastrointestinal (GI) tract can influence the metabolism, immunity, and behavior of animal hosts. Increasing evidence suggests that communication between the host and the microbiome also occurs in the opposite direction, with hormones and other host-secreted compounds being sensed by microorganisms. Here, we addressed one key aspect of the host-microbe communication by studying chemotaxis of a model commensal bacterium, Escherichia coli, to several compounds present abundantly in the GI tract, namely catecholamines, thyroid hormones, and polyamines. Our results show that E. coli reacts to five out of ten analyzed chemicals, sensing melatonin, and spermidine as chemorepellents and showing mixed responses to dopamine, norepinephrine and 3,4-dihydroxymandelic acid. The strongest repellent response was observed for the polyamine spermidine, and we demonstrate that this response involves the low-abundance chemoreceptor Trg and the periplasmic binding protein PotD of the spermidine uptake system. The chemotactic effects of the tested compounds apparently correlate with their influence on growth and their stability in the GI tract, pointing to the specificity of the observed behavior. We hypothesize that the repellent responses observed at high concentrations of chemoeffective compounds might enable bacteria to avoid harmful levels of hormones and polyamines in the gut and, more generally, antimicrobial activities of the mucous layer.


Assuntos
Catecolaminas/fisiologia , Quimiotaxia , Escherichia coli/fisiologia , Poliaminas , Hormônios Tireóideos/fisiologia , Proteínas de Escherichia coli/fisiologia , Trato Gastrointestinal/química , Humanos , Proteínas de Membrana/fisiologia , Proteínas de Membrana Transportadoras/fisiologia , Proteínas Periplásmicas de Ligação/fisiologia , Espermidina/metabolismo
17.
J Neurosci ; 38(34): 7476-7491, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30037827

RESUMO

The widely projecting catecholaminergic (norepinephrine and dopamine) neurotransmitter systems profoundly shape the state of neuronal networks in the forebrain. Current models posit that the effects of catecholaminergic modulation on network dynamics are homogeneous across the brain. However, the brain is equipped with a variety of catecholamine receptors with distinct functional effects and heterogeneous density across brain regions. Consequently, catecholaminergic effects on brainwide network dynamics might be more spatially specific than assumed. We tested this idea through the analysis of fMRI measurements performed in humans (19 females, 5 males) at "rest" under pharmacological (atomoxetine-induced) elevation of catecholamine levels. We used a linear decomposition technique to identify spatial patterns of correlated fMRI signal fluctuations that were either increased or decreased by atomoxetine. This yielded two distinct spatial patterns, each expressing reliable and specific drug effects. The spatial structure of both fluctuation patterns resembled the spatial distribution of the expression of catecholamine receptor genes: α1 norepinephrine receptors (for the fluctuation pattern: placebo > atomoxetine), D2-like dopamine receptors (pattern: atomoxetine > placebo), and ß norepinephrine receptors (for both patterns, with correlations of opposite sign). We conclude that catecholaminergic effects on the forebrain are spatially more structured than traditionally assumed and at least in part explained by the heterogeneous distribution of various catecholamine receptors. Our findings link catecholaminergic effects on large-scale brain networks to low-level characteristics of the underlying neurotransmitter systems. They also provide key constraints for the development of realistic models of neuromodulatory effects on large-scale brain network dynamics.SIGNIFICANCE STATEMENT The catecholamines norepinephrine and dopamine are an important class of modulatory neurotransmitters. Because of the widespread and diffuse release of these neuromodulators, it has commonly been assumed that their effects on neural interactions are homogeneous across the brain. Here, we present results from the human brain that challenge this view. We pharmacologically increased catecholamine levels and imaged the effects on the spontaneous covariations between brainwide fMRI signals at "rest." We identified two distinct spatial patterns of covariations: one that was amplified and another that was suppressed by catecholamines. Each pattern was associated with the heterogeneous spatial distribution of the expression of distinct catecholamine receptor genes. Our results provide novel insights into the catecholaminergic modulation of large-scale human brain dynamics.


Assuntos
Encéfalo/fisiologia , Catecolaminas/fisiologia , Conectoma , Inibidores da Captação Adrenérgica/farmacologia , Cloridrato de Atomoxetina/farmacologia , Química Encefálica , Estudos Cross-Over , Conjuntos de Dados como Assunto , Método Duplo-Cego , Feminino , Neuroimagem Funcional , Humanos , Imagem por Ressonância Magnética , Masculino , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Receptores de Catecolaminas/análise , Receptores de Catecolaminas/genética , Descanso
19.
PLoS Biol ; 16(2): e2003453, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29420565

RESUMO

The ascending modulatory systems of the brain stem are powerful regulators of global brain state. Disturbances of these systems are implicated in several major neuropsychiatric disorders. Yet, how these systems interact with specific neural computations in the cerebral cortex to shape perception, cognition, and behavior remains poorly understood. Here, we probed into the effect of two such systems, the catecholaminergic (dopaminergic and noradrenergic) and cholinergic systems, on an important aspect of cortical computation: its intrinsic variability. To this end, we combined placebo-controlled pharmacological intervention in humans, recordings of cortical population activity using magnetoencephalography (MEG), and psychophysical measurements of the perception of ambiguous visual input. A low-dose catecholaminergic, but not cholinergic, manipulation altered the rate of spontaneous perceptual fluctuations as well as the temporal structure of "scale-free" population activity of large swaths of the visual and parietal cortices. Computational analyses indicate that both effects were consistent with an increase in excitatory relative to inhibitory activity in the cortical areas underlying visual perceptual inference. We propose that catecholamines regulate the variability of perception and cognition through dynamically changing the cortical excitation-inhibition ratio. The combined readout of fluctuations in perception and cortical activity we established here may prove useful as an efficient and easily accessible marker of altered cortical computation in neuropsychiatric disorders.


Assuntos
Catecolaminas/fisiologia , Córtex Cerebral/fisiologia , Percepção Visual/fisiologia , Inibidores da Captação Adrenérgica/farmacologia , Cloridrato de Atomoxetina/farmacologia , Mapeamento Encefálico , Córtex Cerebral/efeitos dos fármacos , Humanos , Magnetoencefalografia/métodos , Modelos Neurológicos , Estimulação Luminosa , Placebos , Psicofísica
20.
Memory ; 26(3): 364-376, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-28625108

RESUMO

Stressful events have a major impact on memory. They modulate memory formation in a time-dependent manner, closely linked to the temporal profile of action of major stress mediators, in particular catecholamines and glucocorticoids. Shortly after stressor onset, rapidly acting catecholamines and fast, non-genomic glucocorticoid actions direct cognitive resources to the processing and consolidation of the ongoing threat. In parallel, control of memory is biased towards rather rigid systems, promoting habitual forms of memory allowing efficient processing under stress, at the expense of "cognitive" systems supporting memory flexibility and specificity. In this review, we discuss the implications of this shift in the balance of multiple memory systems for the dynamics of the memory trace. Specifically, stress appears to hinder the incorporation of contextual details into the memory trace, to impede the integration of new information into existing knowledge structures, to impair the flexible generalisation across past experiences, and to hamper the modification of memories in light of new information. Delayed, genomic glucocorticoid actions might reverse the control of memory, thus restoring homeostasis and "cognitive" control of memory again.


Assuntos
Memória/fisiologia , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Animais , Encéfalo/fisiologia , Catecolaminas/fisiologia , Glucocorticoides/fisiologia , Humanos
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