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1.
Ann Palliat Med ; 10(10): 11074-11082, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34763469

RESUMO

BACKGROUND: γ-aminobutyric acid (GABA) is a naturally occurring non-protein amino acid in the nervous system and has a wide range of physiological functions in the body. Walnut peptide (WP) contains high levels of arginine, aspartic acid, and glutamate, and has been shown to improve cognitive deficits and memory impairment in mice, while restoring antioxidant enzyme levels and reducing brain inflammatory mediators. METHODS: This study investigated the effects of GABA and WP, either alone or in combination, on sleep disturbances in mice. The pentobarbital-prolonged sleep test, pentobarbital-threshold sleep test, and barbital-induced sleep test were conducted to assess the effects of GABA and WP on sleep quality by gavage for 30 days as follows: GABA (102.25 mg/kg), WP (102.25 mg/kg), GABA (33.95, 102.25, 306.75 mg/kg)/WP (102.25 mg/kg) mixture. Furthermore, neurotransmitter tests were performed using mice brain tissue to investigate the possible mechanisms of GABA and WP on sleep status. RESULTS: The results showed that the combined use of GABA and WP significantly increased sleep duration compared with single administration of either WP or GABA. Increasing doses of GABA in mice treated with combined GABA and WP elevated the sleep rate to 50.00%, 64.28%, and 64.28%, respectively, compared to mice treated with GABA alone (35.71%) or mice treated with WP alone (28.57%). In mice that received a combination of GABA and WP orally, the latency time was significantly decreased after 30 days compared to control mice (P<0.05). Additionally, in mice treated with GABA, WP, or the combination of GABA and WP, the concentrations of GABA and acetylcholine (Ach) in the brain were significantly elevated and the concentration of serotonin (5-HT) was decreased compared to untreated mice. CONCLUSIONS: These results demonstrated that the combined administration of GABA and WP could prolong the sleep duration, increase sleep rate, and shorten the sleep latency more effectively than the administration of either GABA or WP alone. The mechanisms of action may be related to the regulation of neurotransmitters in the brain tissue by the combination of GABA and WP.


Assuntos
Juglans , Animais , Camundongos , Pentobarbital , Peptídeos , Sono , Ácido gama-Aminobutírico
3.
Biomed Khim ; 67(5): 402-410, 2021 Sep.
Artigo em Russo | MEDLINE | ID: mdl-34730553

RESUMO

The closed enriched cross maze test was employed as a new experimental model of the attention deficit disorder (ADD) for evaluation of the behavioral and neurochemical effects of the nootropic drug pantogam (100 mg/kg, intraperitoneally) and atomoxetine hydrochloride (3 mg/kg, intraperitoneally) administered subchronically to CD-1 outbred mice. Two subpopulations of rodents differed spontaneously in attention to enriched compartments (ED-Low and ED-High), were estimated on the basis of time spent by the mice in the empty or enriched compartments. The ED-Low and ED-High mice insignificantly differed in parameters associated with anxiety, exploratory efficacy and motor activity. Subchronic administration of both drugs in selected doses produced corrective effect on animal behavior seen as a selective increase in the ED-ratio values in the ED-Low subpopulation. Differences in the distribution of dopamine D2 and GABAB receptors (Bmax) between placebo-treated ED-Low and ED-High mice were found in the prefrontal cortex using the radioligand binding method. The neuroreceptor effects of atomoxetine were seen in prefrontal cortex of ED-Low mice as decrease in the Bmax values of D2 receptors by 14%. Pantogam in the prefrontal cortex of ED-Low subpopulation showed a decrease in the Bmax values of D2 receptors by 22% and an increase for GABAB receptors by 44%. Therefore, subchronic administration of pantogam had a positive corrective effect on the behavior parameters and the density of the studied receptor subtypes in animals with severe attention deficit.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Animais , Cloridrato de Atomoxetina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Dopamina , Camundongos , Ácido Pantotênico/análogos & derivados , Ácido gama-Aminobutírico/análogos & derivados
4.
Transl Psychiatry ; 11(1): 529, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650032

RESUMO

Recent advances in the genetics of neurodevelopmental disorders (NDDs) have identified the transcription factor FOXP2 as one of numerous risk genes, e.g. in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). FOXP2 function is suggested to be involved in GABAergic signalling and numerous studies demonstrate that GABAergic function is altered in NDDs, thus disrupting the excitation/inhibition balance. Interestingly, GABAergic signalling components, including glutamate-decarboxylase 1 (Gad1) and GABA receptors, are putative transcriptional targets of FOXP2. However, the specific role of FOXP2 in the pathomechanism of NDDs remains elusive. Here we test the hypothesis that Foxp2 affects behavioural dimensions via GABAergic signalling using zebrafish as model organism. We demonstrate that foxp2 is expressed by a subset of GABAergic neurons located in brain regions involved in motor functions, including the subpallium, posterior tuberculum, thalamus and medulla oblongata. Using CRISPR/Cas9 gene-editing we generated a novel foxp2 zebrafish loss-of-function mutant that exhibits increased locomotor activity. Further, genetic and/or pharmacological disruption of Gad1 or GABA-A receptors causes increased locomotor activity, resembling the phenotype of foxp2 mutants. Application of muscimol, a GABA-A receptor agonist, rescues the hyperactive phenotype induced by the foxp2 loss-of-function. By reverse translation of the therapeutic effect on hyperactive behaviour exerted by methylphenidate, we note that application of methylphenidate evokes different responses in wildtype compared to foxp2 or gad1b loss-of-function animals. Together, our findings support the hypothesis that foxp2 regulates locomotor activity via GABAergic signalling. This provides one targetable mechanism, which may contribute to behavioural phenotypes commonly observed in NDDs.


Assuntos
Transtornos do Neurodesenvolvimento , Peixe-Zebra , Animais , Neurônios GABAérgicos , Locomoção , Ácido gama-Aminobutírico
5.
J Agric Food Chem ; 69(41): 12171-12186, 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34610747

RESUMO

Quinoa (Chenopodium quinoa Willd.) with a history of 5000 years as food is extremely rich in nutrients and bioactive compounds, including γ-aminobutyric acid (GABA), a natural four-carbon non-protein amino acid with great benefits to human health. In quinoa, GABA generally increases with the germination time, but the underlying molecular mechanism is unclear. Here, we found that the GABA content in quinoa varied significantly among 25 varieties using an automatic amino acid analyzer. Next, six varieties (three low-GABA and three high-GABA varieties) were used for further analyses. The content of GABA in six varieties all showed an increasing trend after germination. In addition, Pearson's correlation analysis showed that the changes in GABA content were closely related to the transcript level or enzyme activity of three key enzymes including glutamate decarboxylase (GAD), GABA transaminase (GABA-T), and succinate-semialdehyde dehydrogenase (SSADH) in the GABA shunt, especially GAD. Based on RNA-sequencing analysis, eight GAD genes, two GABA-T genes, one SSADH gene, nine polyamine oxidase (PAO) genes, five diamine oxidase (DAO) genes, four 4-aminobutyraldehyde dehydrogenase (BADH) genes, and three thermospermine synthase ACAULIS5 (ACL5) genes were identified. Among these, CqGAD8 and CqGABA-T2 may make a greater contribution to GABA accumulation during quinoa germination.


Assuntos
Chenopodium quinoa , Chenopodium quinoa/genética , Perfilação da Expressão Gênica , Germinação , Humanos , Nutrientes , Ácido gama-Aminobutírico
6.
Nat Commun ; 12(1): 5740, 2021 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-34593806

RESUMO

NG2 glia, also known as oligodendrocyte precursor cells (OPCs), play an important role in proliferation and give rise to myelinating oligodendrocytes during early brain development. In contrast to other glial cell types, the most intriguing aspect of NG2 glia is their ability to directly sense synaptic inputs from neurons. However, whether this synaptic interaction is bidirectional or unidirectional, or its physiological relevance has not yet been clarified. Here, we report that NG2 glia form synaptic complexes with hippocampal interneurons and that selective photostimulation of NG2 glia (expressing channelrhodopsin-2) functionally drives GABA release and enhances inhibitory synaptic transmission onto proximal interneurons in a microcircuit. The mechanism involves GAD67 biosynthesis and VAMP-2 containing vesicular exocytosis. Further, behavioral assays demonstrate that NG2 glia photoactivation triggers anxiety-like behavior in vivo and contributes to chronic social defeat stress.


Assuntos
Ansiedade/psicologia , Hipocampo/patologia , Células Precursoras de Oligodendrócitos/metabolismo , Estresse Psicológico/complicações , Ácido gama-Aminobutírico/metabolismo , Animais , Ansiedade/etiologia , Ansiedade/patologia , Diferenciação Celular , Modelos Animais de Doenças , Exocitose , Glutamato Descarboxilase/biossíntese , Hipocampo/citologia , Humanos , Interneurônios/patologia , Masculino , Camundongos , Camundongos Transgênicos , Técnicas de Patch-Clamp , Derrota Social , Estresse Psicológico/patologia , Estresse Psicológico/psicologia , Sinapses/patologia , Transmissão Sináptica/fisiologia , Proteína 2 Associada à Membrana da Vesícula/metabolismo
7.
Elife ; 102021 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622779

RESUMO

The brain has a remarkable capacity to acquire and store memories that can later be selectively recalled. These processes are supported by the hippocampus which is thought to index memory recall by reinstating information stored across distributed neocortical circuits. However, the mechanism that supports this interaction remains unclear. Here, in humans, we show that recall of a visual cue from a paired associate is accompanied by a transient increase in the ratio between glutamate and GABA in visual cortex. Moreover, these excitatory-inhibitory fluctuations are predicted by activity in the hippocampus. These data suggest the hippocampus gates memory recall by indexing information stored across neocortical circuits using a disinhibitory mechanism.


Assuntos
Hipocampo/fisiologia , Rememoração Mental , Neocórtex/fisiologia , Inibição Neural , Plasticidade Neuronal , Estimulação Acústica , Associação , Vias Auditivas/fisiologia , Percepção Auditiva , Mapeamento Encefálico , Sinais (Psicologia) , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/metabolismo , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Neocórtex/diagnóstico por imagem , Neocórtex/metabolismo , Estimulação Luminosa , Fatores de Tempo , Vias Visuais/fisiologia , Percepção Visual , Adulto Jovem , Ácido gama-Aminobutírico/metabolismo
8.
J Appl Clin Med Phys ; 22(11): 151-164, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34633758

RESUMO

PURPOSE: To evaluate the effectiveness of Kami Guibi-tang (KGT) in the treatment of mild cognitive impairment (MCI) using magnetic resonance imaging (MRI) on brain metabolites, neurotransmitter, and cerebral blood flow (CBF). METHODS: We randomly allocated a total of 30 MCI patients to a KGT (N = 16) or a placebo (N = 14) group and performed MRI scans before and after 24 weeks of treatment. The participants underwent brain magnetic resonance spectroscopy and MRI scans to obtain brain metabolites using Point-RESolved Spectroscopy (PRESS) single-voxel spectroscopy, gamma-aminobutyric acid (GABA) neurotransmitter using Mescher-Garwood PRESS, and CBF using pseudocontinuous arterial spin labeling sequences using a 3.0 Tesla MRI system. We analyzed metabolite and neurotransmitter levels and CBF using repeated-measure analysis of variance to evaluate between-subject group effect, within-subject treatment condition effect, and interaction of group by condition (group x condition). RESULTS: The GABA+/creatine (Cr) ratio values were not significantly different between the before and after treatment conditions. The glutamate complex/Cr ratio difference before and after treatment was lower in the KGT group than in the placebo group, but was not statistically significant (p = 0.077). The result of region of interest-based CBF measurement showed that CBF values were significantly lower after treatment at Cluster 2 for the KGT group (p = 0.003) and the placebo group (p = 0.011), at hippocampus for the KGT group (p = 0.004) and the placebo group (p = 0.008), and at the fusiform gyrus for the KGT group (p = 0.002). Furthermore, the absolute CBF difference before and after treatment in the fusiform gyrus was significantly lower in the KGT group than in the placebo group (p = 0.024). CONCLUSIONS: Although a KGT treatment of 24 weeks showed some significant impact on the level of CBF, the Korean version of the mini-mental state examination score was not significantly different between before and after treatment conditions, indicating that there was no memory function improvement after treatment in amnestic MCI patients. Therefore, further studies should be performed with a relatively larger population and extending the duration of the KGT treatment.


Assuntos
Disfunção Cognitiva , Encéfalo/diagnóstico por imagem , Circulação Cerebrovascular , Disfunção Cognitiva/tratamento farmacológico , Medicamentos de Ervas Chinesas , Humanos , Imageamento por Ressonância Magnética , Ácido gama-Aminobutírico
9.
Front Cell Infect Microbiol ; 11: 694443, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34490139

RESUMO

Postpartum depression (PPD) is a mental disorder that affects pregnant women around the world, with serious consequences for mothers, families, and children. Its pathogenesis remains unclear, and medications for treating PPD that can be used during lactation remain to be identified. 919 syrup (919 TJ) is a Chinese herbal medicine that has been shown to be beneficial in the treatment of postpartum depression in both clinical and experimental studies. The mechanism of action of 919 TJ is unclear. 919 syrup is ingested orally, making the potential interaction between the drug and the gut microbiome impossible to ignore. We therefore hypothesized that 919 syrup could improve the symptoms of postpartum depression by affecting the structure and function of the intestinal flora, thereby altering hippocampal metabolism. We compared changes in hippocampal metabolism, fecal metabolism, and intestinal microflora of control BALB/c mice, mice with induced untreated PPD, and mice with induced PPD treated with 919 TJ, and found that 4-aminobutyric acid (GABA) in the hippocampus corresponded with PPD behaviors. Based on changes in GABA levels, multiple key gut bacterial species (Mucispirillum schaedleri, Bifidobacterium pseudolongum, Desulfovibrio piger, Alloprevotella tannerae, Bacteroides sp.2.1.33B and Prevotella sp. CAG:755) were associated with PPD. Metabolic markers that may represent the function of the intestinal microbiota in mice with PPD were identified (Met-Arg, urocanic acid, thioetheramide-PC, L-pipecolic acid, and linoleoyl ethanolamide). The relationship between these factors is not a simple one-to-one correspondence, but more likely a network of staggered functions. We therefore believe that the composition and function of the entire intestinal flora should be emphasized in research studying the gut and PPD, rather than changes in the abundance of individual bacterial species. The introduction of this concept of "GutBalance" may help clarify the relationship between gut bacteria and systemic disease.


Assuntos
Depressão Pós-Parto , Microbioma Gastrointestinal , Animais , Bactérias , Bacteroidetes , Bifidobacterium , Depressão Pós-Parto/tratamento farmacológico , Desulfovibrio , Feminino , Ácido Glutâmico , Hipocampo , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Gravidez , Ácido gama-Aminobutírico
10.
ACS Chem Neurosci ; 12(19): 3567-3578, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34550670

RESUMO

Syringomyelia (SM) is primarily characterized by the formation of a fluid-filled cyst that forms in the parenchyma of the spinal cord following injury or other pathology. Recent omics studies in animal models have identified dysregulation of solute carriers, channels, transporters, and small molecules associated with osmolyte regulation during syrinx formation/expansion in the spinal cord. However, their connections to syringomyelia etiology are poorly understood. In this study, the biological functions of the potent osmolyte betaine and its associated solute carrier betaine/γ-aminobutyric acid (GABA) transporter 1 (BGT1) were studied in SM. First, a rat post-traumatic SM model was used to demonstrate that the BGT1 was primarily expressed in astrocytes in the vicinity of syrinxes. In an in vitro system, we found that astrocytes uptake betaine through BGT1 to regulate cell size under hypertonic conditions. Treatment with BGT1 inhibitors, especially NNC 05-2090, demonstrated midhigh micromolar range potency in vitro that reversed the osmoprotective effects of betaine. Finally, the specificity of these BGT1 inhibitors in the CNS was demonstrated in vivo, suggesting feasibility for targeting betaine transport in SM. In summary, these data provide an enhanced understanding of the role of betaine and its associated solute carrier BGT1 in cell osmoregulation and implicates the active role of betaine and BGT1 in syringomyelia progression.


Assuntos
Betaína , Siringomielia , Animais , Betaína/farmacologia , Proteínas da Membrana Plasmática de Transporte de GABA , Osmorregulação , Ratos , Ácido gama-Aminobutírico/metabolismo
11.
Int J Mol Sci ; 22(18)2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34575986

RESUMO

Amino acids, as nutrients, are expected to improve sleep disorders. This study aimed to evaluate the generation- and age-dependent sleep-improving effects of γ-aminobutyric acid (GABA) and 5-hydroxytryptophan (5-HTP) coadministration. The differentially expressed genes and generation-related behavior after the administration of a GABA/5-HTP mixture were measured in a Drosophila model, while age-related changes in gene expression and oxidative stress-related parameters were measured in a mouse model. The GABA/5-HTP-treated group showed significant behavioral changes compared to the other groups. Sequencing revealed that the GABA/5-HTP mixture influenced changes in nervous system-related genes, including those involved in the regulation of the expression of behavioral and synaptic genes. Additionally, total sleep time increased with age, and nighttime sleep time in the first- and third-generation flies was significantly different from that of the control groups. The GABA/5-HTP mixture induced significant changes in the expression of sleep-related receptors in both models. Furthermore, the GABA/5-HTP mixture reduced levels of ROS and ROS reaction products in an age-dependent manner. Therefore, the increase in behavioral changes caused by GABA/5-HTP mixture administration was effective in eliminating ROS activity across generations and ages.


Assuntos
5-Hidroxitriptofano/farmacologia , Aminoácidos/farmacologia , Locomoção/efeitos dos fármacos , Transtornos do Sono-Vigília/tratamento farmacológico , Ácido gama-Aminobutírico/farmacologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/genética , Envelhecimento/patologia , Animais , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Locomoção/fisiologia , Camundongos , Nutrientes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transtornos do Sono-Vigília/metabolismo , Transtornos do Sono-Vigília/patologia
12.
Nat Commun ; 12(1): 5457, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526505

RESUMO

GABAA receptors are vital for controlling neuronal excitability and can display significant levels of constitutive activity that contributes to tonic inhibition. However, the mechanisms underlying spontaneity are poorly understood. Here we demonstrate a strict requirement for ß3 subunit incorporation into receptors for spontaneous gating, facilitated by α4, α6 and δ subunits. The crucial molecular determinant involves four amino acids (GKER) in the ß3 subunit's extracellular domain, which interacts with adjacent receptor subunits to promote transition to activated, open channel conformations. Spontaneous activity is further regulated by ß3 subunit phosphorylation and by allosteric modulators including neurosteroids and benzodiazepines. Promoting spontaneous activity reduced neuronal excitability, indicating that spontaneous currents will alter neural network activity. This study demonstrates how regional diversity in GABAA receptor isoform, protein kinase activity, and neurosteroid levels, can impact on tonic inhibition through the modulation of spontaneous GABAA receptor gating.


Assuntos
Hipocampo/fisiologia , Ativação do Canal Iônico/fisiologia , Neurônios/fisiologia , Receptores de GABA-A/fisiologia , Algoritmos , Sequência de Aminoácidos , Animais , Células Cultivadas , Células HEK293 , Hipocampo/citologia , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Ativação do Canal Iônico/genética , Camundongos , Modelos Moleculares , Modelos Neurológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp/métodos , Conformação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/genética , Subunidades Proteicas/fisiologia , Ratos Sprague-Dawley , Receptores de GABA-A/química , Receptores de GABA-A/genética , Homologia de Sequência de Aminoácidos , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia
13.
Int J Mol Sci ; 22(18)2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34576299

RESUMO

γ-aminobutyric acid (GABA) is a non-protein amino acid involved in various physiological processes; it aids in the protection of plants against abiotic stresses, such as drought, heavy metals, and salinity. GABA tends to have a protective effect against drought stress in plants by increasing osmolytes and leaf turgor and reducing oxidative damage via antioxidant regulation. Guard cell GABA production is essential, as it may provide the benefits of reducing stomatal opening and transpiration and controlling the release of tonoplast-localized anion transporter, thus resulting in increased water-use efficiency and drought tolerance. We summarized a number of scientific reports on the role and mechanism of GABA-induced drought tolerance in plants. We also discussed existing insights regarding GABA's metabolic and signaling functions used to increase plant tolerance to drought stress.


Assuntos
Secas , Plantas/metabolismo , Estresse Fisiológico , Ácido gama-Aminobutírico/metabolismo , Transpiração Vegetal , Transdução de Sinais
14.
J Agric Food Chem ; 69(39): 11582-11591, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34555899

RESUMO

The ionotropic γ-aminobutyric acid (iGABA) receptor is commonly considered as a fast inhibitory channel and is an important insecticide target. Since 1990, RDL, LCCH3, and GRD have been successively isolated and found to be potential subunits of the insect iGABA receptor. More recently, one orphan gene named 8916 was found and considered to be another potential iGABA receptor subunit according to its amino acid sequence. However, little information about 8916 has been reported. Here, the 8916 subunit from Chilo suppressalis was studied to determine whether it can form part of a functional iGABA receptor by co-expressing this subunit with CsRDL1 or CsLCCH3 in the Xenopus oocyte system. Cs8916 or CsLCCH3 did not form functional ion channels when expressed alone. However, Cs8916 was able to form heteromeric ion channels when expressed with either CsLCCH3 or CsRDL1. The recombinant heteromeric Cs8916/LCCH3 channel was a cation-selective channel, which was sensitive to GABA or ß-alanine. The current of the Cs8916/LCCH3 channel was inhibited by dieldrin, endosulfan, fipronil, or ethiprole. In contrast, fluralaner, broflanilide, and avermectin showed little effect on the Cs8916/LCCH3 channel (IC50s > 10 000 nM). The Cs8916/RDL1 channel was sensitive to GABA, but was significantly different in EC50 and Imax for GABA to those of homomeric CsRDL1. Fluralaner, fipronil, or dieldrin showed antagonistic actions on Cs8916/RDL1. In conclusion, Cs8916 is a potential iGABA receptor subunit, which can interact with CsLCCH3 to generate a cation-selective channel that is sensitive to several insecticides. Also, as Cs8916/RDL1 has a higher EC50 than homomeric CsRDL1, Cs8916 may affect the physiological functions of CsRDL1 and therefore play a role in fine-tuning GABAergic signaling.


Assuntos
Inseticidas , Mariposas , Sequência de Aminoácidos , Animais , Inseticidas/farmacologia , Mariposas/metabolismo , Receptores de GABA/genética , Receptores de GABA/metabolismo , Receptores de GABA-A , Ácido gama-Aminobutírico
15.
FASEB J ; 35(10): e21930, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34533886

RESUMO

The orexinergic system delivers excitation for multiple brain centers to facilitate behavioral arousal, with its malfunction resulting in narcolepsy, somnolence, and notably, visual hallucinations. Since the circadian clock underlies the daily arousal, a timed coordination is expected between the orexin system and its target subcortical visual system, including the superior colliculus (SC). Here, we use a combination of electrophysiological, immunohistochemical, and molecular approaches across 24 h, together with the neuronal tract-tracing methods to investigate the daily coordination between the orexin system and the rodent SC. Higher orexinergic input was found to occur nocturnally in the superficial layers of the SC, in time for nocturnal silencing of spontaneous firing in this visual brain area. We identify autonomous daily and circadian expression of clock genes in the SC, which may underlie these day-night changes. Additionally, we establish the lateral hypothalamic origin of the orexin innervation to the SC and that the SC neurons robustly respond to orexin A via OX2 receptor in both excitatory and GABAA receptor-dependent inhibitory manners. Together, our evidence elucidates the combination of intrinsic and extrinsic clock mechanisms that shape the daily function of the visual layers of the SC.


Assuntos
Relógios Circadianos , Orexinas/metabolismo , Colículos Superiores/metabolismo , Visão Ocular/fisiologia , Animais , Relógios Circadianos/genética , Relógios Circadianos/fisiologia , Escuridão , Região Hipotalâmica Lateral/metabolismo , Masculino , Camundongos , Neurônios/metabolismo , Receptores de Orexina/metabolismo , Ratos , Ratos Sprague-Dawley , Ácido gama-Aminobutírico/metabolismo
16.
Neuron ; 109(19): 3088-3103.e5, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34582785

RESUMO

Single-cell gene expression technologies are powerful tools to study cell types in the human brain, but efforts have largely focused on cortical brain regions. We therefore created a single-nucleus RNA-sequencing resource of 70,615 high-quality nuclei to generate a molecular taxonomy of cell types across five human brain regions that serve as key nodes of the human brain reward circuitry: nucleus accumbens, amygdala, subgenual anterior cingulate cortex, hippocampus, and dorsolateral prefrontal cortex. We first identified novel subpopulations of interneurons and medium spiny neurons (MSNs) in the nucleus accumbens and further characterized robust GABAergic inhibitory cell populations in the amygdala. Joint analyses across the 107 reported cell classes revealed cell-type substructure and unique patterns of transcriptomic dynamics. We identified discrete subpopulations of D1- and D2-expressing MSNs in the nucleus accumbens to which we mapped cell-type-specific enrichment for genetic risk associated with both psychiatric disease and addiction.


Assuntos
Encéfalo/fisiologia , Núcleo Celular/genética , Núcleo Celular/fisiologia , Perfilação da Expressão Gênica , Rede Nervosa/fisiologia , Recompensa , Mapeamento Encefálico , Estudo de Associação Genômica Ampla , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Interneurônios/fisiologia , Transtornos Mentais/genética , Neurônios/fisiologia , Análise de Sequência de RNA , Transtornos Relacionados ao Uso de Substâncias/genética , Ácido gama-Aminobutírico/fisiologia
17.
Molecules ; 26(18)2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34576907

RESUMO

The assessment of greenness of analytical protocols is of great importance now to preserve the environment. Some studies have analyzed either only the neurotransmitters, dopamine, serotonin, glutamate, and gamma-aminobutyric acid (GABA), together or with other neurotransmitters and biomarkers. However, these methods have not been investigated for their greenness and were not compared with each other to find the optimum one. Therefore, this study aims to compare seven published chromatographic methods that analyzed the four neurotransmitters and their mixtures using the National Environmental Method Index, Analytical Eco-Scale Assessment (ESA), and Green Analytical Procedure Index (GAPI). As these methods cover both qualitative and quantitative aspects, they offer better transparency. Overall, GAPI showed maximum greenness throughout the analysis. Method 6 was proven to be the method of choice for analyzing the mixture, owing to its greenness, according to NEMI, ESA, and GAPI. Additionally, method 6 has a wide scope of application (13 components can be analyzed), high sensitivity (low LOQ values), and fast analysis (low retention times, especially for glutamate and GABA).


Assuntos
Dopamina , Ácido Glutâmico , Serotonina , Ácido gama-Aminobutírico , Química Verde , Neurotransmissores
18.
Sci Rep ; 11(1): 18566, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34535725

RESUMO

The primary motor cortex (M1) is crucial for motor learning; however, its interaction with other brain areas during motor learning remains unclear. We hypothesized that the fronto-parietal execution network (FPN) provides learning-related information critical for the flexible cognitive control that is required for practice. We assessed network-level changes during sequential finger tapping learning under speed pressure by combining magnetic resonance spectroscopy and task and resting-state functional magnetic resonance imaging. There was a motor learning-related increase in preparatory activity in the fronto-parietal regions, including the right M1, overlapping the FPN and sensorimotor network (SMN). Learning-related increases in M1-seeded functional connectivity with the FPN, but not the SMN, were associated with decreased GABA/glutamate ratio in the M1, which were more prominent in the parietal than the frontal region. A decrease in the GABA/glutamate ratio in the right M1 was positively correlated with improvements in task performance (p = 0.042). Our findings indicate that motor learning driven by cognitive control is associated with local variations in the GABA/glutamate ratio in the M1 that reflects remote connectivity with the FPN, representing network-level motor sequence learning formations.


Assuntos
Cognição , Córtex Motor/fisiologia , Destreza Motora , Ácido gama-Aminobutírico/metabolismo , Adolescente , Adulto , Feminino , Humanos , Aprendizagem , Masculino , Análise e Desempenho de Tarefas , Adulto Jovem
19.
Int J Mol Sci ; 22(18)2021 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-34576177

RESUMO

Eye-drop recombinant human nerve growth factor (ed-rhNGF) has proved to recover the retina and optic nerve damage in animal models, including the unilateral optic nerve crush (ONC), and to improve visual acuity in humans. These data, associated with evidence that ed-rhNGF stimulates the brain derived neurotrophic factor (BDNF) in retina and cortex, suggests that NGF might exert retino-fugal effects by affecting BDNF and its receptor TrkB. To address these questions, their expression and relationship with the GABAergic and glutamatergic transmission markers, GAD65 and GAD67, vesicular inhibitory amino acid transporter (VGAT), and vesicular glutamate transporters 1 and 2 (VGLUT-1 and VGLUT-2) were investigated in adult ONC rats contralateral and ipsilateral visual cortex (VCx). Ed-rhNGF recovers the ONC-induced alteration of GABAergic and glutamatergic markers in contralateral VCx, induces an upregulation of TrkB, which is positively correlated with BDNF precursor (proBDNF) decrease in both VCx sides, and strongly enhances TrkB+ cell soma and neuronal endings surrounded by GAD65 immuno-reactive afferents. These findings contribute to enlarging the knowledge on the mechanism of actions and cellular targets of exogenously administrated NGF, and suggest that ed-rhNGF might act by potentiating the activity-dependent TrkB expression in GAD+ cells in VCx following retina damage and/or ONC.


Assuntos
Fator de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/metabolismo , Animais , Western Blotting , Ensaio de Imunoadsorção Enzimática , Glutamato Descarboxilase/genética , Glutamato Descarboxilase/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Microscopia Confocal , Fator de Crescimento Neural/genética , Fatores de Crescimento Neural/genética , Ratos , Proteínas Recombinantes/metabolismo , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/genética , Proteínas Vesiculares de Transporte de Aminoácidos Inibidores/metabolismo , Córtex Visual/metabolismo , Córtex Visual/fisiologia , Ácido gama-Aminobutírico/metabolismo
20.
J R Soc Interface ; 18(182): 20210454, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34520693

RESUMO

In the suprachiasmatic nucleus (SCN), γ-aminobutyric acid (GABA) is a primary neurotransmitter. GABA can signal through two types of GABAA receptor subunits, often referred to as synaptic GABAA (gamma subunit) and extra-synaptic GABAA (delta subunit). To test the functional roles of these distinct GABAA in regulating circadian rhythms, we developed a multicellular SCN model where we could separately compare the effects of manipulating GABA neurotransmitter or receptor dynamics. Our model predicted that blocking GABA signalling modestly increased synchrony among circadian cells, consistent with published SCN pharmacology. Conversely, the model predicted that lowering GABAA receptor density reduced firing rate, circadian cell fraction, amplitude and synchrony among individual neurons. When we tested these predictions, we found that the knockdown of delta GABAA reduced the amplitude and synchrony of clock gene expression among cells in SCN explants. The model further predicted that increasing gamma GABAA densities could enhance synchrony, as opposed to increasing delta GABAA densities. Overall, our model reveals how blocking GABAA receptors can modestly increase synchrony, while increasing the relative density of gamma over delta subunits can dramatically increase synchrony. We hypothesize that increased gamma GABAA density in the winter could underlie the tighter phase relationships among SCN cells.


Assuntos
Núcleo Supraquiasmático , Ácido gama-Aminobutírico , Ritmo Circadiano , Neurônios , Receptores de GABA
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