RESUMEN
Paired-pulse transcranial magnetic stimulation is a valuable tool for investigating inhibitory mechanisms in motor cortex. We recently demonstrated its use in measuring cortical inhibition in visual cortex, using an approach in which participants trace the size of phosphenes elicited by stimulation to occipital cortex. Here, we investigate age-related differences in primary visual cortical inhibition and the relationship between primary visual cortical inhibition and local GABA+ in the same region, estimated using magnetic resonance spectroscopy. GABA+ was estimated in 28 young (18 to 28 years) and 47 older adults (65 to 84 years); a subset (19 young, 18 older) also completed a paired-pulse transcranial magnetic stimulation session, which assessed visual cortical inhibition. The paired-pulse transcranial magnetic stimulation measure of inhibition was significantly lower in older adults. Uncorrected GABA+ in primary visual cortex was also significantly lower in older adults, while measures of GABA+ that were corrected for the tissue composition of the magnetic resonance spectroscopy voxel were unchanged with age. Furthermore, paired-pulse transcranial magnetic stimulation-measured inhibition and magnetic resonance spectroscopy-measured tissue-corrected GABA+ were significantly positively correlated. These findings are consistent with an age-related decline in cortical inhibition in visual cortex and suggest paired-pulse transcranial magnetic stimulation effects in visual cortex are driven by GABAergic mechanisms, as has been demonstrated in motor cortex.
Asunto(s)
Envejecimiento , Espectroscopía de Resonancia Magnética , Inhibición Neural , Estimulación Magnética Transcraneal , Corteza Visual , Ácido gamma-Aminobutírico , Humanos , Estimulación Magnética Transcraneal/métodos , Adulto , Anciano , Masculino , Femenino , Adulto Joven , Espectroscopía de Resonancia Magnética/métodos , Inhibición Neural/fisiología , Ácido gamma-Aminobutírico/metabolismo , Anciano de 80 o más Años , Adolescente , Envejecimiento/fisiología , Corteza Visual/fisiología , Corteza Visual/diagnóstico por imagenRESUMEN
Bestrophin-1 (Best1) is an anion channel genetically linked to vision-threatening retinal degenerative channelopathies. Here, we identify interactions between Best1 and both isoforms of glutamic acid decarboxylases (GAD65 and GAD67), elucidate the distinctive influences of GAD65 and GAD67 on Best1's permeability to various anions/neurotransmitters, discover the functionality of Best1 as a γ-Aminobutyric acid (GABA) type A receptor, and solve the structure of GABA-bound Best1. GAD65 and GAD67 both promote Best1-mediated Cl- currents, but only GAD65 drastically enhances the permeability of Best1 to glutamate and GABA, for which GAD67 has no effect. GABA binds to Best1 on an extracellular site and stimulates Best1-mediated Cl- currents at the nano-molar concentration level. The physiological role of GAD65 as a cell type-specific binding partner and facilitator of Best1 is demonstrated in retinal pigment epithelial cells. Together, our results reveal critical regulators of Best1 and inform a network of membrane transport metabolons formed between bestrophin channels and glutamate metabolic enzymes.
Asunto(s)
Bestrofinas , Glutamato Descarboxilasa , Ácido Glutámico , Ácido gamma-Aminobutírico , Glutamato Descarboxilasa/metabolismo , Glutamato Descarboxilasa/genética , Bestrofinas/metabolismo , Bestrofinas/genética , Humanos , Ácido gamma-Aminobutírico/metabolismo , Ácido Glutámico/metabolismo , Células HEK293 , Animales , Epitelio Pigmentado de la Retina/metabolismo , Neurotransmisores/metabolismo , Unión Proteica , Receptores de GABA-A/metabolismo , Receptores de GABA-A/genéticaRESUMEN
BACKGROUND: High GABA levels and its conversion to succinate via the GABA shunt are known to be associated with abiotic and biotic stress tolerance in plants. The exact mode of action is still under debate and it is not yet clear whether GABA is a common component of the plant stress defense process or not. We hypothesized that if it is a common route for stress tolerance, activation of GABA-shunt by a biotic stressor might also function in increased abiotic stress tolerance. To test this, Brassica napus plants treated with Flagellin-22 (Flg-22) were exposed to drought stress and the differences in GABA levels along with GABA-shunt components (biosynthetic and catabolic enzyme activities) in the leaf and root samples were compared. In order to provide a better outlook, MYC2, MPK6 and ZAT12, expression profiles were also analyzed since these genes were recently proposed to function in abiotic and biotic stress tolerance. RESULTS: Briefly, we found that Flg treatment increased drought stress tolerance in B. napus via GABA-shunt and the MAPK cascade was involved while the onset was different between leaves and roots. Flg treatment promoted GABA biosynthesis with increased GABA content and GAD activity in the leaves. Better performance of the Flg treated plants under drought stress might be dependent on the activation of GABA-shunt which provides succinate to TCA since GABA-T and SSADH activities were highly induced in the leaves and roots. In the transcript analysis, Flg + drought stressed groups had higher MYC2 transcript abundances correlated well with the GABA content and GABA-shunt while, MPK6 expression was induced only in the roots of the Flg + drought stressed groups. ZAT12 was also induced both in leaves and roots as a result of Flg-22 treatment. However, correlation with GABA and GABA-shunt could be proposed only in Flg + drought stressed group. CONCLUSION: We provided solid data on how GABA-shunt and Fgl-22 are interacting against abiotic stress in leaf and root tissues. Fgl-22 induced ETI activated GABA-shunt with a plausible cross talk between MYC2 and ZAT12 transcription factors for drought stress tolerance in B. napus.
Asunto(s)
Brassica napus , Sequías , Flagelina , Ácido gamma-Aminobutírico , Brassica napus/genética , Brassica napus/fisiología , Brassica napus/efectos de los fármacos , Brassica napus/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Flagelina/farmacología , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas , Raíces de Plantas/metabolismo , Raíces de Plantas/fisiología , Raíces de Plantas/genética , Hojas de la Planta/metabolismo , Hojas de la Planta/fisiología , Hojas de la Planta/genética , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genéticaRESUMEN
This study hypothesized that SCFA, acetate impacts positively on hypothalamic pyroptosis and its related abnormalities in experimentally induced PCOS rat model, possibly through NrF2/HIF1-α modulation. Eight-week-old female Wister rats were divided into groups (n = 5), namely control, PCOS, acetate and PCOS + acetate groups. Induction of PCOS was performed by administering 1 mg/kg body weight of letrozole for 21 days. After PCOS confirmation, the animals were treated with 200 mg/kg of acetate for 6 weeks. Rats with PCOS were characterized with insulin resistance, leptin resistance, increased plasma testosterone as well as degenerated ovarian follicles. There was also a significant increase in hypothalamic triglyceride level, triglyceride-glucose index, inflammatory biomarkers (SDF-1 and NF-kB) and caspase-6 as well as plasma LH and triglyceride. A decrease was observed in plasma adiponectin, GnRH, FSH, and hypothalamic GABA with severe inflammasome expression in PCOS rats. These were accompanied by decreased level of NrF2/HIF1-α, and the alterations were reversed when treated with acetate. Collectively, the present results suggest the therapeutic impact of acetate on hypothalamic pyroptosis and its related comorbidity in PCOS, a beneficial effect that is accompanied by modulation of NrF2/HIF1-α.
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Hipotálamo , Subunidad alfa del Factor 1 Inducible por Hipoxia , Síndrome del Ovario Poliquístico , Piroptosis , Ratas Wistar , Síndrome del Ovario Poliquístico/inducido químicamente , Síndrome del Ovario Poliquístico/metabolismo , Síndrome del Ovario Poliquístico/tratamiento farmacológico , Síndrome del Ovario Poliquístico/patología , Femenino , Animales , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Hipotálamo/patología , Piroptosis/efectos de los fármacos , Ratas , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Resistencia a la Insulina , Factor 2 Relacionado con NF-E2/metabolismo , Modelos Animales de Enfermedad , Letrozol/farmacología , Triglicéridos/sangre , Triglicéridos/metabolismo , Hormona Luteinizante/sangre , Hormona Folículo Estimulante/sangre , Adiponectina/metabolismo , Adiponectina/sangre , Testosterona/sangre , Leptina/sangre , Leptina/metabolismo , Hormona Liberadora de Gonadotropina/metabolismo , Ácido gamma-Aminobutírico/metabolismoRESUMEN
BACKGROUND: The relationship between neurotransmitters and oxidative stress in Major Depressive Disorder (MDD) patients, considering HPA axis activity and psychological and cognitive states, is unclear. This study examines changes in neurotransmitters (GABA, Glx) and antioxidants (GSH) in the dorsal anterior cingulate cortex (dACC) of MDD patients under varying levels of ACTH, and their relationship with psychological and cognitive conditions. METHODS: Forty-five MDD patients were divided into high-ACTH (>65 pg/mL; n = 16) and normal-ACTH (7-65 pg/mL; n = 29) groups based on blood ACTH levels, along with 12 healthy controls (HC). All participants underwent HAM-D, HAM-A assessments, and most completed MMSE and MoCA tests. GABA+, Glx, and GSH levels in the dACC were measured using the MEGA-PRESS sequence. Intergroup differences and correlations between clinical factors, HPA axis activity, and metabolites were analyzed. RESULTS: Compared to HC, the normal ACTH group showed higher Glx and lower GSH levels. Glx and GSH were negatively correlated with MDD severity. In the high-ACTH MDD group, Glx positively correlated with delayed memory, and GSH positively correlated with abstraction. Factors influencing GABA included ACTH levels, depression duration, and negative events. Predictive factors for HAM-D scores were GSH and GABA. LIMITATIONS: The sample size is small. CONCLUSION: MDD patients exhibit neurochemical differences in the brain related to HPA axis levels, MDD severity, and cognitive function. Clinical factors, neurotransmitters, and neuroendocrine levels significantly influence depression severity.
Asunto(s)
Hormona Adrenocorticotrópica , Antioxidantes , Trastorno Depresivo Mayor , Giro del Cíngulo , Neurotransmisores , Ácido gamma-Aminobutírico , Humanos , Trastorno Depresivo Mayor/sangre , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Hormona Adrenocorticotrópica/sangre , Femenino , Masculino , Adulto , Antioxidantes/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/sangre , Persona de Mediana Edad , Neurotransmisores/sangre , Neurotransmisores/metabolismo , Giro del Cíngulo/metabolismo , Glutatión/sangre , Glutatión/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipotálamo-Hipofisario/fisiopatología , Sistema Hipófiso-Suprarrenal/metabolismo , Sistema Hipófiso-Suprarrenal/fisiopatología , Estrés Oxidativo/fisiología , Estudios de Casos y ControlesRESUMEN
Neurotensin (Nts) is a neuropeptide acting as a neuromodulator in the brain. Pharmacological studies have identified Nts as a potent hypothermic agent. The medial preoptic area, a region that plays an important role in the control of thermoregulation, contains a high density of neurotensinergic neurons and Nts receptors. The conditions in which neurotensinergic neurons play a role in thermoregulation are not known. In this study, optogenetic stimulation of preoptic Nts neurons induced a small hyperthermia. In vitro, optogenetic stimulation of preoptic Nts neurons resulted in synaptic release of GABA and net inhibition of the preoptic pituitary adenylate cyclase-activating polypeptide (Adcyap1) neurons firing activity. GABA-A receptor antagonist or genetic deletion of Slc32a1 (VGAT) in Nts neurons unmasked also an excitatory effect that was blocked by a Nts receptor 1 antagonist. Stimulation of preoptic Nts neurons lacking Slc32a1 resulted in excitation of Adcyap1 neurons and hypothermia. Mice lacking Slc32a1 expression in Nts neurons presented changes in the fever response and in the responses to heat or cold exposure as well as an altered circadian rhythm of body temperature. Chemogenetic activation of all Nts neurons in the brain induced a 4-5°C hypothermia, which could be blocked by Nts receptor antagonists in the preoptic area. Chemogenetic activation of preoptic neurotensinergic projections resulted in robust excitation of preoptic Adcyap1 neurons. Taken together, our data demonstrate that endogenously released Nts can induce potent hypothermia and that excitation of preoptic Adcyap1 neurons is the cellular mechanism that triggers this response.
Asunto(s)
Temperatura Corporal , Neuronas , Neurotensina , Área Preóptica , Ácido gamma-Aminobutírico , Animales , Área Preóptica/metabolismo , Área Preóptica/fisiología , Área Preóptica/efectos de los fármacos , Neurotensina/metabolismo , Ratones , Neuronas/metabolismo , Neuronas/fisiología , Neuronas/efectos de los fármacos , Ácido gamma-Aminobutírico/metabolismo , Masculino , Optogenética , Receptores de Neurotensina/metabolismo , Receptores de Neurotensina/genética , Ratones Noqueados , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/metabolismo , Proteínas del Transporte Vesicular de Aminoácidos Inhibidores/genética , Regulación de la Temperatura Corporal/fisiologíaRESUMEN
BACKGROUND: Magnetic resonance spectroscopy (MRS) studies have indicated that the imbalance between gamma-aminobutyric acid (GABA) and glutamate/glutamine (Glx) levels was the potential cause of migraine development. However, the changes in the GABA and Glx levels in patients with New daily persistent headache (NDPH) remain unclear. This study aimed to investigate the changes in GABA and Glx levels in the periaqueductal gray (PAG) and dentate nucleus (DN) in patients with NDPH using the MEGA-PRESS sequence. METHODS: Twenty-one NDPH patients and 22 age- and sex-matched healthy controls (HCs) were included and underwent a 3.0T MRI examination, using the MEGA-PRESS sequence to analyze GABA and Glx levels of PAG and DN. The correlations between these neurotransmitter levels and clinical characteristics were also analyzed. RESULTS: There were no significant differences in the GABA+/Water, GABA+/Cr, Glx/Water, and Glx/Cr levels in both PAG and DN between the two groups (all p > 0.05). Moderate-severe NDPH patients had lower levels of Glx/Water (p = 0.034) and Glx/Cr (p = 0.012) in DN than minimal-mild NDPH patients. In patients with NDPH, higher Glx/Water levels in the PAG (r=-0.471, p = 0.031, n = 21) and DN (r=-0.501, p = 0.021, n = 21) and higher Glx/Cr levels in DN (r=-0.483, p = 0.026, n = 21) were found to be correlated with lower Visual Analogue Scale scores. Additionally, a positive correlation was observed between the GABA+/Cr levels in the DN and the Generalized Anxiety Disorder-7 scores (r = 0.519, p = 0.039, n = 16). CONCLUSIONS: The results of this study indicated that the GABA and Glx levels in the PAG and DN may not be the primary contributor to the development of NDPH. The correlations between certain clinical scales and the neurotransmitter levels may be derived from the NDPH related symptoms.
Asunto(s)
Núcleos Cerebelosos , Ácido Glutámico , Glutamina , Espectroscopía de Resonancia Magnética , Sustancia Gris Periacueductal , Ácido gamma-Aminobutírico , Humanos , Femenino , Masculino , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Adulto , Ácido gamma-Aminobutírico/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Sustancia Gris Periacueductal/metabolismo , Sustancia Gris Periacueductal/diagnóstico por imagen , Persona de Mediana Edad , Núcleos Cerebelosos/metabolismo , Núcleos Cerebelosos/diagnóstico por imagen , Trastornos de Cefalalgia/metabolismo , Imagen por Resonancia MagnéticaRESUMEN
Gamma-aminobutyric acid (GABA), the most important inhibitory neurotransmitter in the human brain, has long been considered essential in human behavior in general and learning in particular. GABA concentration can be quantified using magnetic resonance spectroscopy (MRS). Using this technique, numerous studies have reported associations between baseline GABA levels and various human behaviors. However, regional GABA concentration is not fixed and may exhibit rapid modulation as a function of environmental factors. Hence, quantification of GABA levels at several time points during the performance of tasks can provide insights into the dynamics of GABA levels in distinct brain regions. This review reports on findings from studies using repeated measures (n = 41) examining the dynamic modulation of GABA levels in humans in response to various interventions in the perceptual, motor, and cognitive domains to explore associations between GABA modulation and human behavior. GABA levels in a specific brain area may increase or decrease during task performance or as a function of learning, depending on its precise involvement in the process under investigation. Here, we summarize the available evidence and derive two overarching hypotheses regarding the role of GABA modulation in performance and learning. Firstly, training-induced increases in GABA levels appear to be associated with an improved ability to differentiate minor perceptual differences during perceptual learning. This observation gives rise to the 'GABA increase for better neural distinctiveness hypothesis'. Secondly, converging evidence suggests that reducing GABA levels may play a beneficial role in effectively filtering perceptual noise, enhancing motor learning, and improving performance in visuomotor tasks. Additionally, some studies suggest that the reduction of GABA levels is related to better working memory and successful reinforcement learning. These observations inspire the 'GABA decrease to boost learning hypothesis', which states that decreasing neural inhibition through a reduction of GABA in dedicated brain areas facilitates human learning. Additionally, modulation of GABA levels is also observed after short-term physical exercise. Future work should elucidate which specific circumstances induce robust GABA modulation to enhance neuroplasticity and boost performance.
Asunto(s)
Encéfalo , Aprendizaje , Espectroscopía de Resonancia Magnética , Ácido gamma-Aminobutírico , Humanos , Ácido gamma-Aminobutírico/metabolismo , Aprendizaje/fisiología , Encéfalo/metabolismo , Encéfalo/fisiología , Espectroscopía de Resonancia Magnética/métodos , Desempeño Psicomotor/fisiología , Análisis y Desempeño de TareasRESUMEN
Major depressive disorder (MDD) is a form of glial cell-based synaptic dysfunction disease in which glial cells interact closely with neuronal synapses and perform synaptic information processing. Glial cells, particularly astrocytes, are active components of the brain and are responsible for synaptic activity through the release gliotransmitters. A reduced density of astrocytes and astrocyte dysfunction have both been identified the brains of patients with MDD. Furthermore, gliotransmission, i.e., active information transfer mediated by gliotransmitters between astrocytes and neurons, is thought to be involved in the pathogenesis of MDD. However, the mechanism by which astrocyte-mediated gliotransmission contributes to depression remains unknown. This review therefore summarizes the alterations in astrocytes in MDD, including astrocyte marker, connexin 43 (Cx43) expression, Cx43 gap junctions, and Cx43 hemichannels, and describes the regulatory mechanisms of astrocytes involved in synaptic plasticity. Additionally, we investigate the mechanisms acting of the glutamatergic, gamma-aminobutyric acidergic, and purinergic systems that modulate synaptic function and the antidepressant mechanisms of the related receptor antagonists. Further, we summarize the roles of glutamate, gamma-aminobutyric acid, d-serine, and adenosine triphosphate in depression, providing a basis for the identification of diagnostic and therapeutic targets for MDD.
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Astrocitos , Conexina 43 , Trastorno Depresivo Mayor , Plasticidad Neuronal , Humanos , Astrocitos/metabolismo , Trastorno Depresivo Mayor/metabolismo , Trastorno Depresivo Mayor/fisiopatología , Plasticidad Neuronal/fisiología , Animales , Conexina 43/metabolismo , Transmisión Sináptica/fisiología , Ácido Glutámico/metabolismo , Neuroglía/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Sinapsis/metabolismo , Sinapsis/fisiologíaRESUMEN
Insomnia is a common sleep disorder with significant societal and economic impacts. Current pharmacotherapies for insomnia are often accompanied by side effects, necessitating the development of new therapeutic drugs. In this study, the hypnotic effects and mechanisms of Sedum kamtschaticum 30% ethanol extract (ESK) and one of its active compounds, myricitrin, were investigated using pentobarbital-induced sleep experiments, immunohistochemistry (IHC), receptor binding assays, and enzyme-linked immunosorbent assay (ELISA). The pentobarbital-induced sleep experiments revealed that ESK and myricitrin reduced sleep latency and prolonged total sleep time in a dose-dependent manner. Based on c-Fos immunostaining, ESK, and myricitrin enhanced the GABAergic neural activity in sleep-promoting ventrolateral preoptic nucleus (VLPO) GABAergic. By measuring the level of GABA released from VLPO GABAergic neurons, ESK and myricitrin were found to increase GABA release in the hypothalamus. These effects were significantly inhibited by SCH. Moreover, ESK exhibited a concentration-dependent binding affinity for the adenosine A2A receptors (A2AR). In conclusion, ESK and myricitrin have hypnotic effects, and their underlying mechanisms may be related to the activation of A2AR.
Asunto(s)
Hipnóticos y Sedantes , Extractos Vegetales , Receptor de Adenosina A2A , Animales , Receptor de Adenosina A2A/metabolismo , Hipnóticos y Sedantes/farmacología , Ratones , Masculino , Extractos Vegetales/farmacología , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , Pentobarbital/farmacología , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Flavonoides/farmacología , Área Preóptica/efectos de los fármacos , Área Preóptica/metabolismoRESUMEN
γ-Aminobutyric acid (GABA) is a widely distributed non-protein amino acid that serves as a crucial inhibitory neurotransmitter in the brain, regulating various physiological functions. As a result of its potential benefits, GABA has gained substantial interest in the functional food and pharmaceutical industries. The enzyme responsible for GABA production is glutamic acid decarboxylase (GAD), which catalyzes the irreversible decarboxylation of glutamate. Understanding the crystal structure and catalytic mechanism of GAD is pivotal in advancing our knowledge of GABA production. This article provides an overview of GAD's sources, structure, and catalytic mechanism, and explores strategies for enhancing GABA production through fermentation optimization, metabolic engineering, and genetic engineering. Furthermore, the effects of GABA on the physiological functions of animal organisms are also discussed. To meet the increasing demand for GABA, various strategies have been investigated to enhance its production, including optimizing fermentation conditions to facilitate GAD activity. Additionally, metabolic engineering techniques have been employed to increase the availability of glutamate as a precursor for GABA biosynthesis. By fine-tuning fermentation conditions and utilizing metabolic and genetic engineering techniques, it is possible to achieve higher yields of GABA, thus opening up new avenues for its application in functional foods and pharmaceuticals. Continuous research in this field holds immense promise for harnessing the potential of GABA in addressing various health-related challenges.
Asunto(s)
Biotecnología , Fermentación , Glutamato Descarboxilasa , Ingeniería Metabólica , Ácido gamma-Aminobutírico , Ácido gamma-Aminobutírico/biosíntesis , Ácido gamma-Aminobutírico/metabolismo , Glutamato Descarboxilasa/metabolismo , Ingeniería Metabólica/métodos , Biotecnología/métodos , Animales , Humanos , Ingeniería Genética , Ácido Glutámico/metabolismoRESUMEN
The majority of somatosensory DRG neurons express GABAA receptors (GABAAR) and depolarise in response to its activation based on the high intracellular chloride concentration maintained by the Na-K-Cl cotransporter type 1 (NKCC1). The translation of this response to peripheral nerve terminals in people is so far unclear. We show here that GABA (EC50 = 16.67µM) acting via GABAAR produces an influx of extracellular calcium in approximately 20% (336/1720) of isolated mouse DRG neurons. In contrast, upon injection into forearm skin of healthy volunteers GABA (1mM, 100µl) did not induce any overt sensations nor a specific flare response and did not sensitize C-nociceptors to slow depolarizing electrical sinusoidal stimuli. Block of the inward chloride transporter NKCC1 by furosemide (1mg/100µl) did not reduce electrically evoked pain ratings nor did repetitive GABA stimulation in combination with an inhibited NKCC1 driven chloride replenishment by furosemide. Finally, we generated a sustained period of C-fiber firing by iontophoretically delivering codeine or histamine to induce tonic itch. Neither the intensity nor the duration of histamine or codeine itch was affected by prior injection of furosemide. We conclude that although GABA can evoke calcium transients in a proportion of isolated mouse DRG neurons, it does not induce or modify pain or itch ratings in healthy human skin even when chloride gradients are altered by inhibition of the sodium coupled NKCC1 transporter.
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Furosemida , Ganglios Espinales , Voluntarios Sanos , Hiperalgesia , Miembro 2 de la Familia de Transportadores de Soluto 12 , Ácido gamma-Aminobutírico , Humanos , Animales , Ratones , Ácido gamma-Aminobutírico/metabolismo , Masculino , Adulto , Furosemida/farmacología , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Hiperalgesia/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/fisiopatología , Femenino , Neuronas/metabolismo , Neuronas/efectos de los fármacos , Dolor Agudo/metabolismo , Dolor Agudo/fisiopatología , Calcio/metabolismo , Receptores de GABA-A/metabolismo , Prurito/inducido químicamente , Prurito/metabolismo , Prurito/fisiopatología , Adulto JovenRESUMEN
Neurons coordinate inter-tissue protein homeostasis to systemically manage cytotoxic stress. In response to neuronal mitochondrial stress, specific neuronal signals coordinate the systemic mitochondrial unfolded protein response (UPRmt) to promote organismal survival. Yet, whether chemical neurotransmitters are sufficient to control the UPRmt in physiological conditions is not well understood. Here, we show that gamma-aminobutyric acid (GABA) inhibits, and acetylcholine (ACh) promotes the UPRmt in the Caenorhabditis elegans intestine. GABA controls the UPRmt by regulating extra-synaptic ACh release through metabotropic GABAB receptors GBB-1/2. We find that elevated ACh levels in animals that are GABA-deficient or lack ACh-degradative enzymes induce the UPRmt through ACR-11, an intestinal nicotinic α7 receptor. This neuro-intestinal circuit is critical for non-autonomously regulating organismal survival of oxidative stress. These findings establish chemical neurotransmission as a crucial regulatory layer for nervous system control of systemic protein homeostasis and stress responses.
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Acetilcolina , Caenorhabditis elegans , Mitocondrias , Transducción de Señal , Animales , Acetilcolina/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Receptor Nicotínico de Acetilcolina alfa 7/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiología , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Ácido gamma-Aminobutírico/metabolismo , Intestinos/fisiología , Mitocondrias/metabolismo , Neuronas/metabolismo , Estrés Oxidativo , Receptores de GABA-B/metabolismo , Receptores de GABA-B/genética , Estrés Fisiológico , Transmisión Sináptica/fisiología , Respuesta de Proteína DesplegadaRESUMEN
Cognitive flexibility represents the capacity to switch among different mental schemes, providing an adaptive advantage to a changing environment. The neural underpinnings of this executive function have been deeply studied in humans through fMRI, showing that the left inferior frontal cortex (IFC) and the left inferior parietal lobule (IPL) are crucial. Here, we investigated the inhibitory-excitatory balance in these regions by means of γ-aminobutyric acid (GABA+) and glutamate + glutamine (Glx), measured with magnetic resonance spectroscopy, during a cognitive flexibility task and its relationship with the performance level and the local task-induced blood oxygenation level-dependent (BOLD) response in 40 young (18-35â years; 26 female) and 40 older (18-35â years; 21 female) human adults. As the IFC and the IPL are richly connected regions, we also examined whole-brain effects associated with their local metabolic activity. Results did not show absolute metabolic modulations associated with flexibility performance, but the performance level was related to the direction of metabolic modulation in the IPL with opposite patterns in young and older individuals. The individual inhibitory-excitatory balance modulation showed an inverse relationship with the local BOLD response in the IPL. Finally, the modulation of inhibitory-excitatory balance in IPL was related to whole-brain effects only in older individuals. These findings show disparities in the metabolic mechanisms underlying cognitive flexibility in young and older adults and their association with the performance level and BOLD response. Such metabolic differences are likely to play a role in executive functioning during aging and specifically in cognitive flexibility.
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Envejecimiento , Cognición , Imagen por Resonancia Magnética , Humanos , Femenino , Masculino , Adulto , Adulto Joven , Adolescente , Cognición/fisiología , Envejecimiento/fisiología , Encéfalo/fisiología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Función Ejecutiva/fisiología , Mapeo Encefálico , Ácido gamma-Aminobutírico/metabolismo , Espectroscopía de Resonancia Magnética , Ácido Glutámico/metabolismoRESUMEN
We studied the effect of enteral administration of GABA on the gastric mucosa in male Wistar rats (n=47) with modeled metabolic stress (food deprivation for 9 days with free access to water). The relative weights of the adrenal glands and thymus were determined, and histological examination of the stomach was performed. In control rats, modeling the metabolic stress was accompanied by the development of erosive damage to the gastric mucosa related to blood supply disturbances. Administration of GABA prevented erosions and exhibited a pronounced gastroprotective effect. Thus, administration of GABA can be a promising method for the prevention and treatment of erosive gastric lesions associated with metabolic stress.
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Mucosa Gástrica , Ratas Wistar , Estrés Fisiológico , Ácido gamma-Aminobutírico , Animales , Masculino , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacología , Ratas , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Estrés Fisiológico/efectos de los fármacos , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Glándulas Suprarrenales/patología , Timo/efectos de los fármacos , Timo/patología , Timo/metabolismo , Privación de Alimentos , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patología , Úlcera Gástrica/prevención & control , Úlcera Gástrica/inducido químicamente , Úlcera Gástrica/tratamiento farmacológicoRESUMEN
Aging-related biochemical changes in nerve cells lead to dysfunctional synapses and disrupted neuronal circuits, ultimately affecting vital processes such as brain plasticity, learning, and memory. The imbalance between excitation and inhibition in synaptic function during aging contributes to cognitive impairment, emphasizing the importance of compensatory mechanisms. Fear conditioning-related plasticity of the somatosensory barrel cortex, relying on the proper functioning and extensive up regulation of the GABAergic system, in particular interneurons containing somatostatin, is compromised in aging (one-year-old) mice. The present research explores two potential interventions, taurine supplementation, and environmental enrichment, revealing their effectiveness in supporting learning-induced plasticity in the aging mouse brain. They do not act through a mechanism normalizing the Glutamate/GABA balance that is disrupted in aging. Still, they allow for increased somatostatin levels, an effect observed in young animals after learning. These findings highlight the potential of lifestyle interventions and diet supplementation to mitigate age-related cognitive decline by promoting experience-dependent plasticity.
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Envejecimiento , Suplementos Dietéticos , Plasticidad Neuronal , Taurina , Animales , Plasticidad Neuronal/fisiología , Envejecimiento/fisiología , Taurina/metabolismo , Taurina/farmacología , Taurina/administración & dosificación , Ratones , Masculino , Somatostatina/metabolismo , Ratones Endogámicos C57BL , Aprendizaje/fisiología , Ambiente , Miedo/fisiología , Ácido gamma-Aminobutírico/metabolismo , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/prevención & control , Encéfalo/metabolismo , Encéfalo/fisiologíaRESUMEN
BACKGROUND: Psychobiotic bacteria are probiotics able to influence stress-related behavior, sleep, and cognitive outcomes. Several in vitro and human studies were performed to assess their physiological potential, to find strains having psychotropic activity in humans, and to elucidate the metabolic pathways involved. In our previous in vitro study, we identified two strains Levilactobacillus brevis P30021 and Lactiplantibacillus plantarum P30025, able to produce GABA and acetylcholine, being promising candidates to provide an effect on mood and cognitive performance. AIM: To investigate the effects of probiotics in the alleviation on the cognitive performance of moderately stressed healthy adults. Secondary outcomes were related to mood improvement, production of GABA, glutamate, acetylcholine, and choline and modification of the microbiota composition. METHODS: A 12-week randomized, double-blind, placebo-controlled, cross-over study investigated the effects of a probiotic formulation (Levilactobacillus brevis P30021 and Lactiplantibacillus plantarum P30025) on psychological, memory, and cognition parameters in 44 (Probiotic = 44, Placebo = 43) adults with a mean age of 29 ± 5.7 years old by CogState Battery test. Subjects-inclusion criteria was a mild-moderate (18.7 ± 4.06) stress upon diagnosis using the DASS-42 questionnaire. RESULTS: Probiotic treatment had no effect on subjective stress measures. The probiotic formulation showed a significant beneficial effect on depressive symptoms by reducing cognitive reactivity to sad mood (p = 0.034). Rumination significantly improved after intake of the probiotic (p = 0.006), suggesting a potential benefit in reducing the negative cognitive effects associated with depression and improving overall mental health. When stratifying the treated subjects according to the response, we found an increase in the abundance of the probiotic genera in the gut microbiota of positive responders (p = 0.009 for Lactiplantibacillus and p = 0.004 for L.brevis). No relevant correlations were observed between the neurotransmitter concentration in the faecal sample, scores of LEIDS, DASS-42, and cognitive tests. CONCLUSION: We highlight the potential of this probiotic preparation to act as psycobiotics for the relief of negative mood feelings. The assessment of the psychotropic effects of dietary interventions in human participants has many challenges. Further interventional studies investigating the effect of these psychobiotic bacteria in populations with stressed-related disorders are required including longer period of intervention and larger sample size in order to verify the effects of the treatment on further stress-related indicators.
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Afecto , Cognición , Estudios Cruzados , Lactobacillus , Probióticos , Ácido gamma-Aminobutírico , Humanos , Método Doble Ciego , Adulto , Probióticos/farmacología , Masculino , Cognición/fisiología , Femenino , Ácido gamma-Aminobutírico/metabolismo , Lactobacillus/metabolismo , Adulto Joven , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Estrés Psicológico/microbiología , Levilactobacillus brevis/metabolismoRESUMEN
The impacts of L-glutamate (L-Glu) treatment on chilling injury (CI), Ca2+ signaling, mitochondrial ultrastructure, and metabolisms of reactive oxygen species (ROS), γ-aminobutyric acid (GABA), energy of prune fruit under chilling stress were studied. The results found that the optimal concentration of L-Glu to suppress CI occurrence and maintain quality in prune fruit was 0.1 g L-1, which also enhanced the PdGLRs expression, cytoplasmic Ca2+ concentration, the contents of CaM, and CML under cold stress. Moreover, L-Glu treatment could reduce ROS accumulation and increase GABA content, and energy level, contributing to maintaining the integrity of the mitochondrial structure in cold-stored prune fruit. More importantly, PdGLRs expression and CaM/CML content positively correlated with antioxidant enzyme activities, GABA shunt, and energy status in prune fruit. These results indicated that the enhanced cold resistance of L-Glu-treated prunes might be attributed to the activated Ca2+ signaling, thus improving the antioxidant capacity, GABA, and energy levels.
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Frío , Metabolismo Energético , Frutas , Ácido Glutámico , Especies Reactivas de Oxígeno , Ácido gamma-Aminobutírico , Especies Reactivas de Oxígeno/metabolismo , Frutas/química , Frutas/metabolismo , Frutas/efectos de los fármacos , Ácido Glutámico/metabolismo , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/análisis , Metabolismo Energético/efectos de los fármacos , Homeostasis/efectos de los fármacosRESUMEN
NVA1309 is a non-brain penetrant next-generation gabapentinoid shown to bind Cavα2δ at R243 within a triple Arginine motif forming the binding site for gabapentin and pregabalin. In this study we have compared the effects of NVA1309 with Mirogabalin, a gabapentinoid drug with higher affinity for the voltage-gated calcium channel subunit Cavα2δ-1 than pregabalin which is approved for post-herpetic neuralgia in Japan, Korea and Taiwan. Both NVA1309 and mirogabalin inhibit Cav2.2 currents in vitro and decrease Cav2.2 plasma membrane expression with higher efficacy than pregabalin. Mutagenesis of the classical binding residue arginine R243 and the newly identified binding residue lysine K615 reverse the effect of mirogabalin on Cav2.2 current, but not that of NVA1309.
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Gabapentina , Humanos , Gabapentina/farmacología , Animales , Unión Proteica , Subunidades de Proteína/metabolismo , Subunidades de Proteína/química , Células HEK293 , Ácido gamma-Aminobutírico/metabolismo , Membrana Celular/metabolismo , Membrana Celular/efectos de los fármacos , Canales de Calcio Tipo N/metabolismo , Canales de Calcio Tipo N/genética , Pregabalina/farmacología , Canales de Calcio/metabolismo , Compuestos Bicíclicos con PuentesRESUMEN
Several studies suggest that hearing loss results in changes in the balance between inhibition and excitation in the inferior colliculus (IC). The IC is an integral nucleus within the auditory brainstem. The majority of ascending pathways from the lateral lemniscus (LL), superior olivary complex (SOC), and cochlear nucleus (CN) synapse in the IC before projecting to the thalamus and cortex. Many of these ascending projections provide inhibitory innervation to neurons within the IC. However, the nature and the distribution of this inhibitory input have only been partially elucidated in the rat. The inhibitory neurotransmitter, gamma aminobutyric acid (GABA), from the ventral nucleus of the lateral lemniscus (VNLL), provides the primary inhibitory input to the IC of the rat with GABA from other lemniscal and SOC nuclei providing lesser, but prominent innervation. There is evidence that hearing related conditions can result in dysfunction of IC neurons. These changes may be mediated in part by changes in GABA inputs to IC neurons. We have previously used gene micro-arrays in a study of deafness-related changes in gene expression in the IC and found significant changes in GAD as well as the GABA transporters and GABA receptors (Holt 2005). This is consistent with reports of age and trauma related changes in GABA (Bledsoe et al., 1995; Mossop et al., 2000; Salvi et al., 2000). Ototoxic lesions of the cochlea produced a permanent threshold shift. The number, intensity, and density of GABA positive axon terminals in the IC were compared in normal hearing and deafened rats. While the number of GABA immunolabeled puncta was only minimally different between groups, the intensity of labeling was significantly reduced. The ultrastructural localization and distribution of labeling was also examined. In deafened animals, the number of immuno gold particles was reduced by 78 % in axodendritic and 82 % in axosomatic GABAergic puncta. The affected puncta were primarily associated with small IC neurons. These results suggest that reduced inhibition to IC neurons contribute to the increased neuronal excitability observed in the IC following noise or drug induced hearing loss. Whether these deafness diminished inhibitory inputs originate from intrinsic or extrinsic CNIC sources awaits further study.