GABAergic disinhibition from the BNST to PNOCARC neurons promotes HFD-induced hyperphagia.

Activation of prepronociceptin (PNOC)-expressing neurons in the arcuate nucleus (ARC) promotes high-fat-diet (HFD)-induced hyperphagia. In turn, PNOCARC neurons can inhibit the anorexic response of proopiomelanocortin (POMC) neurons. Here, we validate the necessity of PNOCARC activity for HFD-induced inhibition of POMC neurons in mice and find that PNOCARC-neuron-dependent inhibition of POMC neurons is mediated by gamma-aminobutyric acid (GABA) release. When monitoring individual PNOCARC neuron activity via Ca2+ imaging, we find a subpopulation of PNOCARC neurons that is inhibited upon gastrointestinal calorie sensing and disinhibited upon HFD feeding. Combining retrograde rabies tracing and circuit mapping, we find that PNOC neurons from the bed nucleus of the stria terminalis (PNOCBNST) provide inhibitory input to PNOCARC neurons, and this inhibitory input is blunted upon HFD feeding. This work sheds light on how an increase in caloric content of the diet can rewire a neuronal circuit, paving the way to overconsumption and obesity development.

γ-Aminobutyric acid (GABA) priming alleviates acid-aluminum toxicity to roots of creeping bentgrass via enhancements in antioxidant defense and organic metabolites remodeling.

MAIN CONCLUSION: γ-Aminobutyric acid alleviates acid-aluminum toxicity to roots associated with enhanced antioxidant metabolism as well as accumulation and transportation of citric and malic acids. Aluminum (Al) toxicity has become the main limiting factor for crop growth and development in acidic soils and is further being aggravated worldwide due to continuous industrial pollution. The current study was designed to examine effects of GABA priming on alleviating acid-Al toxicity in terms of root growth, antioxidant defense, citrate and malate metabolisms, and extensive metabolites remodeling in roots under acidic conditions. Thirty-seven-day-old creeping bentgrass (Agrostis stolonifera) plants were used as test materials. Roots priming with or without 0.5 mM GABA for 3 days were cultivated in standard nutrient solution for 15 days as control or subjected to nutrient solution containing 5 mM AlCl3·6H2O for 15 days as acid-Al stress treatment. Roots were sampled for determinations of root characteristics, physiological and biochemical parameters, and metabolomics. GABA priming significantly alleviated acid-Al-induced root growth inhibition and oxidative damage, despite it promoted the accumulation of Al in roots. Analysis of metabolomics showed that GABA priming significantly increased accumulations of organic acids, amino acids, carbohydrates, and other metabolites in roots under acid-Al stress. In addition, GABA priming also significantly up-regulated key genes related to accumulation and transportation of malic and citric acids in roots under acid-Al stress. GABA-regulated metabolites participated in tricarboxylic acid cycle, GABA shunt, antioxidant defense system, and lipid metabolism, which played positive roles in reactive oxygen species scavenging, energy conversion, osmotic adjustment, and Al ion chelation in roots.

Effect of Dietary L-Theanine on Protein Expression in the Hippocampus of Senescence-Accelerated Mice (SAMP8).

L-Theanine is contained in green tea at 1-3% per dry matter as an amino acid with an umami taste, and the antidepressant effect and protective effect against stress-induced brain atrophy in mice, as well as the related mechanism have been reported. However, effects of theanine on the hippocampus from the proteome analysis and the action mechanism have not been examined. In this study, we mainly investigated the possibility of theanine's cognitive impairment-preventing function and the action mechanism by proteomics in the hippocampus of SAMP8 administered with theanine. In addition to improvement in the aging score with theanine administration, in proteomics, significant suppressions in the expressions of synapsin 2, α-synuclein, ß-synuclein, and protein tau were observed by theanine administration, and the expression of CAM kinase II beta and alpha exhibited a significant increase and increasing tendency with theanine administration, respectively. The expression of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein tended to increase by theanine administration. On the other hand, serotonin/tryptophan, GABA/glutamic acid and glutamine/glutamic acid ratios in the hippocampus showed an increasing tendency, a significant increase, and an increasing tendency with theanine administration, respectively. These results suggested that theanine might have been involved in the improvement of neurodegeneration or cognitive impairment by suppressing the productions of synapsin, synuclein and protein tau which are considered to be produced along with aging and oxidation, and by enhancing the production of serotonin by increasing the expression of CAM kinase II, and further by affecting the metabolism of glutamate.

Short-chain fatty acid valerate reduces voluntary alcohol intake in male mice.

BACKGROUND: Despite serious health and social consequences, effective intervention strategies for habitual alcohol binge drinking are lacking. The development of novel therapeutic and preventative approaches is highly desirable. Accumulating evidence in the past several years has established associations between the gut microbiome and microbial metabolites with drinking behavior, but druggable targets and their underlying mechanism of action are understudied. RESULTS: Here, using a drink-in-the-dark mouse model, we identified a microbiome metabolite-based novel treatment (sodium valerate) that can reduce excessive alcohol drinking. Sodium valerate is a sodium salt of valeric acid short-chain fatty acid with a similar structure as γ-aminobutyric acid (GABA). Ten days of oral sodium valerate supplementation attenuates excessive alcohol drinking by 40%, reduces blood ethanol concentration by 53%, and improves anxiety-like or approach-avoidance behavior in male mice, without affecting overall food and water intake. Mechanistically, sodium valerate supplementation increases GABA levels across stool, blood, and amygdala. It also significantly increases H4 acetylation in the amygdala of mice. Transcriptomics analysis of the amygdala revealed that sodium valerate supplementation led to changes in gene expression associated with functional pathways including potassium voltage-gated channels, inflammation, glutamate degradation, L-DOPA degradation, and psychological behaviors. 16S microbiome profiling showed that sodium valerate supplementation shifts the gut microbiome composition and decreases microbiome-derived neuroactive compounds through GABA degradation in the gut microbiome. CONCLUSION: Our findings suggest that sodium valerate holds promise as an innovative therapeutic avenue for the reduction of habitual binge drinking, potentially through multifaceted mechanisms. Video Abstract.

Gephyrin promotes autonomous assembly and synaptic localization of GABAergic postsynaptic components without presynaptic GABA release.

Synapses containing γ-aminobutyric acid (GABA) constitute the primary centers for inhibitory neurotransmission in our nervous system. It is unclear how these synaptic structures form and align their postsynaptic machineries with presynaptic terminals. Here, we monitored the cellular distribution of several GABAergic postsynaptic proteins in a purely glutamatergic neuronal culture derived from human stem cells, which virtually lacks any vesicular GABA release. We found that several GABAA receptor (GABAAR) subunits, postsynaptic scaffolds, and major cell-adhesion molecules can reliably coaggregate and colocalize at even GABA-deficient subsynaptic domains, but remain physically segregated from glutamatergic counterparts. Genetic deletions of both Gephyrin and a Gephyrin-associated guanosine di- or triphosphate (GDP/GTP) exchange factor Collybistin severely disrupted the coassembly of these postsynaptic compositions and their proper apposition with presynaptic inputs. Gephyrin-GABAAR clusters, developed in the absence of GABA transmission, could be subsequently activated and even potentiated by delayed supply of vesicular GABA. Thus, molecular organization of GABAergic postsynapses can initiate via a GABA-independent but Gephyrin-dependent intrinsic mechanism.

GABAergic synaptic scaling is triggered by changes in spiking activity rather than AMPA receptor activation.

Homeostatic plasticity represents a set of mechanisms that are thought to recover some aspect of neural function. One such mechanism called AMPAergic scaling was thought to be a likely candidate to homeostatically control spiking activity. However, recent findings have forced us to reconsider this idea as several studies suggest AMPAergic scaling is not directly triggered by changes in spiking. Moreover, studies examining homeostatic perturbations in vivo have suggested that GABAergic synapses may be more critical in terms of spiking homeostasis. Here, we show results that GABAergic scaling can act to homeostatically control spiking levels. We found that perturbations which increased or decreased spiking in cortical cultures triggered multiplicative GABAergic upscaling and downscaling, respectively. In contrast, we found that changes in AMPA receptor (AMPAR) or GABAR transmission only influence GABAergic scaling through their indirect effect on spiking. We propose that GABAergic scaling represents a stronger candidate for spike rate homeostat than AMPAergic scaling.

Ameliorative impacts of gamma-aminobutyric acid (GABA) on seedling growth, physiological biomarkers, and gene expression in eight wheat (Triticum aestivum L.) cultivars under salt stress.

Plants spontaneously accumulate γ-aminobutyric acid (GABA), a nonprotein amino acid, in response to various stressors. Nevertheless, there is limited knowledge regarding the precise molecular mechanisms that plants employ to cope with salt stress. The objective of this study was to investigate the impact of GABA on the salt tolerance of eight distinct varieties of bread wheat (Triticum aestivum L.) by examining plant growth rates and physiological and molecular response characteristics. The application of salt stress had a detrimental impact on plant growth markers. Nevertheless, the impact was mitigated by the administration of GABA in comparison to the control treatment. When the cultivars Gemmiza 7, Gemmiza 9, and Gemmiza 12 were exposed to GABA at two distinct salt concentrations, there was a substantial increase in both the leaf chlorophyll content and photosynthetic rate. Both the control wheat cultivars and the plants exposed to salt treatment and GABA treatment showed alterations in stress-related biomarkers and antioxidants. This finding demonstrated that GABA plays a pivotal role in mitigating the impact of salt treatments on wheat cultivars. Among the eight examined kinds of wheat, CV. Gemmiza 7 and CV. Gemmiza 11 exhibited the most significant alterations in the expression of their TaSOS1 genes. CV. Misr 2, CV. Sakha 94, and CV. Sakha 95 exhibited the highest degree of variability in the expression of the NHX1, DHN3, and GR genes, respectively. The application of GABA to wheat plants enhances their ability to cope with salt stress by reducing the presence of reactive oxygen species (ROS) and other stress indicators, regulating stomatal aperture, enhancing photosynthesis, activating antioxidant enzymes, and upregulating genes involved in salt stress tolerance.

Effect of exogenous γ-aminobutyric acid on physiological property, antioxidant activity, and cadmium uptake of quinoa seedlings under cadmium stress.

Increasing cadmium (Cd) pollution has negative effects on quinoa growth and production. Gamma-aminobutyric acid (GABA) confers plants with stress resistance to heavy metals; however, the mechanism remains unclear. We explored the effects of exogenous GABA on the physiological characteristics, antioxidant capacity, and Cd accumulation of quinoa seedlings under Cd stress using hydroponic experiments. Partial least-squares regression was used to identify key physical and chemical indices of seedlings affecting Cd accumulation. Compared with those of the CK group, exposure to 10 and 25 µmol·L-1 Cd significantly reduced the photosynthetic pigment contents, photosynthesis, and biomass accumulation of quinoa seedlings; resulted in shorter and thicker roots; decreased the length of the lateral roots; decreased the activities of superoxide dismutase (SOD) and peroxide (POD); and increased H2O2 and malondialdehyde (MDA) contents. Exogenous GABA reduced the Cd content in the stem/leaves and roots of quinoa seedlings under Cd stress by 13.22-21.63% and 7.92-28.32%, decreased Cd accumulation by 5.37-6.71% and 1.91-4.09%, decreased the H2O2 content by 38.21-47.46% and 45.81-55.73%, and decreased the MDA content by 37.65-48.12% and 29.87-32.51%, respectively. GABA addition increased the SOD and POD activities in the roots by 2.78-5.61% and 13.81-18.33%, respectively, under Cd stress. Thus, exogenous GABA can reduce the content and accumulation of Cd in quinoa seedlings by improving the photosynthetic characteristics and antioxidant enzyme activity and reducing the degree of lipid peroxidation in the cell membrane to alleviate the toxic effect of Cd stress on seedling growth.

GABAergic implications in anxiety and related disorders.

Evidence indicates that anxiety disorders arise from an imbalance in the functioning of brain circuits that govern the modulation of emotional responses to possibly threatening stimuli. The circuits under consideration in this context include the amygdala's bottom-up activity, which signifies the existence of stimuli that may be seen as dangerous. Moreover, these circuits encompass top-down regulatory processes that originate in the prefrontal cortex, facilitating the communication of the emotional significance associated with the inputs. Diverse databases (e.g., Pubmed, ScienceDirect, Web of Science, Google Scholar) were searched for literature using a combination of different terms e.g., "anxiety", "stress", "neuroanatomy", and "neural circuits", etc. A decrease in GABAergic activity is present in both anxiety disorders and severe depression. Research on cerebral functional imaging in depressive individuals has shown reduced levels of GABA within the cortical regions. Additionally, animal studies demonstrated that a reduction in the expression of GABAA/B receptors results in a behavioral pattern resembling anxiety. The amygdala consists of inhibitory networks composed of GABAergic interneurons, responsible for modulating anxiety responses in both normal and pathological conditions. The GABAA receptor has allosteric sites (e.g., α/γ, γ/ß, and α/ß) which enable regulation of neuronal inhibition in the amygdala. These sites serve as molecular targets for anxiolytic medications such as benzodiazepine and barbiturates. Alterations in the levels of naturally occurring regulators of these allosteric sites, along with alterations to the composition of the GABAA receptor subunits, could potentially act as mechanisms via which the extent of neuronal inhibition is diminished in pathological anxiety disorders.

6-Methoxyflavone antagonizes chronic constriction injury and diabetes associated neuropathic nociception expression.

Neuropathy is a disturbance of function or a pathological change in nerves causing poor health and quality of life. A proportion of chronic pain patients in the community suffer persistent neuropathic pain symptoms because current drug therapies may be suboptimal so there is a need for new therapeutic modalities. This study investigated the neuroprotective flavonoid, 6-methoxyflavone (6MF), as a potential therapeutic agent and gabapentin as the standard comparator, against neuropathic models. Thus, neuropathic-like states were induced in Sprague-Dawley rats using sciatic nerve chronic constriction injury (CCI) mononeuropathy and systemic administration of streptozotocin (STZ) to induce polyneuropathy. Subsequent behaviors reflecting allodynia, hyperalgesia, and vulvodynia were assessed and any possible motoric side-effects were evaluated including locomotor activity, as well as rotarod discoordination and gait disruption. 6MF (25-75 mg/kg) antagonized neuropathic-like nociceptive behaviors including static- (pressure) and dynamic- (light brushing) hindpaw allodynia plus heat/cold and pressure hyperalgesia in the CCI and STZ models. 6MF also reduced static and dynamic components of vulvodynia in the STZ induced polyneuropathy model. Additionally, 6MF reversed CCI and STZ suppression of locomotor activity and rotarod discoordination, suggesting a beneficial activity on motor side effects, in contrast to gabapentin. Hence, 6MF possesses anti-neuropathic-like activity not only against different nociceptive modalities but also impairment of motoric side effects.

Correlation of striatal dopamine D2/3 receptor availability with GABA level in the anterior cingulate cortex in healthy controls but not in alcohol-dependent subjects and individuals at high risk: A multimodal magnetic resonance spectroscopy and positron emission tomography study.

BACKGROUND: The association of impaired dopaminergic neurotransmission with the development and maintenance of alcohol use disorder is well known. More specifically, reduced dopamine D2/3 receptors in the striatum of subjects with alcohol dependence (AD) compared to healthy controls have been found in previous studies. Furthermore, alterations of gamma-aminobutyric acid (GABA) and glutamate (Glu) levels in the anterior cingulate cortex (ACC) of AD subjects have been documented in several studies. However, the interaction between cortical Glu levels and striatal dopamine D2/3 receptors has not been investigated in AD thus far. METHODS: This study investigated dopamine D2/3 receptor availability via 18F-fallypride positron emission tomography (PET) and GABA as well as Glu levels via magnetic resonance spectroscopy (MRS) in 19 detoxified AD subjects, 18 healthy controls (low risk, LR) controls and 19 individuals at high risk (HR) for developing AD, carefully matched for sex, age and smoking status. RESULTS: We found a significant negative correlation between GABA levels in the ACC and dopamine D2/3 receptor availability in the associative striatum of LR but not in AD or HR individuals. Contrary to our expectations, we did not observe a correlation between Glu concentrations in the ACC and striatal D2/3 receptor availability. CONCLUSIONS: The results may reflect potential regulatory cortical mechanisms on mesolimbic dopamine receptors and their disruption in AD and individuals at high risk, mirroring complex neurotransmitter interactions associated with the pathogenesis of addiction. This is the first study combining 18F-fallypride PET and MRS in AD subjects and individuals at high risk.

ON and OFF starburst amacrine cells are controlled by distinct cholinergic pathways.

Cholinergic signaling in the retina is mediated by acetylcholine (ACh) released from starburst amacrine cells (SACs), which are key neurons for motion detection. SACs comprise ON and OFF subtypes, which morphologically show mirror symmetry to each other. Although many physiological studies on SACs have targeted ON cells only, the synaptic computation of ON and OFF SACs is assumed to be similar. Recent studies demonstrated that gene expression patterns and receptor types differed between ON and OFF SACs, suggesting differences in their functions. Here, we compared cholinergic signaling pathways between ON and OFF SACs in the mouse retina using the patch clamp technique. The application of ACh increased GABAergic feedback, observed as postsynaptic currents to SACs, in both ON and OFF SACs; however, the mode of GABAergic feedback differed. Nicotinic receptors mediated GABAergic feedback in both ON and OFF SACs, while muscarinic receptors mediated GABAergic feedback in ON SACs only in adults. Neither tetrodotoxin, which blocked action potentials, nor LY354740, which blocked neurotransmitter release from SACs, eliminated ACh-induced GABAergic feedback in SACs. These results suggest that ACh-induced GABAergic feedback in ON and OFF SACs is regulated by different feedback mechanisms in adults and mediated by non-spiking amacrine cells other than SACs.

Gamma amino butyric acid (GABA) application modulated the morpho-physiological and yield traits of fragrant rice under well-watered and drought conditions.

BACKGROUND: Changing climate is causing erratic rainfall and prolonged drought periods, thus posing serious threats to crop productivity. Owing to severity of drought events, it is imperative to take proactive measures to enhance the resilience of drought sensitive crops like rice. Therefore, the present study was carried out to improve the drought stress tolerance in rice through gamma amino butyric acid (GABA) application. METHODS: The experiment was included four GABA concentrations i.e., 0 mM as control, 1 mM, 1.5 mM, and 2 mM, two water levels i.e., 100% and 50% field capacity (referred as FC100 for well-watered and FC50 for drought conditions, respectively), and two fragrant rice cultivars i.e., Super Basmati and Basmati-515. RESULTS: The findings unveiled a comprehensive improvement in various parameters with GABA application in fragrant rice under both well-watered (FC100) and water-limited (FC50) conditions, compared to the control. Specifically, GABA induced enhancements were observed in plant height, root length, fresh weight, dry weight, total soluble protein content, and total free amino acid content across both cultivars. Moreover, GABA application significantly improved peroxidase (POD) and catalase (CAT) enzyme activities, alongside elevating anthocyanin levels, while concurrently reducing H2O2 contents in both FC100 and FC50 treatments. Furthermore, the positive impact of GABA extended to morphological traits, with notable increases in panicle length, total tillers and productive tillers per hill, branch and grain numbers per panicle, and 1000-grain weight for Super Basmati and Basmati 515 cultivars under both water regimes, compared to Ck. Similarly, the grain yield increased by 31.01% and 27.32% under FC100 and 36.85% and 27.71% under FC50 in Super Basmati and Basmati-515, respectively, in response to GABA application, compared to Ck. Additionally, principal component analysis (PCA) revealed significant variances attributed to Dim1 and Dim2, with 86.1% and 4.0% of the variance, respectively, across three bi-plots encompassing rice cultivars, water levels, and GABA treatments. Notably, all tested indices, except for H2O2 and non-productive tillers per hill, exhibited positive correlations amongst themselves and with rice yield, further emphasizing the beneficial effects of GABA application on fragrant rice under well-watered and drought conditions. CONCLUSIONS: GABA significantly improved fragrant rice performance under both well-watered (FC100) and water-limited (FC50) conditions. Moreover, integrating GABA application into rice cultivation practices could not only improve the crop resilience to drought stress but also potentially benefiting the future food and nutritional security globally. However, however; further research is needed to understand the cellular and molecular mechanisms of the functionality of GABA in fragrant rice, particularly under drought conditions.

Interplay between microbial-derived GABA and host GABA receptor signaling collectively influence the tumorigenic function of GABA in colon cancer.

Although classically recognized as a neurotransmitter, gamma aminobutyric acid (GABA) has also been identified in colonic tumors. Moreover, the gut microbiome represents another potential source of GABA. Both GABAA and GABAB receptors have been implicated in contributing to the effects of GABA in colorectal cancer, with both pro- and anti-tumorigenic functions identified. However, their subunit composition is often overlooked. Studies to date have not addressed whether the GABA-producing potential of the microbiome changes over the course of colon tumor development or whether receptor subunit expression patterns are altered in colon cancer. Therefore, we investigated the clusters of orthologous group frequencies of glutamate decarboxylase (GAD) in feces from two murine models of colon cancer and found that the frequency of microbial GAD was significantly decreased early in the tumorigenic process. We also determined that microbial-derived GABA inhibited proliferation of colon cancer cells in vitro and that this effect of GABA on SW480 cells involved both GABAA and GABAB receptors. GABA also inhibited prostaglandin E2 (PGE2)-induced proliferation and interleukin-6 (IL-6) expression in these cells. Gene expression correlations were assessed using the "Cancer Exploration" suite of the TIMER2.0 web tool and identified that GABA receptor subunits were differentially expressed in human colon cancer. Moreover, GABAA receptor subunits were predominantly positively associated with PGE2 synthase, cyclooxygenase-2 and IL-6. Collectively, these data demonstrate decreased potential of the microbiome to produce GABA during tumorigenesis, a novel anti-tumorigenic pathway for GABA, and that GABA receptor subunit expression adds a further layer of complexity to GABAergic signaling in colon cancer.

Engineering Chimeric Chemoreceptors and Two-Component Systems for Orthogonal and Leakless Biosensing of Extracellular γ-Aminobutyric Acid.

Two-component systems (TCSs) sensing and responding to various stimuli outside and inside cells are valuable resources for developing biosensors with synthetic biology applications. However, the use of TCS-based biosensors suffers from a limited effector spectrum, hypersensitivity, low dynamic range, and unwanted signal crosstalk. Here, we developed a tailor-made Escherichia coli whole-cell γ-aminobutyric acid (GABA) biosensor by engineering a chimeric GABA chemoreceptor PctC and TCS. By testing different TCSs, the chimeric PctC/PhoQ showed the response to GABA. Chimera-directed evolution and introduction of the insulated chimeric pair PctC/PhoQ*PhoP* produced biosensors with up to 3.50-fold dynamic range and good orthogonality. To further enhance the dynamic range and lower the basal leakage, three strategies, engineering of PhoP DNA binding sites, fine-tuning reporter expression by optimizing transcription/translation components, and a tobacco etch virus protease-controlled protein degradation, were integrated. This chimeric biosensor displayed a low basal leakage, a large dynamic range (15.8-fold), and a high threshold level (22.7 g L-1). Finally, the optimized biosensor was successfully applied in the high-throughput microdroplet screening of GABA-overproducing Corynebacterium glutamicum, demonstrating its desired properties for extracellular signal biosensing.

Unveiling the crucial role of betaine: modulation of GABA homeostasis via SLC6A1 transporter (GAT1).

Betaine is an endogenous osmolyte that exhibits therapeutic potential by mitigating various neurological disorders. However, the underlying cellular and molecular mechanisms responsible for its neuroprotective effects remain puzzling.In this study, we describe a possible mechanism behind the positive impact of betaine in preserving neurons from excitotoxicity. Here we demonstrate that betaine at low concentration modulates the GABA uptake by GAT1 (slc6a1), the predominant GABA transporter in the central nervous system. This modulation occurs through the temporal inhibition of the transporter, wherein prolonged occupancy by betaine impedes the swift transition of the transporter to the inward conformation. Importantly, the modulatory effect of betaine on GAT1 is reversible, as the blocking of GAT1 disappears with increased extracellular GABA. Using electrophysiology, mass spectroscopy, radiolabelled cellular assay, and molecular dynamics simulation we demonstrate that betaine has a dual role in GAT1: at mM concentration acts as a slow substrate, and at µM as a temporal blocker of GABA, when it is below its K0.5. Given this unique modulatory characteristic and lack of any harmful side effects, betaine emerges as a promising neuromodulator of the inhibitory pathways improving GABA homeostasis via GAT1, thereby conferring neuroprotection against excitotoxicity.

Transcranial electrical stimulation modulates emotional experience and metabolites in the prefrontal cortex in a donation task.

Understanding the neural, metabolic, and psychological mechanisms underlying human altruism and decision-making is a complex and important topic both for science and society. Here, we investigated whether transcranial Direct Current Stimulation (tDCS) applied to two prefrontal cortex regions, the ventromedial prefrontal cortex (vmPFC, anode) and the right dorsolateral prefrontal cortex (DLPFC, cathode) can induce changes in self-reported emotions and to modulate local metabolite concentrations. We employed in vivo quantitative MR Spectroscopy in healthy adult participants and quantified changes in GABA and Glx (glutamate + glutamine) before and after five sessions of tDCS delivered at 2 mA for 20 min (active group) and 1 min (sham group) while participants were engaged in a charitable donation task. In the active group, we observed increased levels of GABA in vmPFC. Glx levels decreased in both prefrontal regions and self-reported happiness increased significantly over time in the active group. Self-reported guiltiness in both active and sham groups tended to decrease. The results indicate that self-reported happiness can be modulated, possibly due to changes in Glx concentrations following repeated stimulation. Therefore, local changes may induce remote changes in the reward network through interactions with other metabolites, previously thought to be unreachable with noninvasive stimulation techniques.

Emerging Trends in Non-Protein Amino Acids as Potential Priming Agents: Implications for Stress Management Strategies and Unveiling Their Regulatory Functions.

Plants endure the repercussions of environmental stress. As the advancement of global climate change continues, it is increasingly crucial to protect against abiotic and biotic stress effects. Some naturally occurring plant compounds can be used effectively to protect the plants. By externally applying priming compounds, plants can be prompted to trigger their defensive mechanisms, resulting in improved immune system effectiveness. This review article examines the possibilities of utilizing exogenous alpha-, beta-, and gamma-aminobutyric acid (AABA, BABA, and GABA), which are non-protein amino acids (NPAAs) that are produced naturally in plants during instances of stress. The article additionally presents a concise overview of the studies' discoveries on this topic, assesses the particular fields in which they might be implemented, and proposes new avenues for future investigation.

From the Microbiome to the Electrome: Implications for the Microbiota-Gut-Brain Axis.

The gut microbiome plays a fundamental role in metabolism, as well as the immune and nervous systems. Microbial imbalance (dysbiosis) can contribute to subsequent physical and mental pathologies. As such, interest has been growing in the microbiota-gut-brain brain axis and the bioelectrical communication that could exist between bacterial and nervous cells. The aim of this study was to investigate the bioelectrical profile (electrome) of two bacterial species characteristic of the gut microbiome: a Proteobacteria Gram-negative bacillus Escherichia coli (E. coli), and a Firmicutes Gram-positive coccus Enterococcus faecalis (E. faecalis). We analyzed both bacterial strains to (i) validate the fluorescent probe bis-(1,3-dibutylbarbituric acid) trimethine oxonol, DiBAC4(3), as a reliable reporter of the changes in membrane potential (Vmem) for both bacteria; (ii) assess the evolution of the bioelectric profile throughout the growth of both strains; (iii) investigate the effects of two neural-type stimuli on Vmem changes: the excitatory neurotransmitter glutamate (Glu) and the inhibitory neurotransmitter γ-aminobutyric acid (GABA); (iv) examine the impact of the bioelectrical changes induced by neurotransmitters on bacterial growth, viability, and cultivability using absorbance, live/dead fluorescent probes, and viable counts, respectively. Our findings reveal distinct bioelectrical profiles characteristic of each bacterial species and growth phase. Importantly, neural-type stimuli induce Vmem changes without affecting bacterial growth, viability, or cultivability, suggesting a specific bioelectrical response in bacterial cells to neurotransmitter cues. These results contribute to understanding the bacterial response to external stimuli, with potential implications for modulating bacterial bioelectricity as a novel therapeutic target.

Association of Cortical Lesions With Regional Glutamate, GABA, N-Acetylaspartate, and Myoinositol Levels in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Cortical lesions contribute to disability in multiple sclerosis (MS), but their impact on regional neurotransmitter levels remains to be clarified. We tested the hypothesis that cortical lesions are associated with regional glutamate and gamma-aminobutyric acid (GABA) concentrations within the affected cortical region. METHODS: In this cross-sectional study, we used structural 7T MRI to segment cortical lesions and 7T proton MR-spectroscopy of the bilateral sensorimotor hand areas to quantify regional GABA, glutamate, N-acetylaspartate, and myoinositol concentrations in patients with MS (inclusion criteria: diagnosis of relapsing-remitting [RR] or secondary progressive MS [SPMS]; age 18-80 years) and age and sex-matched healthy controls. Data were collected at a single center between August 2018 and September 2020. Linear mixed-effects models were used to test for associations between metabolite concentrations and cortical lesion volumes within the same MR-spectroscopy voxel. RESULTS: Forty-seven patients with MS (34 RRMS, 13 SPMS; 45.1 ± 12.5 years; 31 women) and 23 healthy controls (44.4 ± 13 years, 15 women) were studied. In patients, higher regional glutamate and lower regional GABA concentrations were associated with larger cortical lesion volume within the MR-spectroscopy voxel [glutamate: 0.61 (95% CI 0.19-1.03) log(mm3), p = 0.005, GABA: -0.71 (-1.24 to -0.18) log(mm3), p = 0.01]. In addition, lower N-acetylaspartate levels [-0.37 (-0.67 to -0.07) log(mm3), p = 0.016] and higher myoinositol levels [0.48 (0.03-0.93) log(mm3), p = 0.037] were associated with a larger regional cortical lesion volume. Furthermore, glutamate concentrations were reduced in patients with SPMS compared with healthy participants [-0.75 (-1.3 to -0.19) mM, p = 0.005] and patients with RRMS [-0.55 (-1.07 to -0.02) mM, p = 0.04]. N-acetylaspartate levels were lower in both patients with RRMS [-0.81 (-1.39 to -0.24) mM, p = 0.003] and SPMS [-1.31 (-2.07 to -0.54) mM, p < 0.001] when compared with healthy controls. Creatine-normalized N-acetylaspartate levels were associated with performance in the 9-hole peg test of the contralateral hand [-0.004 (-0.007 to -0.002) log(s), p = 0.002], and reduced mean creatine-normalized glutamate was associated with increased Expanded Disability Status Scale (R = -0.39, p = 0.02). DISCUSSION: Cortical lesions are associated with local increases in glutamate and a reduction in GABA concentration within the lesional or perilesional tissue. Further studies are needed to investigate the causal relationship between cortical lesions and changes in neurotransmitter concentrations.