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1.
Behav Brain Res ; 437: 114157, 2023 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-36241070

RESUMO

Vocal communication, cognition, and affective state are key features of sustained health and wellness, and because vocalizations are often socially-motivated, social experience likely plays a role in these behaviors. The monoaminergic systems of the ventral tegmental area (VTA) and the locus coeruleus (LC) are associated with social and reward processing, vocalization production, and neurotransmitter changes in response to environmental stressors. The effect of social isolation on these complex behaviors and the underlying neural mechanisms is relatively unknown. To add to this body of literature, we randomized adult male Long-Evans rats to control (housed with a cagemate) or isolated (housed individually) conditions and assayed ultrasonic vocalizations, cognition (novel object recognition test), anxiety (elevated plus maze) and anhedonia (sucrose preference test) at 2, 4, 6, 8, and 10 months of age. At 10 months, VTA and LC samples were assayed for dopamine, norepinephrine, and serotonin using high performance liquid chromatography. We tested the hypotheses that isolation 1) diminishes vocalizations and cognition, 2) increases anxiety and depression, and 3) increases levels of dopamine, norepinephrine, and serotonin in the VTA and LC. Results showed isolation significantly reduced vocalization tonality (signal-to-noise ratio) and increased maximum frequency. There were no significant findings for cognition, anxiety, or anhedonia. Dopamine and serotonin and their respective metabolites were significantly increased in the VTA in isolated rats. These findings suggest chronic changes to social condition such as isolation affects vocalization production and levels of VTA neurotransmitters.


Assuntos
Locus Cerúleo , Ultrassom , Animais , Masculino , Ratos , Anedonia , Cognição , Dopamina/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Ratos Long-Evans , Serotonina/metabolismo , Isolamento Social , Área Tegmentar Ventral , Vocalização Animal/fisiologia
2.
Methods Mol Biol ; 2565: 179-186, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36205894

RESUMO

Hormones and neurotransmitters are released from (neuro)endocrine cells by regulated exocytosis of secretory granules. During exocytosis, the granule membrane fuses with the plasma membrane, which allows release of the stored content into the bloodstream or the surrounding tissue. Here, we give a detailed description of two complementary methods to observe and quantify exocytosis in single cells: high-resolution TIRF microscopy and patch-clamp capacitance recordings. Precise stimulation of exocytosis is achieved by local pressure application or voltage-clamp depolarizations. While the chapter is focused on insulin-secreting cells as an accessible and disease-relevant model system, the methodology is applicable to a wide variety of secretory cells including chromaffin and PC12 cells.


Assuntos
Exocitose , Células Secretoras de Insulina , Animais , Membrana Celular/metabolismo , Exocitose/fisiologia , Hormônios/metabolismo , Células Secretoras de Insulina/metabolismo , Neurotransmissores/metabolismo , Ratos , Vesículas Secretórias/metabolismo
3.
Proc Natl Acad Sci U S A ; 119(45): e2119044119, 2022 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-36322725

RESUMO

Robust neural information transfer relies on a delicate molecular nano-architecture of chemical synapses. Neurotransmitter release is controlled by a specific arrangement of proteins within presynaptic active zones. How the specific presynaptic molecular architecture relates to postsynaptic organization and how synaptic nano-architecture is transsynaptically regulated to enable stable synaptic transmission remain enigmatic. Using time-gated stimulated emission-depletion microscopy at the Drosophila neuromuscular junction, we found that presynaptic nanorings formed by the active-zone scaffold Bruchpilot (Brp) align with postsynaptic glutamate receptor (GluR) rings. Individual rings harbor approximately four transsynaptically aligned Brp-GluR nanocolumns. Similar nanocolumn rings are formed by the presynaptic protein Unc13A and GluRs. Intriguingly, acute GluR impairment triggers transsynaptic nanocolumn formation on the minute timescale during homeostatic plasticity. We reveal distinct phases of structural transsynaptic homeostatic plasticity, with postsynaptic GluR reorganization preceding presynaptic Brp modulation. Finally, homeostatic control of transsynaptic nano-architecture and neurotransmitter release requires the auxiliary GluR subunit Neto. Thus, transsynaptic nanocolumn rings provide a substrate for rapid homeostatic stabilization of synaptic efficacy.


Assuntos
Proteínas de Drosophila , Junção Neuromuscular , Animais , Junção Neuromuscular/metabolismo , Drosophila/metabolismo , Transmissão Sináptica , Sinapses/metabolismo , Receptores de Glutamato/metabolismo , Proteínas de Drosophila/metabolismo , Neurotransmissores/metabolismo , Proteínas de Membrana/metabolismo
4.
Cells ; 11(21)2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36359767

RESUMO

Sodium-glucose cotransporter-2 inhibitors (SGLT2is), such as empagliflozin, lower blood glucose in type 2 diabetes mellitus and improve cardiorenal outcomes regardless of diabetes presence. Whether SGLT2is exert any effects on the brain's metabolism has not been studied. We conducted a single-arm clinical trial to investigate the effects of once daily administration of oral empagliflozin (25 mg) for 14 days on systemic and brain metabolism in 21 non-diabetics aged 55 years old or older. Empagliflozin lowered circulating insulin and elevated ß-hydroxybutyrate over 34-h periods, both following its first administration and after 14 days of daily administration, with minor alterations in glucose homeostasis. Levels of phosphorylated insulin-like growth factor-1 receptor (pIGF-1R), phosphorylated insulin receptor (pIR), phosphorylated-in-tyrosine insulin receptor substrate-1 (pY-IRS-1), and phosphorylated protein kinase B or AKT (pAKT) were increased in extracellular vesicles enriched for neuronal origin (NEVs) following the first empagliflozin administration, but not after 14 days. Our finding of IGF-1R upregulation in NEVs is promising because several post-mortem and epidemiological studies support the idea that upregulation of IGF signaling may protect against Alzheimer's disease (AD). Moreover, our finding showing activation of insulin signaling and, in particular, the canonical pathway (pIR, pY-IRS-1, pAKT) in NEVs is important because such changes have been repeatedly associated with neuronal survival. Using brain magnetic resonance spectroscopy (MRS), we detected decreased concentrations of the excitatory neurotransmitter glutamate and its precursor glutamine after empagliflozin administration. This finding is also encouraging since glutamatergic excitotoxicity has long been implicated in AD pathology. Overall, our findings may motivate the repurposing of SGLT2is for use in AD and other, related diseases that are characterized by downregulation of IGF-1/insulin signaling in neurons and excitotoxicity.


Assuntos
Doença de Alzheimer , Diabetes Mellitus Tipo 2 , Cetose , Inibidores do Transportador 2 de Sódio-Glicose , Feminino , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/metabolismo , Glicemia/metabolismo , Encéfalo/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Ácido Glutâmico/metabolismo , Insulina/metabolismo , Insulina Regular Humana/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Cetose/metabolismo , Neurônios/metabolismo , Neurotransmissores/metabolismo , Fator de Crescimento Placentário/metabolismo , Fator de Crescimento Placentário/farmacologia , Receptor de Insulina/metabolismo , Transdução de Sinais , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
5.
J Neurosci ; 42(46): 8694-8708, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36319118

RESUMO

Enteric glia are a unique population of peripheral neuroglia that regulate homeostasis in the enteric nervous system (ENS) and intestinal functions. Despite existing in functionally diverse regions of the gastrointestinal tract, enteric glia have been approached scientifically as a homogeneous group of cells. This assumption is at odds with the functional specializations of gastrointestinal organs and recent data suggesting glial heterogeneity in the brain and ENS. Here, we used calcium imaging in transgenic mice of both sexes expressing genetically encoded calcium sensors in enteric glia and conducted contractility studies to investigate functional diversity among myenteric glia in two functionally distinct intestinal organs: the duodenum and the colon. Our data show that myenteric glia exhibit regionally distinct responses to neuromodulators that require intercellular communication with neurons to differing extents in the duodenum and colon. Glia regulate intestinal contractility in a region-specific and pathway-specific manner, which suggests regionally diverse engagement of enteric glia in local motor patterns through discrete signaling pathways. Further, functional response profiles delineate four unique subpopulations among myenteric glia that are differentially distributed between the colon and duodenum. Our findings support the conclusion that myenteric glia exhibit both intraregional and interregional heterogeneity that contributes to region-specific mechanisms that regulate digestive functions. Glial heterogeneity adds an unexpected layer of complexity in peripheral neurocircuits, and understanding the specific functions of specialized glial subtypes will provide new insight into ENS physiology and pathophysiology.SIGNIFICANCE STATEMENT Enteric glia modulate gastrointestinal functions through intercellular communication with enteric neurons. Whether heterogeneity exists among neuron-glia interactions in the digestive tract is not understood. Here, we show that myenteric glia display regional heterogeneity in their responses to neuromodulators in the duodenum and the colon, which are functionally distinct organs. Glial-mediated control of intestinal motility is region and pathway specific. Four myenteric glial subtypes are present within a given gut region that are differently distributed between gut regions. These data provide functional and regional insights into enteric circuit specificity in the adult enteric nervous system.


Assuntos
Cálcio , Sistema Nervoso Entérico , Masculino , Feminino , Camundongos , Animais , Cálcio/metabolismo , Neuroglia/metabolismo , Sistema Nervoso Entérico/metabolismo , Colo/fisiologia , Duodeno/metabolismo , Neurotransmissores/metabolismo , Camundongos Transgênicos , Plexo Mientérico/metabolismo
6.
Int J Mol Sci ; 23(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36362437

RESUMO

The main neurotransmitters in the brain-dopamine, γ-aminobutyric acid (GABA), glutamate, and opioids-are recognized to be the most important for the regulation of aggression and addiction. The aim of this work was to study differentially expressed genes (DEGs) in the main reward-related brain regions, including the ventral tegmental area (VTA), dorsal striatum (STR), ventral striatum (nucleus accumbens, NAcc), prefrontal cortex (PFC), and midbrain raphe nuclei (MRNs), in male mice with 20-day positive fighting experience in daily agonistic interactions. Expression of opioidergic, catecholaminergic, glutamatergic, and GABAergic genes was analyzed to confirm or refute the influence of repeated positive fighting experience on the development of "addiction-like" signs shown in our previous studies. High-throughput RNA sequencing was performed to identify differentially expressed genes in the brain regions of chronically aggressive mice. In the aggressive mice, upregulation of opioidergic genes was shown (Oprk1 in VTA, Pdyn in NAcc, Penk in PFC, and Oprd1 in MRNs and PFC), as was downregulation of genes Opcml and Oprk1 in STR and Pomc in VTA and NAcc. Upregulation of catecholaminergic genes in VTA (Ddc and Slc6a2) and in NAcc (Th and Drd2) and downregulation of some differentially expressed genes in MRNs (Th, Ddc, Dbh, Drd2, Slc18a2, and Sncg) and in VTA (Adra2c, Sncg, and Sncb) were also documented. The expression of GABAergic and glutamatergic genes that participate in drug addiction changed in all brain regions. According to literature data, the proteins encoded by genes Drd2, Oprk1, Oprd1, Pdyn, Penk, and Pomc are directly involved in drug addiction in humans. Thus, our results confirm our earlier claim about the formation of addiction-like signs following repeated positive fighting experience in mice, as shown previously in our biobehavioral studies.


Assuntos
Pró-Opiomelanocortina , Área Tegmentar Ventral , Humanos , Animais , Camundongos , Masculino , Pró-Opiomelanocortina/metabolismo , Área Tegmentar Ventral/metabolismo , Núcleo Accumbens/metabolismo , Encéfalo/metabolismo , Neurotransmissores/metabolismo , Recompensa , Ácido Glutâmico/metabolismo , Moléculas de Adesão Celular/metabolismo , Proteínas Ligadas por GPI/metabolismo
7.
Sci Rep ; 12(1): 17854, 2022 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-36284120

RESUMO

Hepatic encephalopathy (HE) is a deterioration of brain function in patients suffering from chronic liver disease, cirrhosis as a result of elevated blood ammonia and the production of pseudo-neurotransmitters. Herein, we investigated the chemical composition of hexane extract from Origanum vulgare (O. vulgare) leaves as well as its possible protective effects against thioacetamide (TAA)-induced HE in rats. GC-MS analysis of the extract revealed tentative identification of twenty-five compounds (82.93%), predominated by cholesten-3-one (27.30%), followed by γ-tocopherol (13.52%), α-tocopherol (5.01%), ß-amyrin (5.24%) and α-amyrin (4.89%). Albino rats were distributed into seven groups (n = 7). G1 served as negative control; G2 and G3 served as controls treated with O. vulgare (100 and 200 mg/kg/p.o b.w, respectively); G4 served as TAA-positive control group (100 mg/kg/day/i.p., three alternative days per week for six weeks); G5, G6, and G7 served as TAA -induced HE rat model that received O. vulgare 100, O. vulgare 200, and silymarin (100 mg/kg of SILY, as standard drug), respectively. TAA showed depressive and anxiety-like behaviors in forced swimming test (FST) and reduction of cognitive score in elevated plus-maze test (EPMT) as well as impairment of locomotor and exploratory activities in open-field test (OFT). TAA caused a significant decline in body weight gain; however, the relative liver weight and brain water content were statistically increased. TAA-intoxicated rats showed significant increase of serum biomarker enzymes, proinflammatory cytokines, blood ammonia levels, brain serotonin, acetyl cholinesterase and cellular lipid peroxidation with significant decrease of brain dopamine, norepinephrine, antioxidant status. The hepatoprotective/neuro-protective activities of O. vulgare was found to be comparable with that of SILY in HE rats model. Where, treatment of TAA-intoxicated rats with O. vulgare attenuated anxiety, depressive-related behaviors, and reduced the biochemical changes in HE-induced by TAA. Therefore, O. vulgare could be an excellent hepato-/neuroprotective against hepatic injury and HE via improving the oxidative/inflammatory status through its antioxidant and neuro-modulatory properties and its effect is equal to that of SILY.


Assuntos
Encefalopatia Hepática , Origanum , Silimarina , Animais , Ratos , alfa-Tocoferol/metabolismo , Amônia/metabolismo , Antioxidantes/metabolismo , Biomarcadores/metabolismo , Colinesterases/metabolismo , Citocinas/metabolismo , Dopamina/metabolismo , gama-Tocoferol/farmacologia , Encefalopatia Hepática/metabolismo , Hexanos , Fígado/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Origanum/química , Estresse Oxidativo , Ratos Wistar , Serotonina/metabolismo , Silimarina/farmacologia , Tioacetamida , Água/metabolismo
8.
Nutrients ; 14(19)2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36235829

RESUMO

BACKGROUND: The hypothalamic paraventricular nucleus (PVN) is an important nucleus in the brain that plays a key role in regulating sympathetic nerve activity (SNA) and blood pressure. Silent mating-type information regulation 2 homolog-1 (sirtuin1, SIRT1) not only protects cardiovascular function but also reduces inflammation and oxidative stress in the periphery. However, its role in the central regulation of hypertension remains unknown. It is hypothesized that SIRT1 activation by resveratrol may reduce SNA and lower blood pressure through the regulation of intracellular reactive oxygen species (ROS) and neurotransmitters in the PVN. METHODS: The two-kidney one-clip (2K1C) method was used to induce renovascular hypertension in male Sprague-Dawley rats. Then, bilaterally injections of vehicle (artificial cerebrospinal fluid, aCSF, 0.4 µL) or resveratrol (a SIRT1 agonist, 160 µmol/L, 0.4 µL) into rat PVN were performed for four weeks. RESULTS: PVN SIRT1 expression was lower in the hypertension group than the sham surgery (SHAM) group. Activated SIRT1 within the PVN lowered systolic blood pressure and plasma norepinephrine (NE) levels. It was found that PVN of 2K1C animals injected with resveratrol exhibited increased expression of SIRT1, copper-zinc superoxide dismutase (SOD1), and glutamic acid decarboxylase (GAD67), as well as decreased activity of nuclear factor-kappa B (NF-κB) p65 and NAD(P)H oxidase (NOX), particularly NOX4. Treatment with resveratrol also decreased expression of ROS and tyrosine hydroxylase (TH). CONCLUSION: Resveratrol within the PVN attenuates hypertension via the SIRT1/NF-κB pathway to decrease ROS and restore the balance of excitatory and inhibitory neurotransmitters.


Assuntos
Hipertensão , Núcleo Hipotalâmico Paraventricular , Animais , Cobre/metabolismo , Glutamato Descarboxilase/metabolismo , Masculino , NADPH Oxidases/metabolismo , NF-kappa B/metabolismo , Neurotransmissores/metabolismo , Norepinefrina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Resveratrol/metabolismo , Resveratrol/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Superóxido Dismutase-1/metabolismo , Sistema Nervoso Simpático/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Zinco/metabolismo
9.
Int J Mol Sci ; 23(19)2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-36232945

RESUMO

Dopamine regulates emotional behaviors, including rewarding and aversive behaviors, through the mesolimbic dopaminergic pathway, which projects dopamine neurons from the ventral tegmental area to the nucleus accumbens (NAc). Protein phosphorylation is critical for intracellular signaling pathways and physiological functions, which are regulated by neurotransmitters in the brain. Previous studies have demonstrated that dopamine stimulated the phosphorylation of intracellular substrates, such as receptors, ion channels, and transcription factors, to regulate neuronal excitability and synaptic plasticity through dopamine receptors. We also established a novel database called KANPHOS that provides information on phosphorylation signals downstream of monoamines identified by our kinase substrate screening methods, including dopamine, in addition to those reported in the literature. Recent advances in proteomics techniques have enabled us to clarify the mechanisms through which dopamine controls rewarding and aversive behaviors through signal pathways in the NAc. In this review, we discuss the intracellular phosphorylation signals regulated by dopamine in these two emotional behaviors.


Assuntos
Dopamina , Área Tegmentar Ventral , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Neurotransmissores/metabolismo , Núcleo Accumbens/metabolismo , Fosforilação , Receptores Dopaminérgicos/metabolismo , Fatores de Transcrição/metabolismo , Área Tegmentar Ventral/metabolismo
10.
Sci Adv ; 8(43): eabq1780, 2022 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-36288320

RESUMO

Histamine is an important monoamine neurotransmitter that regulates multiple physiological activities in both vertebrates and invertebrates. Clearance and recycling of histamine are critical for sustaining histaminergic transmission. However, unlike other monoamine neurotransmitters, a histamine-specific transporter capable of clearing histamine from the synaptic cleft has not been identified. Here, through an in vitro histamine uptake screening, we identified an epithelial glia-expressing transporter, HisT (Histamine Transporter), that specifically transports histamine into cells. HisT misexpression in both pre- and postsynaptic neurons revealed a critical in vivo role for HisT in histamine transport and synaptic transmission. Last, we generated null hist alleles and demonstrated key physiological roles of HisT in maintaining histamine pools and sustaining visual transmission when the de novo synthesis of histamine synthesis was reduced. Our work identifies the first transporter that specifically recycles histamine and further indicates that the histamine clearance pathway may involve both the uptake-1 and uptake-2 transport systems.


Assuntos
Proteínas de Drosophila , Drosophila , Animais , Drosophila/metabolismo , Histamina/metabolismo , Proteínas de Drosophila/metabolismo , Neuroglia/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Neurotransmissores/metabolismo
11.
Eur J Med Chem ; 244: 114820, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36242989

RESUMO

Neurotransmitters are chemical compounds released by neurons acting as messengers that transmit signals to other neurons, called postsynaptic neurons, or other types of cells. These neurotransmitters play a crucial role in the nervous system, and abnormalities in their levels have been associated with physical, psychotic, and neurodegenerative diseases such as Alzheimer's, Parkinson's, dementia, addiction, depression, and schizophrenia. This makes it necessary to develop sensitive and reliable techniques for their detection and monitoring in order to screen diseases. Meanwhile, neurotransmitters' detection remains a challenge and continues to attract considerable attention. Fluorescent and colorimetric organic probes were and still efficient tools for rapid, selective and low-cost detection of a large scale of analytes. Neurotransmitters can interact with the sensing molecule leading to the formation of complexes or new molecules displaying photophysical properties different from the starting fluorophore or/and chromophore and thus through different sensing mechanisms. Diverse applications of the sensors like live cell imaging are being reported. This review is a collection of recent development in the design of new organic receptors utilized for the detection of neurotransmitters including monoamines (catecholamines, serotonin and histamine), amino acids (glutamate, aspartate and glycine), gasotransmitters, and acetylcholine.


Assuntos
Colorimetria , Neurotransmissores , Neurotransmissores/metabolismo , Catecolaminas , Serotonina , Fluorometria
12.
Sci Rep ; 12(1): 17176, 2022 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229560

RESUMO

The use of human derived induced pluripotent stem cells (hiPSCs) differentiated to dopaminergic (DA) neurons offers a valuable experimental model to decorticate the cellular and molecular mechanisms of Parkinson's disease (PD) pathogenesis. However, the existing approaches present with several limitations, notably the lengthy time course of the protocols and the high variability in the yield of DA neurons. Here we report on the development of an improved approach that combines neurogenin-2 programming with the use of commercially available midbrain differentiation kits for a rapid, efficient, and reproducible directed differentiation of hiPSCs to mature and functional induced DA (iDA) neurons, with minimum contamination by other brain cell types. Gene expression analysis, associated with functional characterization examining neurotransmitter release and electrical recordings, support the functional identity of the iDA neurons to A9 midbrain neurons. iDA neurons showed selective vulnerability when exposed to 6-hydroxydopamine, thus providing a viable in vitro approach for modeling PD and for the screening of small molecules with neuroprotective proprieties.


Assuntos
Células-Tronco Pluripotentes Induzidas , Doença de Parkinson , Diferenciação Celular/genética , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Humanos , Mesencéfalo/metabolismo , Neurotransmissores/metabolismo , Oxidopamina/metabolismo , Oxidopamina/farmacologia , Doença de Parkinson/metabolismo
13.
Food Chem Toxicol ; 169: 113434, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36126889

RESUMO

The effects of Type II pyrethroid lambda-cyhalothrin on dopamine (DA) and serotonin (5-HT) synthesis in rat brain regions (striatum, hippocampus, prefrontal cortex, hypothalamus and midbrain) were studied. Lambda-cyhalothrin (1, 4 and 8 mg/kg bw, oral gavage, 6 days) induced a decrease of DA, 5-HT and metabolites contents, in a brain regional- and dose-related manner. The major decreases in DA and 5-HT contents were observed in hippocampus and prefrontal cortex tissues. This research study also showed in hippocampus and prefrontal cortex, that lambda-cyhalothrin modified the mRNA levels of DA transporter gene (Dat1 up-regulation), 5-HT transporter gene (SERT down-regulation), DA receptor genes (Drd1and Drd2 down-regulation), 5-HT receptor genes (5-HT1A and 5-HT2A down-regulation/up-regulation), DA synthesis gene (TH down-regulation), 5-HT synthesis gene (TPH2 down-regulation), DA and 5-HT degradation genes (MAOA and MAOB up-regulation). These results reveal that lambda-cyhalothrin altered central nervous system (CNS) monoaminergic neurotransmitters. Lambda-cyhalothrin evoked a selective neurotoxic injury to dopaminergic and serotoninergic pathways. These findings may clarify on the pyrethroids-induced neurotoxicity mechanisms and could involve pyrethroids as environmental risk factors leading to the development of neurodegenerative diseases.


Assuntos
Dopamina , Piretrinas , Animais , Encéfalo , Dopamina/metabolismo , Neurotransmissores/metabolismo , Nitrilas , Piretrinas/toxicidade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Serotonina/metabolismo
14.
Glia ; 70(12): 2378-2391, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36097958

RESUMO

Much of the Ca2+ activity in astrocytes is spatially restricted to microdomains and occurs in fine processes that form a complex anatomical meshwork, the so-called spongiform domain. A growing body of literature indicates that those astrocytic Ca2+ signals can influence the activity of neuronal synapses and thus tune the flow of information through neuronal circuits. Because of technical difficulties in accessing the small spatial scale involved, the role of astrocyte morphology on Ca2+ microdomain activity remains poorly understood. Here, we use computational tools and idealized 3D geometries of fine processes based on recent super-resolution microscopy data to investigate the mechanistic link between astrocytic nanoscale morphology and local Ca2+ activity. Simulations demonstrate that the nano-morphology of astrocytic processes powerfully shapes the spatio-temporal properties of Ca2+ signals and promotes local Ca2+ activity. The model predicts that this effect is attenuated upon astrocytic swelling, hallmark of brain diseases, which we confirm experimentally in hypo-osmotic conditions. Upon repeated neurotransmitter release events, the model predicts that swelling hinders astrocytic signal propagation. Overall, this study highlights the influence of the complex morphology of astrocytes at the nanoscale and its remodeling in pathological conditions on neuron-astrocyte communication at so-called tripartite synapses, where astrocytic processes come into close contact with pre- and postsynaptic structures.


Assuntos
Astrócitos , Sinalização do Cálcio , Astrócitos/metabolismo , Cálcio/metabolismo , Sinalização do Cálcio/fisiologia , Neurônios/metabolismo , Neurotransmissores/metabolismo , Sinapses/metabolismo
15.
Biomed Pharmacother ; 155: 113685, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36137407

RESUMO

Despite decades of research in the field of substance withdrawal, molecular biomarkers and related mechanistic study have generally been lacking. In addition to known neurotransmitters, circulating miRNAs are found in small vesicles known as exosomes within blood that have diagnostic potential and are known to contribute to psychiatric disorders. The aim of this work was to characterize the changes in neurotransmitter and exosomal miRNA profiles during heroin and methamphetamine withdrawal using a cross-sectional study design, and to determine their associations to psychiatric comorbidities in a large group of patients with substance use disorders (SUDs). Using weighted gene co-expression network analysis, a series of known, conserved, and novel exosomal miRNAs were identified as being associated with the severity of anxiety and depression, as well as the concentrations of neurotransmitters GABA, choline, and serotonin. Bioinformatics analyses established that the differences in the miRNA profile target signaling pathways are significantly associated with developmental and intellectual abnormalities. Notably, a set of dysregulated miRNA signatures including hsa-mia-451a and hsa-mir-21a resulted in an AUC of 0.966 and 0.861, respectively, for predicting the patients with SUDs. Furthermore, hsa-miR-744a-5p was positively correlated with serotonin, and its important role in maintaining neuronal development and function was revealed using an in vitro human induced pluripotent stem cells derived neuronal model. Our results suggest that the miRNA content of circulating exosomes represent a biomolecular "fingerprint" of the progression of substance withdrawal and may uncover the putative mechanism of how these exosomal miRNAs contribute to psychiatric symptoms.


Assuntos
Exossomos , Células-Tronco Pluripotentes Induzidas , Metanfetamina , MicroRNAs , Humanos , MicroRNAs/metabolismo , Heroína , Serotonina/metabolismo , Estudos Transversais , Células-Tronco Pluripotentes Induzidas/metabolismo , Exossomos/genética , Exossomos/metabolismo , Biomarcadores/metabolismo , Neurotransmissores/metabolismo , Colina/metabolismo , Metanfetamina/efeitos adversos , Ácido gama-Aminobutírico/metabolismo
16.
Neuron ; 110(20): 3302-3317.e7, 2022 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-36070750

RESUMO

Homeostatic plasticity (HP) encompasses a suite of compensatory physiological processes that counteract neuronal perturbations, enabling brain resilience. Currently, we lack a complete description of the homeostatic processes that operate within the mammalian brain. Here, we demonstrate that acute, partial AMPAR-specific antagonism induces potentiation of presynaptic neurotransmitter release in adult hippocampus, a form of compensatory plasticity that is consistent with the expression of presynaptic homeostatic plasticity (PHP) documented at peripheral synapses. We show that this compensatory plasticity can be induced within minutes, requires postsynaptic NMDARs, and is expressed via correlated increases in dendritic spine volume, active zone area, and docked vesicle number. Further, simultaneous postsynaptic genetic reduction of GluA1, GluA2, and GluA3 in triple heterozygous knockouts induces potentiation of presynaptic release. Finally, induction of compensatory plasticity at excitatory synapses induces a parallel, NMDAR-dependent potentiation of inhibitory transmission, a cross-modal effect consistent with the anti-epileptic activity of AMPAR-specific antagonists used in humans.


Assuntos
Receptores de N-Metil-D-Aspartato , Sinapses , Humanos , Animais , Sinapses/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Hipocampo/fisiologia , Homeostase/fisiologia , Neurotransmissores/metabolismo , Plasticidade Neuronal/fisiologia , Mamíferos/metabolismo
17.
Arch Toxicol ; 96(12): 3279-3290, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36104498

RESUMO

3,4-Methylenedioximethamphetamine (MDMA; "ecstasy") is a psychotropic drug with well-known neurotoxic effects mediated by hitherto not fully understood mechanisms. The Na+- and K+-activated adenosine 5'-triphosphatase (Na+/K+ ATPase), by maintaining the ion gradient across the cell membrane, regulates neuronal excitability. Thus, a perturbation of its function strongly impacts cell homeostasis, ultimately leading to neuronal dysfunction and death. Nevertheless, whether MDMA affects the Na+/K+ ATPase remains unknown. In this study, we used synaptosomes obtained from whole mouse brain to test the effects of MDMA, three of its major metabolites [α-methyldopamine, N-methyl-α-methyldopamine and 5-(glutathion-S-yl)-α-methyldopamine], serotonin (5-HT), dopamine, 3,4-dihydroxy-L-phenylalanine (L-Dopa) and 3,4-dihydroxyphenylacetic acid (DOPAC) on the Na+/K+ ATPase function. A concentration-dependent increase of Na+/K+ ATPase activity was observed in synaptosomes exposed to the tested compounds (concentrations ranging from 0.0625 to 200 µM). These effects were independent of protein kinases A and C activities. Nevertheless, a rescue of the compounds' effects was observed in synaptosomes pre-incubated with the antioxidant N-acetylcysteine (1 mM), suggesting a role for reactive species-regulated pathways on the Na+/K+ ATPase effects. In agreement with this hypothesis, a similar increase in the pump activity was found in synaptosomes exposed to the chemical generator of superoxide radicals, phenazine methosulfate (1-250 µM). This study demonstrates the ability of MDMA metabolites, monoamine neurotransmitters, L-Dopa and DOPAC to alter the Na+/K+ ATPase function. This could represent a yet unknown mechanism of action of MDMA and its metabolites in the brain.


Assuntos
N-Metil-3,4-Metilenodioxianfetamina , Animais , Camundongos , N-Metil-3,4-Metilenodioxianfetamina/toxicidade , Sinaptossomos/metabolismo , Serotonina/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/metabolismo , Ácido 3,4-Di-Hidroxifenilacético/farmacologia , Dopamina/metabolismo , Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Levodopa/metabolismo , Levodopa/farmacologia , Adenosina Trifosfatases/metabolismo , Adenosina Trifosfatases/farmacologia , Superóxidos/metabolismo , Metilfenazônio Metossulfato/metabolismo , Metilfenazônio Metossulfato/farmacologia , Encéfalo , Neurotransmissores/metabolismo , Neurotransmissores/farmacologia , Adenosina/metabolismo , Proteínas Quinases/metabolismo
18.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142117

RESUMO

Hirschsprung's disease (HSCR) is a common developmental anomaly of the gastrointestinal tract in children. The most significant characteristics of aganglionic segments in HSCR are hyperplastic extrinsic nerve fibers and the absence of endogenous ganglion plexus. Double C2 domain alpha (DOC2A) is mainly located in the nucleus and is involved in Ca2+-dependent neurotransmitter release. The loss function of DOC2A influences postsynaptic protein synthesis, dendrite morphology, postsynaptic receptor density and synaptic plasticity. It is still unknown why hyperplastic extrinsic nerve fibers grow into aganglionic segments in HSCR. We detected the expression of DOC2A in HSCR aganglionic segment colons and established three DOC2A-knockdown models in the Neuro-2a cell line, neural spheres and zebrafish separately. First, we detected the protein and mRNA expression of DOC2A and found that DOC2A was negatively correlated with AChE+ grades. Second, in the Neuro-2a cell lines, we found that the amount of neurite outgrowth and mean area per cell were significantly increased, which suggested that the inhibition of DOC2A promotes nerve fiber formation and the neuron's polarity. In the neural spheres, we found that the DOC2A knockdown was manifested by a more obvious connection of nerve fibers in neural spheres. Then, we knocked down Doc2a in zebrafish and found that the down-regulation of Doc2a accelerates the formation of hyperplastic nerve fibers in aganglionic segments in zebrafish. Finally, we detected the expression of MUNC13-2 (UNC13B), which was obviously up-regulated in Grade3/4 (lower DOC2A expression) compared with Grade1/2 (higher DOC2A expression) in the circular muscle layer and longitudinal muscle layer. The expression of UNC13B was up-regulated with the knocking down of DOC2A, and there were protein interactions between DOC2A and UNC13B. The down-regulation of DOC2A may be an important factor leading to hyperplastic nerve fibers in aganglionic segments of HSCR. UNC13B seems to be a downstream molecule to DOC2A, which may participate in the spasm of aganglionic segments of HSCR patient colons.


Assuntos
Doença de Hirschsprung , Animais , Domínios C2 , Colo/metabolismo , Regulação para Baixo , Doença de Hirschsprung/genética , Doença de Hirschsprung/metabolismo , Fibras Nervosas/metabolismo , Neurotransmissores/metabolismo , RNA Mensageiro/genética , Peixe-Zebra/genética
19.
Int J Mol Sci ; 23(18)2022 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-36142469

RESUMO

Glyght is a new photochromic compound described as an effective modulator of glycine receptors at heterologous expression, in brain slices and in zebrafish larvae. Glyght also caused weak inhibition of GABAA-mediated currents in a cell line expressing α1/ß2/γ2 GABAA receptors. However, the effects of Glyght on GABAergic transmission in the brain have not been analysed, which does not allow a sufficiently comprehensive assessment of the effects of the compound on the nervous system. Therefore, in this study using whole-cell patch-clamp recording, we analysed the Glyght (100 µM) action on evoked GABAergic inhibitory postsynaptic currents (eIPSCs) in mice hippocampal slices. Two populations of cells were found: the first responded by reducing the GABAergic eIPSCs' amplitude, whereas the second showed no sensitivity to the compound. Glyght did not affect the ionic currents' amplitude induced by GABA application, suggesting the absence of action on postsynaptic GABA receptors. Additionally, Glyght had no impact on the paired-pulse modulation of GABAergic eIPSCs, indicating that Glyght does not modulate the neurotransmitter release mechanisms. In the presence of strychnine, an antagonist of glycine receptors, the Glyght effect on GABAergic synaptic transmission was absent. Our results suggest that Glyght can modulate GABAergic synaptic transmission via action on extrasynaptic glycine receptors.


Assuntos
Receptores de Glicina , Estricnina , Animais , Encéfalo/metabolismo , Camundongos , Neurônios/metabolismo , Neurotransmissores/metabolismo , Receptores de GABA/metabolismo , Receptores de GABA-A/metabolismo , Receptores de Glicina/metabolismo , Estricnina/farmacologia , Transmissão Sináptica , Peixe-Zebra/metabolismo , Ácido gama-Aminobutírico/metabolismo
20.
Int J Mol Sci ; 23(18)2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36142716

RESUMO

Adversity is particularly pernicious in early life, increasing the likelihood of developing psychiatric disorders in adulthood. Juvenile and adult rats exposed to social isolation show differences in anxiety-like behaviors and significant changes in dopamine (DA) neurotransmission in the nucleus accumbens (NAc). Brain response to stress is partly mediated by the corticotropin-releasing factor (CRF) system, composed of CRF and its two main receptors, CRF-R1 and CRF-R2. In the NAc shell of adult rats, CRF induces anxiety-like behavior and changes local DA balance. However, the role of CRF receptors in the control of neurotransmission in the NAc is not fully understood, nor is it known whether there are differences between life stages. Our previous data showed that infusion of a CRF-R1 antagonist into the NAc of juvenile rats increased DA levels in response to a depolarizing stimulus and decreased basal glutamate levels. To extend this analysis, we now evaluated the effect of a CRF-R1 antagonist infusion in the NAc of adult rats. Here, we describe that the opposite occurred in the NAc of adult compared to juvenile rats. Infusion of a CRF-R1 antagonist decreased DA and increased glutamate levels in response to a depolarizing stimulus. Furthermore, basal levels of DA, glutamate, and γ-Aminobutyric acid (GABA) were similar in juvenile animals compared to adults. CRF-R1 protein levels and localization were not different in juvenile compared to adult rats. Interestingly, we observed differences in the signaling pathways of CRF-R1 in the NAc of juveniles compared to adult rats. We propose that the function of CRF-R1 receptors is differentially modulated in the NAc according to life stage.


Assuntos
Núcleo Accumbens , Receptores de Hormônio Liberador da Corticotropina , Animais , Hormônio Liberador da Corticotropina/metabolismo , Dopamina/metabolismo , Glutamatos/metabolismo , Humanos , Microdiálise , Neurotransmissores/metabolismo , Núcleo Accumbens/metabolismo , Ratos , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Ácido gama-Aminobutírico/metabolismo
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