RESUMO
Loss of the gene (Fmr1) encoding Fragile X mental retardation protein (FMRP) causes increased mRNA translation and aberrant synaptic development. We find neurons of the Fmr1-/y mouse have a mitochondrial inner membrane leak contributing to a "leak metabolism." In human Fragile X syndrome (FXS) fibroblasts and in Fmr1-/y mouse neurons, closure of the ATP synthase leak channel by mild depletion of its c-subunit or pharmacological inhibition normalizes stimulus-induced and constitutive mRNA translation rate, decreases lactate and key glycolytic and tricarboxylic acid (TCA) cycle enzyme levels, and triggers synapse maturation. FMRP regulates leak closure in wild-type (WT), but not FX synapses, by stimulus-dependent ATP synthase ß subunit translation; this increases the ratio of ATP synthase enzyme to its c-subunit, enhancing ATP production efficiency and synaptic growth. In contrast, in FXS, inability to close developmental c-subunit leak prevents stimulus-dependent synaptic maturation. Therefore, ATP synthase c-subunit leak closure encourages development and attenuates autistic behaviors.
Assuntos
Trifosfato de Adenosina/metabolismo , Síndrome do Cromossomo X Frágil/metabolismo , Subunidades Proteicas/metabolismo , Animais , Linhagem Celular , Ciclo do Ácido Cítrico/fisiologia , Fibroblastos/metabolismo , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Células HEK293 , Humanos , Camundongos , Neurônios/metabolismo , RNA Mensageiro , Sinapses/metabolismoRESUMO
The dorsal (DS) and ventral striatum (VS) receive dopaminergic projections that control motor functions and reward-related behavior. It remains poorly understood how dopamine release dynamics across different temporal scales in these regions are coupled to behavioral outcomes. Here, we employ the dopamine sensor dLight1.3b together with multiregion fiber photometry and machine learning-based analysis to decode dopamine dynamics across the striatum during self-paced exploratory behavior in mice. Our data show a striking coordination of rapidly fluctuating signal in the DS, carrying information across dopamine levels, with a slower signal in the VS, consisting mainly of slow-paced transients. Importantly, these release dynamics correlated with discrete behavioral motifs, such as turns, running, and grooming on a subsecond-to-minute time scale. Disruption of dopamine dynamics with cocaine caused randomization of action selection sequencing and disturbance of DS-VS coordination. The data suggest that distinct dopamine dynamics of DS and VS jointly encode behavioral sequences during unconstrained activity with DS modulating the stringing together of actions and VS the signal to initiate and sustain the selected action.
Assuntos
Cocaína , Estriado Ventral , Camundongos , Animais , Dopamina , RecompensaRESUMO
New tasks are often learned in stages with each stage reflecting a different learning challenge. Accordingly, each learning stage is likely mediated by distinct neuronal processes. And yet, most rodent studies of the neuronal correlates of goal-directed learning focus on individual outcome measures and individual brain regions. Here, we longitudinally studied mice from naïve to expert performance in a head-fixed, operant conditioning whisker discrimination task. In addition to tracking the primary behavioral outcome of stimulus discrimination, we tracked and compared an array of object-based and temporal-based behavioral measures. These behavioral analyses identify multiple, partially overlapping learning stages in this task, consistent with initial response implementation, early stimulus-response generalization, and late response inhibition. To begin to understand the neuronal foundations of these learning processes, we performed widefield Ca2+ imaging of dorsal neocortex throughout learning and correlated behavioral measures with neuronal activity. We found distinct and widespread correlations between neocortical activation patterns and various behavioral measures. For example, improvements in sensory discrimination correlated with target stimulus evoked activations of response-related cortices along with distractor stimulus evoked global cortical suppression. Our study reveals multidimensional learning for a simple goal-directed learning task and generates hypotheses for the neuronal modulations underlying these various learning processes.
Assuntos
Condicionamento Operante , Objetivos , Neocórtex , Vibrissas , Animais , Neocórtex/fisiologia , Condicionamento Operante/fisiologia , Vibrissas/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Feminino , Aprendizagem por Discriminação/fisiologia , Aprendizagem/fisiologia , Neurônios/fisiologiaRESUMO
Prostaglandins are bioactive compounds, and the activation of their receptors affects the expression of clock genes. However, the prostaglandin F receptor (Ptgfr) has no known relationship with biological rhythms. Here, we first measured the locomotor period lengths of Ptgfr-KO (B6.129-Ptgfrtm1Sna) mice and found that they were longer under constant dark conditions (DD) than those of wild-type (C57BL/6J) mice. We then investigated the clock gene patterns within the suprachiasmatic nucleus in Ptgfr-KO mice under DD and observed a decrease in the expression of the clock gene cryptochrome 1 (Cry1), which is related to the circadian cycle. Moreover, the expression of Cry1, Cry2, and Period2 (Per2) mRNA were significantly altered in the mouse liver in Ptgfr-KO mice under DD. In the wild-type mouse, the plasma prostaglandin F2α (PGF2α) levels showed a circadian rhythm under a 12 h cycle of light-dark conditions. In addition, in vitro experiments showed that the addition of PTGFR agonists altered the amplitude of Per2::luc activity, and this alteration differed with the timing of the agonist addition. These results lead us to hypothesize that the plasma rhythm of PGF2α is important for driving clock genes, thus suggesting the involvement of PGF2α- and Ptgfr-targeting drugs in the biological clock cycle.
Assuntos
Ritmo Circadiano , Dinoprosta , Camundongos , Animais , Dinoprosta/metabolismo , Camundongos Endogâmicos C57BL , Ritmo Circadiano/genética , Relógios Biológicos , Núcleo Supraquiasmático/metabolismo , Expressão Gênica , Criptocromos/genética , Criptocromos/metabolismoRESUMO
A strong bidirectional link between metabolic and psychiatric disorders exists; yet, the molecular basis underlying this interaction remains unresolved. Here we explored the role of the brown adipose tissue (BAT) as modulatory interface, focusing on the involvement of uncoupling protein 1 (UCP-1), a key metabolic regulator highly expressed in BAT, in the control of emotional behavior. Male and female constitutive UCP-1 knock-out (KO) mice were used to investigate the consequences of UCP-1 deficiency on anxiety-related and depression-related behaviors under mild thermogenic (23°C) and thermoneutral (29°C) conditions. UCP-1 KO mice displayed a selective enhancement of anxiety-related behavior exclusively under thermogenic conditions, but not at thermoneutrality. Neural and endocrine stress mediators were not affected in UCP-1 KO mice, which showed an activation of the integrated stress response alongside enhanced fibroblast-growth factor-21 (FGF-21) levels. However, viral-mediated overexpression of FGF-21 did not phenocopy the behavioral alterations of UCP-1 KO mice and blocking FGF-21 activity did not rescue the anxiogenic phenotype of UCP-1 KO mice. No effects of surgical removal of the intrascapular BAT on anxiety-like behavior or FGF-21 levels were observed in either UCP-1 KO or WT mice. We provide evidence for a novel role of UCP-1 in the regulation of emotions that manifests as inhibitory constraint on anxiety-related behavior, exclusively under thermogenic conditions. We propose this function of UCP-1 to be independent of its activity in the BAT and likely mediated through a central role of UCP-1 in brain regions with converging involvement in energy and emotional control.SIGNIFICANCE STATEMENT In this first description of a temperature-dependent phenotype of emotional behavior, we propose uncoupling protein-1 (UCP-1), the key component of the thermogenic function of the brown adipose tissue, as molecular break controlling anxiety-related behavior in mice. We suggest the involvement of UCP-1 in fear regulation to be mediated through its expression in brain regions with converging roles in energy and emotional control. These data are important and relevant in light of the largely unexplored bidirectional link between metabolic and psychiatric disorders, which has the potential for providing insight into novel therapeutic strategies for the management of both conditions.
Assuntos
Canais Iônicos , Proteínas Mitocondriais , Camundongos , Masculino , Feminino , Animais , Temperatura , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Canais Iônicos/genética , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Tecido Adiposo Marrom/metabolismo , Camundongos Knockout , AnsiedadeRESUMO
Animals are able to detect the nutritional content of sugar independently of taste. When given a choice between nutritive sugar and nonnutritive sugar, animals develop a preference for nutritive sugar over nonnutritive sugar during a period of food deprivation (Buchanan et al., 2022; Dus et al., 2011; 2015; Tan et al., 2020; Tellez et al., 2016). To quantify behavioral features during an episode of licking nutritive versus nonnutritive sugar, we implemented a multi-vision, deep learning-based 3D pose estimation system, termed the AI Vision Analysis for Three-dimensional Action in Real-Time (AVATAR)(Kim et al., 2022). Using this method, we found that mice exhibit significantly different approach behavioral responses toward nutritive sugar versus nonnutritive sugar even before licking a sugar solution. Notably, the behavioral sequences during the approach toward nutritive versus nonnutritive sugar became significantly different over time. These results suggest that the nutritional value of sugar not only promotes its consumption but also elicits distinct repertoires of feeding behavior in deprived mice.
Assuntos
Aprendizado Profundo , Açúcares , Camundongos , Animais , Comportamento Alimentar/fisiologia , Comportamento Animal/fisiologiaRESUMO
C1q/TNF-related protein (CTRP) family comprises fifteen highly conserved secretory proteins with diverse central and peripheral functions. In zebrafish, mouse, and human, CTRP4 is most highly expressed in the brain. We previously showed that CTRP4 is a metabolically responsive regulator of food intake and energy balance, and mice lacking CTRP4 exhibit sexually dimorphic changes in ingestive behaviors and systemic metabolism. Recent single-cell RNA sequencing also revealed Ctrp4/C1qtnf4 expression in diverse neuronal cell types across distinct anatomical brain regions, hinting at additional roles in the central nervous system not previously characterized. To uncover additional central functions of CTRP4, we subjected Ctrp4 knockout (KO) mice to a battery of behavioral tests. Relative to wild-type (WT) littermates, loss of CTRP4 does not alter exploratory, anxiety-, or depressive-like behaviors, motor function and balance, sensorimotor gating, novel object recognition, and spatial memory. While pain-sensing mechanisms in response to thermal stress and mild shock are intact, both male and female Ctrp4 KO mice have increased sensitivity to pain induced by higher-level shock, suggesting altered nociceptive function. Importantly, CTRP4 deficiency impairs hippocampal-dependent associative learning and memory as assessed by trace fear conditioning paradigm. This deficit is sex-dependent, affects only female mice, and is associated with altered expression of learning and memory genes (Arc, c-fos, and Pde4d) in the hippocampus and cortex. Altogether, our behavioral and gene expression analyses have uncovered novel aspects of the CTRP4 function and provided a physiological context to further investigate its mechanism of action in the central and peripheral nervous system.
Assuntos
Adipocinas/genética , Expressão Gênica , Técnicas de Inativação de Genes/métodos , Aprendizagem em Labirinto , Memória Espacial , Adipocinas/metabolismo , Animais , Ansiedade/genética , Comportamento Animal , Córtex Cerebelar/metabolismo , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Teste de Desempenho do Rota-RodRESUMO
Imbalance in the metabolic pathway linking excitatory and inhibitory neurotransmission has been implicated in multiple psychiatric and neurologic disorders. Recently, we described enantiomer-specific effects of 2-methylglutamate, which is not decarboxylated to the corresponding methyl analogue of gamma-aminobutyric acid (GABA): 4-aminopentanoic acid (4APA). Here, we tested the hypothesis that 4APA also has enantiomer-specific actions in brain. Mouse cerebral synaptosome uptake (nmol/mg protein over 30 min) of (R)-4APA or (S)-4APA was time and temperature dependent; however, the R enantiomer had greater uptake, reduction of endogenous GABA concentration, and release following membrane depolarization than did the S enantiomer. (S)-4APA exhibited some weak agonist (GABAA α4ß3δ, GABAA α5ß2γ2, and GABAB B1/B2) and antagonist (GABAA α6ß2γ2) activity while (R)-4APA showed weak agonist activity only with GABAA α5ß2γ2. Both 4APA enantiomers (100 mg/kg IP) were detected in mouse brain 10 min after injection, and by 1 hr had reached concentrations that were stable over 6 hr; both enantiomers were cleared rapidly from mouse serum over 6 hr. Two-month-old mice had no mortality following 100-900 mg/kg IP of each 4APA enantiomer but did have similar dose-dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100 mg/kg impacted outcomes in 23 measures of well-being, activity chamber, or withdrawal from hot plate. Our results suggest that enantiomers of 4APA are active in mouse brain, and that (R)-4APA may act as a novel false neurotransmitter of GABA. Future work will focus on disease models and on possible applications as neuroimaging agents.
Assuntos
Comportamento Exploratório/fisiologia , Locomoção/fisiologia , Neurotransmissores/química , Ácidos Pentanoicos/química , Ácido gama-Aminobutírico/química , Animais , Encéfalo/metabolismo , Química Encefálica , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Ácidos Pentanoicos/metabolismo , Ácidos Pentanoicos/farmacologia , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Estereoisomerismo , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
15q13.3 microdeletion syndrome is characterized by a wide spectrum of neurodevelopmental disorders, including developmental delay, intellectual disability, epilepsy, language impairment, abnormal behaviors, neuropsychiatric disorders, and hypotonia. This syndrome is caused by a deletion on chromosome 15q, which typically encompasses six genes. Here, through studies on OTU deubiquitinase 7A (Otud7a) knockout mice, we identify OTUD7A as a critical gene responsible for many of the cardinal phenotypes associated with 15q13.3 microdeletion syndrome. Otud7a-null mice show reduced body weight, developmental delay, abnormal electroencephalography patterns and seizures, reduced ultrasonic vocalizations, decreased grip strength, impaired motor learning/motor coordination, and reduced acoustic startle. We show that OTUD7A localizes to dendritic spines and that Otud7a-null mice have decreased dendritic spine density compared to their wild-type littermates. Furthermore, frequency of miniature excitatory postsynaptic currents (mEPSCs) is reduced in the frontal cortex of Otud7a-null mice, suggesting a role of Otud7a in regulation of dendritic spine density and glutamatergic synaptic transmission. Taken together, our results suggest decreased OTUD7A dosage as a major contributor to the neurodevelopmental phenotypes associated with 15q13.3 microdeletion syndrome, through the misregulation of dendritic spine density and activity.
Assuntos
Transtornos Cromossômicos/enzimologia , Transtornos Cromossômicos/genética , Enzimas Desubiquitinantes/genética , Endopeptidases/genética , Deficiência Intelectual/enzimologia , Deficiência Intelectual/genética , Convulsões/enzimologia , Convulsões/genética , Potenciais de Ação , Animais , Sequência de Bases , Comportamento Animal , Deleção Cromossômica , Cromossomos Humanos Par 15/enzimologia , Cromossomos Humanos Par 15/genética , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Endopeptidases/deficiência , Epilepsia/enzimologia , Epilepsia/genética , Epilepsia/fisiopatologia , Feminino , Homozigoto , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Sinapses/metabolismoRESUMO
While the original protein Toll in Drosophila melanogaster regulates both host defense and morphogenesis, the role of its ortholog Toll-like receptors (TLRs), the interleukin 1 receptor (IL-1R) family, and the associated signaling pathways in mammalian brain development and structure is poorly understood. Because the adaptor protein myeloid differentiation primary response protein 88 (MyD88) is essential for downstream signaling of most TLRs and IL-1R, we systematically investigated the effect of MyD88 deficiency on murine brain structure during development and on behavior. In neonatal Myd88-/- mice, neocortical thickness was reduced, while density of cortical neurons was increased. In contrast, microglia, astrocyte, oligodendrocyte, and proliferating cell numbers were unchanged in these mice compared to wild-type mice. In adult Myd88-/- mice, neocortical thickness was unaltered, but neuronal density in neocortex and hippocampus was increased. Neuron arborization was less pronounced in adult Myd88-/- mice compared to wild-type animals. In addition, numbers of microglia and proliferating cells were increased in the neocortex and subventricular zone, respectively, with unaltered astrocyte and oligodendrocyte numbers, and myelinization was enhanced in the adult Myd88-/- neocortex. These morphologic changes in the brain of adult Myd88-/- mice were accompanied by specific behavioral traits, such as decreased locomotor activity, increased anxiety-like behavior, but normal day/light activity, satisfactory learning, short- and long-term spatial memory, potential cognitive inflexibility, and increased hanging and locomotor behavior within their home cage. Taken together, MyD88 deficiency results in morphologic and cellular changes in the mouse brain, as well as in altered natural and specific behaviors. Our data indicate a pathophysiological significance of MyD88 for mammalian CNS development, structure, and function.
Assuntos
Comportamento Animal , Encéfalo/patologia , Fator 88 de Diferenciação Mieloide , Proteínas Adaptadoras de Transdução de Sinal , Animais , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores de Interleucina-1/metabolismoRESUMO
Interkingdom communication between bacteria and host organisms is one of the most interesting research topics in biology. Quorum sensing molecules produced by Gram-negative bacteria, such as acylated homoserine lactones and quinolones, have been shown to interact with host cell receptors, stimulating innate immunity and bacterial clearance. To our knowledge, there is no evidence that these molecules influence CNS function. Here, we have found that low micromolar concentrations of the Pseudomonas aeruginosa quorum sensing autoinducer, 2-heptyl-3-hydroxy-4-quinolone (PQS), inhibited polyphosphoinositide hydrolysis in mouse brain slices, whereas four selected acylated homoserine lactones were inactive. PQS also inhibited forskolin-stimulated cAMP formation in brain slices. We therefore focused on PQS in our study. Biochemical effects of PQS were not mediated by the bitter taste receptors, T2R4 and T2R16. Interestingly, submicromolar concentrations of PQS could be detected in the serum and brain tissue of adult mice under normal conditions. Levels increased in five selected brain regions after single i.p. injection of PQS (10 mg/kg), peaked after 15 min, and returned back to normal between 1 and 4 h. Systemically administered PQS reduced spontaneous locomotor activity, increased the immobility time in the forced swim test, and largely attenuated motor response to the psychostimulant, methamphetamine. These findings offer the first demonstration that a quorum sensing molecule specifically produced by Pseudomonas aeruginosa is centrally active and influences cell signaling and behavior. Quorum sensing autoinducers might represent new interkingdom signaling molecules between ecological communities of commensal, symbiotic, and pathogenic microorganisms and the host CNS.
Assuntos
Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , AMP Cíclico/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Pseudomonas aeruginosa/metabolismo , Quinolonas/farmacologia , Percepção de Quorum , Transdução de Sinais/efeitos dos fármacos , Animais , Encéfalo/metabolismo , Interações Hospedeiro-Patógeno , Hidrólise , Técnicas In Vitro , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Teste do Labirinto Aquático de Morris/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Quinolonas/metabolismoRESUMO
The cortical code that underlies perception must enable subjects to perceive the world at time scales relevant for behavior. We find that mice can integrate visual stimuli very quickly (<100 ms) to reach plateau performance in an orientation discrimination task. To define features of cortical activity that underlie performance at these time scales, we measured single-unit responses in the mouse visual cortex at time scales relevant to this task. In contrast to high-contrast stimuli of longer duration, which elicit reliable activity in individual neurons, stimuli at the threshold of perception elicit extremely sparse and unreliable responses in the primary visual cortex such that the activity of individual neurons does not reliably report orientation. Integrating information across neurons, however, quickly improves performance. Using a linear decoding model, we estimate that integrating information over 50-100 neurons is sufficient to account for behavioral performance. Thus, at the limits of visual perception, the visual system integrates information encoded in the probabilistic firing of unreliable single units to generate reliable behavior.
Assuntos
Discriminação Psicológica/fisiologia , Neurônios/fisiologia , Córtex Visual/fisiologia , Percepção Visual/fisiologia , Animais , Feminino , Masculino , Camundongos , Estimulação Luminosa , PsicometriaRESUMO
Huntington's disease (HD) is a progressive neurodegenerative disorder caused by an expanded CAG repeat within the huntingtin (HTT) gene. The Q140 and HdhQ150 knock-in HD mouse models were generated such that HdhQ150 mice have an expanded CAG repeat inserted into the mouse Htt gene, whereas in the Q140s, mouse exon 1 Htt was replaced with a mutated version of human exon 1. By standardizing mouse strain background, breeding to homozygosity and employing sensitive behavioral tests, we demonstrate that the onset of behavioral phenotypes occurs earlier in the Q140 than the HdhQ150 knock-in mouse models and that huntingtin (HTT) aggregation appears earlier in the striata of Q140 mice. We have previously found that the incomplete splicing of mutant HTT from exon 1 to exon 2 results in the production of a small polyadenylated transcript that encodes the highly pathogenic mutant HTT exon 1 protein. In this report, we have identified a functional consequence of the sequence differences between these two models at the RNA level, in that the level of incomplete splicing, and of the mutant exon 1 HTT protein, are greater in the brains of Q140 mice. While differences in the human and mouse exon 1 HTT proteins (e.g., proline rich sequences) could also contribute to the phenotypic differences, our data indicate that the incomplete splicing of HTT and approaches to lower the levels of the exon 1 HTT transcript should be pursued as therapeutic targets.
Assuntos
Comportamento Animal/fisiologia , Modelos Animais de Doenças , Proteína Huntingtina/genética , Doença de Huntington/genética , Doença de Huntington/psicologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Técnicas de Introdução de Genes , Proteína Huntingtina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , FenótipoRESUMO
CaMKII is a pivotal kinase that plays essential roles in synaptic plasticity. Apart from its signaling function, the structural function of CaMKII is becoming clear. CaMKII - F-actin interaction stabilizes actin cytoskeleton in a dendritic spine. A transient autophosphorylation at the F-actin binding region during LTP releases CaMKII from F-actin and opens a brief time-window of actin reorganization. However, the physiological relevance of this finding in learning and memory was not presented. Using a knock-in (KI) mouse carrying phosphoblock mutations in the actin-binding domain of CaMKIIß, we demonstrate that proper regulation of CaMKII - F-actin interaction is important for fear conditioning memory tasks. The KI mice show poor performance in contextual and cued versions of fear conditioning test. These results suggest the importance of CaMKII - F-actin interactions in learning and memory.
Assuntos
Actinas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Condicionamento Clássico/fisiologia , Medo/fisiologia , Actinas/genética , Animais , Feminino , Técnicas de Introdução de Genes , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , FosforilaçãoRESUMO
Previous studies have brought to light the toxic effect of cerium chloride (CeCl3) but very little is known about the oxidative brain injury caused by this metal. Medical plants have a well-recognized role in the management of damage caused by pollutants such as CeCl3. Syzygium aromaticum, a potent natural source of bioactive compounds and rich in secondary metabolites, has a broad range of biological functions. The aim of this study is to investigate the capacity of Syzygium aromaticum ethanol extract (ESA) to improve the adverse effects of CeCl3 in the brain tissue. Adult mice were exposed to CeCl3 (20 mg/kg body weight [BW]), with or without ESA, for 60 days. We investigate mice's behavior, damages of cholinergic system and oxidative stress parameters in mice brain. In the present study, in vitro test confirmed that ESA has antioxidant capacity attributed to the presence of flavonoids, polyphenols, and tannins contents. In vivo study showed that CeCl3 caused brain injuries manifested in memory impairment, increase in acetylcholinesterase activity, oxidative stress biomarkers (lipid, proteins, enzymatic and non-enzymatic antioxidant systems), and histopathological alteration in brain tissue. Addition of ESA repaired memory impairment, decreased acetylcholinesterase activity, restored oxidative state, and prevented histopathological alteration. In conclusion, the experimental results showed the protective effects of ethanol extract of Syzygium aromaticum against cerium-induced brain damage.
Assuntos
Encéfalo/efeitos dos fármacos , Cério/toxicidade , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Syzygium/química , Animais , Antioxidantes/metabolismo , Encéfalo/metabolismo , Camundongos , Fármacos Neuroprotetores/isolamento & purificação , Síndromes Neurotóxicas/etiologia , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/isolamento & purificaçãoRESUMO
Deleterious mutations in the glutamate receptor metabotropic 1 gene (GRM1) cause a recessive form of cerebellar ataxia, SCAR13. GRM1 and GRM5 code for the metabotropic glutamate type 1 (mGlu1) and type 5 (mGlu5) receptors, respectively. Their different expression profiles suggest they could have distinct functional roles. In a previous study, homozygous mice lacking mGlu1 receptors (Grm1crv4/crv4) and exhibiting ataxia presented cerebellar overexpression of mGlu5 receptors, that was proposed to contribute to the mouse phenotype. To test this hypothesis, we here crossed Grm1crv4 and Grm5ko mice to generate double mutants (Grm1crv4/crv4Grm5ko/ko) lacking both mGlu1 and mGlu5 receptors. Double mutants and control mice were analyzed for spontaneous behavior and for motor activity by rotarod and footprint analyses. In the same mice, the release of glutamate from cerebellar nerve endings (synaptosomes) elicited by 12mM KCl or by α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) was also evaluated. Motor coordination resulted improved in double mutants when compared to Grm1crv4/crv4 mice. Furthermore, in in vitro studies, glutamate release elicited by both KCl depolarization and activation of AMPA autoreceptors resulted reduced in Grm1crv4/crv4 mice compared to wild type mice, while it presented normal levels in double mutants. Moreover, we found that Grm1crv4/crv4 mice showed reduced expression of GluA2/3 AMPA receptor subunits in cerebellar synaptosomes, while it resulted restored to wild type level in double mutants. To conclude, blocking of mGlu5 receptor reduced the dysregulation of glutamate transmission and improved motor coordination in the Grm1crv4 mouse model of SCAR13, thus suggesting the possible usefulness of pharmacological therapies based on modulation of mGlu5 receptor activity for the treatment of this type of ataxia.
Assuntos
Ataxia Cerebelar/genética , Ataxia Cerebelar/fisiopatologia , Atividade Motora , Receptor de Glutamato Metabotrópico 5/genética , Receptores de Glutamato Metabotrópico/genética , Animais , Autorreceptores/metabolismo , Cerebelo/metabolismo , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Subunidades Proteicas , Receptores de AMPA/metabolismo , Teste de Desempenho do Rota-RodRESUMO
In the mammalian neocortex, the capacity to dynamically route and coordinate the exchange of information between areas is a critical feature of cognitive function, enabling processes such as higher-level sensory processing and sensorimotor integration. Despite the importance attributed to long-range connections between cortical areas, their exact operations and role in cortical function remain an open question. In recent years, progress has been made in understanding long-range cortical circuits through work focused on the mouse sensorimotor whisker system. In this review, we examine recent studies dissecting long-range circuits involved in whisker sensorimotor processing as an entry point for understanding the rules that govern long-range cortical circuit function.
Assuntos
Córtex Sensório-Motor/fisiologia , Vibrissas/fisiologia , Animais , Conectoma , Camundongos , Vibrissas/inervaçãoRESUMO
Neuroinflammation is a pervasive feature of Alzheimer's disease (AD) and characterized by activated microglia, increased proinflammatory cytokines and/or infiltrating immune cells. T helper 17 (Th17) cells are found in AD brain parenchyma and interleukin-17A (IL-17A) is identified around deposits of aggregated amyloid ß protein (Aß). However, the role of IL-17A in AD pathogenesis remains elusive. We overexpressed IL-17A in an AD mouse model via recombinant adeno-associated virus serotype 5 (rAAV5)-mediated intracranial gene delivery. AD model mice subjected to injection of a vehicle (PBS) or rAAV5 carrying the lacZ gene served as controls. IL-17A did not exacerbate neuroinflammation in IL-17A-overexpressing mice. We found that IL-17A overexpression markedly improved glucose metabolism, decreased soluble Aß levels in the hippocampus and cerebrospinal fluid, drastically reduced cerebral amyloid angiopathy, and modestly but significantly improved anxiety and learning deficits. Moreover, the ATP-binding cassette subfamily A member 1 (ABCA1), which can transport Aß from the brain into the blood circulation, significantly increased in IL-17A-overexpressing mice. In vitro treatment of brain endothelial bEnd.3 cells with IL-17A induced a dose-dependent increase in protein expression of ABCA1 through ERK activation. Our study suggests that IL-17A may decrease Aß levels in the brain by upregulating ABCA1 in blood-brain barrier endothelial cells.
Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Angiopatia Amiloide Cerebral/genética , Interleucina-17/farmacologia , Transportador 1 de Cassete de Ligação de ATP/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Angiopatia Amiloide Cerebral/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Hipocampo/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Microglia/metabolismo , Células Th17/metabolismo , Ativação Transcricional , Regulação para CimaRESUMO
We have previously shown that treatment with erythropoietin (EPO) improves cognition in patients with neuropsychiatric disorders as well as in healthy mice, and that transgenic expression of a constitutively active form of the EPO receptor (cEPOR) in glutamatergic neurons boosts higher cognitive functions in mice. In the present work, we examined whether selective activation of EPOR signaling in GABAergic neurons would also modulate cognitive performance. We generated transgenic mice that express cEPOR under the control of the vesicular inhibitory amino acid transporter (Viaat) promoter and subjected them to comprehensive behavioral, cognitive, and electrophysiological analyses. We demonstrate that transgenic expression of cEPOR in GABAergic neurons alters hippocampal gamma-oscillations and enhances long-term potentiation but neither impairs nor improves cognition. To conclude, constitutively active EPOR in GABAergic neurons changes hippocampal network properties without affecting cognition, which suggests that the effect of EPO on cognition is dominated by its effect on the glutamatergic system. Treatment with EPO improves cognitive performance. We previously demonstrated that this effect is replicated by constitutive autoactivation of cEPOR in glutamatergic neurons. By contrast, cEPOR in GABAergic neurons changes hippocampal network properties but neither impairs nor enhances cognition. Thus, EPO modulates neuronal plasticity, and the cognitive benefits may be mainly attributable to its effect on the glutamatergic system.
RESUMO
Animals learn both whether and when a reward will occur. Neural models of timing posit that animals learn the mean time until reward perturbed by a fixed relative uncertainty. Nonetheless, animals can learn to perform actions for reward even in highly variable natural environments. Optimal inference in the presence of variable information requires probabilistic models, yet it is unclear whether animals can infer such models for reward timing. Here, we develop a behavioral paradigm in which optimal performance required knowledge of the distribution from which reward delays were chosen. We found that mice were able to accurately adjust their behavior to the SD of the reward delay distribution. Importantly, mice were able to flexibly adjust the amount of prior information used for inference according to the moment-by-moment demands of the task. The ability to infer probabilistic models for timing may allow mice to adapt to complex and dynamic natural environments.