RESUMO
Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity symptoms. Neuroimaging studies have revealed a delayed cortical and subcortical development pattern in children diagnosed with ADHD. This study followed up on the development in vitro of frontal cortical neurons from Spontaneously hypertensive rats (SHR), an ADHD rat model, and Wistar-Kyoto rats (WKY), control strain, over their time in culture, and in response to BDNF treatment at two different days in vitro (DIV). These neurons were also evaluated for synaptic proteins, brain-derived neurotrophic factor (BDNF), and related protein levels. Frontal cortical neurons from the ADHD rat model exhibited shorter dendrites and less dendritic branching over their time in culture. While pro- and mature BDNF levels were not altered, the cAMP-response element-binding (CREB) decreased at 1 DIV and SNAP-25 decreased at 5 DIV. Different from control cultures, exogenous BDNF promoted less dendritic branching in neurons from the ADHD model. Our data revealed that neurons from the ADHD model showed decreased levels of an important transcription factor at the beginning of their development, and their delayed outgrowth and maturation had consequences in the levels of SNAP-25 and may be associated with less response to BDNF. These findings provide an alternative tool for studies on synaptic dysfunctions in ADHD. They may also offer a valuable tool for investigating drug effects and new treatment opportunities.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Fator Neurotrófico Derivado do Encéfalo , Ratos , Animais , Ratos Endogâmicos SHR , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ratos Endogâmicos WKY , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/metabolismo , Neurônios/metabolismo , Modelos Animais de DoençasRESUMO
Molecular and functional abnormalities of astrocytes have been implicated in the etiology and pathogenesis of schizophrenia (SCZ). In this study, we examined the proteome, inflammatory responses, and secretome effects on vascularization of human induced pluripotent stem cell (hiPSC)-derived astrocytes from patients with SCZ. Proteomic analysis revealed alterations in proteins related to immune function and vascularization. Reduced expression of the nuclear factor kappa B (NF-κB) p65 subunit was observed in these astrocytes, with no incremental secretion of cytokines after tumor necrosis factor alpha (TNF-α) stimulation. Among inflammatory cytokines, secretion of interleukin (IL)-8 was particularly elevated in SCZ-patient-derived-astrocyte-conditioned medium (ASCZCM). In a chicken chorioallantoic membrane (CAM) assay, ASCZCM reduced the diameter of newly grown vessels. This effect could be mimicked with exogenous addition of IL-8. Taken together, our results suggest that SCZ astrocytes are immunologically dysfunctional and may consequently affect vascularization through secreted factors.
Assuntos
Células-Tronco Pluripotentes Induzidas , Esquizofrenia , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Astrócitos/metabolismo , Proteômica , Esquizofrenia/metabolismo , Citocinas/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , FenótipoRESUMO
Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that presents sex differences in the severity and presentation of symptoms, whose neurobiological basis is still unknown. Both Growth-associated Protein 43 (GAP-43) and Sonic hedgehog (Shh) are considered essential proteins for the appropriate brain development, but their participation in ADHD neurobiology have not been investigated yet. In this study, we hypothesized that alterations in these proteins could be related to behavioral traits to ADHD phenotype. Thus, both sexes of infant Spontaneously hypertensive rats (SHR, used as ADHD animal model) were evaluated for developmental milestones, locomotor activity, olfactory and recognition memory. Both GAP-43 and Shh were assessed in the olfactory bulb, frontal cortex and hippocampus in early and late infancy. During early infancy, SHR reached three developmental milestones later, and females showed olfactory memory impairment accompanied by increased levels of Shh in the olfactory bulb. In later infancy, hyperlocomotion, impaired recognition memory, and decreased Shh in the hippocampus were observed in SHR from both sexes. While in early infancy GAP-43 was not altered, it was decreased in the frontal cortex and hippocampus of female SHR in late infancy. Therefore, both Shh and GAP-43 are involved in the sex-dependent behavioral alterations showed by infant SHR. Despite the disorder's complexity and heterogeneity, our findings reveal important developmental parameters during SHR development and also emphasizes the relevance of studying sex differences in the ADHD context.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Proteínas Hedgehog , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Proteína GAP-43/metabolismo , Proteínas Hedgehog/metabolismo , Masculino , Transtornos da Memória/metabolismo , Odorantes , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Caracteres SexuaisRESUMO
OBJECTIVE: We investigated the influence of dietary omega-3 polyunsaturated fatty acids (n-3 PUFAs) on glutamatergic system modulation after a single episode of neonatal seizures and their possible effects on seizure-induced long-lasting behavioral deficits. METHODS: Male Wistar rats receiving an omega-3 diet (n-3) or an n-3 deficient diet (D) from the prenatal period were subjected to a kainate-induced seizure model at P7. Glutamate transporter activity and immunocontents (GLT-1 and GLAST) were assessed in the hippocampus at 12, 24, and 48 h after the seizure episode. Fluorescence intensity for glial cells (GFAP) and neurons (NeuN) was assessed 24â h after seizure in the hippocampus. Behavioral analysis (elevated-plus maze and inhibitory avoidance memory task) was performed at 60 days of age. RESULTS: The D group showed a decrease in glutamate uptake 24â h after seizure. In this group only, the GLT1 content increased at 12â h, followed by a decrease at 24â h. GLAST increased up to 24â h after seizure. GFAP fluorescence was higher, and NeuN fluorescence decreased, in the D group independent of seizures. In adulthood, the D group presented memory deficits independent of seizures, but short-term memory (1.5â h after a training session) was abolished in the D group treated with kainate. SIGNIFICANCE: N-3 PUFA positively influenced the glutamatergic system during seizure and prevented seizure-related memory deficits in adulthood.
Assuntos
Epilepsia , Ácidos Graxos Ômega-3 , Animais , Dieta , Ácidos Graxos Ômega-3/efeitos adversos , Feminino , Ácido Glutâmico , Hipocampo , Ácido Caínico , Masculino , Transtornos da Memória/prevenção & controle , Gravidez , Ratos , Ratos Wistar , Convulsões/induzido quimicamente , Convulsões/prevenção & controleRESUMO
Over the past years, brain development has been investigated in rodent models, which were particularly relevant to establish the role of specific genes in this process. However, the cytoarchitectonic features, which determine neuronal network formation complexity, are unique to humans. This implies that the developmental program of the human brain and neurological disorders can only partly be reproduced in rodents. Advancement in the study of the human brain surged with cultures of human brain tissue in the lab, generated from induced pluripotent cells reprogrammed from human somatic tissue. These cultures, termed brain organoids, offer an invaluable model for the study of the human brain. Brain organoids reproduce the cytoarchitecture of the cortex and can develop multiple brain regions and cell types. Integration of functional activity of neural cells within brain organoids with genetic, cellular, and morphological data in a comprehensive model for human development and disease is key to advance in the field. Because the functional activity of neural cells within brain organoids relies on cell repertoire and time in culture, here, we review data supporting the gradual formation of complex neural networks in light of cell maturity within brain organoids. In this context, we discuss how the technology behind brain organoids brought advances in understanding neurodevelopmental, pathogen-induced, and neurodegenerative diseases.
RESUMO
Attention deficit and hyperactivity disorder (ADHD) is characterized by impaired levels of hyperactivity, impulsivity, and inattention. Adenosine and endocannabinoid systems tightly interact in the modulation of dopamine signaling, involved in the neurobiology of ADHD. In this study, we evaluated the modulating effects of the cannabinoid and adenosine systems in a tolerance to delay of reward task using the most widely used animal model of ADHD. Spontaneous Hypertensive Rats (SHR) and Wistar-Kyoto rats were treated chronically or acutely with caffeine, a non-selective adenosine receptor antagonist, or acutely with a cannabinoid agonist (WIN55212-2, WIN) or antagonist (AM251). Subsequently, animals were tested in the tolerance to delay of reward task, in which they had to choose between a small, but immediate, or a large, but delayed, reward. Treatment with WIN decreased, whereas treatment with AM251 increased the choices of the large reward, selectively in SHR rats, indicating a CB1 receptor-mediated increase in impulsive behavior. An acute pre-treatment with caffeine blocked WIN effects. Conversely, a chronic treatment with caffeine increased the impulsive phenotype and potentiated the WIN effects. The results indicate that both cannabinoid and adenosine receptors modulate impulsive behavior in SHR: the antagonism of cannabinoid receptors might be effective in reducing impulsive symptoms present in ADHD; in addition, caffeine showed the opposite effects on impulsive behavior depending on the length of treatment. These observations are of particular importance to consider when therapeutic manipulation of CB1 receptors is applied to ADHD patients who consume coffee.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Cafeína/farmacologia , Agonistas de Receptores de Canabinoides/farmacologia , Antagonistas de Receptores de Canabinoides/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Psicotrópicos/farmacologia , Animais , Benzoxazinas/farmacologia , Modelos Animais de Doenças , Masculino , Morfolinas/farmacologia , Naftalenos/farmacologia , Piperidinas/farmacologia , Antagonistas de Receptores Purinérgicos P1/farmacologia , Pirazóis/farmacologia , Distribuição Aleatória , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
Traumatic brain injury (TBI) is a leading cause of disability worldwide, triggering chronic neurodegeneration underlying cognitive and mood disorder still without therapeutic prospects. Based on our previous observations that guanosine (GUO) attenuates short-term neurochemical alterations caused by TBI, this study investigated the effects of chronical GUO treatment in behavioral, molecular, and morphological disturbances 21 days after trauma. Rats subject to TBI displayed mood (anxiety-like) and memory dysfunction. This was accompanied by a decreased expression of both synaptic (synaptophysin) and plasticity proteins (BDNF and CREB), a loss of cresyl violet-stained neurons, and increased astrogliosis and microgliosis in the hippocampus. Notably, chronic GUO treatment (7.5 mg/kg i.p. daily starting 1 h after TBI) prevented all these TBI-induced long-term behavioral, neurochemical, and morphological modifications. This neuroprotective effect of GUO was abrogated in the presence of the adenosine A1 receptor antagonist DPCPX (1 mg/kg) but unaltered by the adenosine A2A receptor antagonist SCH58261 (0.05 mg/kg). These findings show that a chronic GUO treatment prevents the long-term mood and memory dysfunction triggered by TBI, which involves adenosinergic receptors.
Assuntos
Comportamento Animal/efeitos dos fármacos , Lesões Encefálicas Traumáticas/tratamento farmacológico , Guanosina/uso terapêutico , Receptores Purinérgicos P1/metabolismo , Animais , Ansiedade/tratamento farmacológico , Ansiedade/etiologia , Biomarcadores/metabolismo , Lesões Encefálicas Traumáticas/complicações , Gliose/complicações , Gliose/patologia , Guanosina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Masculino , Transtornos da Memória/complicações , Microglia/efeitos dos fármacos , Microglia/patologia , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Plasticidade Neuronal/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Ratos WistarRESUMO
Few studies have addressed the effects of caffeine in the puberty and/or adolescence in a sex dependent manner. Considering that caffeine intake has increased in this population, we investigated the behavioral and synaptic proteins changes in pubescent male and female rats after maternal consumption of caffeine. Adult female Wistar rats started to receive water or caffeine (0.1 and 0.3g/L in drinking water; low and moderate dose, respectively) during the active cycle at weekdays, two weeks before mating. The treatment lasted up to weaning and the offspring received caffeine until the onset of puberty (30-34days old). Behavioral tasks were performed to evaluate locomotor activity (open field task), anxious-like behavior (elevated plus maze task) and recognition memory (object recognition task) and synaptic proteins levels (proBDNF, BDNF, GFAP and SNAP-25) were verified in the hippocampus and cerebral cortex. While hyperlocomotion was observed in both sexes after caffeine treatment, anxiety-related behavior was attenuated by caffeine (0.3g/L) only in females. While moderate caffeine worsened recognition memory in females, an improvement in the long-term memory was observed in male rats for both doses. Coincident with memory improvement in males, caffeine increased pro- and BDNF in the hippocampus and cortex. Females presented increased proBDNF levels in both brain regions, with no effects of caffeine. While GFAP was not altered, moderate caffeine intake increased SNAP-25 in the cortex of female rats. Our findings revealed that caffeine promoted cognitive benefits in males associated with increased BDNF levels, while females showed less anxiety. Our findings revealed that caffeine promotes distinct behavioral outcomes and alterations in synaptic proteins during brain development in a sex dependent manner.
Assuntos
Ansiedade , Encéfalo/crescimento & desenvolvimento , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Animais , Ansiedade/etiologia , Ansiedade/metabolismo , Ansiedade/patologia , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Relação Dose-Resposta a Droga , Água Potável , Feminino , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Memória/fisiologia , Atividade Motora/fisiologia , Ratos Wistar , Caracteres Sexuais , Maturidade Sexual , Proteína 25 Associada a Sinaptossoma/metabolismoRESUMO
Caffeine is the psychostimulant most consumed worldwide. Anxiogenic effects of caffeine have been described in adult animals with controversial findings about its anxiogenic potential. Besides, the effects of caffeine on anxiety with aging are still poorly known. In this study, adult mice (6months old) started to receive caffeine (0.3 and 1.0mg/mL, drinking water) during 12-14months only in the light cycle and at weekdays. The open field (OF) and elevated plus maze (EPM) testing were used to determine the effects of caffeine on anxiety-related behavior in adult and aged mice (18-20months old). Because aging alters synaptic proteins, we also evaluated SNAP-25 (as a nerve terminals marker), GFAP (as an astrocyte marker) and adenosine A1 and A2A receptors levels in the cortex. According to the OF analysis, caffeine did not change both hypolocomotion and anxiety with aging. However, aged mice showed less anxiety behavior in the EPM, but after receiving caffeine (0.3mg/mL) during adulthood they were anxious as adult mice. While SNAP-25 and adenosine A2A receptors increased with aging, both GFAP and adenosine A1 receptors were not affected. Caffeine at moderate dose prevented the age-related increase of the SNAP-25, with no effect on adenosine A2A receptors. The absence of effect for the highest dose suggests that tolerance to caffeine may have developed over time. Aged mice showed high responsiveness to the OF, being difficult to achieve any effect of caffeine. On the other hand this substance sustained the adult anxious behavior over time in a less stressful paradigm, and this effect was coincident with changes in the SNAP-25, suggesting the involvement of this synaptic protein in the ability of caffeine to preserve changes related to emotionality with aging.
Assuntos
Envelhecimento/efeitos dos fármacos , Ansiedade/tratamento farmacológico , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Atividade Motora/efeitos dos fármacos , Psicotrópicos/farmacologia , Envelhecimento/fisiologia , Envelhecimento/psicologia , Animais , Ansiedade/fisiopatologia , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Relação Dose-Resposta a Droga , Água Potável , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Camundongos , Atividade Motora/fisiologia , Receptor A2A de Adenosina/metabolismo , Proteína 25 Associada a Sinaptossoma/metabolismoRESUMO
It is well known that adenine-based purines exert multiple effects on pain transmission. Recently, we have demonstrated that guanine-based purines may produce some antinociceptive effects against chemical and thermal pain in mice. The present study was designed to investigate the antinociceptive effects of intrathecal (i.t.) administration of inosine or guanine in mice. Additionally, investigation into the mechanisms of action of these purines, their general toxicity and measurements of CSF purine levels were performed. Animals received an i.t. injection of vehicle (30mN NaOH), inosine or guanine (up to 600nmol) and submitted to several pain models and behavioural paradigms. Guanine and inosine produced dose-dependent antinociceptive effects in the tail-flick, hot-plate, intraplantar (i.pl.) glutamate, i.pl. capsaicin and acetic acid pain models. Additionally, i.t. inosine inhibited the biting behaviour induced by spinal injection of capsaicin and i.t. guanine reduced the biting behaviour induced by spinal injection of glutamate or AMPA. Intrathecal administration of inosine (200nmol) induced an approximately 115-fold increase on CSF inosine levels. This study provides new evidence on the mechanism of action of extracellular guanine and inosine presenting antinociceptive effects following spinal administration. These effects seem to be related, at least partially, to the modulation of A1 adenosine receptors.
Assuntos
Analgésicos/administração & dosagem , Analgésicos/farmacologia , Guanina/administração & dosagem , Guanina/farmacologia , Injeções Espinhais , Inosina/administração & dosagem , Inosina/farmacologia , Analgésicos/efeitos adversos , Animais , Guanina/efeitos adversos , Inosina/efeitos adversos , Masculino , Camundongos , Nociceptividade/efeitos dos fármacos , Dor/fisiopatologia , Purinas/líquido cefalorraquidiano , Receptores Purinérgicos P1/metabolismoRESUMO
Caffeine is the psychostimulant most consumed worldwide. However, little is known about its effects during fetal brain development. In this study, adult female Wistar rats received caffeine in drinking water (0.1, 0.3 and 1.0 g/L) during the active cycle in weekdays, two weeks before mating and throughout pregnancy. Cerebral cortex and hippocampus from embryonic stages 18 or 20 (E18 or E20, respectively) were collected for immunodetection of the following synaptic proteins: brain-derived neurotrophic factor (BDNF), TrkB receptor, Sonic Hedgehog (Shh), Growth Associated Protein 43 (GAP-43) and Synaptosomal-associated Protein 25 (SNAP-25). Besides, the estimation of NeuN-stained nuclei (mature neurons) and non-neuronal nuclei was verified in both brain regions and embryonic periods. Caffeine (1.0 g/L) decreased the body weight of embryos at E20. Cortical BDNF at E18 was decreased by caffeine (1.0 g/L), while it increased at E20, with no major effects on TrkB receptors. In the hippocampus, caffeine decreased TrkB receptor only at E18, with no effects on BDNF. Moderate and high doses of caffeine promoted an increase in Shh in both brain regions at E18, and in the hippocampus at E20. Caffeine (0.3g/L) decreased GAP-43 only in the hippocampus at E18. The NeuN-stained nuclei increased in the cortex at E20 by lower dose and in the hippocampus at E18 by moderate dose. Our data revealed that caffeine transitorily affect synaptic proteins during fetal brain development. The increased number of NeuN-stained nuclei by prenatal caffeine suggests a possible acceleration of the telencephalon maturation. Although some modifications in the synaptic proteins were transient, our data suggest that caffeine even in lower doses may alter the fetal brain development.
Assuntos
Encéfalo/metabolismo , Cafeína/toxicidade , Estimulantes do Sistema Nervoso Central/toxicidade , Desenvolvimento Fetal/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Sinapses/metabolismo , Fatores Etários , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cafeína/metabolismo , Relação Dose-Resposta a Droga , Embrião de Mamíferos , Feminino , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Proteínas do Tecido Nervoso/genética , Neurônios/metabolismo , Neurônios/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/patologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Sinapses/efeitos dos fármacosRESUMO
Intracerebroventricular (icv) streptozotocin (STZ) administration induces pathological and behavioral alterations similar to those observed in Alzheimer's disease (AD) and is thus considered an experimental model of sporadic AD. Since caffeine (an adenosine receptor antagonist) and selective antagonists of adenosine A2A receptors modify the course of memory impairment in different amyloid-ß-based experimental models of AD, we now tested the impact of caffeine on STZ-induced dementia and associated neurodegeneration in the hippocampus as well as on the expression and density of adenosine receptors. Adult male rats received a bilateral infusion of saline or STZ (3 mg/kg, icv), which triggered memory deficits after four weeks, as gauged by impaired object recognition memory. This was accompanied by a reduced NeuN immunoreactivity in the hippocampal CA1 region and an increased expression and density of adenosine A2A receptors (A2AR), but not A1R, in the hippocampus. Caffeine consumption (1 g/L in the drinking water starting 2 weeks before the STZ challenge) prevented the STZ-induced memory impairment and neurodegeneration as well as the upregulation of A2AR. These findings provide the first demonstration that caffeine prevents sporadic dementia and implicate the control of central A2AR as its likely mechanism of action.
Assuntos
Cafeína/administração & dosagem , Demência/prevenção & controle , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Receptor A2A de Adenosina , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Animais , Demência/metabolismo , Demência/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Transtornos da Memória/patologia , Neurônios/efeitos dos fármacos , Neurônios/patologia , Ratos , Ratos Wistar , Receptor A2A de Adenosina/biossíntese , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Beneficial effects of caffeine on memory processes have been observed in animal models relevant to neurodegenerative diseases and aging, although the underlying mechanisms remain unknown. Because brain-derived neurotrophic factor (BDNF) is associated with memory formation and BDNF's actions are modulated by adenosine receptors, the molecular targets for the psychostimulant actions of caffeine, we here compare the effects of chronic caffeine (1 mg/mL drinking solution for 30 days) on short- and long term memory and on levels of hippocampal proBDNF, mature BDNF, TrkB and CREB in young (3 month old) and middle-aged (12 month old) rats. Caffeine treatment substantially reduced i) age-related impairments in the two types of memory in an inhibitory avoidance paradigm, and ii) parallel increases in hippocampal BDNF levels. In addition, chronic caffeine increased proBDNF and CREB concentrations, and decreased TrkB levels, in hippocampus regardless of age. These data provide new evidence in favor of the hypothesis that modifications in BDNF and related proteins in the hippocampus contribute to the pro-cognitive effects of caffeine on age-associated losses in memory encoding. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
Assuntos
Envelhecimento , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cafeína/uso terapêutico , Disfunção Cognitiva/prevenção & controle , Hipocampo/metabolismo , Neurônios/metabolismo , Nootrópicos/uso terapêutico , Precursores de Proteínas/metabolismo , Animais , Aprendizagem da Esquiva , Comportamento Animal , Estimulantes do Sistema Nervoso Central/uso terapêutico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/crescimento & desenvolvimento , Masculino , Memória de Longo Prazo , Memória de Curto Prazo , Inibição Neural , Ratos , Ratos Wistar , Receptor trkB/metabolismoRESUMO
Physical exercise protocols have varied widely across studies raising the question of whether there is an optimal intensity, duration and frequency that would produce maximal benefits in attenuating symptoms related to anxiety disorders. Although physical exercise causes modifications in neurotransmission systems, the involvement of neuromodulators such as adenosine has not been investigated after chronic exercise training. Anxiety-related behavior was assessed in the elevated plus-maze in adult and middle-aged rats submitted to 8 weeks of treadmill running 1, 3 or 7 days/week. The speed of running was weekly adjusted to maintain moderate intensity. The hippocampal adenosine A1 and A2A receptors densities were also assessed. Treadmill running protocol was efficient in increasing physical exercise capacity in adult and middle-aged rats. All frequencies of treadmill running equally decreased the time spent in the open arms in adult animals. Middle-aged treadmill control rats presented lower time spent in the open arms than adult treadmill control rats. However, treadmill running one day/week reversed this age effect. Adenosine A1 receptor was not changed between groups, but treadmill running counteracted the age-related increase in adenosine A2A receptors. Although treadmill running, independent from frequency, triggered anxiety in adult rats and treadmill running one day/week reversed the age-related anxiety, no consistent relationship was found with hippocampal adenosine receptors densities. Thus, our data suggest that as a complementary therapy in the management of mental disturbances, the frequency and intensity of physical exercise should be taken into account according to age. Besides, this is the first study reporting the modulation of adenosine receptors after chronic physical exercise, which could be important to prevent neurological disorders associated to increase in adenosine A2A receptors.
Assuntos
Ansiedade/metabolismo , Teste de Esforço , Hipocampo/metabolismo , Receptor A1 de Adenosina/metabolismo , Receptor A2A de Adenosina/metabolismo , Corrida/fisiologia , Envelhecimento/fisiologia , Envelhecimento/psicologia , Animais , Ansiedade/psicologia , Teste de Esforço/métodos , Teste de Esforço/psicologia , Masculino , Ratos , Ratos Wistar , Corrida/psicologiaRESUMO
Impairment in the activity and expression of glutamate transporters has been found in experimental models of epilepsy in adult animals. However, there are few studies investigating alterations on glutamate transporters caused by epilepsy in newborn animals, especially in the early periods after seizures. In this study, alterations in the hippocampal glutamate transporters activity and immunocontent were investigated in neonatal rats (7 days old) submitted to kainate-induced seizures model. Glutamate uptake, glutamate transporters (GLT-1, GLAST, EAAC1) and glutamine synthetase (GS) were assessed in hippocampal slices obtained 12 h, 24 h, 48 h, 72 h and 60 days after seizures. Immunoreactivity for hippocampal GFAP, NeuN and DAPI were assessed 24 h after seizure. Behavioral analysis (elevated-plus maze and inhibitory avoidance task) was also investigated in the adult animals (60 days old). The decrease on glutamate uptake was observed in hippocampal slices obtained 24 h after seizures. The immunocontent of GLT-1 increased at 12 h and decreased at 24 h (+62% and -20%, respectively), while GLAST increased up to 48 h after seizures. No alterations were observed for EAAC1 and GS. It should be mentioned that there were no long-term changes in tested glutamate transporters at 60 days after kainate treatment. GFAP immunoreactivity increased in all hippocampal subfields (CA1, CA3 and dentate gyrus) with no alterations in NeuN and DAPI staining. In the adulthood, kainate-treated rats showed anxiety-related behavior and lower performance in the inhibitory avoidance task. Our findings indicate that acute modifications on hippocampal glutamate transporters triggered by a single convulsive event in early life may play a role in the behavioral alterations observed in adulthood.
Assuntos
Glutamatos/metabolismo , Hipocampo/metabolismo , Convulsões/metabolismo , Animais , Animais Recém-Nascidos , Aprendizagem da Esquiva , Transporte Biológico , Western Blotting , Aprendizagem em Labirinto , Ratos , Ratos Wistar , Convulsões/fisiopatologiaRESUMO
Environmental enrichment (EE) has been largely used to investigate behavioral modifications and neuroplasticity in the adult brain both in normal and pathological conditions. The interaction between individual behavioral traits with EE responsiveness has not been investigated within the same strain. By using two extremes of CF1 mice that differ by their exploratory behavior in the Open Field (OF) task (Kazlauckas V, 2005), denominated as Low (LE) and High (HE) Exploratory Mice, the present study evaluated if EE during adulthood could modify the putative differences between LE and HE mice on exploratory behavior, memory performance and hippocampal BDNF levels. To this end, we investigated the effect of adult LE and HE mice after 2 months of enriched or standard housing conditions on the open field, on novel object recognition, on the inhibitory avoidance task and on hippocampal BDNF immunocontent. LE showed low exploratory behavior, less retention in the inhibitory avoidance and lower hippocampal BDNF levels. EE enhanced exploratory behavior, memory performance and hippocampal BDNF levels both in LE and HE mice. Importantly, the general profile of LE mice submitted to EE was similar to HE mice housed in standard conditions. These results show that internalized behavior of LE mice can be significantly modified by exposure to an enriched environment even during adulthood. These observations may contribute to investigate biological mechanisms and therapeutical interventions for individuals with internalized psychiatric disorders.
Assuntos
Comportamento Animal/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Meio Ambiente , Comportamento Exploratório/fisiologia , Memória/fisiologia , Animais , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Plasticidade Neuronal/fisiologia , FenótipoRESUMO
Methylphenidate (MPH) is the preferred treatment used for attention-deficit/hyperactivity disorder (ADHD). Recently, misuse for MPH due to its apparent cognitive enhancer properties has been reported. Adenosine is a neuromodulator known to exert influence on the dopaminergic neurotransmission, which is the main pharmacological target of MPH. We have reported that an overdosage of MPH up-regulates adenosine A(1) receptors in the frontal cortex, but this receptor was not involved in its anxiolytic effects. In this study, the role of adenosine A(1) receptor was investigated on MPH-induced effects on aversive and recognition memory in adult mice. Adult mice received acute and chronic (15 days) administration of methylphenidate (5mg/kg, i.p.), or an acute overdosage (50mg/kg, i.p) in order to model misuse. Memory was assessed in the inhibitory avoidance and object recognition task. Acute administration 5mg/kg improved whereas 50mg/kg disrupted recognition memory and decreased performance in the inhibitory avoidance task. Chronic administration did not cause any effect on memory, but decreased adenosine A(1) receptors immunocontent in the frontal cortex. The selective adenosine A(1) receptor antagonist, (DPCPX 1mg/kg, i.p.), prevented methylphenidate-triggered recognition memory impairment. Our findings showed that recognition memory rather than aversive memory was differently affected by acute administration at both doses. Memory recognition was fully impaired by the overdosage, suggesting that misuse can be harmful for cognitive functions. The adenosinergic system via A(1) receptors may play a role in the methylphenidate actions probably by interfering with dopamine-enhancing properties of this drug.
Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Transtornos da Memória , Metilfenidato/toxicidade , Receptor A1 de Adenosina/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Antagonistas do Receptor A1 de Adenosina/administração & dosagem , Análise de Variância , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Esquema de Medicação , Reação de Fuga/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inibição Psicológica , Masculino , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismo , Transtornos da Memória/prevenção & controle , Camundongos , Reconhecimento Psicológico/fisiologia , Xantinas/administração & dosagemRESUMO
Stress affects learning and memory processes and sensitivity to stress greatly varies between individuals. We studied behavioral and neurobiological effects of unpredictable subchronic stress (USCS) in two behavioral extremes of mice from the same strain (CF1) selected by their exploratory behavior of the central arena of an open field. The top and bottom 25% explorers were classified as low exploratory (LE) and high exploratory (HE) mice, respectively. The open field task, the novel object recognition task (NOR), sucrose intake and tail suspension task were evaluated in LE and HE groups exposed to USCS for two weeks or control conditions. Also serum corticosterone and hippocampal BDNF and S100B levels were analyzed. Both stressed groups exhibited less exploratory activity when submitted to USCS, but their difference in exploratory behavior remained. This short stress protocol did not induce changes in sucrose intake or immobility in the tail suspension task. Also, LE mice exhibited impaired NOR performance after USCS, whereas HE mice changed their pattern of exploration towards less exploration of the familiar object. HE had lower corticosterone levels than LE mice, but corticosterone levels increased after stress only in HE mice. Hippocampal BDNF in LE was lower than in HE but decreased after USCS only in HE mice, whereas S100B levels were not different between groups and did not change with USCS. In conclusion, our results suggest that individual differences in exploratory behavior in rodents from the same strain influence cognitive and biochemical response to stress.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corticosterona/sangue , Comportamento Exploratório/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Estresse Fisiológico/fisiologia , Estresse Psicológico/fisiopatologia , Análise de Variância , Animais , Comportamento Animal/fisiologia , Ensaio de Imunoadsorção Enzimática , Masculino , Camundongos , Fenótipo , Estresse Psicológico/metabolismoRESUMO
In recent years misuse of methylphenidate (MPH) has been reported. The main pharmacological target of methylphenidate is the dopaminergic system. Adenosine is a neuromodulator that influences the dopaminergic neurotransmission, but studies on MPH and adenosine are still lacking. In this study, adult mice were acutely treated with MPH (5mg/kg, i.p.) and to model misuse, they received an acute overdosage (50mg/kg, i.p). The involvement of adenosine A(1) receptors in anxiety-related behavior and locomotor and exploratory activity was examined. The administration of methylphenidate (5 and 50mg/kg) 30 min before the exposure to open field arena did not modify locomotor activity. The anxiolytic-like behavior was observed with both doses of MPH as revealed by the increase on the number of entries and the time spent in the open arms in the elevated plus-maze. Pre treatment with selective adenosine A(1) receptor antagonist (DPCPX 1mg/kg, i.p.) did not prevent anxiolytic effect caused by MPH 50mg/kg. Immunoblotting of frontal cortex and hippocampal extracts revealed that MPH 50mg/kg increased 88% adenosine A(1) receptor density in the frontal cortex. Extracts from hippocampus did not reveal any differences in the adenosine A(1) receptor density. Our findings ruled out the participation of adenosine A(1) receptors on the MPH-triggered anxiolytic effects. However, the density of adenosine A(1) receptors increased in a brain area strictly involved in the MPH-mediated effects. Thus, the adenosinergic system may play a role in the methylphenidate actions in the central nervous system.
Assuntos
Ansiedade/tratamento farmacológico , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Metilfenidato/farmacologia , Atividade Motora/efeitos dos fármacos , Receptor A1 de Adenosina/metabolismo , Antagonistas do Receptor A1 de Adenosina/farmacologia , Análise de Variância , Animais , Ansiedade/metabolismo , Western Blotting , Estimulantes do Sistema Nervoso Central/farmacologia , Masculino , Camundongos , Atividade Motora/fisiologia , Xantinas/farmacologiaRESUMO
Caffeine is a psychostimulant with positive effects on cognition. Recent studies have suggested the participation of the cholinergic system in the effects of caffeine on wakefulness. However, there are few studies assessing the contribution of cholinergic system in the cognitive enhancer properties of caffeine. In the present study, the effects of a dose and schedule of administration of caffeine that improved memory recognition were investigated on scopolamine-induced impairment of memory in adult mice. Inhibitory avoidance and novel object recognition tasks were used to assess learning and memory. Caffeine (10mg/kg, i.p.) was administered during 4 consecutive days, and the treatment was interrupted 24h before scopolamine administration (2mg/kg, i.p.). Scopolamine was administered prior to or immediately after training. Short-term and long-term memory was evaluated in both tasks. In the novel object recognition task, pre treatment with caffeine prevented the disruption of short- and long-term memory by scopolamine. In the inhibitory avoidance task, caffeine prevented short- but not long-term memory disruption by pre training administration of scopolamine. Caffeine prevented short- and long-term memory disruption by post training administration of scopolamine. Both treatments did not affect locomotor activity of the animals. These findings suggest that acute treatment with caffeine followed by its withdrawal may be effective against cholinergic-induced disruption of memory assessed in an aversive and non-aversive task. Finally, our results revealed that the cholinergic system is involved in the positive effects of caffeine on cognitive functions.