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1.
Adv Neurobiol ; 24: 207-222, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32006362

RESUMO

Autism spectrum disorder (ASD) encompasses a cluster of neurodevelopmental and genetic disorders that has been characterized mainly by social withdrawal, repetitive behavior, restricted interests, and deficits in language processing mainly in children. ASD has been known to severely impair behavioral patterns and cognitive functions including learning and memory due to defects in neuroplasticity. The biology of the ASD appears to be highly complex and heterogeneous, and thus, finding a therapeutic target for autism remains obscure. There has been no complete prevention or disease-modifying cure for this disorder. Recently, individuals with autism have been characterized by reactive neurogenesis, obstructions in axonal growth, heterotopia, resulting from dysplasia of neuroblasts in different brain regions. Therefore, it can be assumed that the aforementioned neuropathological correlates seen in the autistic individuals might originate from the defects mainly in the regulation of neuroblasts in the developing as well as adult brain. Nutrient deficiencies during early brain development and intake of certain allergic foods have been proposed as main reasons for the development of ASD. However, the integrated understanding of neurodevelopment and functional aspects of neuroplasticity working through neurogenesis in ASD is highly limited. Moreover, neurogenesis at the level of neuroblasts can be regulated by nutrition. Hence, defects in neuroblastosis underlying the severity of autism potentially could be rectified by appropriate implementation of nutraceuticals.


Assuntos
Transtorno do Espectro Autista/dietoterapia , Transtorno do Espectro Autista/patologia , Suplementos Nutricionais , Plasticidade Neuronal/efeitos dos fármacos , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/psicologia , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Humanos
2.
J Agric Food Chem ; 68(7): 1808-1815, 2020 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-31532659

RESUMO

Major depressive disorder (MDD) is associated with stress-induced immune dysregulation and reduced brain-derived neurotrophic factor (BDNF) levels in sensitive brain regions associated with depression. Elevated levels of proinflammatory cytokines and reduced BDNF levels lead to impaired synaptic plasticity mechanisms that contribute to the pathophysiology of MDD. There is accumulating evidence that the administration of polyphenols at doses ranging from 5 to 180 mg/kg of body weight can normalize elevated levels of proinflammatory cytokines and abnormal levels of BDNF and, thus, restore impaired synaptic plasticity mechanisms that mediate depressive behavior in animal models of stress. This review will focus on the mechanisms by which grape-derived polyphenols normalize impaired synaptic plasticity and reduce depressive behavior in animal models of stress.


Assuntos
Transtorno Depressivo Maior/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Polifenóis/administração & dosagem , Vitis/química , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Transtorno Depressivo Maior/fisiopatologia , Humanos , Extratos Vegetais/química , Polifenóis/química
3.
Nat Neurosci ; 22(11): 1782-1792, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636451

RESUMO

Microglia are the brain's resident innate immune cells and also have a role in synaptic plasticity. Microglial processes continuously survey the brain parenchyma, interact with synaptic elements and maintain tissue homeostasis. However, the mechanisms that control surveillance and its role in synaptic plasticity are poorly understood. Microglial dynamics in vivo have been primarily studied in anesthetized animals. Here we report that microglial surveillance and injury response are reduced in awake mice as compared to anesthetized mice, suggesting that arousal state modulates microglial function. Pharmacologic stimulation of ß2-adrenergic receptors recapitulated these observations and disrupted experience-dependent plasticity, and these effects required the presence of ß2-adrenergic receptors in microglia. These results indicate that microglial roles in surveillance and synaptic plasticity in the mouse brain are modulated by noradrenergic tone fluctuations between arousal states and emphasize the need to understand the effect of disruptions of adrenergic signaling in neurodevelopment and neuropathology.


Assuntos
Microglia/fisiologia , Plasticidade Neuronal/fisiologia , Norepinefrina/fisiologia , Córtex Visual/fisiologia , Animais , Benzilaminas/farmacologia , Receptor 1 de Quimiocina CX3C/genética , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Ritmo Circadiano/fisiologia , Clembuterol/farmacologia , Dexmedetomidina/farmacologia , Dominância Ocular , Feminino , Fentanila/farmacologia , Locus Cerúleo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Transgênicos , Microglia/citologia , Microglia/efeitos dos fármacos , Nadolol/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Norepinefrina/metabolismo , Propanolaminas/farmacologia , Restrição Física/fisiologia , Terbutalina/farmacologia , Vigília , Ferimentos e Lesões/fisiopatologia
4.
Nat Neurosci ; 22(12): 1975-1985, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31611707

RESUMO

The increased legal availability of cannabis has led to a common misconception that it is a safe natural remedy for, among others, pregnancy-related ailments such as morning sickness. Emerging clinical evidence, however, indicates that prenatal cannabis exposure (PCE) predisposes offspring to various neuropsychiatric disorders linked to aberrant dopaminergic function. Yet, our knowledge of how cannabis exposure affects the maturation of this neuromodulatory system remains limited. Here, we show that male, but not female, offspring of Δ9-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit extensive molecular and synaptic changes in dopaminergic neurons of the ventral tegmental area, including altered excitatory-to-inhibitory balance and switched polarity of long-term synaptic plasticity. The resulting hyperdopaminergic state leads to increased behavioral sensitivity to acute THC exposure during pre-adolescence. The neurosteroid pregnenolone, a US Food and Drug Administration (FDA) approved drug, rescues synaptic defects and normalizes dopaminergic activity and behavior in PCE offspring, thus suggesting a therapeutic approach for offspring exposed to cannabis during pregnancy.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Dronabinol/efeitos adversos , Dronabinol/farmacologia , Pregnenolona/farmacologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Dronabinol/antagonistas & inibidores , Endofenótipos , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Atividade Motora/efeitos dos fármacos , Inibição Neural/fisiologia , Plasticidade Neuronal/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Gravidez , Inibição Pré-Pulso/efeitos dos fármacos , Inibição Pré-Pulso/fisiologia , Ratos , Assunção de Riscos , Filtro Sensorial/efeitos dos fármacos , Filtro Sensorial/fisiologia , Caracteres Sexuais , Área Tegmentar Ventral/metabolismo
5.
Life Sci ; 238: 116969, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628912

RESUMO

AIMS: Glutamatergic dysfunction is posed as a main stage in neurodegenerative disorders such as Alzheimer's disease (AD). Glutamate-mediated excitotoxicity contributes to cognitive dysfunction and cell death in AD. Ceftriaxone (CFT), a well-known upregulator of GLT-1, selectively induces the expression of glutamate transporter-1 (GLT-1) in different brain regions and therefore can be posed as a potential candidate for elimination of glutamate-induced excitotoxicity which is an early prominent event in AD brains. This study was designed to investigate the electrophysiological and behavioral effects of the ß-lactam antibiotic ceftriaxone in okadaic acid (OKA)-induced model of AD. MATERIALS AND METHODS: Male Wistar rats divided into four control, ceftriaxone (CFT), OKA, and OKA plus ceftriaxone (OKA + CFT) groups. OKA was injected intracerebroventricularly (i.c.v., 200 ng/5 µl) into lateral ventricles and after two weeks the evoked field potential recorded from hippocampal perforant path-DG synapses in order to evaluate the effect of ceftriaxone treatment (200 mg/kg/day, i.p.) on long-term potentiation (LTP) and paired-pulse responses. KEY FINDINGS: Results of this study revealed that ceftriaxone treatment significantly ameliorates the OKA-induced attenuation of field excitatory post-synaptic potential (fEPSP) slope and population spike (PS) amplitude following high-frequency stimulation and paired-pulse paradigm indicating its beneficial effects on both short-term and long-term plasticity in these neurons. Ceftriaxone also has an improving effect on OKA-induced impairment in short- and long-term memories evaluated by alternation behavior and passive avoidance tasks in rats. SIGNIFICANCE: Therefore, this study suggests that GLT-1 might be a promising therapeutic target for treatment of neurodegenerative disorders such as AD in the future.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ceftriaxona/farmacologia , Giro Denteado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Animais , Antibacterianos/farmacologia , Carcinógenos/toxicidade , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/patologia , Ácido Okadáico/toxicidade , Ratos , Ratos Wistar , Sinapses/efeitos dos fármacos
6.
Nat Commun ; 10(1): 4140, 2019 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515501

RESUMO

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.


Assuntos
Proteínas dos Microfilamentos/metabolismo , Neuropeptídeos/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Heroína/efeitos adversos , Histona Desacetilase 2/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Núcleo Accumbens/metabolismo , Alcaloides Opiáceos/efeitos adversos , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Dor/metabolismo , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Sinapses/metabolismo
7.
J Stroke Cerebrovasc Dis ; 28(10): 104299, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371141

RESUMO

Cognitive dysfunction is the most common nonphysical impairment in the stroke survivors. This impairment has a negative impact on patients' quality of life affects their daily living activities. Both pharmacological and nonpharmacological interventions are employed to improve cognitive impairment. Recently, nonpharmacological interventions have attracted great attention. Cognitive rehabilitation is considered as a therapeutic strategy to improve and maintain cognitive skills in patients with stroke. Enriched environment (EE), as a cognitive rehabilitation strategy, has been shown to facilitate physical, cognitive, as well as social abilities. Moreover, EE has been shown to increase endogenous growth factors. Growth factors have pivotal role in neurogenesis, synaptogenesis, as well as brain remodeling through neuron development, differentiation, and survival. In addition, administration of exogenous growth factors prevents cognitive dysfunction. Here, we review preclinical and clinical evidence of cognitive rehabilitation and role of growth factors in treating poststroke cognitive impairment.


Assuntos
Isquemia Encefálica/reabilitação , Encéfalo/efeitos dos fármacos , Cognição/efeitos dos fármacos , Terapia Cognitivo-Comportamental , Disfunção Cognitiva/reabilitação , Peptídeos e Proteínas de Sinalização Intercelular/uso terapêutico , Reabilitação do Acidente Vascular Cerebral/métodos , Acidente Vascular Cerebral/terapia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/fisiopatologia , Isquemia Encefálica/psicologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/psicologia , Resultado do Tratamento
8.
Exp Neurol ; 321: 113039, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442443

RESUMO

Neonatal hypoxic-ischemic brain damage (HIBD) survivors present with long-term neurological disorders affecting their quality of life, and there remains a lack of effective treatment. Toll-like receptor 4 (TLR4) is widely distributed in nerve cells and its inhibition has a neuroprotective effect against brain injury. The present study aimed to evaluate the long-term neuroprotective effects of early inhibition of TLR4 during HIBD. Seven-day-old rat pups were subjected to left carotid artery ligation followed by 2 h of hypoxia (8.0% O2). A single dose of TAK-242 (0.5 mg/kg), a TLR4-specific antagonist, was intraperitoneally injected half an hour prior to hypoxic ischemia (HI). The long-term effects of TAK-242 inhibition on the induced hippocampal injury were investigated by assessing behaviour at P28, and then using a variety of methods to exploring the mechanism, including immunofluorescence, Golgi silver staining, Western blotting and real-time polymerase chain reaction (RT-PCR). TAK-242 treatment significantly reduced the expression levels of TLR4 and its downstream signalling molecules in the ipsilateral lesion of the hippocampus 24 h after HIBD. The Morris water maze (MWM) test demonstrated that TAK-242 treatment reduced the loss of HI-induced learning and memory functions. Immunofluorescence experiments showed that TAK-242 administration attenuated HI-induced loss of neurons, prevented the activation of microglia and astrocytes, and increased the expression of the glutamate receptor subtype, N-methyl d-aspartate 2A (NR2A) in the ipsilateral hippocampus region. Golgi silver staining revealed that TAK-242 prevented an HI-induced decline in spine density in the ipsilateral hippocampus. Western blot and RT-PCR results indicated that the expression of NR2A protein and mRNA in the ipsilateral hippocampi of adolescent rats decreased after neonatal HIBD; early TAK-242 administration may reverse these effects. In conclusion, our findings indicate that early inhibition of TLR4 signalling may improve the long-term prognosis of neonatal HIBD. The mechanisms contributing to this improvement involve reductions in neuronal loss, a decrease in glial cell activation, and an improvement in synaptic plasticity.


Assuntos
Hipocampo/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , Plasticidade Neuronal/fisiologia , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/imunologia , Hipóxia-Isquemia Encefálica/complicações , Plasticidade Neuronal/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/efeitos dos fármacos , Sulfonamidas/farmacologia
9.
Nutrients ; 11(9)2019 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-31461895

RESUMO

Creatine plays a crucial role in developing the brain, so much that its genetic deficiency results in mental dysfunction and cognitive impairments. Moreover, creatine supplementation is currently under investigation as a preventive measure to protect the fetus against oxidative stress during difficult pregnancies. Although creatine use is considered safe, posing minimal risk to clinical health, we found an alteration in morpho-functional maturation of neurons when male rats were exposed to creatine loads during brain development. In particular, increased excitability and enhanced long-term potentiation (LTP) were observed in the hippocampal pyramidal neurons of weaning pups. Since these effects were observed a long time after creatine treatment had been terminated, long-lasting modifications persisting into adulthood were hypothesized. Such modifications were investigated in the present study using morphological, electrophysiological, and calcium imaging techniques applied to hippocampal Cornu Ammonis 1 (CA1) neurons of adult rats born from dams supplemented with creatine. When compared to age-matched controls, the treated adult offspring were found to retain enhanced neuron excitability and an improved LTP, the best-documented neuronal substrate for memory formation. While translating data from rats to humans does have limitations, our findings suggest that prenatal creatine supplementation could have positive effects on adult cognitive abilities.


Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Creatina/administração & dosagem , Suplementos Nutricionais , Plasticidade Neuronal/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Células Piramidais/efeitos dos fármacos , Fatores Etários , Fenômenos Fisiológicos da Nutrição Animal , Animais , Comportamento Animal/efeitos dos fármacos , Região CA1 Hipocampal/crescimento & desenvolvimento , Região CA1 Hipocampal/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Cognição/efeitos dos fármacos , Feminino , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Memória/efeitos dos fármacos , Gravidez , Células Piramidais/metabolismo , Ratos Sprague-Dawley , Fatores de Tempo
10.
Life Sci ; 234: 116775, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31425697

RESUMO

AIMS: The activation of the angiotensin (Ang) II after acute kidney injury (AKI) triggers oxidative stress and inflammatory cascade which involved not only the kidneys but also the brain. Ang II through the Ang II type 1 receptor (AT1R) may have deleterious effects on hippocampal synaptic transmission and cognitive functions under uremic encephalopathy. The present study was conducted to examine the effects of AT1R antagonist on AKI-induced cognitive and synaptic plasticity impairment. MAIN METHODS: Here, we investigated the effect of AKI and possible pathophysiological roles of AT1R with the selective AT1R antagonist losartan (10 mg/kg/day for consecutive 9 days) on cognitive performance using passive avoidance and Morris water maze tests. In order to understand the synaptic transmission, in vivo short and long-term plasticity were evaluated at the Schaffer collateral-CA1 synapse. Biochemical analysis was also performed to detect possible hippocampal nitric oxide and oxidative stress mechanisms. KEY FINDINGS: Our data provide evidence of hippocampal complication following AKI with increased level of nitrite (P < 0.01 vs. sham) as well as oxidative stress (P < 0.01 vs. sham) that may be responsible for behavioral dysfunction under uremia (spatial memory, P < 0.001; passive avoidance P < 0.01 vs. sham). Losartan treatment effectively protects against cognitive (spatial memory, P < 0.01; passive avoidance P < 0.05 vs. AKI-veh) and synaptic plasticity impairments induced by AKI possibly via modulation of oxidative stress in the hippocampus (P < 0.01 vs. AKI-veh). SIGNIFICANCE: The present study conclusively demonstrated a protective role of AT1R antagonist losartan in hippocampal complication and neurocognitive dysfunction after AKI via modulating oxidative stress.


Assuntos
Lesão Renal Aguda/complicações , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Hipocampo/efeitos dos fármacos , Losartan/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/fisiopatologia , Animais , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Masculino , Memória/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo
11.
Int J Mol Sci ; 20(13)2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31324059

RESUMO

Anti-inflammatory cytokines are known to exert neuroprotective action ameliorating aberrant neuronal network activity associated with inflammatory responses. Yet, it is still not fully understood if anti-inflammatory cytokines play a significant role in the regulation of synaptic activity under normal conditions. Thus, the aim of our study was to investigate the effect of Interleukin-10 (IL-10) on neuronal synaptic transmission and plasticity. For this we tested the effect of IL-10 on miniature excitatory postsynaptic currents (mEPSC) and intracellular Ca2+ responses using whole-cell patch clamp and fluorescence microscopy in 13-15 DIV primary hippocampal neuroglial culture. We found that IL-10 significantly potentiated basal glutamatergic excitatory synaptic transmission within 15 min after application. Obtained results revealed a presynaptic nature of the effect, as IL-10 in a dose-dependent manner significantly increased the frequency but not the amplitude of mEPSC. Further, we tested the effect of IL-10 on mEPSC in a model of homeostatic synaptic plasticity (HSP) induced by treatment of primary hippocampal culture with 1 µM of tetrodotoxin (TTX) for a 24 h. It was found that 15 min application of IL-10 at established HSP resulted in enhanced mEPSC frequency, thus partially compensating for a decrease in the mEPSC frequency associated with TTX-induced HSP. Next, we studied if IL-10 can influence induction of HSP. We found that co-incubation of IL-10 with 1 µM of TTX for 24 h induced synaptic scaling, significantly increasing the amplitude of mEPSC and Ca2+ responses to application of the AMPA agonist, 5-Fluorowillardiine, thus facilitating a compensatory postsynaptic mechanism at HSP condition. Our results indicate that IL-10 potentiates synaptic activity in a dose- and time-dependent manner exerting both presynaptic (short-term exposure) and postsynaptic (long-term exposure) action. Obtained results demonstrate involvement of IL-10 in the regulation of basal glutamatergic synaptic transmission and plasticity at normal conditions.


Assuntos
Hipocampo/citologia , Interleucina-10/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/farmacologia , Animais , Células Cultivadas , Microscopia de Fluorescência , Plasticidade Neuronal/efeitos dos fármacos , Técnicas de Patch-Clamp , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tetrodotoxina/farmacologia
12.
Nat Methods ; 16(8): 699-702, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31308551

RESUMO

Chemical inhibitors have revealed requirements for protein synthesis that drive cellular plasticity. We developed a genetically encodable protein synthesis inhibitor (gePSI) to achieve cell-type-specific temporal control of protein synthesis. Controlled expression of the gePSI in neurons or glia resulted in rapid, potent and reversible cell-autonomous inhibition of protein synthesis. Moreover, gePSI expression in a single neuron blocked the structural plasticity induced by single-synapse stimulation.


Assuntos
Engenharia Genética , Hipocampo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/metabolismo , Biossíntese de Proteínas , Inibidores da Síntese de Proteínas/farmacologia , Sinapses/metabolismo , Animais , Células Cultivadas , Células HeLa , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Humanos , Neuroglia/citologia , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Inibidores da Síntese de Proteínas/química , Ratos , Sinapses/efeitos dos fármacos
13.
Sci Total Environ ; 689: 1012-1022, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31280147

RESUMO

The etiology of depression is not known, it is thought that endocrine-disrupting chemicals (EDCs) contribute to the disease. Results of our previous research have shown that nonylphenol (NP), a well-known EDC, has neurotoxic effects, however, whether NP can induce depressive behavior by affecting synaptic plasticity has not yet been clearly elucidated. The depressive behavior induced by subchronic exposure to NP and its effect on the neuronal synaptic plasticity in rats are dynamically observed. Thirty Sprague-Dawley rats were randomly divided into 3 groups: control group (C, corn oil), NP group (NP, 4 mg/kg), and depression model group (D, corticosterone 20 mg/kg). There were 8 rats in each group. The depressive behavior of rats was tested by sucrose preference test, open-field test, and forced swimming test once a month for 3 months. The serum levels of brain-derived neurotrophic factor (BDNF) and corticosterone were detected by ELISA assay, and cellular morphological changes were observed by hematoxylin-eosin (HE) staining. The number of nerve cells, the length of dendrites, and the density of dendritic spines were observed by Golgi staining, and the synaptic cleft width, the postsynaptic density (PSD) thickness, and the synaptic interface curvature were observed by transmission electron microscope. Compared with the control group, the consumption of sucrose solution decreased in the NP group at the 2nd and 3rd month compared to the 1st month (F = 9.887, P = 0.002). The number of central square entries, the central square duration, and the total distance of movement were all decreased, and the decreasing degrees at the 3rd month were greater than those at the 1st month (F = 21.191, P < 0.001; F = 9.836, P = 0.002). The time of immobility for the NP group at the 1st month was higher than that in the control group (F = 6.912, P = 0.002). The expression of BDNF in the NP-treated group was higher than the control, while the expression of corticosterone in the NP-treated group was lower than the control. In the NP group, the cytoplasm of nerve cells contracted and appeared disordered. The neuron arrangement was disordered, and the number of cells, the length of the apex, the length of the basal dendrites, and the dendritic spine density were all lower in the NP group than those in the control group. The PSD thickness, the synaptic cleft width, and synaptic interface curvatures were all decreased in the NP group when compared to the control group. Subchronic exposure to 4 mg/kg NP led to depressive behavior in rats, and the depressive behavior and alterations in synaptic plasticity were more obvious with longer exposure time.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/sangue , Depressão/fisiopatologia , Disruptores Endócrinos/toxicidade , Glucocorticoides/sangue , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/toxicidade , Animais , Depressão/induzido quimicamente , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
14.
Int J Mol Sci ; 20(14)2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31336695

RESUMO

Caspases are a family of conserved cysteine proteases that play key roles in multiple cellular processes, including programmed cell death and inflammation. Recent evidence shows that caspases are also involved in crucial non-apoptotic functions, such as dendrite development, axon pruning, and synaptic plasticity mechanisms underlying learning and memory processes. The activated form of caspase-3, which is known to trigger widespread damage and degeneration, can also modulate synaptic function in the adult brain. Thus, in the present study, we tested the hypothesis that caspase-3 modulates synaptic plasticity at corticostriatal synapses in the phosphatase and tensin homolog (PTEN) induced kinase 1 (PINK1) mouse model of Parkinson's disease (PD). Loss of PINK1 has been previously associated with an impairment of corticostriatal long-term depression (LTD), rescued by amphetamine-induced dopamine release. Here, we show that caspase-3 activity, measured after LTD induction, is significantly decreased in the PINK1 knockout model compared with wild-type mice. Accordingly, pretreatment of striatal slices with the caspase-3 activator α-(Trichloromethyl)-4-pyridineethanol (PETCM) rescues a physiological LTD in PINK1 knockout mice. Furthermore, the inhibition of caspase-3 prevents the amphetamine-induced rescue of LTD in the same model. Our data support a hormesis-based double role of caspase-3; when massively activated, it induces apoptosis, while at lower level of activation, it modulates physiological phenomena, like the expression of corticostriatal LTD. Exploring the non-apoptotic activation of caspase-3 may contribute to clarify the mechanisms involved in synaptic failure in PD, as well as in view of new potential pharmacological targets.


Assuntos
Caspase 3/metabolismo , Doença de Parkinson/etiologia , Doença de Parkinson/metabolismo , Proteínas Quinases/genética , Animais , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Ativação Enzimática , Genótipo , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo , Camundongos , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Quinases/metabolismo
15.
Nutrients ; 11(7)2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31311133

RESUMO

Obesity, caused by a high-fat diet (HFD), leads to insulin resistance, which is a precursor of diabetes and a risk factor for impaired cognitive function, dementia, and brain diseases, such as Alzheimer's disease. Physical exercise has positive effects on obesity and brain functions. We investigated whether the decline in cognitive function caused by a HFD could be improved through exercise by examining insulin signaling pathways and neuroplasticity in the hippocampus. Four-week-old C57BL/6 male mice were fed a HFD or a regular diet for 20 weeks, followed by 12 weeks of treadmill exercise. To ascertain the effects of treadmill exercise on impaired cognitive function caused by obesity, the present study implemented behavioral testing (Morris water maze, step-down). Moreover, insulin-signaling and neuroplasticity were measured in the hippocampus and dentate gyrus. Our results demonstrated that HFD-fed obesity-induced insulin resistance was improved by exercise. In addition, the HFD group showed a decrease in insulin signaling and neuroplasticity in the hippocampus and the dentate gyrus and increased cognitive function impairment, which were reversed by physical exercise. Overall, our findings indicate that physical exercise may act as a non-pharmacologic method that protects against cognitive dysfunction caused by obesity by improving hippocampal insulin signaling and neuroplasticity.


Assuntos
Cognição , Dieta Hiperlipídica/efeitos adversos , Hipocampo/fisiologia , Insulina/metabolismo , Obesidade/induzido quimicamente , Condicionamento Físico Animal , Ração Animal , Animais , Dieta/veterinária , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
16.
Horm Behav ; 114: 104545, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31228421

RESUMO

The memory-enhancing effects of 17ß-estradiol (E2) depend upon rapid activation of several cell-signaling cascades within the dorsal hippocampus (DH). Among the many cell-signaling pathways that mediate memory processes, Wnt/ß-catenin signaling has emerged as a potential key player because of its importance to hippocampal development and synaptic plasticity. However, whether E2 interacts with Wnt/ß-catenin signaling to promote memory consolidation is unknown. Therefore, the present study examined whether Wnt/ß-catenin signaling within the DH is necessary for E2-induced memory consolidation in ovariectomized mice tested in the object recognition and object placement tasks. Ovariectomized C57BL/6 mice received immediate post-training infusions of E2 or vehicle into the dorsal third ventricle plus the endogenous Wnt/ß-catenin antagonist Dickkopf-1 (Dkk-1) or vehicle into the DH to assess whether the memory-enhancing effects of E2 depend on activation of Wnt/ß-catenin signaling. Our results suggest that Dkk-1 blocks E2-induced memory enhancement as hypothesized, but may do so by only moderately blunting Wnt/ß-catenin signaling while concurrently activating Wnt/JNK signaling. The current study provides novel insights into the mechanisms through which E2 enhances memory consolidation in the DH, as well as critical information about the mechanistic actions of Dkk-1.


Assuntos
Estradiol/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Consolidação da Memória/efeitos dos fármacos , Animais , Feminino , Hipocampo/efeitos dos fármacos , Infusões Intraventriculares , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Neuroproteção/efeitos dos fármacos , Ovariectomia , Transdução de Sinais/efeitos dos fármacos
17.
Int J Mol Sci ; 20(12)2019 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-31234498

RESUMO

Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) leads to the formation of fragments, among which the intracellular domain of APP (AICD) was also identified to be a causative of early pathological events. AICD-counteracting proteins, such as Fe65, may serve as alternative therapeutic targets of Alzheimer's disease (AD). The detection of elevated levels of Fe65 in the brains of both human patients and APP transgenic mice may further strengthen the hypothesis that influencing the interaction between Fe65 and APP may have a beneficial effect on the course of AD. Based on a PXP motif, proven to bind to the WW domain of Fe65, a new pentapeptide was designed and tested. The impedimental effect of P33 on the production of beta amyloid (Aß) (soluble fraction and aggregated plaques) and on the typical features of the AD pathology (decreased dendritic spine density, synaptic markers, elevated inflammatory reactions) was also demonstrated. Significant enhancements of both learning ability and memory function were observed in a Morris water maze paradigm. The results led us to formulate the theory that P33 acts by altering the conformation of Fe65 via binding to its WW domain, consequently hindering any interactions between Fe65 and key members involved in APP processing.


Assuntos
Precursor de Proteína beta-Amiloide/metabolismo , Memória/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Proteínas Nucleares/metabolismo , Oligopeptídeos/farmacologia , Doença de Alzheimer/metabolismo , Animais , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Proteínas do Tecido Nervoso/química , Proteínas Nucleares/química , Oligopeptídeos/química , Conformação Proteica
18.
J Agric Food Chem ; 67(27): 7684-7693, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31203623

RESUMO

This study investigated the alleviative effect of caffeic acid (CA) on Alzheimer's disease (AD) pathogenesis and associated mechanisms in high-fat (HF) diet-induced hyperinsulinemic rats. The results of a Morris water maze indicated that, by administrating CA (30 mg/kg b.w./day) for 30 weeks, the memory and learning impairments in HF-induced hyperinsulinemic rats were significantly ameliorated. CA also enhanced superoxide dismutase and glutathione free radical scavenger activity in hyperinsulinemic rats. The Western blot data further confirmed that protein expressions of phosphorylated-glycogen synthase kinase 3ß (GSK3ß) were significantly increased, whereas the expression of phosphorylated-tau protein decreased in the hippocampus of rats administered with CA in comparison with the HF group. Moreover, the expression of amyloid precursor protein (APP) and ß-site APP cleaving enzyme were attenuated, subsequently lowering the level of ß-amyloid 1-42 (Aß 1-42) in the hippocampus of CA-treated hyperinsulinemic rats. CA also significantly increased the expression of synaptic proteins in HF rats.


Assuntos
Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Ácidos Cafeicos/administração & dosagem , Insulina/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Doença de Alzheimer/metabolismo , Animais , Antioxidantes/química , Córtex Cerebral/química , Córtex Cerebral/enzimologia , Córtex Cerebral/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Glutationa/metabolismo , Glicogênio Sintase Quinase 3 beta/análise , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/química , Hipocampo/enzimologia , Hipocampo/metabolismo , Hiperinsulinismo/etiologia , Hiperinsulinismo/metabolismo , Masculino , Fosforilação , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Proteínas tau/análise , Proteínas tau/metabolismo
19.
Gen Comp Endocrinol ; 282: 113209, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31226256

RESUMO

The highly conserved brain-pituitary-gonadal (BPG) axis controls reproduction in all vertebrates, so analyzing the regulation of this signaling cascade is important for understanding reproductive competence. The protein kinase mechanistic target of rapamycin (mTOR) functions as a conserved regulator of cellular growth and metabolism in all eukaryotes, and also regulates the reproductive axis in mammals. However, whether mTOR might also regulate the BPG axis in non-mammalian vertebrates remains unexplored. We used complementary experimental approaches in an African cichlid fish, Astatotilapia burtoni, to demonstrate that mTOR is involved in regulation of the brain, pituitary, and testes when males rise in rank to social dominance. mTOR or downstream components of its signaling pathway (p-p70S6K) were detected in gonadotropin-releasing hormone (GnRH1) neurons, the pituitary, and testes. Transcript levels of mtor in the pituitary and testes also varied when reproductively-suppressed subordinate males rose in social rank to become dominant reproductively-active males, a transition similar to puberty in mammals. Intracerebroventricular injection of the mTORC1 inhibitor, rapamycin, revealed a role for mTOR in the socially-induced hypertrophy of GnRH1 neurons. Rapamycin treatment also had effects at the pituitary and testes, suggesting involvement of the mTORC1 complex at multiple levels of the reproductive axis. Thus, we show that mTOR regulation of BPG function is conserved to fishes, likely playing important roles in regulating reproduction and fertility across all male vertebrates.


Assuntos
Ciclídeos/fisiologia , Reprodução/fisiologia , Predomínio Social , Serina-Treonina Quinases TOR/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclídeos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Hormônio Liberador de Gonadotropina/metabolismo , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosforilação/efeitos dos fármacos , Hipófise/efeitos dos fármacos , Hipófise/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reprodução/efeitos dos fármacos , Maturidade Sexual/efeitos dos fármacos , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Testículo/efeitos dos fármacos , Testículo/metabolismo
20.
Int J Mol Sci ; 20(11)2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31195662

RESUMO

The initiation of protein synthesis is suppressed under several stress conditions, inducing phosphorylation of the α-subunit of the eukaryotic initiation factor 2 (eIF2α), thereby inactivating the GTP-GDP recycling protein eIF2B. By contrast, the mammalian activating transcription factor 4 (ATF4, also known as cAMP response element binding protein 2 (CREB2)) is still translated under stress conditions. Four protein kinases (general control nonderepressible-2 (GCN2) kinase, double-stranded RNA-activated protein kinase (PKR), PKR-endoplasmic reticulum (ER)-related kinase (PERK), and heme-regulated inhibitor kinase (HRI)) phosphorylate eIF2α in the presence of stressors such as amino acid starvation, viral infection, ER stress, and heme deficiency. This signaling reaction is known as the integrated stress response (ISR). Here, we review ISR signaling in the brain in a mouse model of Alzheimer's disease (AD). We propose that targeting ISR signaling with quercetin has therapeutic potential, because it suppresses amyloid-ß (Aß) production in vitro and prevents cognitive impairments in a mouse model of AD.


Assuntos
Memória/efeitos dos fármacos , Quercetina/farmacologia , Estresse Fisiológico/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Animais , Humanos , Plasticidade Neuronal/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
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