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1.
Nat Commun ; 11(1): 5083, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033259

RESUMO

In hippocampal pyramidal cells, a small subset of dendritic spines contain endoplasmic reticulum (ER). In large spines, ER frequently forms a spine apparatus, while smaller spines contain just a single tubule of smooth ER. Here we show that the ER visits dendritic spines in a non-random manner, targeting spines during periods of high synaptic activity. When we blocked ER motility using a dominant negative approach against myosin V, spine synapses became stronger compared to controls. We were not able to further potentiate these maxed-out synapses, but long-term depression (LTD) was readily induced by low-frequency stimulation. We conclude that the brief ER visits to active spines have the important function of preventing runaway potentiation of individual spine synapses, keeping most of them at an intermediate strength level from which both long-term potentiation (LTP) and LTD are possible.


Assuntos
Espinhas Dendríticas/metabolismo , Retículo Endoplasmático/metabolismo , Sinapses/metabolismo , Animais , Hipocampo/metabolismo , Potenciação de Longa Duração , Miosina Tipo V/metabolismo , Ratos Wistar , Imagem com Lapso de Tempo
2.
Nat Commun ; 11(1): 5073, 2020 10 08.
Artigo em Inglês | MEDLINE | ID: mdl-33033238

RESUMO

Brain cells continuously produce and release protons into the extracellular space, with the rate of acid production corresponding to the levels of neuronal activity and metabolism. Efficient buffering and removal of excess H+ is essential for brain function, not least because all the electrogenic and biochemical machinery of synaptic transmission is highly sensitive to changes in pH. Here, we describe an astroglial mechanism that contributes to the protection of the brain milieu from acidification. In vivo and in vitro experiments conducted in rodent models show that at least one third of all astrocytes release bicarbonate to buffer extracellular H+ loads associated with increases in neuronal activity. The underlying signalling mechanism involves activity-dependent release of ATP triggering bicarbonate secretion by astrocytes via activation of metabotropic P2Y1 receptors, recruitment of phospholipase C, release of Ca2+ from the internal stores, and facilitated outward HCO3- transport by the electrogenic sodium bicarbonate cotransporter 1, NBCe1. These results show that astrocytes maintain local brain extracellular pH homeostasis via a neuronal activity-dependent release of bicarbonate. The data provide evidence of another important metabolic housekeeping function of these glial cells.


Assuntos
Astrócitos/metabolismo , Bicarbonatos/metabolismo , Encéfalo/metabolismo , Espaço Extracelular/metabolismo , Acetazolamida/farmacologia , Trifosfato de Adenosina/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Anidrases Carbônicas/metabolismo , Células Cultivadas , Estimulação Elétrica , Fluorescência , Hipocampo/metabolismo , Concentração de Íons de Hidrogênio , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Antagonistas Purinérgicos/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptores Purinérgicos/metabolismo , Transdução de Sinais , Simportadores de Sódio-Bicarbonato/metabolismo
3.
Yakugaku Zasshi ; 140(10): 1207-1212, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-32999199

RESUMO

T-type calcium channels are low-threshold voltage-gated calcium channel and characterized by unique electrophysiological properties such as fast inactivation and slow deactivation kinetics. All subtypes of T-type calcium channel (Cav3.1, 3.2 and 3.3) are widely expressed in the central nerve system, and they have an important role in homeostasis of sleep, pain response, and development of epilepsy. Recently, several reports suggest that T-type calcium channels may mediate neuronal plasticity in the mouse brain. We succeeded to develop T-type calcium channel enhancer ethyl 8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo[1,2-a]pyridine]-2-ene-3-carboxylate (SAK3) which enhances Cav3.1 and 3.3 currents in each-channel expressed neuro2A cells. SAK3 can promote acetylcholine (ACh) release in the mouse hippocampus via enhancing T-type calcium channel. In this review, we have introduced the role of T-type calcium channel, especially Cav3.1 channel in the mouse hippocampus based on our previous data using SAK3 and Cav3.1 knockout mice.


Assuntos
Canais de Cálcio Tipo T/efeitos dos fármacos , Canais de Cálcio Tipo T/fisiologia , Imidazóis/farmacologia , Neurônios/fisiologia , Compostos de Espiro/farmacologia , Acetilcolina/metabolismo , Animais , Encéfalo/fisiologia , Canais de Cálcio Tipo T/genética , Canais de Cálcio Tipo T/metabolismo , Células Cultivadas , Sistema Nervoso Central/metabolismo , Fenômenos Eletrofisiológicos , Epilepsia/etiologia , Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Homeostase , Camundongos , Plasticidade Neuronal , Dor/etiologia , Ratos , Sono/fisiologia
4.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 45(8): 892-900, 2020 Aug 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33053529

RESUMO

OBJECTIVES: To investigate the effects of environmental enrichment on cognitive behavior and the expression of adenosine triphosphate binding cassette transporter A7 (ABCA7) in hippocampus of the adolescent mice with high fat diet. METHODS: A total of healthy 3-week-old male C57BL/6J mice were randomly divided into 3 groups: a control (Con) group, a high fat diet (HFD) group, and a high fat diet+environmental enrichment (HFD+EE) group, with 10 mice in each group. The Con group was given normal diet. The HFD group was given high fat diet. The HFD+EE group was given high fat diet; at the same time, they treated by environmental enrichment. After 10 weeks, open field test was used to detect activity. Novel object recognition test and Y maze test were used to detect cognitive behavior. After the test, the brain was collected and used to detect the protein expression of ABCA7 in the hippocampus by immunohistochemistry and Western blotting. And quantitative RT-PCR (RT-qPCR) was used to detect the ABCA7 mRNA expression level in the hippocampus. RESULTS: There was no significant difference in the total movement distance in the mice among the 3 groups (P>0.05). In the novel object recognition test, the discrimination index of the HFD group was much lower than that of the Con group, and the difference was significant (P<0.01). The discrimination index of the HFD+EE group was higher than that of the HFD group, and the difference was significant (P<0.01). In the Y maze test, there was no significant difference in the percentage of time spent on the new arm among the mice in the 3 groups (P=0.1279). The percentage of entries in new arm in the HFD group was much lower than that in the Con group, and the difference was significant (P<0.01). The percentage of the entries in new arm in the HFD+EE group was significantly higher than that in the HFD group (P<0.05). The results of immunohistochemistry showed that ABCA7 was positively expressed in the cytoplasm of hippocampal neurons in the mice from these 3 groups, and the expression of ABCA7 in the hippocampus of the HFD group was lower than that of the Con group (CA1: P<0.01, CA3: P=0.06), while the expression of ABCA7 in hippocampus of HFD+EE group was higher than that of HFD group (CA1: P=0.23, CA3: P<0.05). Western blotting results showed that compared with the Con group, the protein level of ABCA7 in the hippocampus of the HFD group was significantly reduced (P<0.05), while compared with the Con group, the protein level of ABCA7 in the hippocampus of the HFD+EE group showed an upward trend (P=0.06). The results of RT-qPCR showed that the mRNA level of ABCA7 in the hippocampus of HFD group was significantly lower than that of the Con group (P<0.01), while the mRNA level of ABCA7 in the hippocampus of HFD+EE group was significantly higher than that of the HFD group (P<0.01). CONCLUSIONS: High fat diet in adolescent can impair cognitive function with a decrease in the expression of ABCA7 in hippocampus, which can be ameliorate by environmental enrichment.


Assuntos
Transportadores de Cassetes de Ligação de ATP , Trifosfato de Adenosina , Dieta Hiperlipídica , Hipocampo , Animais , Cognição , Dieta Hiperlipídica/efeitos adversos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
5.
Medicine (Baltimore) ; 99(33): e21711, 2020 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-32872049

RESUMO

BACKGROUND: This study will investigate the effects of Spore Powder of Ganoderma Lucidum (SPGL) on CaSR and apoptosis-related proteins (ARP) in hippocampus tissue of epilepsy following dementia. METHODS: This study will retrieve all potential studies from both electronic databases (Cochrane Library, EMBASE, MEDLINE, CINAHL, AMED, and CNKI) and other literature sources to assess the effects of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. We will search all literature sources from the inception to the present. All eligible case-control studies will be included in this study. Two authors will independently carry out literature selection, data collection, and study quality evaluation. Any divergence will be resolved by another author through discussion. RevMan 5.3 software will be employed for data analysis. RESULTS: This study will summarize existing evidence to assess the effects of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. CONCLUSIONS: The findings of this study may provide helpful evidence of SPGL on CaSR and ARP in hippocampus tissue of epilepsy following dementia. SYSTEMATIC REVIEW REGISTRATION: INPLASY202070041.


Assuntos
Demência/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Epilepsia/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Reishi , Animais , Demência/complicações , Medicamentos de Ervas Chinesas/farmacologia , Epilepsia/etiologia , Hipocampo/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Revisões Sistemáticas como Assunto
6.
Braz J Med Biol Res ; 53(10): e8826, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32901686

RESUMO

This study determined the expression of plasminogen activator inhibitor-1 (PAI-1) and microRNA (miR)-17 in a mouse depression model. Forty male mice were divided evenly into control and depression groups. A chronic unpredictable mild stress (CUMS) model was constructed. qRT-PCR was used to determine the expression of PAI-1 mRNA and miR-17. Western blotting and ELISA were used to determine expression of PAI-1 protein. Dual luciferase reporter assay was carried out to identify direct interaction between miR-17 and PAI-1 mRNA. The mice with depression had elevated PAI-1 mRNA and protein in hippocampal tissues and blood. Expression of miR-17 was decreased in hippocampal tissues and blood from mice with depression. miR-17 bound with the 3'-UTR of PAI-1 mRNA to regulate its expression. This study demonstrated that miR-17 expression in hippocampal tissues and blood from mice with depression was decreased while expression of PAI-1 mRNA and protein was up-regulated. miR-17 participated in depression in mice by regulating PAI-1.


Assuntos
Depressão/metabolismo , MicroRNAs , Inibidor 1 de Ativador de Plasminogênio , Animais , Hipocampo/metabolismo , Masculino , Camundongos , RNA Mensageiro
7.
Proc Natl Acad Sci U S A ; 117(37): 23073-23084, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32873638

RESUMO

The small GTPase ARL4C participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The ARL4C signaling cascade starts by the recruitment of the ARF-GEF cytohesins to the plasma membrane, which, in turn, bind and activate the small GTPase ARF6. However, the role of ARL4C-cytohesin-ARF6 signaling during hippocampal development remains elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/RBX2 (CRL5) controls the stability of ARL4C and its signaling effectors to regulate hippocampal morphogenesis. Both RBX2 knockout and Cullin 5 knockdown cause hippocampal pyramidal neuron mislocalization and development of multiple apical dendrites. We used quantitative mass spectrometry to show that ARL4C, Cytohesin-1/3, and ARF6 accumulate in the RBX2 mutant telencephalon. Furthermore, we show that depletion of ARL4C rescues the phenotypes caused by Cullin 5 knockdown, whereas depletion of CYTH1 or ARF6 exacerbates overmigration. Finally, we show that ARL4C, CYTH1, and ARF6 are necessary for the dendritic outgrowth of pyramidal neurons to the superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered ARL4C, CYTH1, and ARF6 as CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.


Assuntos
Fatores de Ribosilação do ADP/metabolismo , Proteínas Culina/metabolismo , Hipocampo/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Morfogênese/fisiologia , Animais , Membrana Celular/metabolismo , Movimento Celular/fisiologia , Dendritos/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Camundongos , Neurogênese/fisiologia , Células Piramidais/metabolismo , Transdução de Sinais/fisiologia , Ubiquitina-Proteína Ligases/metabolismo
8.
PLoS Biol ; 18(8): e3000826, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32776935

RESUMO

Ca2+/calmodulin-dependent kinase II (CaMKII) regulates synaptic plasticity in multiple ways, supposedly including the secretion of neuromodulators like brain-derived neurotrophic factor (BDNF). Here, we show that neuromodulator secretion is indeed reduced in mouse α- and ßCaMKII-deficient (αßCaMKII double-knockout [DKO]) hippocampal neurons. However, this was not due to reduced secretion efficiency or neuromodulator vesicle transport but to 40% reduced neuromodulator levels at synapses and 50% reduced delivery of new neuromodulator vesicles to axons. αßCaMKII depletion drastically reduced neuromodulator expression. Blocking BDNF secretion or BDNF scavenging in wild-type neurons produced a similar reduction. Reduced neuromodulator expression in αßCaMKII DKO neurons was restored by active ßCaMKII but not inactive ßCaMKII or αCaMKII, and by CaMKII downstream effectors that promote cAMP-response element binding protein (CREB) phosphorylation. These data indicate that CaMKII regulates neuromodulation in a feedback loop coupling neuromodulator secretion to ßCaMKII- and CREB-dependent neuromodulator expression and axonal targeting, but CaMKIIs are dispensable for the secretion process itself.


Assuntos
Astrócitos/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Cálcio/metabolismo , Neurônios/metabolismo , Subunidades Proteicas/genética , Animais , Astrócitos/citologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/deficiência , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Retroalimentação Fisiológica , Regulação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Camundongos Transgênicos , Neurônios/citologia , Fosforilação , Cultura Primária de Células , Subunidades Proteicas/deficiência , Sinapses/fisiologia , Transmissão Sináptica , Imagem com Lapso de Tempo
9.
PLoS Biol ; 18(8): e3000851, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32822389

RESUMO

High levels of the amyloid-beta (Aß) peptide have been shown to disrupt neuronal function and induce hyperexcitability, but it is unclear what effects Aß-associated hyperexcitability may have on tauopathy pathogenesis or propagation in vivo. Using a novel transgenic mouse line to model the impact of human APP (hAPP)/Aß accumulation on tauopathy in the entorhinal cortex-hippocampal (EC-HIPP) network, we demonstrate that hAPP overexpression aggravates EC-Tau aggregation and accelerates pathological tau spread into the hippocampus. In vivo recordings revealed a strong role for hAPP/Aß, but not tau, in the emergence of EC neuronal hyperactivity and impaired theta rhythmicity. Chronic chemogenetic attenuation of EC neuronal hyperactivity led to reduced hAPP/Aß accumulation and reduced pathological tau spread into downstream hippocampus. These data strongly support the hypothesis that in Alzheimer's disease (AD), Aß-associated hyperactivity accelerates the progression of pathological tau along vulnerable neuronal circuits, and demonstrates the utility of chronic, neuromodulatory approaches in ameliorating AD pathology in vivo.


Assuntos
Doença de Alzheimer/genética , Precursor de Proteína beta-Amiloide/genética , Córtex Entorrinal/metabolismo , Tauopatias/genética , Proteínas tau/genética , Potenciais de Ação/fisiologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/terapia , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Dependovirus/genética , Dependovirus/metabolismo , Modelos Animais de Doenças , Eletrodos Implantados , Córtex Entorrinal/patologia , Feminino , Regulação da Expressão Gênica , Vetores Genéticos/química , Vetores Genéticos/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/metabolismo , Neurônios/patologia , Agregados Proteicos , Técnicas Estereotáxicas , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/terapia , Ritmo Teta/fisiologia , Transdução Genética , Transgenes , Proteínas tau/metabolismo
10.
Life Sci ; 257: 118046, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32622948

RESUMO

Orexin-A is an endogenous peptide with receptors throughout the brain. According to some recent research, learning and memory are affected by the central administration of orexin; however, no study so far has investigated the long-term inhibition of the orexinergic system. The present study has evaluated the effect of pretraining administration of orexin 1 receptor (OXR1) antagonist, SB-334867, on the acquisition of memory. The Morris water maze (MWM) task was used for training and trial purposes in all groups. Memory performance was analyzed by measuring escape latency, traveled distance, and time spent in the target quadrant. Moreover, the effect of SB-334867 on phospholipase Cß3 (PLCß3) levels in the CA1 region of hippocampus slices was examined. Hippocampus slices were prepared using an immunohistochemistry (IHC) approach. SB-334867 (20 mg/kg) increased escape latency in SB-treated rats compared to SB-vehicle group (P < 0.01). SB-treated rats spent less time in the target quadrant compared to the SB-vehicle group (P < 0.001). Distance traveled in the target quadrant was significantly more in SB-treated rats compared to the SB-vehicle group (P < 0.001). Furthermore, SB-334867 decreased PLCß3 levels in the CA1 of the hippocampus (P < 0.01 and P < 0.05, respectively). Put together, our results suggest that the long-term inhibition of OXR1 plays a prominent role in spatial learning and memory, probably by attenuating PLCß3 in CA1 neurons.


Assuntos
Memória/efeitos dos fármacos , Memória/fisiologia , Fosfolipase C beta/metabolismo , Animais , Benzoxazóis/farmacologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Naftiridinas/farmacologia , Receptores de Orexina/metabolismo , Orexinas/metabolismo , Fosfolipase C beta/fisiologia , Ratos , Ratos Wistar , Ureia/análogos & derivados , Ureia/farmacologia
11.
Life Sci ; 257: 118049, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32634430

RESUMO

AIMS: Mild traumatic brain injury (mTBI) is an important risk factor for cognitive impairment. Despite intense efforts to develop efficient treatments, the current therapies are not often effective and far from satisfactory. Silymarin has been suggested as a therapeutic agent in the treatment of traumatic brain injury. This study aimed to determine whether silymarin can exert neuroprotective effects on memory impairment following mTBI in mice. MAIN METHODS: After mTBI induction, mice were treated with silymarin once daily for 20 consecutive days by oral gavage. To investigate cognitive functions, animals were subjected to Y-maze, novel-object recognition, and Morris-water maze. Levels of tumor necrosis factor (TNF)-α, glutamate, and brain derived neurotrophic factor (BDNF) were measured in the hippocampus. KEY FINDINGS: Our findings showed that mTBI resulted in a significant decline in memory in the Y-maze and Morris-water maze in both sexes, whereas only impaired cognitive function in males in the novel-object recognition. We found notable increases in TNF-α and glutamate levels in the hippocampus of both sexes, while there was only a significant decrease in hippocampal BDNF in mTBI-induced females. In addition, silymarin treatment improved cognitive impairments in mTBI-induced males but not in females. Silymarin significantly reduced TNF-α and glutamate levels, and increased BDNF levels in the hippocampus of mTBI-induced male but not in female mice. SIGNIFICANCE: This study demonstrates that silymarin treatment sex-dependently improves cognitive impairment in mTBI-induced mice, and suggests that silymarin may be a therapeutic agent for cognitive decline following mTBI in males. Further studies are needed to establish the validity of these findings in humans.


Assuntos
Concussão Encefálica/tratamento farmacológico , Cognição/efeitos dos fármacos , Silimarina/uso terapêutico , Animais , Animais não Endogâmicos , Concussão Encefálica/metabolismo , Lesões Encefálicas/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fatores Sexuais , Silimarina/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
12.
Toxicol Lett ; 332: 192-201, 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-32693020

RESUMO

Fenvalerate, a synthetic pyrethroid insecticide, is an environmental endocrine disruptor and neurodevelopmental toxicant. An early report found that pubertal exposure to high-dose fenvalerate impaired cognitive and behavioral development. Here, we aimed to further investigate the effect of pubertal exposure to low-dose fenvalerate on cognitive and behavioral development. Mice were orally administered with fenvalerate (0.2, 1.0 and 5.0 mg/kg) daily from postnatal day (PND) 28 to PND56. Learning and memory were assessed by Morris water maze. Anxiety-related activities were detected by open-field and elevated plus-maze. Increased anxiety activities were observed only in females exposed to fenvalerate. Spatial learning and memory were damaged only in females exposed to fenvalerate. Histopathology observed numerous scattered shrinking neurons and nuclear pyknosis in hippocampal CA1 region. Neuronal density was reduced in hippocampal CA1 region of fenvalerate-exposed mice. Mechanistically, hippocampal thyroid hormone receptor (TR)ß1 was down-regulated in a dose-dependent manner in females. In addition, TRα1 was declined only in females exposed to 5.0 mg/kg fenvalerate. Taken together, these suggests that pubertal exposure to low-dose fenvalerate impairs cognitive and behavioral development in a gender-dependent manner. Hippocampal TR signaling may be, at least partially, involved in fenvalerate-induced impairment of cognitive and behavioral development.


Assuntos
Transtornos Cognitivos/induzido quimicamente , Hipocampo/metabolismo , Inseticidas/toxicidade , Nitrilos/toxicidade , Piretrinas/toxicidade , Transdução de Sinais/efeitos dos fármacos , Hormônios Tireóideos , Animais , Ansiedade/induzido quimicamente , Ansiedade/psicologia , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/metabolismo , Transtornos Cognitivos/psicologia , Relação Dose-Resposta a Droga , Regulação para Baixo/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Disruptores Endócrinos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Neurônios/patologia , Receptores dos Hormônios Tireóideos/efeitos dos fármacos , Caracteres Sexuais
13.
Cell Prolif ; 53(8): e12856, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32648622

RESUMO

OBJECTIVES: Glial cell activation contributes to the inflammatory response and occurrence of epilepsy. Our preliminary study demonstrated that the long non-coding RNA, H19, promotes hippocampal glial cell activation during epileptogenesis. However, the precise mechanisms underlying this effect remain unclear. MATERIALS AND METHODS: H19 and let-7b were overexpressed or silenced using an adeno-associated viral vector in vivo. Their expression in a kainic acid-induced epilepsy model was evaluated by real-time quantitative PCR, fluorescence in situ hybridization, and cytoplasmic and nuclear RNA isolation. A dual-luciferase reporter assay was used to evaluate the direct binding of let-7b to its target genes and H19. Western blot, video camera monitoring and Morris water maze were performed to confirm the role of H19 and let7b on epileptogenesis. RESULTS: H19 was increased in rat hippocampus neurons after status epilepticus, which might be due to epileptic seizure-induced hypoxia. Increased H19 aggravated the epileptic seizures, memory impairment and mossy fibre sprouting of the epileptic rats. H19 could competitively bind to let-7b to suppress its expression. Overexpression of let-7b inhibited hippocampal glial cell activation, inflammatory response and epileptic seizures by targeting Stat3. Moreover, overexpressed H19 reversed the inhibitory effect of let-7b on glial cell activation. CONCLUSIONS: LncRNA H19 could competitively bind to let-7b to promote hippocampal glial cell activation and epileptic seizures by targeting Stat3 in a rat model of temporal lobe epilepsy.


Assuntos
Epilepsia do Lobo Temporal/genética , Hipocampo/metabolismo , MicroRNAs/genética , RNA Longo não Codificante/genética , Fator de Transcrição STAT3/metabolismo , Animais , Modelos Animais de Doenças , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia do Lobo Temporal/metabolismo , Genes Supressores de Tumor/fisiologia , Masculino , Ratos Sprague-Dawley , Convulsões/genética , Convulsões/metabolismo
14.
Nat Commun ; 11(1): 3451, 2020 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-32651370

RESUMO

When our experience violates our predictions, it is adaptive to upregulate encoding of novel information, while down-weighting retrieval of erroneous memory predictions to promote an updated representation of the world. We asked whether mnemonic prediction errors promote hippocampal encoding versus retrieval states, as marked by distinct network connectivity between hippocampal subfields. During fMRI scanning, participants were cued to internally retrieve well-learned complex room-images and were then presented with either an identical or a modified image (0-4 changes). In the left hemisphere, we find that CA1-entorhinal connectivity increases, and CA1-CA3 connectivity decreases, with the number of changes. Further, in the left CA1, the similarity between activity patterns during cued-retrieval of the learned room and during the image is lower when the image includes changes, consistent with a prediction error signal in CA1. Our findings provide a mechanism by which mnemonic prediction errors may drive memory updating-by biasing hippocampal states.


Assuntos
Cognição/fisiologia , Hipocampo/metabolismo , Hipocampo/fisiologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiologia , Córtex Entorrinal/metabolismo , Córtex Entorrinal/fisiologia , Humanos , Aprendizagem/fisiologia , Imagem por Ressonância Magnética , Memória de Longo Prazo/fisiologia
15.
Life Sci ; 257: 118081, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32663576

RESUMO

Temporal lobe epilepsy (TLE) is the most common form of epilepsy with focal seizures, and currently available drugs may fail to provide a thorough treatment of the patients. The present study demonstrates the utility of glucose-coated gold nanoparticles (GNPs) as selective carriers of an antiepileptic drug, lacosamide (LCM), in developing a strategy to cross the blood-brain barrier to overcome drug resistance. Intravenous administration of LCM-loaded GNPs to epileptic animals yielded significantly higher nanoparticle levels in the hippocampus compared to the nanoparticle administration to intact animals. The amplitude and frequency of EEG-waves in both ictal and interictal stages decreased significantly after LCM-GNP administration to animals with TLE, while a decrease in the number of seizures was also observed though statistically insignificant. In these animals, malondialdehyde was unaffected, and glutathione levels were lower in the hippocampus compared to sham. Ultrastructurally, LCM-GNPs were observed in the brain parenchyma after intravenous injection to animals with TLE. We conclude that glucose-coated GNPs can be efficient in transferring effective doses of LCM into the brain enabling elimination of the need to administer high doses of the drug, and hence, may represent a new approach in the treatment of drug-resistant TLE.


Assuntos
Anticonvulsivantes/administração & dosagem , Sistemas de Liberação de Medicamentos , Epilepsia do Lobo Temporal/tratamento farmacológico , Lacosamida/administração & dosagem , Nanopartículas Metálicas , Animais , Anticonvulsivantes/farmacocinética , Anticonvulsivantes/farmacologia , Encéfalo/metabolismo , Modelos Animais de Doenças , Eletroencefalografia , Ouro/química , Hipocampo/metabolismo , Injeções Intravenosas , Lacosamida/farmacocinética , Lacosamida/farmacologia , Masculino , Ratos , Ratos Wistar , Distribuição Tecidual
16.
Nat Commun ; 11(1): 3594, 2020 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681011

RESUMO

Circular RNAs (circRNAs) are abundant in mammalian brain and some show age-dependent expression patterns. Here, we report that circGRIA1, a conserved circRNA isoform derived from the genomic loci of α-mino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subunit Gria1, shows an age-related and male-specific increase in expression in the rhesus macaque prefrontal cortex and hippocampus. We show circGRIA1 is predominantly localized to the nucleus, and find an age-related increase in its association with the promoter region of Gria1 gene, suggesting it has a regulatory role in Gria1 transcription. In vitro and in vivo manipulation of circGRIA1 negatively regulates Gria1 mRNA and protein levels. Knockdown of circGRIA1 results in an age-related improvement of synaptogenesis, and GluR1 activity-dependent synaptic plasticity in the hippocampal neurons in males. Our findings underscore the importance of circRNA regulation and offer an insight into the biology of brain aging.


Assuntos
Encéfalo/fisiologia , Macaca mulatta/metabolismo , Plasticidade Neuronal , RNA Circular/metabolismo , Receptores de AMPA/genética , Sinapses/metabolismo , Fatores Etários , Envelhecimento , Animais , Feminino , Hipocampo/metabolismo , Macaca mulatta/genética , Macaca mulatta/crescimento & desenvolvimento , Masculino , RNA Circular/genética , Receptores de AMPA/metabolismo , Sinapses/genética
17.
Chem Biol Interact ; 328: 109195, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32707044

RESUMO

A previous study demonstrated that glutathione (GSH) produces specific antidepressant-like effect in the forced swimming test (FST), a predictive test of antidepressant activity. The present study investigated the involvement of multiple cellular targets implicated in the antidepressant-like effect of GSH in the FST. The antidepressant-like effect of GSH (300 nmol/site, icv) lasted up to 3 h when mice were submitted to FST. The central administration of oxidized GSH (GSSG, 3-300 nmol/site) did not alter the behavior of mice submitted to the FST. Furthermore, the combined treatment of sub-effective doses of GSH (100 nmol/site, icv) with a sub-effective dose of classical antidepressants (fluoxetine 10 mg/kg, and imipramine 5 mg/kg, ip) presented synergistic effect by decreasing the immobility time in the FST. The antidepressant-like effect of GSH was abolished by prazosin (1 mg/kg, ip, α1-adrenoceptor antagonist), baclofen (1 mg/kg, ip, GABAB receptor agonist), bicuculline (1 mg/kg, ip, GABAA receptor antagonist), l-arginine (750 mg/kg, ip, NO precursor), SNAP (25 µg/site, icv, NO donor), but not by yohimbine (1 mg/kg, ip, α2-adrenoceptor antagonist). The NMDA receptor antagonists, MK-801(0.001 mg/kg, ip) or GMP (0.5 mg/kg, ip), potentiated the effect of a sub-effective dose of GSH in the FST. These results suggest that the antidepressant-like effect induced by GSH is connected to the activation of α1 adrenergic and GABAA receptors, as well as the inhibition of GABAB and NMDA receptors and NO biosyntesis. We speculate that redox-mediated signaling on the extracelular portion of cell membrane receptors would be a common mechanism of action of GSH.


Assuntos
Antidepressivos/farmacologia , Glutationa/farmacologia , Terapia de Alvo Molecular , Antagonistas Adrenérgicos/farmacologia , Animais , Arginina/farmacologia , Sinergismo Farmacológico , Feminino , Glutationa/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imobilização , Masculino , Camundongos , Receptores Adrenérgicos/metabolismo , Receptores de GABA/metabolismo , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , S-Nitroso-N-Acetilpenicilamina/farmacologia , Natação
18.
Proc Natl Acad Sci U S A ; 117(27): 15977-15988, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581127

RESUMO

Temporal lobe epilepsy is the most common drug-resistant form of epilepsy in adults. The reorganization of neural networks and the gene expression landscape underlying pathophysiologic network behavior in brain structures such as the hippocampus has been suggested to be controlled, in part, by microRNAs. To systematically assess their significance, we sequenced Argonaute-loaded microRNAs to define functionally engaged microRNAs in the hippocampus of three different animal models in two species and at six time points between the initial precipitating insult through to the establishment of chronic epilepsy. We then selected commonly up-regulated microRNAs for a functional in vivo therapeutic screen using oligonucleotide inhibitors. Argonaute sequencing generated 1.44 billion small RNA reads of which up to 82% were microRNAs, with over 400 unique microRNAs detected per model. Approximately half of the detected microRNAs were dysregulated in each epilepsy model. We prioritized commonly up-regulated microRNAs that were fully conserved in humans and designed custom antisense oligonucleotides for these candidate targets. Antiseizure phenotypes were observed upon knockdown of miR-10a-5p, miR-21a-5p, and miR-142a-5p and electrophysiological analyses indicated broad safety of this approach. Combined inhibition of these three microRNAs reduced spontaneous seizures in epileptic mice. Proteomic data, RNA sequencing, and pathway analysis on predicted and validated targets of these microRNAs implicated derepressed TGF-ß signaling as a shared seizure-modifying mechanism. Correspondingly, inhibition of TGF-ß signaling occluded the antiseizure effects of the antagomirs. Together, these results identify shared, dysregulated, and functionally active microRNAs during the pathogenesis of epilepsy which represent therapeutic antiseizure targets.


Assuntos
Epilepsia do Lobo Temporal/tratamento farmacológico , Epilepsia do Lobo Temporal/metabolismo , MicroRNAs/efeitos dos fármacos , MicroRNAs/metabolismo , Oligonucleotídeos Antissenso/farmacologia , Convulsões/tratamento farmacológico , Convulsões/metabolismo , Animais , Antagomirs/farmacologia , Proteínas Argonauta/genética , Proteínas Argonauta/metabolismo , Biomarcadores , Modelos Animais de Doenças , Epilepsia , Feminino , Hipocampo/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteômica , Ratos , Ratos Sprague-Dawley , Convulsões/genética , Análise de Sistemas , Regulação para Cima/efeitos dos fármacos
19.
PLoS Pathog ; 16(6): e1008381, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32525948

RESUMO

HIV invades the brain during acute infection. Yet, it is unknown whether long-lived infected brain cells release productive virus that can egress from the brain to re-seed peripheral organs. This understanding has significant implication for the brain as a reservoir for HIV and most importantly HIV interplay between the brain and peripheral organs. Given the sheer number of astrocytes in the human brain and their controversial role in HIV infection, we evaluated their infection in vivo and whether HIV infected astrocytes can support HIV egress to peripheral organs. We developed two novel models of chimeric human astrocyte/human peripheral blood mononuclear cells: NOD/scid-IL-2Rgc null (NSG) mice (huAstro/HuPBMCs) whereby we transplanted HIV (non-pseudotyped or VSVg-pseudotyped) infected or uninfected primary human fetal astrocytes (NHAs) or an astrocytoma cell line (U138MG) into the brain of neonate or adult NSG mice and reconstituted the animals with human peripheral blood mononuclear cells (PBMCs). We also transplanted uninfected astrocytes into the brain of NSG mice and reconstituted with infected PBMCs to mimic a biological infection course. As expected, the xenotransplanted astrocytes did not escape/migrate out of the brain and the blood brain barrier (BBB) was intact in this model. We demonstrate that astrocytes support HIV infection in vivo and egress to peripheral organs, at least in part, through trafficking of infected CD4+ T cells out of the brain. Astrocyte-derived HIV egress persists, albeit at low levels, under combination antiretroviral therapy (cART). Egressed HIV evolved with a pattern and rate typical of acute peripheral infection. Lastly, analysis of human cortical or hippocampal brain regions of donors under cART revealed that astrocytes harbor between 0.4-5.2% integrated HIV gag DNA and 2-7% are HIV gag mRNA positive. These studies establish a paradigm shift in the dynamic interaction between the brain and peripheral organs which can inform eradication of HIV reservoirs.


Assuntos
Astrócitos , Barreira Hematoencefálica , Infecções por HIV , HIV-1/metabolismo , Hipocampo , Liberação de Vírus , Animais , Antirretrovirais/farmacologia , Astrócitos/metabolismo , Astrócitos/patologia , Astrócitos/virologia , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/virologia , Linhagem Celular Tumoral , Infecções por HIV/genética , Infecções por HIV/metabolismo , Infecções por HIV/patologia , HIV-1/genética , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/virologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID
20.
Life Sci ; 257: 117991, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32569782

RESUMO

Traumatic brain injury (TBI) is a public health problem in which even though 80 to 90% of cases are considered mild, usually starts a sequence of neurological disorders that can last a considerable time. Most of the research of this injury has been focused on oxidative stress and functional deficits; however, mechanisms that underlie the development of neuropsychiatric disorders remain little researched. Due to this, the present authors decided to investigate whether recurrent concussion protocols alter depressive-like phenotype behavior, and whether mitochondria play an indispensable role in this behavior or not. The experimental data revealed, for the first time, that the present protocol of recurrent concussions (4, 7, and 10 injuries) in mice did not alter immobility time during tail suspension tests (TSTs), but decreased hippocampal mitochondrial respiration and increased expression of proteins such as nuclear factor erythroid 2-related factor 2 (Nrf2) and superoxide (SOD2). This experimental data suggests that bioenergetic changes elicited by recurrent concussion did not induce depressive-like behavior, but activated the transcription factor of responsive antioxidant elements (ARE) that delay or prevent secondary cascades in this neurological disease.


Assuntos
Concussão Encefálica/fisiopatologia , Depressão/metabolismo , Mitocôndrias/metabolismo , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Concussão Encefálica/metabolismo , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Depressão/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético , Hipocampo/metabolismo , Masculino , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/fisiologia , Superóxido Dismutase/metabolismo
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