Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 10.971
Filtrar
1.
Nat Commun ; 12(1): 1557, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33692361

RESUMO

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and the best-described monogenic cause of autism. CGG-repeat expansion in the FMR1 gene leads to FMR1 silencing, loss-of-expression of the Fragile X Mental Retardation Protein (FMRP), and is a common cause of FXS. Missense mutations in the FMR1 gene were also identified in FXS patients, including the recurrent FMRP-R138Q mutation. To investigate the mechanisms underlying FXS caused by this mutation, we generated a knock-in mouse model (Fmr1R138Q) expressing the FMRP-R138Q protein. We demonstrate that, in the hippocampus of the Fmr1R138Q mice, neurons show an increased spine density associated with synaptic ultrastructural defects and increased AMPA receptor-surface expression. Combining biochemical assays, high-resolution imaging, electrophysiological recordings, and behavioural testing, we also show that the R138Q mutation results in impaired hippocampal long-term potentiation and socio-cognitive deficits in mice. These findings reveal the functional impact of the FMRP-R138Q mutation in a mouse model of FXS.


Assuntos
Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Proteína do X Frágil de Retardo Mental/metabolismo , Mutação de Sentido Incorreto/fisiologia , Receptores de Glutamato/metabolismo , Animais , Biotinilação , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Células Cultivadas , Disfunção Cognitiva/metabolismo , Feminino , Proteína do X Frágil de Retardo Mental/genética , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Immunoblotting , Potenciação de Longa Duração/genética , Potenciação de Longa Duração/fisiologia , Masculino , Camundongos , Mutação de Sentido Incorreto/genética , Técnicas de Patch-Clamp , Receptores de Glutamato/genética
2.
Nat Commun ; 12(1): 1423, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658509

RESUMO

In the mammalian hippocampus, adult-born granule cells (abGCs) contribute to the function of the dentate gyrus (DG). Disruption of the DG circuitry causes spontaneous recurrent seizures (SRS), which can lead to epilepsy. Although abGCs contribute to local inhibitory feedback circuitry, whether they are involved in epileptogenesis remains elusive. Here, we identify a critical window of activity associated with the aberrant maturation of abGCs characterized by abnormal dendrite morphology, ectopic migration, and SRS. Importantly, in a mouse model of temporal lobe epilepsy, silencing aberrant abGCs during this critical period reduces abnormal dendrite morphology, cell migration, and SRS. Using mono-synaptic tracers, we show silencing aberrant abGCs decreases recurrent CA3 back-projections and restores proper cortical connections to the hippocampus. Furthermore, we show that GABA-mediated amplification of intracellular calcium regulates the early critical period of activity. Our results demonstrate that aberrant neurogenesis rewires hippocampal circuitry aggravating epilepsy in mice.


Assuntos
Epilepsia/fisiopatologia , Hipocampo/fisiopatologia , Neurogênese/fisiologia , Animais , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Modelos Animais de Doenças , Eletroencefalografia , Epilepsia do Lobo Temporal/fisiopatologia , Feminino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurogênese/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Pilocarpina/farmacologia , Retroviridae/genética , Convulsões/fisiopatologia , Ácido gama-Aminobutírico/metabolismo
3.
Arch Oral Biol ; 123: 105039, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33454419

RESUMO

OBJECTIVE: Prolonged mild stress due to tooth loss leads to morphologic and functional alterations of the hippocampus, as well as cognitive memory impairments in aged animals. An enriched environment improves stress-induced hippocampus-dependent cognitive impairments. The potential mechanisms underlying the beneficial effects of an enriched environment, however, remain unclear. In the present study, we investigated whether an enriched environment affects morphologic remodeling of the hippocampal myelin, synapses, and spatial learning deficits caused by tooth loss in aged senescence-accelerated mouse strain P8 (SAMP8) mice. DESIGN: SAMP8 mice (8 months old) with either teeth intact or teeth extracted were raised in a standard or enriched environment for three weeks. Spatial learning and memory ability was evaluated in a Morris water maze test. The morphologic features of the myelin sheath and synapses in the hippocampus were investigated by electron microscopy. RESULTS: Mice with tooth loss had a thinner myelin sheaths and shorter postsynaptic densities in the hippocampal CA1 region, and impaired hippocampus-dependent spatial learning ability. Exposure to an enriched environment ameliorated the hypomyelination and synaptic alterations, and spatial learning and memory impairments induced by tooth loss in aged SAMP8 mice. CONCLUSION: Our findings indicate that an enriched environment ameliorates hippocampal hypomyelination and synapse morphologic abnormalities, as well as learning deficits induced by tooth loss in aged SAMP8 mice.


Assuntos
Meio Ambiente , Hipocampo/fisiopatologia , Transtornos da Memória/etiologia , Bainha de Mielina , Sinapses/patologia , Perda de Dente/complicações , Animais , Aprendizagem em Labirinto , Camundongos
4.
Neuron ; 109(5): 767-777.e5, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33472038

RESUMO

Tau is a major driver of neurodegeneration and is implicated in over 20 diseases. Tauopathies are characterized by synaptic loss and neuroinflammation, but it is unclear if these pathological events are causally linked. Tau binds to Synaptogyrin-3 on synaptic vesicles. Here, we interfered with this function to determine the role of pathogenic Tau at pre-synaptic terminals. We show that heterozygous knockout of synaptogyrin-3 is benign in mice but strongly rescues mutant Tau-induced defects in long-term synaptic plasticity and working memory. It also significantly rescues the pre- and post-synaptic loss caused by mutant Tau. However, Tau-induced neuroinflammation remains clearly upregulated when we remove the expression of one allele of synaptogyrin-3. Hence neuroinflammation is not sufficient to cause synaptic loss, and these processes are separately induced in response to mutant Tau. In addition, the pre-synaptic defects caused by mutant Tau are enough to drive defects in cognitive tasks.


Assuntos
Transtornos da Memória/fisiopatologia , Microglia/fisiologia , Terminações Pré-Sinápticas/fisiologia , Sinaptogirinas/fisiologia , Proteínas tau/fisiologia , Animais , Encefalite/fisiopatologia , Feminino , Hipocampo/fisiopatologia , Hipocampo/ultraestrutura , Masculino , Camundongos Knockout , Plasticidade Neuronal , Terminações Pré-Sinápticas/ultraestrutura , Sinaptogirinas/genética
5.
Neurology ; 96(10): e1470-e1481, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33408146

RESUMO

OBJECTIVE: To determine whether memory tasks with demonstrated sensitivity to hippocampal function can detect variance related to preclinical Alzheimer disease (AD) biomarkers, we examined associations between performance in 3 memory tasks and CSF ß-amyloid (Aß)42/Aß40 and phosopho-tau181 (p-tau181) in cognitively unimpaired older adults (CU). METHODS: CU enrolled in the Stanford Aging and Memory Study (n = 153; age 68.78 ± 5.81 years; 94 female) completed a lumbar puncture and memory assessments. CSF Aß42, Aß40, and p-tau181 were measured with the automated Lumipulse G system in a single-batch analysis. Episodic memory was assayed using a standardized delayed recall composite, paired associate (word-picture) cued recall, and a mnemonic discrimination task that involves discrimination between studied "target" objects, novel "foil" objects, and perceptually similar "lure" objects. Analyses examined cross-sectional relationships among memory performance, age, and CSF measures, controlling for sex and education. RESULTS: Age and lower Aß42/Aß40 were independently associated with elevated p-tau181. Age, Aß42/Aß40, and p-tau181 were each associated with (1) poorer associative memory and (2) diminished improvement in mnemonic discrimination performance across levels of decreased task difficulty (i.e., target-lure similarity). P-tau mediated the effect of Aß42/Aß40 on memory. Relationships between CSF proteins and delayed recall were similar but nonsignificant. CSF Aß42 was not significantly associated with p-tau181 or memory. CONCLUSIONS: Tests designed to tax hippocampal function are sensitive to subtle individual differences in memory among CU and correlate with early AD-associated biomarker changes in CSF. These tests may offer utility for identifying CU with preclinical AD pathology.


Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Hipocampo/fisiopatologia , Transtornos da Memória/líquido cefalorraquidiano , Transtornos da Memória/psicologia , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/psicologia , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Aprendizagem por Associação , Estudos Transversais , Sinais (Psicologia) , Discriminação Psicológica , Feminino , Humanos , Masculino , Memória , Transtornos da Memória/fisiopatologia , Memória Episódica , Rememoração Mental , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Desempenho Psicomotor , Proteínas tau/líquido cefalorraquidiano
6.
Neuroimage ; 227: 117645, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33338613

RESUMO

The dorsolateral prefrontal cortex (DLPFC) and ventral lateral prefrontal cortex (VLPFC) play critical but different roles in working memory (WM) processes. Resting-state functional MRI (rs-fMRI) was employed to investigate the effects of neonatal hippocampal lesions on the functional connectivity (FC) between the hippocampus (H) and the DLPFC and VLPFC and its relation to WM performance in adult monkeys. Adult rhesus monkeys with neonatal H lesions (Neo-H, n = 5) and age- and gender-matched sham-operated monkeys (Neo-C, n = 5) were scanned around 10 years of age. The FC of H-DLPFC and H-VLPFC in Neo-H monkeys was significantly altered as compared to controls, but also switched from being positive in the Neo-C to negative in the Neo-H. In addition, the altered magnitude of FC between right H and bilateral DLPFC was significantly associated with the extent of the hippocampal lesions. In particular, the effects of neonatal hippocampal lesion on FC appeared to be selective to the left hemisphere of the brain (i.e. asymmetric in the two hemispheres). Finally, FC between H and DLPFC correlated with WM task performance on the SU-DNMS and the Obj-SO tasks for the control animals, but only with the H-VLPFC and SU-DNMS task for the Neo-H animals. In conclusion, the present rsfMRI study revealed that the neonatal hippocampal lesions significantly but differently altered the integrity in the functional connectivity of H-DLPFC and H-VLPFC. The similarities between the behavioral, cognitive and neural alterations in Neo-H monkeys and Schizophrenia (SZ) patients provide a strong translational model to develop new therapeutic tools for SZ.


Assuntos
Lesões Encefálicas/fisiopatologia , Hipocampo/lesões , Hipocampo/fisiopatologia , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Animais , Animais Recém-Nascidos , Feminino , Macaca mulatta , Imagem por Ressonância Magnética , Masculino , Memória de Curto Prazo/fisiologia , Esquizofrenia/fisiopatologia
7.
Elife ; 92020 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-33349333

RESUMO

Mesial temporal lobe epilepsy (MTLE) is the most common form of focal, pharmacoresistant epilepsy in adults and is often associated with hippocampal sclerosis. Here, we established the efficacy of optogenetic and electrical low-frequency stimulation (LFS) in interfering with seizure generation in a mouse model of MTLE. Specifically, we applied LFS in the sclerotic hippocampus to study the effects on spontaneous subclinical and evoked generalized seizures. We found that stimulation at 1 Hz for 1 hr resulted in an almost complete suppression of spontaneous seizures in both hippocampi. This seizure-suppressive action during daily stimulation remained stable over several weeks. Furthermore, LFS for 30 min before a pro-convulsive stimulus successfully prevented seizure generalization. Finally, acute slice experiments revealed a reduced efficacy of perforant path transmission onto granule cells upon LFS. Taken together, our results suggest that hippocampal LFS constitutes a promising approach for seizure control in MTLE.


Assuntos
Estimulação Elétrica/métodos , Epilepsia do Lobo Temporal/fisiopatologia , Hipocampo/fisiopatologia , Convulsões/prevenção & controle , Animais , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Convulsões/etiologia , Convulsões/fisiopatologia
8.
PLoS Biol ; 18(8): e3000820, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32866173

RESUMO

Mutations in the gene encoding the microtubule-severing protein spastin (spastic paraplegia 4 [SPG4]) cause hereditary spastic paraplegia (HSP), associated with neurodegeneration, spasticity, and motor impairment. Complicated forms (complicated HSP [cHSP]) further include cognitive deficits and dementia; however, the etiology and dysfunctional mechanisms of cHSP have remained unknown. Here, we report specific working and associative memory deficits upon spastin depletion in mice. Loss of spastin-mediated severing leads to reduced synapse numbers, accompanied by lower miniature excitatory postsynaptic current (mEPSC) frequencies. At the subcellular level, mutant neurons are characterized by longer microtubules with increased tubulin polyglutamylation levels. Notably, these conditions reduce kinesin-microtubule binding, impair the processivity of kinesin family protein (KIF) 5, and reduce the delivery of presynaptic vesicles and postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Rescue experiments confirm the specificity of these results by showing that wild-type spastin, but not the severing-deficient and disease-associated K388R mutant, normalizes the effects at the synaptic, microtubule, and transport levels. In addition, short hairpin RNA (shRNA)-mediated reduction of tubulin polyglutamylation on spastin knockout background normalizes KIF5 transport deficits and attenuates the loss of excitatory synapses. Our data provide a mechanism that connects spastin dysfunction with the regulation of kinesin-mediated cargo transport, synapse integrity, and cognition.


Assuntos
Ácido Glutâmico/metabolismo , Cinesina/metabolismo , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo , Neurônios/metabolismo , Espastina/deficiência , Tubulina (Proteína)/metabolismo , Potenciais de Ação , Animais , Membrana Celular/metabolismo , Espinhas Dendríticas/metabolismo , Espinhas Dendríticas/ultraestrutura , Potenciais Pós-Sinápticos Excitadores , Hipocampo/patologia , Hipocampo/fisiopatologia , Camundongos Knockout , Microtúbulos/metabolismo , Microtúbulos/ultraestrutura , Atividade Motora , Neurônios/patologia , Neurônios/ultraestrutura , Transporte Proteico , Espastina/metabolismo , Sinapses/metabolismo , Sinapses/ultraestrutura , Vesículas Sinápticas/metabolismo
9.
PLoS One ; 15(8): e0237929, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822403

RESUMO

BACKGROUND: Neuroinflammation causes neurodegenerative conditions like Alzheimer's disease (AD). Ipriflavone (IP), therapeutic compound to postmenopausal osteoporosis, has limited estrogenic activity and is accounted as AChE inhibitor. The developing of drug delivery systems to enable drug targeting to specific sites increases the drug therapeutic effect. OBJECTIVE: The aim of the present study was to formulate and evaluate ipriflavone loaded albumin nanoparticles (IP-Np) along with free ipriflavone against lipopolysaccharide (LPS) induced neuroinflammation in rats. METHODS: Neuroinflammation was induced by intra-peritoneal (i.p) injection of LPS (250 µg/kg rat body weight) then treatments were conducted with (1) ipriflavone at two doses 50 mg/kg and 5 mg/kg, (2) IP-Np (5 mg ipriflavone/kg) or (3) IP-Np coated with polysorbate 80 (IP-Np-T80) (5 mg ipriflavone/kg). The alteration of the inflammatory response in male adult Wistar rats' brain hippocampus was investigated by examining associated indices using biochemical and molecular analyses. RESULTS: A significant upsurge in inflammatory mediators and decline in antioxidant status were observed in LPS-induced rats. In one hand, ipriflavone (50 mg/kg), IP-Np and IP-Np-T80 ameliorated LPS induced brain hippocampal inflammation where they depreciated the level of pro-inflammatory cytokines (TNF-α, IL-6, IL-1ß) and enhanced antioxidant status. In another hand, ipriflavone at dose (5 mg/kg) didn't show the same therapeutic effect. CONCLUSION: The current study provides evidence for the potential neuroprotective effect of ipriflavone (50 mg/kg) against LPS-induced neuroinflammation in rats through its anti-inflammatory and antioxidant activities. Moreover, nanoparticles significantly attenuated neuroinflammation in concentration lower than the effective therapeutic dose of free drug ten times.


Assuntos
Hipocampo/efeitos dos fármacos , Inflamação/tratamento farmacológico , Isoflavonas/uso terapêutico , Nanopartículas , Fármacos Neuroprotetores/uso terapêutico , Acetilcolinesterase/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Inibidores da Colinesterase/farmacologia , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Hipocampo/enzimologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Inflamação/metabolismo , Inflamação/fisiopatologia , Isoflavonas/administração & dosagem , Isoflavonas/farmacologia , Lipopolissacarídeos/toxicidade , Masculino , Microscopia Eletrônica de Transmissão , Nanopartículas/química , Nanopartículas/ultraestrutura , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Soroalbumina Bovina/química , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
10.
Nat Commun ; 11(1): 4220, 2020 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-32839437

RESUMO

Post-traumatic stress disorder (PTSD) is characterized by emotional hypermnesia on which preclinical studies focus so far. While this hypermnesia relates to salient traumatic cues, partial amnesia for the traumatic context can also be observed. Here, we show in mice that contextual amnesia is causally involved in PTSD-like memory formation, and that treating the amnesia by re-exposure to all trauma-related cues cures PTSD-like hypermnesia. These findings open a therapeutic perspective based on trauma contextualization and the underlying hippocampal mechanisms.


Assuntos
Amnésia/prevenção & controle , Amnésia/terapia , Condicionamento Psicológico/fisiologia , Memória/fisiologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Transtornos de Estresse Pós-Traumáticos/terapia , Amnésia/fisiopatologia , Animais , Aprendizagem da Esquiva/fisiologia , Sinais (Psicologia) , Emoções , Hipocampo/fisiopatologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Transtornos de Estresse Pós-Traumáticos/fisiopatologia
12.
Life Sci ; 258: 118107, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32682919

RESUMO

Cognitive impairment has been widely recognized as a common symptom of chronic stress. Ginsenoside Rd (GRd), the major active compound in Panax ginseng, was previously reported in various neurological researches. However, little research is available regarding on the effect of GRd on cognitive improvement in mice subjected to chronic stress. In the present study, we investigated the neuroprotective effects of GRd in chronic restraint stress (CRS)-induced cognitive deficits and explored the potential mechanism in male C57BL/6J mice. Our results demonstrated that oral administration of GRd for 28 days markedly increased the spontaneous alternation in Y-maze and the relative discrimination index in novel object or location recognition tests following CRS. Additionally, GRd treatment considerably increased the antioxidant enzymes activities in the hippocampus. The expression levels of hippocampus and serum inflammation factors in the CRS groups were also counter-regulated by GRd treatment. Meanwhile, GRd treatment could reverse CRS-induced the decrease in phosphorylated phosphoinositide 3-kinase (PI3K), camp-reflecting element binding protein (CREB), brain-derived neurotrophic factor (BDNF) and tyrosine kinase B (TrkB) expression in the hippocampus. These findings provided evidences that GRd improves cognitive impairment in CRS mice by mitigating oxidative stress and inflammation, while upregulating the hippocampal BDNF-mediated CREB signaling pathway.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Ginsenosídeos/uso terapêutico , Restrição Física , Transdução de Sinais , Estresse Psicológico/tratamento farmacológico , Animais , Doença Crônica , Disfunção Cognitiva/sangue , Disfunção Cognitiva/fisiopatologia , Modelos Animais de Doenças , Ginsenosídeos/química , Ginsenosídeos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/enzimologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Inflamação/sangue , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Atividade Motora/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Receptor trkB/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estresse Psicológico/sangue , Estresse Psicológico/fisiopatologia
13.
PLoS One ; 15(6): e0235046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579566

RESUMO

Post-ictal emergence of slow wave EEG (electroencephalogram) activity and burst-suppression has been associated with the therapeutic effects of the electroconvulsive therapy (ECT), indicating that mere "cerebral silence" may elicit antidepressant actions. Indeed, brief exposures to burst-suppressing anesthesia has been reported to elicit antidepressant effects in a subset of patients, and produce behavioral and molecular alterations, such as increased expression of brain-derived neurotrophic factor (BDNF), connected with antidepressant responses in rodents. Here, we have further tested the cerebral silence hypothesis by determining whether repeated exposures to isoflurane anesthesia reduce depressive-like symptoms or influence BDNF expression in male Wistar outbred rats (Crl:WI(Han)) subjected to chronic mild stress (CMS), a model which is responsive to repeated electroconvulsive shocks (ECS, a model of ECT). Stress-susceptible, stress-resilient, and unstressed rats were exposed to 5 doses of isoflurane over a 15-day time period, with administrations occurring every third day. Isoflurane dosing is known to reliably produce rapid EEG burst-suppression (4% induction, 2% maintenance; 15 min). Antidepressant and anxiolytic effects of isoflurane were assessed after the first, third, and fifth drug exposure by measuring sucrose consumption, as well as performance on the open field and the elevated plus maze tasks. Tissue samples from the medial prefrontal cortex and hippocampus were collected, and levels of BDNF (brain-derived neurotrophic factor) protein were assessed. We find that isoflurane anesthesia had no impact on the behavior of stress-resilient or anhedonic rats in selected tests; findings which were consistent-perhaps inherently related-with unchanged levels of BDNF.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/prevenção & controle , Isoflurano/farmacologia , Estresse Psicológico/prevenção & controle , Anestésicos Inalatórios , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Eletroconvulsoterapia/métodos , Eletroencefalografia , Eletrochoque/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Isoflurano/administração & dosagem , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos Wistar , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia
14.
J Vis Exp ; (160)2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32568246

RESUMO

Cultures of dissociated hippocampal neuronal and glial cells are a valuable experimental model for studying neural growth and function by providing high cell isolation and a controlled environment. However, the survival of hippocampal cells in vitro is compromised: most cells die during the first week of culture. It is therefore of great importance to identify ways to increase the durability of neural cells in culture. Calcium carbonate in the form of crystalline aragonite derived from the skeleton of corals can be used as a superior, active matrix for neural cultures. By nurturing, protecting, and activating glial cells, the coral skeleton enhances the survival and growth of these cells in vitro better than other matrices. This protocol describes a method for cultivating hippocampal cells on a coralline matrix. This matrix is generated by attaching grains of coral skeletons to culture dishes, flasks, and glass coverslips. The grains assist in improving the environment of the cells by introducing them to a fine three-dimensional (3D) environment to grow on and to form tissue-like structures. The 3D environment introduced by the coral skeleton can be optimized for the cells by grinding, which enables control over the size and density of the grains (i.e., the matrix roughness), a property that has been found to influence glial cells activity. Moreover, the use of grains makes the observation and analysis of the cultures easier, especially when using light microscopy. Hence, the protocol includes procedures for generation and optimization of the coralline matrix as a tool to improve the maintenance and functionality of neural cells in vitro.


Assuntos
Técnicas de Cultura de Células/métodos , Hipocampo/fisiopatologia , Neurônios/metabolismo , Hipocampo/citologia , Humanos , Microscopia , Neurônios/citologia
15.
Sci Rep ; 10(1): 7236, 2020 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-32350298

RESUMO

Emerging evidence points to the role of the endocannabinoid system in long-term stress-induced neural remodeling with studies on stress-induced endocannabinoid dysregulation focusing on cerebral changes that are temporally proximal to stressors. Little is known about temporally distal and sex-specific effects, especially in cerebellum, which is vulnerable to early developmental stress and is dense with cannabinoid receptors. Following limited bedding at postnatal days 2-9, adult (postnatal day 70) cerebellar and hippocampal endocannabinoids, related lipids, and mRNA were assessed, and behavioral performance evaluated. Regional and sex-specific effects were present at baseline and following early-life stress. Limited bedding impaired peripherally-measured basal corticosterone in adult males only. In the CNS, early-life stress (1) decreased 2-arachidonoyl glycerol and arachidonic acid in the cerebellar interpositus nucleus in males only; (2) decreased 2-arachidonoyl glycerol in females only in cerebellar Crus I; and (3) increased dorsal hippocampus prostaglandins in males only. Cerebellar interpositus transcriptomics revealed substantial sex effects, with minimal stress effects. Stress did impair novel object recognition in both sexes and social preference in females. Accordingly, the cerebellar endocannabinoid system exhibits robust sex-specific differences, malleable through early-life stress, suggesting the role of endocannabinoids and stress to sexual differentiation of the brain and cerebellar-related dysfunctions.


Assuntos
Endocanabinoides/metabolismo , Hipocampo , Caracteres Sexuais , Maturidade Sexual , Estresse Psicológico , Animais , Feminino , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Masculino , Ratos , Ratos Long-Evans , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Estresse Psicológico/fisiopatologia
16.
Nat Commun ; 11(1): 2261, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385304

RESUMO

Prolonged exposure to negative stressors could be harmful if a subject cannot respond appropriately. Strategies evolved to respond to stress, including repetitive displacement behaviours, are important in maintaining behavioural homoeostasis. In rodents, self-grooming is a frequently observed repetitive behaviour believed to contribute to post-stress de-arousal with adaptive value. Here we identified a rat limbic di-synaptic circuit that regulates stress-induced self-grooming with positive affective valence. This circuit links hippocampal ventral subiculum to ventral lateral septum (LSv) and then lateral hypothalamus tuberal nucleus. Optogenetic activation of this circuit triggers delayed but robust excessive grooming with patterns closely resembling those evoked by emotional stress. Consistently, the neural activity of LSv reaches a peak before emotional stress-induced grooming while inhibition of this circuit significantly suppresses grooming triggered by emotional stress. Our results uncover a previously unknown limbic circuitry involved in regulating stress-induced self-grooming and pinpoint a critical role of LSv in this ethologically important behaviour.


Assuntos
Emoções/fisiologia , Sistema Límbico/fisiopatologia , Rede Nervosa/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Cálcio/metabolismo , Asseio Animal , Hipocampo/fisiopatologia , Masculino , Modelos Biológicos , Neurônios/patologia , Optogenética , Probabilidade , Ratos Sprague-Dawley , Sinapses/patologia
17.
Am J Trop Med Hyg ; 103(2): 639-645, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32431269

RESUMO

The parasitic helminth infection neurocysticercosis (NCC) is the most common cause of adult-acquired epilepsy in the world. Despite the serious consequences of epilepsy due to this infection, an in-depth review of the distinct characteristics of epilepsy due to neurocysticercosis has never been conducted. In this review, we evaluate the relationship between NCC and epilepsy and the unique characteristics of epilepsy caused by NCC. We also discuss recent advances in our understanding of NCC-related epilepsy, including the importance of anti-inflammatory therapies, the association between NCC and temporal lobe epilepsy, and the recent discovery of biomarkers of severe epilepsy development in individuals with NCC and seizures.


Assuntos
Encéfalo/fisiopatologia , Epilepsia/fisiopatologia , Neurocisticercose/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/imunologia , Calcinose/diagnóstico por imagem , Calcinose/imunologia , Calcinose/fisiopatologia , Citocinas/imunologia , Epilepsia/etiologia , Epilepsia/imunologia , Hipocampo/diagnóstico por imagem , Hipocampo/imunologia , Hipocampo/patologia , Hipocampo/fisiopatologia , Humanos , Inflamação/imunologia , Inflamação/fisiopatologia , Neurocisticercose/complicações , Neurocisticercose/diagnóstico por imagem , Neurocisticercose/imunologia , Fatores de Risco , Esclerose
18.
J Neurosci ; 40(26): 5116-5136, 2020 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-32439703

RESUMO

Memory disruption in mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the microcircuitry underlying these disruptions is under-explored. We tested whether a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs in ex vivo slices from male and female three-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs (sPCs) having a higher probability of spiking during SWRs. Both deep PCs (dPCs) and sPCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC microcircuit also contribute to impairment.SIGNIFICANCE STATEMENT We demonstrate that a specific subtype of inhibitory neuron, parvalbumin-expressing (PV) basket cells, have selectively reduced activity in a model of Alzheimer's disease (AD) during activity critical for the consolidation of memory. These results identify a potential cellular target for therapeutic intervention to restore aberrant network activity in early amyloid pathology. While PV cells have previously been identified as a potential therapeutic target, this study for the first time recognizes that other PV neuronal subtypes, including bistratified and axo-axonic cells, are spared. These experiments are the first to record synaptic and spiking activity during sharp wave ripple (SWR) events in early amyloid pathology and reveal that a selective decrease in excitatory synaptic drive to PV basket cells (PVBCs) likely underlies reduced function.


Assuntos
Doença de Alzheimer/fisiopatologia , Hipocampo/fisiopatologia , Interneurônios/fisiologia , Animais , Modelos Animais de Doenças , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Parvalbuminas/metabolismo , Células Piramidais/fisiologia
19.
J Acupunct Meridian Stud ; 13(3): 94-103, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32278077

RESUMO

BACKGROUND AND OBJECTIVE: Perimenopausal depression is caused by the impaired function of the ovarium before menopause and with a series of symptoms. Electroacupuncture (EA) therapy has been demonstrated to improve clinically depression. However, the mechanism underlying its therapeutic activity remains unknown. This study aimed to investigat the effects of EA treatment on the hippocampal neural proliferation through Wnt signaling pathway. METHODS: Chronic unpredictable mild stress (CUMS) combined with bilateral ovariectomy (OVX) were used to establish a rat model of perimenopausal depression. The open field test (OFT) and sucrose preference test (SPT) were used to assess depression-like behaviors in rats. ELISAs were used to measure estrogen (E2), luteinizing hormone (LH) and gonadotropin-releasing hormone (GnRH) levels in the serum. RT-PCR and Western blot assay were utilized for measuring the mRNA expressions and protein expressions of GSK-3ß/ß-catenin. RESULTS: Four-week EA treatment at three points including "Shenshu" (BL23), "Baihui" (GV20) and "Sanyinjiao" (SP6) simultaneously ameliorated depression-like behaviors in rats with CUMS and OVX, whereas rescued the decreased serum level of E2 and prevented the increased serum levels of GnRH and LH. EA treatment ameliorated CUMS and OVX-induced alterations of glycogen synthase kinase-3ß (GSK-3ß) and ß-catenin mRNA levels, ß-catenin and phosphorylated ß-catenin (p-ß-catenin) protein levels. CONCLUSIONS: The results showed that EA treatment promoted hippocampal neural proliferation in perimenopausal depression rats via activating the Wnt/ß-catenin signaling pathway, indicating that EA may represent an efficacious therapy for perimenopausal depression.


Assuntos
Depressão/terapia , Hipocampo/metabolismo , Neurônios/citologia , Perimenopausa/psicologia , Via de Sinalização Wnt , beta Catenina/metabolismo , Animais , Proliferação de Células , Depressão/etiologia , Depressão/genética , Depressão/metabolismo , Modelos Animais de Doenças , Eletroacupuntura , Feminino , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/fisiopatologia , Humanos , Masculino , Neurônios/metabolismo , Perimenopausa/metabolismo , Ratos , Ratos Sprague-Dawley , beta Catenina/genética
20.
Neuron ; 106(6): 992-1008.e9, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32320644

RESUMO

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Aprendizagem/fisiologia , Fatores de Transcrição NFI/genética , Animais , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Camundongos , Camundongos Knockout , Vias Neurais , Plasticidade Neuronal , Neurônios , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiopatologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Memória Espacial/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...