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1.
J Pharmacol Sci ; 144(4): 212-217, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33070840

RESUMO

The hippocampus is a brain region well-known to exhibit structural and functional changes in temporal lobe epilepsy. Studies analyzing the brains of patients with epilepsy and those from animal models of epilepsy have revealed that microglia are excessively activated, especially in the hippocampus. These findings suggest that microglia may contribute to the onset and aggravation of epilepsy; however, direct evidence for microglial involvement or the underlying mechanisms by which this occurs remain to be fully discovered. To date, neuron-microglia interactions have been vigorously studied in adult epilepsy models; such studies have clarified microglial responses to excessive synchronous firing of neurons. In contrast, the role of microglia in the postnatal brain of patients with epileptic seizures remain largely unclear. Some early-life seizures, such as complex febrile seizures, have been shown to cause structural and functional changes in the brain, which is a risk factor for future development of epilepsy. Because brain structure and function are actively modulated by microglia in both health and disease, it is essential to clarify the role of microglia in early-life seizures and its impact on epileptogenesis.


Assuntos
Comunicação Celular , Epilepsia do Lobo Temporal/etiologia , Epilepsia do Lobo Temporal/patologia , Hipocampo/citologia , Hipocampo/patologia , Microglia/patologia , Microglia/fisiologia , Fatores Etários , Idade de Início , Animais , Giro Denteado/citologia , Giro Denteado/patologia , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios/fisiologia , Ratos , Fatores de Risco , Convulsões Febris/etiologia , Convulsões Febris/patologia , Sinapses/fisiologia
2.
PLoS One ; 15(7): e0234255, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726311

RESUMO

'Normal aging' in the brain refers to age-related changes that occur independent of disease, in particular Alzheimer's disease. A major barrier to mapping normal brain aging has been the difficulty in excluding the earliest preclinical stages of Alzheimer's disease. Here, before addressing this issue we first imaged a mouse model and learn that the best MRI measure of dendritic spine loss, a known pathophysiological driver of normal aging, is one that relies on the combined use of functional and structural MRI. In the primary study, we then deployed the combined functional-structural MRI measure to investigate over 100 cognitively-normal people from 20-72 years of age. Next, to cover the tail end of aging, in secondary analyses we investigated structural MRI acquired from cognitively-normal people, 60-84 years of age, who were Alzheimer's-free via biomarkers. Collectively, the results from the primary functional-structural study, and the secondary structural studies revealed that the dentate gyrus is a hippocampal region differentially affected by aging, and that the entorhinal cortex is a region most resistant to aging. Across the cortex, the primary functional-structural study revealed and that the inferior frontal gyrus is differentially affected by aging, however, the secondary structural studies implicated other frontal cortex regions. Together, the results clarify how normal aging may affect the brain and has possible mechanistic and therapeutic implications.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Senescência Celular/fisiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/metabolismo , Mapeamento Encefálico/métodos , Disfunção Cognitiva/fisiopatologia , Espinhas Dendríticas/patologia , Giro Denteado/patologia , Córtex Entorrinal/patologia , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Camundongos , Pessoa de Meia-Idade
3.
Proc Natl Acad Sci U S A ; 117(32): 19578-19589, 2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32727894

RESUMO

The CreER/LoxP system is widely accepted to track neural lineages and study gene functions upon tamoxifen (TAM) administration. We have observed that prenatal TAM treatment caused high rates of delayed delivery and fetal mortality. This substance could produce undesired results, leading to data misinterpretation. Here, we report that administration of TAM during early stages of cortical neurogenesis promoted precocious neural differentiation, while it inhibited neural progenitor cell (NPC) proliferation. The TAM-induced inhibition of NPC proliferation led to deficits in cortical neurogenesis, dendritic morphogenesis, synaptic formation, and cortical patterning in neonatal and postnatal offspring. Mechanistically, by employing single-cell RNA-sequencing (scRNA-seq) analysis combined with in vivo and in vitro assays, we show TAM could exert these drastic effects mainly through dysregulating the Wnt-Dmrta2 signaling pathway. In adult mice, administration of TAM significantly attenuated NPC proliferation in both the subventricular zone and the dentate gyrus. This study revealed the cellular and molecular mechanisms for the adverse effects of TAM on corticogenesis, suggesting that care must be taken when using the TAM-induced CreER/LoxP system for neural lineage tracing and genetic manipulation studies in both embryonic and adult brains.


Assuntos
Encéfalo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal/patologia , Tamoxifeno/efeitos adversos , Animais , Encéfalo/embriologia , Encéfalo/patologia , Diferenciação Celular , Proliferação de Células , Giro Denteado/efeitos dos fármacos , Giro Denteado/patologia , Feminino , Ventrículos Laterais/efeitos dos fármacos , Ventrículos Laterais/patologia , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , RNA-Seq , Análise de Célula Única , Fatores de Transcrição/metabolismo , Via de Sinalização Wnt/efeitos dos fármacos
4.
Sci Rep ; 10(1): 3760, 2020 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-32111960

RESUMO

Epilepsy is a widespread neurological disease characterized by abnormal neuronal activity resulting in recurrent seizures. There is mounting evidence that a circadian system disruption, involving clock genes and their downstream transcriptional regulators, is associated with epilepsy. In this study, we characterized the hippocampal expression of clock genes and PAR bZIP transcription factors (TFs) in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainic acid (KA). The expression of PAR bZIP TFs was significantly altered following KA injection as well as in other rodent models of acquired epilepsy. Although the PAR bZIP TFs are regulated by proinflammatory cytokines in peripheral tissues, we discovered that the regulation of their expression is inflammation-independent in hippocampal tissue and rather mediated by clock genes and hyperexcitability. Furthermore, we report that hepatic leukemia factor (Hlf), a member of PAR bZIP TFs family, is invariably downregulated in animal models of acquired epilepsy, regulates neuronal activity in vitro and its overexpression in dentate gyrus neurons in vivo leads to altered expression of genes associated with seizures and epilepsy. Overall, our study provides further evidence of PAR bZIP TFs involvement in epileptogenesis and points to Hlf as the key player.


Assuntos
Fatores de Transcrição de Zíper de Leucina Básica/metabolismo , Giro Denteado/metabolismo , Epilepsia/metabolismo , Regulação da Expressão Gênica , Animais , Giro Denteado/patologia , Modelos Animais de Doenças , Epilepsia/induzido quimicamente , Ácido Caínico/efeitos adversos , Ácido Caínico/farmacologia , Masculino , Camundongos
5.
Am J Physiol Cell Physiol ; 318(5): C870-C878, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32186931

RESUMO

Pituitary adenylate cyclase activating polypeptide (PACAP; ADCYAP1) is a pleiotropic neuropeptide widely distributed in both the peripheral and central nervous systems. PACAP and its specific cognate PAC1 receptor (ADCYAP1R1) play critical roles in the homeostatic maintenance of multiple physiological and behavioral systems. Notably, maladaptations in the PACAPergic system have been associated with several psychopathologies related to fear and anxiety. PAC1 receptor transcripts are highly expressed in granule cells of the dentate gyrus (DG). Here, we examined the direct effects of PACAP on DG granule cells in brain slices using whole cell patch recordings in current clamp mode. PACAP significantly increased the intrinsic excitability of DG granule cells via PAC1 receptor activation. This increased excitability was not mediated by adenylyl cyclase/cAMP or phospholipase C/PKC activation, but instead via activation of an extracellular signal-regulated kinase (ERK) signaling pathway initiated through PAC1 receptor endocytosis/endosomal signaling. PACAP failed to increase excitability in DG granule cells pretreated with the persistent sodium current blocker riluzole, suggesting that the observed PACAP effects required this component of the inward sodium current.


Assuntos
Ansiedade/genética , Encéfalo/metabolismo , Giro Denteado/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/genética , Animais , Ansiedade/patologia , Encéfalo/patologia , Proliferação de Células/efeitos dos fármacos , Giro Denteado/patologia , Endocitose/genética , Endossomos/genética , Medo/psicologia , Regulação da Expressão Gênica/genética , Humanos , Sistema de Sinalização das MAP Quinases/genética , Neurônios/metabolismo , Neurônios/patologia , Técnicas de Patch-Clamp , Ratos , Riluzol/farmacologia
6.
J Pharmacol Sci ; 143(2): 97-105, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32173264

RESUMO

Folate deficiency has been suggested as a risk factor for depression in preclinical and clinical studies. Several hypotheses of mechanisms underlying folate deficiency-induced depressive symptoms have been proposed, but the detailed mechanisms are still unclear. In this study, we assessed whether post-weaning folate deficiency affect neurological and psychological function. The low folate diet-fed mice showed depression-like behavior in the forced swim test. In contrast, spontaneous locomotor activity, social behavior, coordinated motor skills, anxiety-like behavior and spatial memory did not differ between control and low folate diet-fed mice. In the dentate gyrus (DG) of the hippocampus, decreased number of newborn mature neurons and increased number of immature neurons were observed in low folate diet-fed mice. Staining with Golgi-Cox method revealed that dendritic complexity, spine density and the number of mature spines of neurons were markedly reduced in the DG of low folate diet-fed mice. Stress response of neurons indicated as c-Fos expression was also reduced in the DG of low folate diet-fed mice. These results suggest that reduction in the degree of maturation of newborn hippocampal neurons underlies folate deficiency-induced depressive symptoms.


Assuntos
Giro Denteado/citologia , Giro Denteado/patologia , Depressão/etiologia , Depressão/patologia , Deficiência de Ácido Fólico/complicações , Neurônios/patologia , Desmame , Animais , Expressão Gênica , Masculino , Camundongos Endogâmicos , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo
7.
J Neuroinflammation ; 17(1): 44, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-32005260

RESUMO

BACKGROUND: Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs. METHODS: This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days post-injury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus. RESULTS: There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = <  0.001 each) and 30 DPI in posterior (8.3% increase; p = <  0.0001) hippocampus. We also found dramatic increases in synapsin staining around mossy cells at 7 DPI in both anterior (74.7% increase in synapsin labeling; p = <  0.0001) and posterior (82.7% increase; p = < 0.0001) hippocampus. Interestingly, these morphological and synaptic alterations correlated with a significant change in microglia in proximity to mossy cells at 7 DPI in anterior and at 30 DPI in the posterior hippocampus. For broader context, while we found that there were significant increases in microglia density in the granule cell layer at 30 DPI (anterior and posterior) and 1 YPI (posterior only) and in the molecular layer at 1 YPI (anterior only), we found no significant changes in overall microglial density in the hilus at any of the time points evaluated post-injury. CONCLUSIONS: The alterations of mossy cell size and synaptic inputs paired with changes in microglia density around the cells demonstrate the susceptibility of hilar mossy cells after even mild TBI. This subtle hilar mossy cell pathology may play a role in aberrant hippocampal function post-TBI, although additional studies are needed to characterize potential physiological and cognitive alterations.


Assuntos
Concussão Encefálica/patologia , Tamanho Celular , Giro Denteado/patologia , Fibras Musgosas Hipocampais/patologia , Sinapses/patologia , Animais , Traumatismos Cranianos Fechados/patologia , Ativação de Macrófagos , Masculino , Microglia , Suínos , Porco Miniatura , Sinapsinas/metabolismo
8.
Neurobiol Aging ; 90: 75-83, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32107063

RESUMO

Several studies have investigated the differential vulnerability of hippocampal subfields during aging and Alzheimer's disease (AD). Results were often contradictory, mainly because these works were based on concatenations of cross-sectional measures in cohorts with different ages or stages of AD, in the absence of a longitudinal design. Here, we investigated 327 participants from a population-based cohort of nondemented older adults with a 14-year clinical follow-up. MRI at baseline and 4 years later were assessed to measure the annualized rates of hippocampal subfields atrophy in each participant using an automatic segmentation pipeline with subsequent quality control. On the one hand, CA4 dentate gyrus was significantly more affected than the other subfields in the whole population (CA1-3: -0.68%/year; subiculum: -0.99%/year; and CA4-DG: -1.39%/year; p < 0.0001). On the other hand, the annualized rate of CA1-3 atrophy was associated with an increased risk of developing Alzheimer's clinical syndrome over time, independently of age, gender, educational level, and ApoE4 genotype (HR = 2.0; CI 95% 1.4-3.0). These results illustrate the natural history of hippocampal subfields atrophy during aging and AD by showing that the dentate gyrus is the most vulnerable subfield to the effects of aging while the cornu-ammonis is the primary target of AD pathophysiological processes, years before symptom onset.


Assuntos
Envelhecimento/patologia , Doença de Alzheimer/patologia , Giro Denteado/patologia , Hipocampo/patologia , Idoso , Doença de Alzheimer/diagnóstico por imagem , Atrofia , Estudos de Coortes , Estudos Transversais , Giro Denteado/diagnóstico por imagem , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Risco
9.
Life Sci ; 248: 117468, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105705

RESUMO

AIMS: Treatment with 5-fluorouracil (5-FU) can cause impairment to adult hippocampal neurogenesis, resulting in cognitive deficits. As melatonin has been shown to enhance memory and hippocampal neurogenesis in animal models, this research investigated the neuroprotective effects of melatonin against spatial memory and hippocampal neurogenesis impairment in 5-fluorouracil (5-FU)-treated rats. MATERIALS AND METHODS: Four-Five weeks old male Spraque-Dawley rats weighing between 180 and 200 g were used. Animals were maintained under standard laboratory conditions with 25 °C and 12 h light/dark cycle. Animal were administered intravenous (i.v.) injections of 5-FU (25 mg/kg) 5 times every 3 days starting on day 9 of the experiment. The rats were divided into preventive, recovery, and throughout groups and co-treated with melatonin (8 mg/kg, i.p.) once daily (at 7.00 pm) for 21 days prior to, after, and throughout 5-FU treatment, respectively. Spatial memory was assessed using a novel object location (NOL) test. Hippocampal neurogenesis was then examined using Ki67, bromodeoxyuridine (BrdU), and doublecortin (DCX) immunohistochemistry staining. KEY FINDINGS: Melatonin administration was able to both protect the subjects from and reverse spatial memory deficits. 5-FU was also found to reduce the generation of hippocampal newborn neurons. However, co-treatment with melatonin ameliorated the reductions in neurogenesis caused by 5-FU. SIGNIFICANCE: These findings suggest that melatonin administration was able to ameliorate the 5-FU-induced spatial memory deficits associated with neurogenesis. The present work will be valuable for patients who suffer memory deficits from 5-FU chemotherapy.


Assuntos
Disfunção Cognitiva/tratamento farmacológico , Fluoruracila/antagonistas & inibidores , Melatonina/farmacologia , Transtornos da Memória/tratamento farmacológico , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Memória Espacial/efeitos dos fármacos , Animais , Antimetabólitos/efeitos adversos , Biomarcadores/metabolismo , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Esquema de Medicação , Fluoruracila/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Injeções Intravenosas , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Neurogênese/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Ratos , Ratos Sprague-Dawley , Memória Espacial/fisiologia
10.
J Neuropathol Exp Neurol ; 79(2): 163-175, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913466

RESUMO

The pathological process underlying Alzheimer disease (AD) unfolds predominantly in the cerebral cortex with the gradual appearance and regional progression of abnormal tau. Intraneuronal tau pathology progresses from the temporal transentorhinal and entorhinal regions into neocortical fields/areas of the temporal allocortex. Here, based on 95 cases staged for AD-related neurofibrillary changes, we propose an ordered progression of abnormal tau in the temporal allocortex. Initially, abnormal tau was limited to distal dendritic segments followed by tau in cell bodies of projection neurons of the transentorhinal/entorhinal layer pre-α. Next, abnormal distal dendrites accumulated in the prosubiculum and extended into the CA1 stratum oriens and lacunosum. Subsequently, altered dendrites developed in the CA2/CA3 stratum oriens and stratum lacunosum-moleculare, combined with tau-positive thorny excrescences of CA3/CA4 mossy cells. Finally, granule cells of the dentate fascia became involved. Such a progression might recapitulate a sequence of transsynaptic spreading of abnormal tau from 1 projection neuron to the next: From pre-α cells to distal dendrites in the prosubiculum and CA1; then, from CA1 or prosubicular pyramids to CA2 principal cells and CA3/CA4 mossy cells; finally, from CA4 mossy cells to dentate granule cells. The lesions are additive: Those from the previous steps persist.


Assuntos
Doença de Alzheimer/patologia , Encéfalo/patologia , Emaranhados Neurofibrilares/patologia , Neurônios/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Córtex Cerebral/patologia , Dendritos/patologia , Giro Denteado/patologia , Progressão da Doença , Córtex Entorrinal/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Temporal/patologia
11.
J Neurosci ; 40(5): 974-995, 2020 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-31959697

RESUMO

Multiple insults to the brain lead to neuronal cell death, thus raising the question to what extent can lost neurons be replenished by adult neurogenesis. Here we focused on the hippocampus and especially the dentate gyrus (DG), a vulnerable brain region and one of the two sites where adult neuronal stem cells (NSCs) reside. While adult hippocampal neurogenesis was extensively studied with regard to its contribution to cognitive enhancement, we focused on their underestimated capability to repair a massively injured, nonfunctional DG. To address this issue, we inflicted substantial DG-specific damage in mice of either sex either by diphtheria toxin-based ablation of >50% of mature DG granule cells (GCs) or by prolonged brain-specific VEGF overexpression culminating in extensive, highly selective loss of DG GCs (thereby also reinforcing the notion of selective DG vulnerability). The neurogenic system promoted effective regeneration by increasing NSCs proliferation/survival rates, restoring a nearly original DG mass, promoting proper rewiring of regenerated neurons to their afferent and efferent partners, and regaining of lost spatial memory. Notably, concomitantly with the natural age-related decline in the levels of neurogenesis, the regenerative capacity of the hippocampus also subsided with age. The study thus revealed an unappreciated regenerative potential of the young DG and suggests hippocampal NSCs as a critical reservoir enabling recovery from catastrophic DG damage.SIGNIFICANCE STATEMENT Adult hippocampal neurogenesis has been extensively studied in the context of its role in cognitive enhancement, but whether, and to what extent can dentate gyrus (DG)-resident neural stem cells drive regeneration of an injured DG has remained unclear. Here we show that DG neurogenesis acts to replace lost neurons and restore lost functions even following massive (>50%) neuronal loss. Age-related decline of neurogenesis is paralleled by a progressive decline of regenerative capacity. Considering also the exceptional vulnerability of the DG to insults, these findings provide a further rationale for maintaining DG neurogenesis in adult life.


Assuntos
Giro Denteado/fisiopatologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Animais , Proliferação de Células , Sobrevivência Celular , Giro Denteado/lesões , Giro Denteado/patologia , Feminino , Masculino , Camundongos Transgênicos
12.
Neuron ; 106(1): 108-125.e12, 2020 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-31995730

RESUMO

Presynaptic neurexins (Nrxs) and type IIa receptor-type protein tyrosine phosphatases (RPTPs) organize synapses through a network of postsynaptic ligands. We show that leucine-rich-repeat transmembrane neuronal proteins (LRRTMs) differentially engage the protein domains of Nrx but require its heparan sulfate (HS) modification to induce presynaptic differentiation. Binding to the HS of Nrx is sufficient for LRRTM3 and LRRTM4 to induce synaptogenesis. We identify mammalian Nrx1γ as a potent synapse organizer and reveal LRRTM4 as its postsynaptic ligand. Mice expressing a mutant form of LRRTM4 that cannot bind to HS show structural and functional deficits at dentate gyrus excitatory synapses. Through the HS of Nrx, LRRTMs also recruit PTPσ to induce presynaptic differentiation but function to varying degrees in its absence. PTPσ forms a robust complex with Nrx, revealing an unexpected interaction between the two presynaptic hubs. These findings underscore the complex interplay of synapse organizers in specifying the molecular logic of a neural circuit.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Giro Denteado/metabolismo , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/genética , Neurônios/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Sinapses/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Giro Denteado/patologia , Heparitina Sulfato/metabolismo , Proteínas de Membrana/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Moléculas de Adesão de Célula Nervosa/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/patologia
13.
Exp Neurol ; 326: 113178, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31926165

RESUMO

Physical exercise can reduce the cognitive decline associated with traumatic brain injury, yet little is known about the optimal administration schedules. Here, different protocols of voluntary wheel running were evaluated for their effects on object recognition memory (ORM), neuroprotection (NeuN+ cells), microglial reactivity (Iba1 staining) and neurogenesis (DCX+ cells) after controlled cortical impact injury (CCI). CCI-lesioned rats were divided into a sedentary group and three exercise groups: early discontinued exercise (3 weeks of exercise initiated 4 days post-injury, followed by 4 weeks in a sedentary state); delayed exercise (3 weeks of exercise initiated 4 weeks post-injury), and early continuous exercise (7 weeks of exercise starting 4 days post-injury). The deficits induced by CCI in a 24 h ORM test were reversed in the delayed exercise group and reduced in the early discontinued and early continuous groups. The early discontinued protocol also reduced the loss of NeuN+ cells in the hilus, while attenuated microglial reactivity was found in the dorsal hippocampus of both the early exercising groups. Running at the end of the experiment increased the number of DCX+ cells in the early continuous and delayed groups, and an inverted U-shaped relationship was found between the mean daily exercise time and the amount of neurogenesis. Thus, exercise had benefits on memory both when it was commenced soon and later after injury, although the neural mechanisms implicated differed. Accordingly, the effects of exercise on memory and neurogenesis appear to not only depend on the specific temporal schedule but also, they may be influenced by the amount of daily exercise.


Assuntos
Lesões Encefálicas Traumáticas/psicologia , Memória , Condicionamento Físico Animal/métodos , Condicionamento Físico Animal/psicologia , Reconhecimento Psicológico , Animais , Antígenos Nucleares/genética , Lesões Encefálicas Traumáticas/patologia , Proteínas de Ligação ao Cálcio/genética , Giro Denteado/patologia , Hipocampo/patologia , Masculino , Proteínas dos Microfilamentos/genética , Microglia/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Tecido Nervoso/genética , Neurogênese , Neuropeptídeos/genética , Neuropeptídeos/metabolismo , Neuroproteção , Desempenho Psicomotor , Ratos , Ratos Sprague-Dawley , Corrida , Fatores de Tempo
14.
Microsc Microanal ; 26(1): 166-172, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31948501

RESUMO

Traumatic brain injury (TBI) is a main cause of death and disabilities in young adults. Although learning and memory impairments are a major clinical manifestation of TBI, the consequences of TBI on the hippocampus are still not well understood. In particular, how lesions to the sensorimotor cortex damage the hippocampus, to which it is not directly connected, is still elusive. Here, we study the effects of sensorimotor cortex ablation (SCA) on the hippocampal dentate gyrus, by applying a highly sensitive gray-level co-occurrence matrix (GLCM) analysis. Using GLCM analysis of granule neurons, we discovered, in our TBI paradigm, subtle changes in granule cell (GC) morphology, including textual uniformity, contrast, and variance, which is not detected by conventional microscopy. We conclude that sensorimotor cortex trauma leads to specific changes in the hippocampus that advance our understanding of the cellular underpinnings of cognitive impairments in TBI. Moreover, we identified GLCM analysis as a highly sensitive method to detect subtle changes in the GC layers that is expected to significantly improve further studies investigating the impact of TBI on hippocampal neuropathology.


Assuntos
Lesões Encefálicas , Giro Denteado/lesões , Giro Denteado/patologia , Hipocampo/patologia , Neurônios/patologia , Animais , Modelos Animais de Doenças , Masculino , Fotomicrografia , Ratos Wistar
15.
Neurochem Res ; 45(2): 465-490, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894463

RESUMO

Protein misfolding and aggregation of amyloid beta (Aß) peptide, as well as formation of neurofibrillary tangles (NFTs) are the signature hallmarks of Alzheimer's disease (AD) pathology. To prevent this, molecular chaperones come into play as they facilitate the refolding of the misfolded proteins and cell protection under stress. Here, we have evaluated the possible effects of Ginkgo biloba (GBE) against aggregation of the Aß through activation of heat shock proteins (HSPs) in the Aluminium (Al) induced AD based model. GBE (100 mg/kg body weight) was administered per oral to the female SD rats in conjunction with intraperitoneal (i.p.) injection of Al lactate (10 mg/kg body weight) for six weeks. Pretreated animals were administered GBE for additional two weeks prior to any exposure of Al. GBE administration resulted in decrease in Aß aggregation, ubiquitin deposition, accompanying a significant decline in APP & Tau protein hyperphosphorylation which can be attributed to activation of Heat shock factor (HSF-1) and upregulation in the protein expression of HSPs. Histopathological investigation studies have also shown the decrease in aggregation of Aß peptide by GBE administration. Additionally, the decrease in ROS levels and Aß aggregation by GBE administration prohibited the decline in the neurotransmitter levels and monoamine oxidase levels in hippocampus and cortex. This further caused improvement in learning and memory of the animals. In conclusion, our results indicate that GBE prevents the symptoms of Al induced AD like pathophysiology by upregulating the HSPs levels and decreasing the aggregation load.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Proteínas de Choque Térmico/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Multimerização Proteica/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Alumínio/toxicidade , Animais , Giro Denteado/patologia , Epinefrina/metabolismo , Feminino , Ginkgo biloba/química , Aprendizagem em Labirinto/efeitos dos fármacos , Monoaminoxidase/metabolismo , Síndromes Neurotóxicas/patologia , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Serotonina/metabolismo , Proteínas tau/metabolismo
16.
Mol Cell Proteomics ; 19(1): 128-141, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31699905

RESUMO

Synaptic dysfunction is an early pathogenic event in Alzheimer disease (AD) that contributes to network disturbances and cognitive decline. Some synapses are more vulnerable than others, including the synapses of the perforant path, which provides the main excitatory input to the hippocampus. To elucidate the molecular mechanisms underlying the dysfunction of these synapses, we performed an explorative proteomic study of the dentate terminal zone of the perforant path. The outer two-thirds of the molecular layer of the dentate gyrus, where the perforant path synapses are located, was microdissected from five subjects with AD and five controls. The microdissected tissues were dissolved and digested by trypsin. Peptides from each sample were labeled with different isobaric tags, pooled together and pre-fractionated into 72 fractions by high-resolution isoelectric focusing. Each fraction was then analyzed by liquid chromatography-mass spectrometry. We quantified the relative expression levels of 7322 proteins, whereof 724 showed significantly altered levels in AD. Our comprehensive data analysis using enrichment and pathway analyses strongly indicated that presynaptic signaling, such as exocytosis and synaptic vesicle cycle processes, is severely disturbed in this area in AD, whereas postsynaptic proteins remained unchanged. Among the significantly altered proteins, we selected three of the most downregulated synaptic proteins; complexin-1, complexin-2 and synaptogyrin-1, for further validation, using a new cohort consisting of six AD and eight control cases. Semi-quantitative analysis of immunohistochemical staining confirmed decreased levels of complexin-1, complexin-2 and synaptogyrin-1 in the outer two-thirds of the molecular layer of the dentate gyrus in AD. Our in-depth proteomic analysis provides extensive knowledge on the potential molecular mechanism underlying synaptic dysfunction related to AD and supports that presynaptic alterations are more important than postsynaptic changes in early stages of the disease. The specific synaptic proteins identified could potentially be targeted to halt synaptic dysfunction in AD.


Assuntos
Doença de Alzheimer/patologia , Giro Denteado/patologia , Via Perfurante/patologia , Proteínas/metabolismo , Proteoma , Sinapses/patologia , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Giro Denteado/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neurônios/metabolismo , Neurônios/patologia , Via Perfurante/metabolismo , Proteômica/métodos , Sinapses/metabolismo , Transmissão Sináptica
17.
BMC Neurosci ; 20(1): 60, 2019 12 18.
Artigo em Inglês | MEDLINE | ID: mdl-31852437

RESUMO

BACKGROUND: Ketamine has been reported to cause neonatal neurotoxicity in a variety of developing animal models. Various studies have been conducted to study the mechanism of neurotoxicity for general anesthetic use during the neonatal period. Previous experiments have suggested that developmentally generated granule neurons in the hippocampus dentate gyrus (DG) supported hippocampus-dependent memory. Therefore, this study aimed to investigate whether ketamine affects the functional integration of developmentally generated granule neurons in the DG. For this purpose,the postnatal day 7 (PND-7) Sprague-Dawley (SD) rats were divided into the control group and the ketamine group (rats who received 4 injections of 40 mg/kg ketamine at 1 h intervals). To label dividing cells, BrdU was administered for three consecutive days after the ketamine exposure; NeuN+/BrdU+cells were observed by using immunofluorescence. To evaluate the developmentally generated granule neurons that support hippocampus-dependent memory, spatial reference memory was tested by using Morris Water Maze at 3 months old, after which the immunofluorescence was used to detect c-Fos expression in the NeuN+/BrdU+ cells. The expression of caspase-3 was measured by western blot to detect the apoptosis in the hippocampal DG. RESULTS: The present results showed that the neonatal ketamine exposure did not influence the survival rate of developmentally generated granule neurons at 2 and 3 months old, but ketamine interfered with the integration of these neurons into the hippocampal DG neural circuits and caused a deficit in hippocampal-dependent spatial reference memory tasks. CONCLUSIONS: In summary, these findings may promote more studies to investigate the neurotoxicity of ketamine in the developing brain.


Assuntos
Giro Denteado/efeitos dos fármacos , Giro Denteado/crescimento & desenvolvimento , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Ketamina/efeitos adversos , Neurônios/efeitos dos fármacos , Animais , Antígenos Nucleares/metabolismo , Bromodesoxiuridina , Caspase 3/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Distribuição Aleatória , Ratos Sprague-Dawley , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
18.
Cells ; 8(12)2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31861141

RESUMO

Stroke increases neurogenesis in the adult dentate gyrus in the short term, however, long-term effects at the cellular and functional level are poorly understood. Here we evaluated the impact of an early stroke lesion on neurogenesis and cognitive function of the aging brain. We hypothesized that a stroke disturbs dentate neurogenesis during aging correlate with impaired flexible learning. To address this issue a stroke was induced in 3-month-old C57Bl/6 mice by a middle cerebral artery occlusion (MCAO). To verify long-term changes of adult neurogenesis the thymidine analogue BrdU (5-Bromo-2'-deoxyuridine) was administrated at different time points during aging. One and half months after BrdU injections learning and memory performance were assessed with a modified version of the Morris water maze (MWM) that includes the re-learning paradigm, as well as hippocampus-dependent and -independent search strategies. After MWM performance mice were transcardially perfused. To further evaluate in detail the stroke-mediated changes on stem- and progenitor cells as well as endogenous proliferation nestin-green-fluorescent protein (GFP) mice were used. Adult nestin-GFP mice received a retroviral vector injection in the hippocampus to evaluate changes in the neuronal morphology. At an age of 20 month the nestin-GFP mice were transcardially perfused after MWM performance and BrdU application 1.5 months later. The early stroke lesion significantly decreased neurogenesis in 7.5- and 9-month-old animals and also endogenous proliferation in the latter group. Furthermore, immature doublecortin (DCX)-positive neurons were reduced in 20-month-old nestin-GFP mice after lesion. All MCAO groups showed an impaired performance in the MWM and mostly relied on hippocampal-independent search strategies. These findings indicate that an early ischemic insult leads to a dramatical decline of neurogenesis during aging that correlates with a premature development of hippocampal-dependent deficits. Our study supports the notion that an early stroke might lead to long-term cognitive deficits as observed in human patients after lesion.


Assuntos
Disfunção Cognitiva/metabolismo , Neurogênese/fisiologia , Acidente Vascular Cerebral/metabolismo , Envelhecimento/fisiologia , Animais , Encéfalo/patologia , Bromodesoxiuridina/farmacologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Giro Denteado/patologia , Hipocampo/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia
19.
Rev. chil. neuropsicol. (En línea) ; 14(2): 35-39, dic. 2019. ilus
Artigo em Espanhol | LILACS | ID: biblio-1102455

RESUMO

La isquemia cerebral es el tipo de accidente cerebrovascular más común, generando altas tasas de mortalidad y morbilidad a nivel mundial. El entendimiento de la fisiopatología de la lesión cerebral ha requerido de la implementación de modelos experimentales que permitan evaluar los fenómenos celulares, sobre todo aquellos a largo plazo. Por tal razón, el objetivo del presente trabajo fue evaluar las áreas exofocales a un mes y cuatro meses post-isquemia cerebral en un modelo experimental. Ratas Wistar fueron sometidas a una isquemia focal transitoria (t-MCAo) y un grupo fueron sacrificados al mes y otro grupo a los cuatro meses post-isquemia para su posterior análisis histológico. Los cortes fueron teñidos con Nissl y se realizó inmunohistoquímica de la proteína Tau. Nuestros resultados muestran tres áreas de lesión exofocal tanto al mes como a los cuatro meses post-isquemia: el giro dentado, la amígdala y el tálamo. Estas regiones se han asociado al control emocional, lo cual sugiere que a largo término post-isquemia se tengan en cuenta hallazgos clínicos que evalúen cambios emocionales en los pacientes que han sufrido un evento isquémico cerebral.


Cerebral ischemia is the most common type of stroke, which generates high mortality and morbidity rates worldwide. The understanding of the pathophysiology of brain injury has required the implementation of experimental models that allow the evaluation of cellular phenomena, especially those in the long-term. For this reason, the objective of the present work was to evaluate the exofocal areas at one month and four months after cerebral ischemia. Wistar rats were subjected to transient focal ischemia (t-MCAo) and one group was sacrificed one month and another group at four months' post-ischemia for subsequent histological analysis. The cuts were stained with Nissl and immunohistochemistry of the Tau protein was performed. Our results show three areas of exofocal lesion both one month and four months' post-ischemia: the thalamus, the dentate gyrus, and the amygdala. These regions have been associated with emotional control, which suggests that in the long-term post-ischemia clinical findings that evaluate emotional changes in patients who have suffered a cerebral ischemic event should be considered.


Assuntos
Animais , Ratos , Tálamo/patologia , Isquemia Encefálica/patologia , Giro Denteado/patologia , Tonsila do Cerebelo/patologia , Imuno-Histoquímica , Modelos Animais de Doenças
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