Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 832
Filtrar
1.
Neuron ; 109(16): 2556-2572.e6, 2021 08 18.
Artigo em Inglês | MEDLINE | ID: mdl-34197732

RESUMO

Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. Here, we studied epileptic circuits using a newly developed computational pipeline that leveraged single-cell calcium imaging of larval zebrafish and chronically epileptic mice, biologically constrained effective connectivity modeling, and higher-order motif-focused network analysis. We uncovered a novel functional cell type that preferentially emerged in the preseizure state, the superhub, that was unusually richly connected to the rest of the network through feedforward motifs, critically enhancing downstream excitation. Perturbation simulations indicated that disconnecting superhubs was significantly more effective in stabilizing epileptic circuits than disconnecting hub cells that were defined traditionally by connection count. In the dentate gyrus of chronically epileptic mice, superhubs were predominately modeled adult-born granule cells. Collectively, these results predict a new maximally selective and minimally invasive cellular target for seizure control.


Assuntos
Comunicação Celular/fisiologia , Epilepsia/fisiopatologia , Neurônios/fisiologia , Convulsões/fisiopatologia , Animais , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Rede Nervosa/fisiopatologia , Peixe-Zebra
2.
Exp Anim ; 70(4): 514-521, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34193681

RESUMO

Ninjin-yoei-to (NYT), a Kampo medicine, has ameliorative effects on cognitive dysfunction via enhancing cholinergic neuron activity. To explore an efficacy of NYT administration for prevention and cure of Alzheimer's disease, here we examined the effect of NYT on amyloid ß1-42 (Aß1-42)-induced neurodegeneration in the dentate gyrus. A diet containing 3% NYT was administered to mice for 2 weeks and human Aß1-42 was intracerebroventricularly injected. Neurodegeneration in the dentate granule cell layer of the hippocampus, which was determined 2 weeks after the injection, was rescued by administration of the diet for 4 weeks. Aß staining (uptake) was not modified in the dentate granule cell layer by pre-administration of the diet for 2 weeks, while Aß1-42-induced increase in intracellular Zn2+ was reduced, suggesting that pre-administration of NYT prior to Aß injection is effective for reducing Aß1-42-induced Zn2+ toxicity in the dentate gyrus. As a matter of fact, Aß1-42-induced neurodegeneration in the dentate gyrus was rescued by pre-administration of NYT. Interestingly, the level of metallothioneins, intracellular Zn2+-binding proteins, which can capture Zn2+ from Zn-Aß1-42 complexes, was elevated in the dentate granule cell layer by pre-administration of NYT. The present study suggests that pre-administration of NYT prevents Aß1-42-mediated neurodegeneration in the dentate gyurs by induced synthesis of metallothioneins, which reduces intracellular Zn2+ toxicity induced by Aß1-42.


Assuntos
Peptídeos beta-Amiloides/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Giro Denteado/fisiopatologia , Medicina Kampo , Panax/química , Substâncias Protetoras/farmacologia , Animais , Giro Denteado/efeitos dos fármacos , Masculino , Camundongos
3.
Epilepsia ; 62(3): 659-670, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33570167

RESUMO

OBJECTIVE: One third of epilepsy patients do not become seizure-free using conventional medication. Therefore, there is a need for alternative treatments. Preclinical research using designer receptors exclusively activated by designer drugs (DREADDs) has demonstrated initial success in suppressing epileptic activity. Here, we evaluated whether long-term chemogenetic seizure suppression could be obtained in the intraperitoneal kainic acid rat model of temporal lobe epilepsy, when DREADDs were selectively expressed in excitatory hippocampal neurons. METHODS: Epileptic male Sprague Dawley rats received unilateral hippocampal injections of adeno-associated viral vector encoding the inhibitory DREADD hM4D(Gi), preceded by a cell-specific promotor targeting excitatory neurons. The effect of clozapine-mediated DREADD activation on dentate gyrus evoked potentials and spontaneous electrographic seizures was evaluated. Animals were systemically treated with single (.1 mg/kg/24 h) or repeated (.1 mg/kg/6 h) injections of clozapine. In addition, long-term continuous release of clozapine and olanzapine (2.8 mg/kg/7 days) using implantable minipumps was evaluated. All treatments were administered during the chronic epileptic phase and between 1.5 and 13.5 months after viral transduction. RESULTS: In the DREADD group, dentate gyrus evoked potentials were inhibited after clozapine treatment. Only in DREADD-expressing animals, clozapine reduced seizure frequency during the first 6 h postinjection. When administered repeatedly, seizures were suppressed during the entire day. Long-term treatment with clozapine and olanzapine both resulted in significant seizure-suppressing effects for multiple days. Histological analysis revealed DREADD expression in both hippocampi and some cortical regions. However, lesions were also detected at the site of vector injection. SIGNIFICANCE: This study shows that inhibition of the hippocampus using chemogenetics results in potent seizure-suppressing effects in the intraperitoneal kainic acid rat model, even 1 year after viral transduction. Despite a need for further optimization, chemogenetic neuromodulation represents a promising treatment prospect for temporal lobe epilepsy.


Assuntos
Anticonvulsivantes/uso terapêutico , Clozapina/uso terapêutico , Epilepsia do Lobo Temporal/tratamento farmacológico , Olanzapina/uso terapêutico , Receptores de Neurotransmissores/genética , Animais , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Potenciais Evocados/fisiologia , Quinases de Receptores Acoplados a Proteína G/efeitos dos fármacos , Quinases de Receptores Acoplados a Proteína G/genética , Edição de Genes/métodos , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Masculino , Ratos , Ratos Sprague-Dawley , Receptores de Neurotransmissores/efeitos dos fármacos , Convulsões/prevenção & controle
4.
Mol Cell Neurosci ; 111: 103601, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33545324

RESUMO

We recently introduced behavioral profiling as a translational approach to increase the validity of animal models of posttraumatic stress disorder (PTSD). Behavioral profiling utilizes the response of a 'normal population' of control animals and compares the performance of animals with a history of traumatic stress in different behavioral tests that can capture PTSD-like symptoms. Thus, affected, PTSD-like individuals can be subdivided from resilient trauma-exposed animals. While in our recent study we focused mainly on tests for activity and anxiety, we now expand the behavioral tests battery and include also fear memory and extinction tasks as well as a spatial object recognition test in our behavioral profiling approach. Utilizing underwater trauma as the traumatic event, we found that only a small subset of animals exposed to underwater trauma showed lasting increases in anxiety-like behavior and heightened emotional memory formation. Adding juvenile stress as a model for childhood adversity increased the prevalence of such affected animals and furthermore and induced additional cognitive deficits in a subgroup of such emotionally affected individuals. In addition, multiple affected individual rats displayed increased local circuit activity in the dorsal dentate gyrus, as measured in vivo with paired pulse protocols in anesthetized animals. Together, our findings highlight behavioral profiling, refined by including multiple behavioral tests, as a valid tool to identify PTSD-like vs. resilient individual animals and further suggest that enhanced local inhibition in specific circuits of the dorsal dentate gyrus may be associated with the observed symptoms.


Assuntos
Comportamento Animal , Giro Denteado/fisiopatologia , Inibição Neural , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Animais , Masculino , Memória , Ratos , Ratos Sprague-Dawley , Potenciais Sinápticos
5.
Mol Brain ; 14(1): 28, 2021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33557888

RESUMO

Neuropathic pain (NP) remains an untreatable disease due to the complex pathophysiology that involves the whole pain neuraxis including the forebrain. Sensory dysfunctions such as allodynia and hyperalgesia are only part of the symptoms associated with neuropathic pain that extend to memory and affectivity deficits. The development of multi-target molecules might be a promising therapeutic strategy against the symptoms associated with NP. 2-pentadecyl-2-oxazoline (PEA-OXA) is a plant-derived agent, which has shown effectiveness against chronic pain and associated neuropsychiatric disorders. The molecular mechanisms by which PEA-OXA exerts its effects are, however, only partially known. In the current study, we show that PEA-OXA, besides being an alpha2 adrenergic receptor antagonist, also acts as a modulator at histamine H3 receptors, and report data on its effects on sensory, affective and cognitive symptoms associated with the spared nerve injury (SNI) model of neuropathic pain in mice. Treatment for 14 days with PEA-OXA after the onset of the symptoms associated with neuropathic pain resulted in the following effects: (i) allodynia was decreased; (ii) affective/cognitive impairment associated with SNI (depression, spatial, and working memories) was counteracted; (iii) long-term potentiation in vivo in the lateral entorhinal cortex-dentate gyrus (perforant pathway, LPP) was ameliorated, (iv) hippocampal glutamate, GABA, histamine, norepinephrine and dopamine level alterations after peripheral nerve injury were reversed, (v) expression level of the TH positive neurons in the Locus Coeruleus were normalized. Thus, a 16-day treatment with PEA-OXA alleviates the sensory, emotional, cognitive, electrophysiological and neurochemical alterations associated with SNI-induced neuropathic pain.


Assuntos
Comportamento Animal , Depressão/complicações , Transtornos da Memória/complicações , Transtornos da Memória/tratamento farmacológico , Neuralgia/tratamento farmacológico , Oxazóis/uso terapêutico , Receptores Adrenérgicos alfa 2/metabolismo , Receptores Histamínicos H3/metabolismo , Sequência de Aminoácidos , Animais , Ansiedade/complicações , Ansiedade/fisiopatologia , Células COS , Chlorocebus aethiops , Cognição/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Córtex Entorrinal/efeitos dos fármacos , Córtex Entorrinal/metabolismo , Córtex Entorrinal/fisiopatologia , Ácido Glutâmico/metabolismo , Humanos , Hiperalgesia/complicações , Hiperalgesia/fisiopatologia , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Transtornos da Memória/fisiopatologia , Camundongos Endogâmicos C57BL , Neuralgia/metabolismo , Norepinefrina/metabolismo , Oxazóis/farmacologia , Receptores Histamínicos H3/química , Homologia Estrutural de Proteína , Ácido gama-Aminobutírico/metabolismo
6.
Int J Mol Sci ; 22(4)2021 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-33562494

RESUMO

The role that thyroid hormone deficiency plays in depression and synaptic plasticity in adults has only begun to be elucidated. This paper analyzes the possible link between depression and hypothyroidism in cognitive function alterations, using Wistar-Kyoto (WKY-an animal model of depression) rats and control Wistar rats under standard and thyroid hormone deficiency conditions (propylthiouracil administration-PTU). A weakening of memory processes in the WKY rats is shown behaviorally, and in the reduction of long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 hippocampal regions. PTU administration decreased LTP and increased basal excitatory transmission in the DG in Wistar rats. A decrease in short-term synaptic plasticity is shown by the paired-pulse ratio measurement, occurring during hypothyroidism in DG and CA1 in WKY rats. Differences between the strains may result from decreases in the p-CaMKII, p-AKT, and the level of acetylcholine, while in the case of the co-occurrence of depression and hypothyroidism, an increase in the p-ERK1-MAP seemed to be important. Obtained results show that thyroid hormones are less involved in the inhibition of glutamate release and/or excitability of the postsynaptic neurons in WKY rats, which may indicate a lower sensitivity of the hippocampus to the action of thyroid hormones in depression.


Assuntos
Disfunção Cognitiva/etiologia , Depressão/etiologia , Hipocampo/fisiopatologia , Hipotireoidismo/complicações , Animais , Região CA1 Hipocampal/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Giro Denteado/fisiopatologia , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Expressão Gênica/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Humanos , Hipotireoidismo/fisiopatologia , Hipotireoidismo/psicologia , Potenciação de Longa Duração/fisiologia , Masculino , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Propiltiouracila/toxicidade , Ratos , Ratos Endogâmicos WKY , Ratos Wistar , Hormônios Tireóideos/deficiência , Hormônios Tireóideos/fisiologia
7.
J Neurosci ; 41(10): 2301-2312, 2021 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-33514675

RESUMO

Why layers II/III of entorhinal cortex (EC) deteriorate in advance of other regions during the earliest stages of Alzheimer's disease is poorly understood. Failure of retrograde trophic support from synapses to cell bodies is a common cause of neuronal atrophy, and we accordingly tested for early-life deterioration in projections of rodent layer II EC neurons. Using electrophysiology and quantitative imaging, changes in EC terminals during young adulthood were evaluated in male rats and mice. Field excitatory postsynaptic potentials, input/output curves, and frequency following capacity by lateral perforant path (LPP) projections from lateral EC to dentate gyrus were unchanged from 3 to 8-10 months of age. In contrast, the unusual presynaptic form of long-term potentiation (LTP) expressed by the LPP was profoundly impaired by 8 months in rats and mice. This impairment was accompanied by a reduction in the spine to terminal endocannabinoid signaling needed for LPP-LTP induction and was offset by an agent that enhances signaling. There was a pronounced age-related increase in synaptophysin within LPP terminals, an effect suggestive of incipient pathology. Relatedly, presynaptic levels of TrkB-receptors mediating retrograde trophic signaling-were reduced in the LPP terminal field. LTP and TrkB content were also reduced in the medial perforant path of 8- to 10-month-old rats. As predicted, performance on an LPP-dependent episodic memory task declined by late adulthood. We propose that memory-related synaptic plasticity in EC projections is unusually sensitive to aging, which predisposes EC neurons to pathogenesis later in life.SIGNIFICANCE STATEMENT Neurons within human superficial entorhinal cortex are particularly vulnerable to effects of aging and Alzheimer's disease, although why this is the case is not understood. Here we report that perforant path projections from layer II entorhinal cortex to the dentate gyrus exhibit rapid aging in rodents, including reduced synaptic plasticity and abnormal protein content by 8-10 months of age. Moreover, there was a substantial decline in the performance of an episodic memory task that depends on entorhinal cortical projections at the same ages. Overall, the results suggest that the loss of plasticity and related trophic signaling predispose the entorhinal neurons to functional decline in relatively young adulthood.


Assuntos
Envelhecimento/patologia , Giro Denteado/fisiopatologia , Potenciação de Longa Duração/fisiologia , Via Perfurante/fisiopatologia , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Ratos Long-Evans
8.
Exp Neurol ; 335: 113512, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33098872

RESUMO

α-actinin-2 (α-actn-2) is an F-actin-crosslinking protein, localized in dendritic spines. In vitro studies suggested that it is involved in spinogenesis, morphogenesis, actin organization, cell migration and anchoring of the NR1 subunit of the N-methyl-D-aspartate (NMDA) receptors in dendritic spines. However, little is known regarding its function in vivo. We examined the levels of α-actn-2 expression within the dentate gyrus (DG) during the development of chronic limbic seizures (epileptogenesis) induced by pilocarpine in rats. In this model, plasticity of the DG glutamatergic granule cells including spine loss, spinogenesis, morphogenesis, neo-synaptogenesis, aberrant migration, and alterations of NMDA receptors have been well characterized. We showed that α-actn-2 immunolabeling was reduced in the inner molecular layer at 1-2 weeks post-status epilepticus (SE), when granule cell spinogenesis and morphogenesis occur. This low level persisted at the chronic stage when new functional synapses are established. This decreased of α-actn-2 protein is concomitant with the recovery of drebrin A (DA), another actin-binding protein, at the chronic stage. Indeed, we demonstrated in cultured cells that in contrast to DA, α-actn-2 did not protect F-actin destabilization and DA inhibited α-actn-2 binding to F-actin. Such alteration could affect the anchoring of NR1 in dendritic spines. Furthermore, we showed that the expression of α-actn-2 and NR1 are co-down-regulated in membrane fractions of pilocarpine animals at chronic stage. Last, we showed that α-actn-2 is expressed in migrating newly born granule cells observed within the hilus of pilocarpine-treated rats. Altogether, our results suggest that α-actn-2 is not critical for the structural integrity and stabilization of granule cell dendritic spines. Instead, its expression is regulated when spinogenesis and morphogenesis occur and within migrating granule cells. Our data also suggest that the balance between α-actn-2 and DA expression levels may modulate NR1 anchoring within dendritic spines.


Assuntos
Actinina/biossíntese , Movimento Celular/genética , Espinhas Dendríticas , Giro Denteado/fisiopatologia , Plasticidade Neuronal/genética , Convulsões/fisiopatologia , Actinina/genética , Actinas/metabolismo , Animais , Convulsivantes , Masculino , Neurogênese/genética , Neuropeptídeos/metabolismo , Pilocarpina , Ratos , Ratos Wistar , Receptores de GABA/metabolismo , Convulsões/induzido quimicamente , Sinapses
9.
J Neurochem ; 157(3): 370-392, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33301616

RESUMO

A comprehensive overview of the interplay between glucocorticoids (GCs) and adult hippocampal neurogenesis (AHN) is presented, particularly, in the context of a diseased brain. The effectors of GCs in the dentate gyrus neurogenic niche of the hippocampal are reviewed, and the consequences of the GC signaling on the generation and integration of new neurons are discussed. Recent findings demonstrating how GC signaling mediates impairments of the AHN in various brain pathologies are overviewed. GC-mediated effects on the generation and integration of adult-born neurons in the hippocampal dentate gyrus depend on the nature, severity, and duration of the acting stress factor. GCs realize their effects on the AHN primarily via specific glucocorticoid and mineralocorticoid receptors. Disruption of the reciprocal regulation between the hypothalamic-pituitary-adrenal (HPA) axis and the generation of the adult-born granular neurons is currently considered to be a key mechanism implicating the AHN into the pathogenesis of numerous brain diseases, including those without a direct hippocampal damage. These alterations vary from reduced proliferation of stem and progenitor cells to increased cell death and abnormalities in morphology, connectivity, and localization of young neurons. Although the involvement of the mutual regulation between the HPA axis and the AHN in the pathogenesis of cognitive deficits and mood impairments is evident, several unresolved critical issues are stated. Understanding the details of GC-mediated mechanisms involved in the alterations in AHN could enable the identification of molecular targets for ameliorating pathology-induced imbalance in the HPA axis/AHN mutual regulation to conquer cognitive and psychiatric disturbances.


Assuntos
Encefalopatias/fisiopatologia , Glucocorticoides/farmacologia , Hipocampo/fisiopatologia , Neurogênese/efeitos dos fármacos , Animais , Grânulos Citoplasmáticos/efeitos dos fármacos , Giro Denteado/fisiopatologia , Hipocampo/crescimento & desenvolvimento , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/fisiopatologia
10.
Nat Commun ; 11(1): 6045, 2020 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-33247136

RESUMO

Touch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion.


Assuntos
Ansiedade/fisiopatologia , Giro Denteado/fisiopatologia , Memória/fisiologia , Tato/fisiologia , Animais , Comportamento Animal/fisiologia , Espinhas Dendríticas/fisiologia , Córtex Entorrinal/fisiopatologia , Feminino , Integrases/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Sinapses/fisiologia , Fatores de Tempo
11.
Int J Mol Sci ; 21(22)2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-33198225

RESUMO

Schizophrenia is a multifactorial developmental neuropsychiatric disorder. This study examined the interplay of maternal infection and postweaning social isolation, which are prenatal and postnatal risk factors, respectively. Pregnant mice received poly I:C or saline injection on gestation day 9 and the pups were weaned at postnatal day 28. After weaning, male offspring were randomly assigned into group-rearing and isolation-rearing groups. In their adulthood, we performed behavioral tests and characterized the histochemical features of their mesocorticolimbic structures. The sociability and anxiety levels were not affected by either manipulation, but synergistic effects of the two hits on stress-coping behavior was observed. Either of the single manipulations caused defects in sensorimotor gating, novel object recognition and spatial memory tests, but the combination of the two hits did not further exacerbate the disabilities. Prenatal infection increased the number of dopaminergic neurons in midbrain, whereas postweaning isolation decreased the GABAergic neurons in cortex. Single manipulation reduced the dendritic complexity and spine densities of neurons in the medial prefrontal cortex (mPFC) and dentate gyrus. Our results support the current perspective that disturbances in brain development during the prenatal or postnatal period influence the structure and function of the brain and together augment the susceptibility to mental disorders, such as schizophrenia.


Assuntos
Giro Denteado/fisiopatologia , Mesencéfalo/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/etiologia , Esquizofrenia/etiologia , Animais , Giro Denteado/efeitos dos fármacos , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Feminino , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/patologia , Masculino , Mesencéfalo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Fatores de Risco , Esquizofrenia/fisiopatologia
12.
Elife ; 92020 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-33084572

RESUMO

In the hippocampus, a widely accepted model posits that the dentate gyrus improves learning and memory by enhancing discrimination between inputs. To test this model, we studied conditional knockout mice in which the vast majority of dentate granule cells (DGCs) fail to develop - including nearly all DGCs in the dorsal hippocampus - secondary to eliminating Wntless (Wls) in a subset of cortical progenitors with Gfap-Cre. Other cells in the Wlsfl/-;Gfap-Cre hippocampus were minimally affected, as determined by single nucleus RNA sequencing. CA3 pyramidal cells, the targets of DGC-derived mossy fibers, exhibited normal morphologies with a small reduction in the numbers of synaptic spines. Wlsfl/-;Gfap-Cre mice have a modest performance decrement in several complex spatial tasks, including active place avoidance. They were also modestly impaired in one simpler spatial task, finding a visible platform in the Morris water maze. These experiments support a role for DGCs in enhancing spatial learning and memory.


Assuntos
Aprendizagem da Esquiva , Giro Denteado/anormalidades , Memória , Receptores Acoplados a Proteínas G/genética , Aprendizagem Espacial , Animais , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiopatologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Knockout , Teste do Labirinto Aquático de Morris , Receptores Acoplados a Proteínas G/metabolismo , Análise de Sequência de RNA
13.
Curr Biol ; 30(21): 4201-4212.e3, 2020 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-32916120

RESUMO

The hippocampal subfields perform distinct operations during acquisition, differentiation, and recollection of episodic memories, and deficits in pattern separation are among the first symptoms of Alzheimer's disease (AD). We investigated how hippocampal subfields contribute to pattern separation and how this is affected by Apolipoprotein-E (APOE), the strongest AD genetic risk factor. Using ultra-high-field (7T) functional magnetic resonance imaging (fMRI), APOE-ε3-ε3 carriers predominantly recruited cornu ammonis 3 (CA3) during a spatial mnemonic discrimination task, whereas APOE-ε3-ε4 and APOE-ε3-ε2 carriers engaged CA3 and dentate gyrus (DG) to the same degree. Specifically, APOE-ε3-ε4 carriers showed reduced pattern separation in CA3, whereas APOE-ε3-ε2 carriers exhibited increased effects in DG and pattern separation-related functional connectivity between DG and CA3. Collectively, these results demonstrate that AD genetic risk alters hemodynamic responses in young pre-symptomatic individuals, paving the way for development of biomarkers for preclinical AD.


Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Região CA3 Hipocampal/fisiopatologia , Giro Denteado/fisiopatologia , Memória Episódica , Adulto , Alelos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/fisiopatologia , Apolipoproteínas E/metabolismo , Mapeamento Encefálico , Região CA3 Hipocampal/diagnóstico por imagem , Giro Denteado/diagnóstico por imagem , Feminino , Predisposição Genética para Doença , Técnicas de Genotipagem , Voluntários Saudáveis , Heterozigoto , Humanos , Imageamento por Ressonância Magnética , Masculino , Fatores de Risco , Adulto Jovem
14.
Neural Plast ; 2020: 9814978, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879625

RESUMO

It was not clear how and whether neural stem cells (NSCs) responded to toll-like receptor 2 (TLR2) in the inflammatory environment after traumatic brain injury (TBI). The current study investigated the correlation of TLR2 and NSC proliferation in the dentate gyrus (DG) using the TBI model of rats. Immunofluorescence (IF) was used to observe the expression of BrdU, nestin, and TLR2 in the DG in morphology. Proliferating cells in the DG were labelled by thymidine analog 5-bromo-2-deoxyuridine (BrdU). Three-labelled BrdU, nestin, and DAPI was used for the identification of newly generated NSCs. Western blotting and real-time polymerase chain reaction (PCR) were used to observe the expression of TLR2 from the level of protein and mRNA. We observed that BrdU+/nestin+/DAPI+ cells accounted for 84.30% ± 6.54% among BrdU+ cells; BrdU+ and nestin+ cells in the DG were also TLR2+ cells. BrdU+ cells and the expression of TLR2 (both protein and mRNA levels) both elevated immediately at 6 hours (h), 24 h, 3 days (d), and 7 d posttrauma and peaked in 3 d. Results indicated that TLR2 was expressed on proliferating cells in the DG (NSCs possibly) and there was a potential correlation between increased TLR2 and proliferated NSCs after TBI. Taken together, these findings suggested that TLR2 was involved in endogenous neurogenesis in the DG after TBI.


Assuntos
Lesões Encefálicas Traumáticas/fisiopatologia , Proliferação de Células , Giro Denteado/fisiopatologia , Células-Tronco Neurais/fisiologia , Neurogênese , Receptor 2 Toll-Like/fisiologia , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Giro Denteado/metabolismo , Giro Denteado/patologia , Masculino , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Receptor 2 Toll-Like/metabolismo
15.
Biochem Biophys Res Commun ; 531(3): 357-363, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32800539

RESUMO

Microgravity can cause body fluids to accumulate in the brain, resulting in brain damage. There are few studies that focus on the detection of electrophysiological signals in simulated microgravity rats, and the precise mechanisms are unknown. In this study, a new device was established to investigate the influence of microgravity on hippocampal neurons. A 16-channel microelectrode array was fabricated for in vivo multichannel electrophysiological recordings. In these experiments, microelectrode array was inserted into normal, 28-day tail suspension model, and 3-day recovered after modulation rats to record electrophysiological signals in the CA1 and DG regions of the hippocampus. Through analysis of electrophysiological signals, we obtained the following results: (1) spike signals of model rats sporadically showed brief periods of suspension involving most of the recorded neurons, which corresponded to slow and smooth peaks in local field potentials. For model rats, the firing rate was reduced, and the power in the frequency spectrum was concentrated in the slow frequency band (0-1 Hz); (2) after the detected hippocampal cells divided into pyramidal cells and interneurons, the spike duration of pyramidal cells showed remarkable latency, and their average firing rates showed a more significant decrease compared to interneurons. These results demonstrate that the hippocampal neurons were impaired after modulation in the cellular dimension, and pyramidal cells were more susceptible than interneurons.


Assuntos
Região CA1 Hipocampal/fisiopatologia , Giro Denteado/fisiopatologia , Eletrodos Implantados , Fenômenos Eletrofisiológicos , Neurônios/fisiologia , Simulação de Ausência de Peso , Potenciais de Ação/fisiologia , Animais , Masculino , Transtornos da Memória/fisiopatologia , Microeletrodos , Teste do Labirinto Aquático de Morris , Células Piramidais/fisiologia , Ratos Sprague-Dawley , Processamento de Sinais Assistido por Computador , Aprendizagem Espacial
16.
Eur J Pharmacol ; 883: 173285, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32697958

RESUMO

Depression is a major health problem for which most patients are not effectively treated. This underscores a need to identify new targets for the development of antidepressants with improved efficacy. Studies have shown that blockade of low-affinity/high-capacity transporters, such as organic cation transporters (OCTs) and the plasma membrane monoamine transporter (PMAT), with decynium-22 can produce antidepressant-like effects and inhibit serotonin clearance in brain when the serotonin transporter is pharmacologically or genetically compromised. In vitro studies show that OCTs/PMAT are also capable of norepinephrine transport, raising the possibility that decynium-22 might enhance the antidepressant-like effects of norepinephrine transporter inhibitors. Using in vivo electrochemistry, we show that local administration of decynium-22 into dentate gyrus of hippocampus enhanced the ability of the norepinephrine transporter blocker, desipramine, but not the dual norepinephrine/serotonin transporter blocker venlafaxine, to inhibit norepinephrine clearance. In parallel, systemic administration of decynium-22 (0.32 mg/kg) enhanced the antidepressant-like effects of desipramine (32 mg/kg), but not those of venlafaxine, in the tail suspension test, underscoring the heterogeneous response of mice to antidepressants, including those that share similar mechanisms of action. Systemic administration of normetanephrine, a potent blocker of OCT3, failed to potentiate the antidepressant-like effects of desipramine, suggesting that the actions of decynium-22 to augment the antidepressant-like effects of desipramine are likely mediated by another OCT isoform and/or PMAT. Taken together with existing literature, concurrent blockade of OCTs and/or PMAT merits further investigation as an adjunctive therapeutic for desipramine-like antidepressant drugs.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antidepressivos/farmacologia , Giro Denteado/efeitos dos fármacos , Depressão/tratamento farmacológico , Desipramina/farmacologia , Norepinefrina/metabolismo , Proteínas de Transporte de Cátions Orgânicos/antagonistas & inibidores , Quinolinas/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Cloridrato de Venlafaxina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Depressão/metabolismo , Depressão/fisiopatologia , Depressão/psicologia , Modelos Animais de Doenças , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Proteínas de Transporte de Cátions Orgânicos/metabolismo
17.
Aging (Albany NY) ; 12(13): 13824-13844, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32554862

RESUMO

Vitamin D is an essential fat-soluble vitamin that participates in several homeostatic functions in mammalian organisms. Lower levels of vitamin D are produced in the older population, vitamin D deficiency being an accelerating factor for the progression of the aging process. In this review, we focus on the effect that vitamin D exerts in the aged brain paying special attention to the neurogenic process. Neurogenesis occurs in the adult brain in neurogenic regions, such as the dentate gyrus of the hippocampus (DG). This region generates new neurons that participate in cognitive tasks. The neurogenic rate in the DG is reduced in the aged brain because of a reduction in the number of neural stem cells (NSC). Homeostatic mechanisms controlled by the Wnt signaling pathway protect this pool of NSC from being depleted. We discuss in here the crosstalk between Wnt signaling and vitamin D, and hypothesize that hypovitaminosis might cause failure in the control of the neurogenic homeostatic mechanisms in the old brain leading to cognitive impairment. Understanding the relationship between vitamin D, neurogenesis and cognitive performance in the aged brain may facilitate prevention of cognitive decline and it can open a door into new therapeutic fields by perspectives in the elderly.


Assuntos
Envelhecimento/fisiologia , Disfunção Cognitiva/epidemiologia , Giro Denteado/crescimento & desenvolvimento , Neurogênese/fisiologia , Deficiência de Vitamina D/epidemiologia , Via de Sinalização Wnt/fisiologia , Animais , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/prevenção & controle , Giro Denteado/citologia , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Suplementos Nutricionais , Modelos Animais de Doenças , Humanos , Células-Tronco Neurais/fisiologia , Fatores de Risco , Fatores de Tempo , Vitamina D/administração & dosagem , Vitamina D/metabolismo , Deficiência de Vitamina D/dietoterapia , Deficiência de Vitamina D/fisiopatologia
18.
Neurotoxicology ; 79: 177-183, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32512026

RESUMO

Adrenergic ß receptor activation prevents human soluble amyloid ß (Aß)-induced impairment of long-term potentiation (LTP) in slices. On the basis of the evidence that human Aß1-42-induced impairment of LTP is due to Aß1-42-mediated Zn2+ toxicity, we postulated that adrenergic ß receptor activation reduces Aß1-42-mediated intracellular Zn2+ toxicity followed by rescuing Aß1-42 toxicity. To test the effect of adrenergic ß receptor activation, LTP was recorded at perforant pathway-dentate granule cell synapses of anesthetized rats 60 min after Aß1-42 injection into the dentate granule cell layer. Human Aß1-42-induced impairment of LTP was rescued by co-injection of isoproterenol, an adrenergic ß receptor agonist, but not by co-injection of phenylephrine, an adrenergic α1 receptor agonist. Isoproterenol did not reduce Aß1-42 uptake into dentate granule cells, but reduced increase in intracellular Zn2+ in dentate granule cells induced by Aß1-42. In contrast, phenylephrine did not reduce both Aß1-42 uptake and increase in intracellular Zn2+ by Aß1-42. In the case of human Aß1-40 and rat Aß1-42, which do not increase intracellular Zn2+, human Aß1-40- and rat Aß1-42-induced impairments of LTP were not rescued by co-injection of isoproterenol. The present study indicates that adrenergic ß receptor activation reduces Aß1-42-mediated increase in intracellular Zn2+ in dentate granule cells, resulting in rescuing Aß1-42-induced impairment of LTP. It is likely that noradrenergic neuron activation by stimulating the locus coeruleus is effective for rescuing Aß1-42-induced cognitive decline that is caused by intracellular Zn2+ dysregulation in the hippocampus.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Peptídeos beta-Amiloides/toxicidade , Giro Denteado/efeitos dos fármacos , Isoproterenol/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos/toxicidade , Zinco/metabolismo , Potenciais de Ação , Animais , Giro Denteado/metabolismo , Giro Denteado/patologia , Giro Denteado/fisiopatologia , Técnicas In Vitro , Masculino , Ratos Wistar
19.
Int J Mol Sci ; 21(9)2020 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-32397562

RESUMO

Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary supplements used worldwide for cognitive health and function. We previously reported that administration of BM alcoholic extract (BME) prevents trimethyltin (TMT)-induced cognitive deficits and hippocampal cell damage and promotes TMT-induced hippocampal neurogenesis. In this study, we demonstrate that administration of BME improves spatial working memory in adolescent (5-week- old) healthy mice but not adult (8-week-old) mice. Moreover, improved spatial working memory was retained even at 4 weeks after terminating 1-week treatment of adolescent mice. One-week BME treatment of adolescent mice significantly enhanced hippocampal BrdU incorporation and expression of genes involved in neurogenesis determined by RNAseq analysis. Cell death, as detected by histochemistry, appeared not to be significant. A significant increase in neurogenesis was observed in the dentate gyrus region 4 weeks after terminating 1-week treatment of adolescent mice with BME. Bacopaside I, an active component of BME, promoted the proliferation of neural progenitor cells in vitro in a concentration-dependent manner via the facilitation of the Akt and ERK1/2 signaling. These results suggest that BME enhances spatial working memory in healthy adolescent mice by promoting hippocampal neurogenesis and that the effects of BME are due, in significant amounts, to bacopaside I.


Assuntos
Bacopa/química , Giro Denteado/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Memória de Curto Prazo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Nootrópicos/uso terapêutico , Extratos Vegetais/uso terapêutico , Memória Espacial/efeitos dos fármacos , Animais , Células Cultivadas , Replicação do DNA/efeitos dos fármacos , Giro Denteado/fisiopatologia , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Medicina Ayurvédica , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/fisiopatologia , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/genética , Nootrópicos/farmacologia , Extratos Vegetais/farmacologia , RNA-Seq , Saponinas/farmacologia , Maturidade Sexual , Transdução de Sinais/efeitos dos fármacos , Compostos de Trimetilestanho/toxicidade , Triterpenos/farmacologia
20.
Cell Rep ; 31(4): 107551, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32348756

RESUMO

Animals can store information about experiences by activating specific neuronal populations, and subsequent reactivation of these neural ensembles can lead to recall of salient experiences. In the hippocampus, granule cells of the dentate gyrus participate in such memory engrams; however, whether there is an underlying logic to granule cell participation has not been examined. Here, we find that a range of novel experiences preferentially activates granule cells of the suprapyramidal blade relative to the infrapyramidal blade. Motivated by this, we identify a suprapyramidal-blade-enriched population of granule cells with distinct spatial, morphological, physiological, and developmental properties. Via transcriptomics, we map these traits onto a sparse and discrete granule cell subtype that is recruited at a 10-fold greater frequency than expected by subtype prevalence, constituting the majority of all recruited granule cells. Thus, in behaviors known to involve hippocampal-dependent memory formation, a rare and spatially localized subtype dominates overall granule cell recruitment.


Assuntos
Encéfalo/fisiopatologia , Giro Denteado/fisiopatologia , Hipocampo/fisiopatologia , Neurônios/metabolismo , Transcriptoma/genética , Animais , Humanos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...