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1.
Nature ; 607(7919): 527-533, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35794479

RESUMO

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3-5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6-8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.


Assuntos
Envelhecimento , Hipocampo , Longevidade , Neurogênese , Neurônios , Adulto , Envelhecimento/genética , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Animais , Proliferação de Células , Giro Denteado/citologia , Giro Denteado/patologia , Perfilação da Expressão Gênica , Hipocampo/citologia , Hipocampo/patologia , Humanos , Longevidade/genética , Aprendizado de Máquina , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/patologia , Neurogênese/genética , Neurônios/citologia , Neurônios/metabolismo , Neurônios/patologia , Reprodutibilidade dos Testes , Análise de Sequência de RNA , Análise de Célula Única , Transcrição Genética
2.
Proc Natl Acad Sci U S A ; 119(22): e2116797119, 2022 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-35613054

RESUMO

Long-term memory formation relies on synaptic plasticity, neuronal activity-dependent gene transcription, and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional, and epigenetic responses that are induced by CI-994, a class I HDACi, combined with contextual fear conditioning (CFC) in mice. We show that CI-994­mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in fear learning. Furthermore, using a combination of bulk and single-cell RNA-sequencing, we find that, when paired with CFC, HDACi treatment engages synaptic plasticity-promoting gene expression more strongly in the hippocampus, specifically in the dentate gyrus (DG). Finally, using chromatin immunoprecipitation-sequencing (ChIP-seq) of DG neurons, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that underlie improved memory performance. Together, these results indicate that systemic HDACi administration amplifies brain region-specific processes that are naturally induced by learning.


Assuntos
Benzamidas , Giro Denteado , Inibidores de Histona Desacetilases , Memória de Longo Prazo , Fenilenodiaminas , Animais , Benzamidas/farmacologia , Comunicação Celular/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Giro Denteado/fisiologia , Inibidores de Histona Desacetilases/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Plasticidade Neuronal , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fenilenodiaminas/farmacologia , RNA-Seq , Análise de Célula Única
3.
Proc Natl Acad Sci U S A ; 119(15): e2109448119, 2022 04 12.
Artigo em Inglês | MEDLINE | ID: mdl-35394871

RESUMO

Genetic studies of hippocampal granule neuron development have been used to elucidate cellular functions of Pten and Fmr1. While mutations in each gene cause neurodevelopmental disorders such as autism and fragile X syndrome, how Pten and Fmr1 function alone or together during normal development is not known. Moreover, Pten mRNA is bound by the fragile X mental retardation protein (FMRP) RNA binding protein, but how this physical interaction impinges on phosphatase and tensin homolog protein (PTEN) expression is not known. To understand the interaction of PTEN and FMRP, we investigated the dentate gyrus granule neuron development in Pten and Fmr1 knockout (KO) mice. Interestingly, heterozygosity of Pten restored Fmr1 KO cellular phenotypes, including dendritic arborization, and spine density, while PTEN protein expression was significantly increased in Fmr1 KO animals. However, complete deletion of both Pten and Fmr1 resulted in a dramatic increase in dendritic length, spine density, and spine length. In addition, overexpression of PTEN in Fmr1 KO Pten heterozygous background reduced dendritic length, arborization, spine density, and spine length including pS6 levels. Our findings suggest that PTEN levels are negatively regulated by FMRP, and some Fmr1 KO phenotypes are caused by dysregulation of PTEN protein. These observations provide evidence for the genetic interaction of PTEN and FMRP and a possible mechanistic basis for the pathogenesis of Fmr1-related fragile X neurodevelopmental disorders.


Assuntos
Proteína do X Frágil de Retardo Mental , Síndrome do Cromossomo X Frágil , PTEN Fosfo-Hidrolase , Animais , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Modelos Animais de Doenças , Proteína do X Frágil de Retardo Mental/genética , Proteína do X Frágil de Retardo Mental/metabolismo , Síndrome do Cromossomo X Frágil/genética , Síndrome do Cromossomo X Frágil/metabolismo , Heterozigoto , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurogênese/genética , Neurônios/metabolismo , Neurônios/patologia , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo
4.
Mol Cell Biochem ; 477(3): 897-914, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-35079926

RESUMO

Neural stem cells (NSCs) are responsible for maintaining the nervous system and repairing damages. Utility of NSCs could provide a novel solution to treat neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. However, we have no idea the exact phenotypic and functional characteristics of NSCs and their precise role in geriatric neurological and aging-related diseases. In this study, C57BL/6 mice were used to isolate and identify CD133+GFAP+CD117+Sca1+ cells in the hippocampal dentate gyrus region of the mouse brain as a novel neural stem cell population, in terms of cell phenotype, self-renewal capacity, and differentiation capability. With increasing in aging, the function, total cell number, and self-renewal capacity of CD133+GFAP+CD117+Sca1+ cells decreased, and the activity of differentiated cells also decreased. Meanwhile, we investigated differentially expressed genes in order to further classify their gene signature and pathways associated with their functional changes. Taken together, these findings demonstrate the existence of a rare population of NSCs in the hippocampal dentate gyrus region. Identification of specific NSCs offers ample opportunities for alleviating neural diseases.


Assuntos
Antígeno AC133/metabolismo , Diferenciação Celular , Giro Denteado/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Células-Tronco Neurais/metabolismo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Animais , Giro Denteado/citologia , Camundongos , Células-Tronco Neurais/citologia
5.
Stem Cell Reports ; 17(2): 259-275, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35063124

RESUMO

Senescent cells are responsible, in part, for tissue decline during aging. Here, we focused on CNS neural precursor cells (NPCs) to ask if this is because senescent cells in stem cell niches impair precursor-mediated tissue maintenance. We demonstrate an aging-dependent accumulation of senescent cells, largely senescent NPCs, within the hippocampal stem cell niche coincident with declining adult neurogenesis. Pharmacological ablation of senescent cells via acute systemic administration of the senolytic drug ABT-263 (Navitoclax) caused a rapid increase in NPC proliferation and neurogenesis. Genetic ablation of senescent cells similarly activated hippocampal NPCs. This acute burst of neurogenesis had long-term effects in middle-aged mice. One month post-ABT-263, adult-born hippocampal neuron numbers increased and hippocampus-dependent spatial memory was enhanced. These data support a model where senescent niche cells negatively influence neighboring non-senescent NPCs during aging, and ablation of these senescent cells partially restores neurogenesis and hippocampus-dependent cognition.


Assuntos
Senescência Celular/fisiologia , Células-Tronco Neurais/metabolismo , Nicho de Células-Tronco/fisiologia , Envelhecimento , Compostos de Anilina/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/metabolismo , Feminino , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Neurogênese/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Sulfonamidas/farmacologia
6.
Elife ; 112022 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-35089129

RESUMO

Advancing age causes reduced hippocampal neurogenesis, associated with age-related cognitive decline. The spatial relationship of age-induced alterations in neural stem cells (NSCs) and surrounding cells within the hippocampal niche remains poorly understood due to limitations of antibody-based cellular phenotyping. We established iterative indirect immunofluorescence imaging (4i) in tissue sections, allowing for simultaneous detection of 18 proteins to characterize NSCs and surrounding cells in 2-, 6-, and 12-month-old mice. We show that reorganization of the dentate gyrus (DG) niche already occurs in middle-aged mice, paralleling the decline in neurogenesis. 4i-based tissue analysis of the DG identifies changes in cell-type contributions to the blood-brain barrier and microenvironments surrounding NSCs to play a pivotal role to preserve neurogenic permissiveness. The data provided represent a resource to characterize the principles causing alterations of stem cell-associated plasticity within the aging DG and provide a blueprint to analyze somatic stem cell niches across lifespan in complex tissues.


Assuntos
Envelhecimento , Giro Denteado/citologia , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Animais , Barreira Hematoencefálica , Encéfalo/embriologia , Giro Denteado/diagnóstico por imagem , Giro Denteado/embriologia , Giro Denteado/metabolismo , Feminino , Imunofluorescência , Células-Tronco Embrionárias Humanas , Humanos , Masculino , Camundongos Endogâmicos C57BL , Organoides , Proteínas/análise , Nicho de Células-Tronco
7.
Cell Rep ; 37(13): 110159, 2021 12 28.
Artigo em Inglês | MEDLINE | ID: mdl-34965435

RESUMO

Specific classes of GABAergic neurons play specific roles in regulating information processing in the brain. In the hippocampus, two major classes, parvalbumin-expressing (PV+) and somatostatin-expressing (SST+), differentially regulate endogenous firing patterns and target subcellular compartments of principal cells. How these classes regulate the flow of information throughout the hippocampus is poorly understood. We hypothesize that PV+ and SST+ interneurons in the dentate gyrus (DG) and CA3 differentially modulate CA3 patterns of output, thereby altering the influence of CA3 on CA1. We find that while suppressing either interneuron class increases DG and CA3 output, the effects on CA1 were very different. Suppressing PV+ interneurons increases local field potential signatures of coupling from CA3 to CA1 and decreases signatures of coupling from entorhinal cortex to CA1; suppressing SST+ interneurons has the opposite effect. Thus, DG and CA3 PV+ and SST+ interneurons bidirectionally modulate the flow of information through the hippocampal circuit.


Assuntos
Região CA1 Hipocampal/fisiologia , Região CA3 Hipocampal/fisiologia , Giro Denteado/fisiologia , Córtex Entorrinal/fisiologia , Neurônios GABAérgicos/fisiologia , Interneurônios/fisiologia , Somatostatina/metabolismo , Potenciais de Ação , Animais , Região CA1 Hipocampal/citologia , Região CA3 Hipocampal/citologia , Giro Denteado/citologia , Córtex Entorrinal/citologia , Feminino , Neurônios GABAérgicos/citologia , Interneurônios/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
8.
Front Immunol ; 12: 782831, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34925362

RESUMO

Inducible nitric oxide synthase (iNOS) is an enzyme upregulated in the brain during neuroimmune stimuli which is associated with an oxidative and pro-inflammatory environment in several brain regions, including the hippocampal formation and the prefrontal cortex. The dentate gyrus of the hippocampal formation is the site of a process known as adult hippocampal neurogenesis (AHN). Although many endogenous and extrinsic factors can modulate AHN, the exact participation of specific proinflammatory mediators such as iNOS in these processes remains to be fully elucidated. Here, we investigated how the total genetic ablation of iNOS impacts the hippocampal neurogenic niche and microglial phenotype and if these changes are correlated to the behavioral alterations observed in iNOS knockout (K.O.) mice submitted or not to the chronic unpredictable stress model (CUS - 21 days protocol). Contrary to our initial hypothesis, at control conditions, iNOS K.O. mice displayed no abnormalities on microglial activation in the dentate gyrus. However, they did exhibit impaired newborn cells and immature neuron survival, which was not affected by CUS. The reduction of AHN in iNOS K.O. mice was accompanied by an increased positive coping response in the tail suspension test and facilitation of anxiety-like behaviors in the novelty suppressed feeding. Next, we investigated whether a pro-neurogenic stimulus would rescue the neurogenic capacity of iNOS K.O. mice by administering in control and CUS groups the antidepressant escitalopram (ESC). The chronic treatment with ESC could not rescue the neurogenic capacity or the behavioral changes observed in iNOS K.O. mice. Besides, in the ventromedial prefrontal (vmPFC) cortex there was no change in the expression or the chronic activation of PV neurons (evaluated by double labeling PV with FOSB) in the prelimbic (PrL) or infralimbic subregions. FOSB expression, however, increased in the PrL of iNOS K.O. mice. Our results suggest that iNOS seems essential for the survival of newborn cells and immature neurons in the hippocampus and seem to partially explain the anxiogenic-like behavior observed in iNOS K.O. mice. On the other hand, the iNOS ablation appears to result in increased activity of the PrL which could explain the antidepressant-like behaviors of iNOS K.O mice.


Assuntos
Giro Denteado/citologia , Neurônios/fisiologia , Óxido Nítrico Sintase Tipo II/fisiologia , Animais , Sobrevivência Celular , Citocinas/fisiologia , Masculino , Camundongos , Camundongos Knockout , Microglia/fisiologia , Neurogênese/efeitos dos fármacos , Óxido Nítrico Sintase Tipo II/genética , Estresse Psicológico/psicologia
9.
Int J Mol Sci ; 22(21)2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34768919

RESUMO

The generation of new neurons in the adult brain is a currently accepted phenomenon. Over the past few decades, the subventricular zone and the hippocampal dentate gyrus have been described as the two main neurogenic niches. Neurogenic niches generate new neurons through an asymmetric division process involving several developmental steps. This process occurs throughout life in several species, including humans. These new neurons possess unique properties that contribute to the local circuitry. Despite several efforts, no other neurogenic zones have been observed in many years; the lack of observation is probably due to technical issues. However, in recent years, more brain niches have been described, once again breaking the current paradigms. Currently, a debate in the scientific community about new neurogenic areas of the brain, namely, human adult neurogenesis, is ongoing. Thus, several open questions regarding new neurogenic niches, as well as this phenomenon in adult humans, their functional relevance, and their mechanisms, remain to be answered. In this review, we discuss the literature and provide a compressive overview of the known neurogenic zones, traditional zones, and newly described zones. Additionally, we will review the regulatory roles of some molecular mechanisms, such as miRNAs, neurotrophic factors, and neurotrophins. We also join the debate on human adult neurogenesis, and we will identify similarities and differences in the literature and summarize the knowledge regarding these interesting topics.


Assuntos
Giro Denteado/citologia , Ventrículos Laterais/citologia , Neurogênese/fisiologia , Neurônios/citologia , Estriado Ventral/citologia , Adulto , Animais , Hipocampo/citologia , Humanos , Camundongos , MicroRNAs/genética , Células-Tronco Neurais/citologia , Neurogênese/genética , Ratos
10.
Cells ; 10(11)2021 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-34831469

RESUMO

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.


Assuntos
Envelhecimento/fisiologia , Comportamento Animal , Técnicas de Silenciamento de Genes , Neurogênese , Serotonina/metabolismo , Animais , Contagem de Células , Proliferação de Células , Giro Denteado/citologia , Feminino , Fenótipo , Córtex Pré-Frontal/metabolismo , Núcleos da Rafe/metabolismo , Ratos Sprague-Dawley , Triptofano Hidroxilase/metabolismo
11.
Nature ; 600(7889): 484-488, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34759316

RESUMO

Could learning that uses cognitive control to judiciously use relevant information while ignoring distractions generally improve brain function, beyond forming explicit memories? According to a neuroplasticity hypothesis for how some cognitive behavioural therapies are effective, cognitive control training (CCT) changes neural circuit information processing1-3. Here we investigated whether CCT persistently alters hippocampal neural circuit function. We show that mice learned and remembered a conditioned place avoidance during CCT that required ignoring irrelevant locations of shock. CCT facilitated learning new tasks in novel environments for several weeks, relative to unconditioned controls and control mice that avoided the same place during reduced distraction. CCT rapidly changes entorhinal cortex-to-dentate gyrus synaptic circuit function, resulting in an excitatory-inhibitory subcircuit change that persists for months. CCT increases inhibition that attenuates the dentate response to medial entorhinal cortical input, and through disinhibition, potentiates the response to strong inputs, pointing to overall signal-to-noise enhancement. These neurobiological findings support the neuroplasticity hypothesis that, as well as storing item-event associations, CCT persistently optimizes neural circuit information processing.


Assuntos
Cognição/fisiologia , Hipocampo/fisiologia , Modelos Neurológicos , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Aprendizagem da Esquiva/fisiologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Terapia Cognitivo-Comportamental , Condicionamento Operante/fisiologia , Giro Denteado/citologia , Giro Denteado/fisiologia , Córtex Entorrinal/citologia , Córtex Entorrinal/fisiologia , Feminino , Neurônios GABAérgicos , Hipocampo/citologia , Potenciação de Longa Duração , Masculino , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Inibição Neural , Processamento Espacial , Sinapses/fisiologia
12.
Biochem Biophys Res Commun ; 585: 1-7, 2021 12 31.
Artigo em Inglês | MEDLINE | ID: mdl-34781055

RESUMO

Recent epidemiological and intervention studies have suggested that polyphenol-rich plant food consumption reduced the risk of cognitive decline. However, the findings were tentative and by no means definitive. In the present study, we examined the impact of short-term oral administration of cinnamtannin A2 (A2), an (-)-epicatechin tetramer, on adult hippocampal neurogenesis and cognitive function in mice. Mice received supplementation with vehicle (20% glycerol) or 100 µg/kg A2 for 10 days. Then, we conducted the open field test, the object location test, and the novel object test. In the open field test, the A2-treated group tended to spend more time in the center of the arena, compared to the vehicle-treated group. The A2-treated group spent significantly more time exploring objects placed in different locations, compared to the vehicle-treated group. There were no significant differences between groups in the object preference index or in the novel object test. In addition, A2 administration significantly increased the number of hippocampal bromodeoxyuridine-labeled cells in the dentate gyrus, but not in the CA1 or CA3 regions. These results suggested that short-term administration of A2 may impact spatial memory by enhancing neurogenesis in the dentate gyrus of adult mice.


Assuntos
Antocianinas/farmacologia , Catequina/farmacologia , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos , Administração Oral , Animais , Antocianinas/administração & dosagem , Antocianinas/química , Bromodesoxiuridina/metabolismo , Catequina/administração & dosagem , Catequina/química , Giro Denteado/citologia , Giro Denteado/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Camundongos Endogâmicos C57BL , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Memória Espacial/fisiologia , Fatores de Tempo
13.
Nature ; 598(7879): 120-128, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34616061

RESUMO

Mammalian brain cells show remarkable diversity in gene expression, anatomy and function, yet the regulatory DNA landscape underlying this extensive heterogeneity is poorly understood. Here we carry out a comprehensive assessment of the epigenomes of mouse brain cell types by applying single-nucleus DNA methylation sequencing1,2 to profile 103,982 nuclei (including 95,815 neurons and 8,167 non-neuronal cells) from 45 regions of the mouse cortex, hippocampus, striatum, pallidum and olfactory areas. We identified 161 cell clusters with distinct spatial locations and projection targets. We constructed taxonomies of these epigenetic types, annotated with signature genes, regulatory elements and transcription factors. These features indicate the potential regulatory landscape supporting the assignment of putative cell types and reveal repetitive usage of regulators in excitatory and inhibitory cells for determining subtypes. The DNA methylation landscape of excitatory neurons in the cortex and hippocampus varied continuously along spatial gradients. Using this deep dataset, we constructed an artificial neural network model that precisely predicts single neuron cell-type identity and brain area spatial location. Integration of high-resolution DNA methylomes with single-nucleus chromatin accessibility data3 enabled prediction of high-confidence enhancer-gene interactions for all identified cell types, which were subsequently validated by cell-type-specific chromatin conformation capture experiments4. By combining multi-omic datasets (DNA methylation, chromatin contacts, and open chromatin) from single nuclei and annotating the regulatory genome of hundreds of cell types in the mouse brain, our DNA methylation atlas establishes the epigenetic basis for neuronal diversity and spatial organization throughout the mouse cerebrum.


Assuntos
Encéfalo/citologia , Metilação de DNA , Epigenoma , Epigenômica , Neurônios/classificação , Neurônios/metabolismo , Análise de Célula Única , Animais , Atlas como Assunto , Encéfalo/metabolismo , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Citosina/química , Citosina/metabolismo , Conjuntos de Dados como Assunto , Giro Denteado/citologia , Elementos Facilitadores Genéticos/genética , Perfilação da Expressão Gênica , Hipocampo/citologia , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Vias Neurais , Neurônios/citologia
14.
Neuron ; 109(19): 3135-3148.e7, 2021 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-34619088

RESUMO

The medial entorhinal cortex (MEC)-hippocampal network plays a key role in the processing, storage, and recall of spatial information. However, how the spatial code provided by MEC inputs relates to spatial representations generated by principal cell assemblies within hippocampal subfields remains enigmatic. To investigate this coding relationship, we employed two-photon calcium imaging in mice navigating through dissimilar virtual environments. Imaging large MEC bouton populations revealed spatially tuned activity patterns. MEC inputs drastically changed their preferred spatial field locations between environments, whereas hippocampal cells showed lower levels of place field reconfiguration. Decoding analysis indicated that higher place field reliability and larger context-dependent activity-rate differences allow low numbers of principal cells, particularly in the DG and CA1, to provide information about location and context more accurately and rapidly than MEC inputs. Thus, conversion of dynamic MEC inputs into stable spatial hippocampal maps may enable fast encoding and efficient recall of spatio-contextual information.


Assuntos
Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Sinalização do Cálcio , Giro Denteado/citologia , Giro Denteado/fisiologia , Córtex Entorrinal/citologia , Hipocampo/citologia , Masculino , Rememoração Mental/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Terminações Pré-Sinápticas/fisiologia , Reprodutibilidade dos Testes , Percepção Espacial/fisiologia , Realidade Virtual
15.
Cell Rep ; 36(11): 109702, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34525354

RESUMO

Modulation of hippocampal dentate gyrus (DG) excitability regulates anxiety. In the DG, glutamatergic mossy cells (MCs) receive the excitatory drive from principal granule cells (GCs) and mediate the feedback excitation and inhibition of GCs. However, the circuit mechanism by which MCs regulate anxiety-related information routing through hippocampal circuits remains unclear. Moreover, the correlation between MC activity and anxiety states is unclear. In this study, we first demonstrate, by means of calcium fiber photometry, that MC activity in the ventral hippocampus (vHPC) of mice increases while they explore anxiogenic environments. Next, juxtacellular recordings reveal that optogenetic activation of MCs preferentially recruits GABAergic neurons, thereby suppressing GCs and ventral CA1 neurons. Finally, chemogenetic excitation of MCs in the vHPC reduces avoidance behaviors in both healthy and anxious mice. These results not only indicate an anxiolytic role of MCs but also suggest that MCs may be a potential therapeutic target for anxiety disorders.


Assuntos
Comportamento Animal/fisiologia , Hipocampo/metabolismo , Fibras Musgosas Hipocampais/patologia , Animais , Região CA1 Hipocampal/metabolismo , Cálcio/metabolismo , Dor Crônica/metabolismo , Dor Crônica/patologia , Giro Denteado/citologia , Modelos Animais de Doenças , Fibromialgia/metabolismo , Fibromialgia/patologia , Neurônios GABAérgicos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Optogenética/métodos , Técnicas de Patch-Clamp
16.
Cells ; 10(8)2021 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-34440859

RESUMO

Hippocampal plasticity is hypothesized to play a role in the etiopathogenesis of depression and the antidepressant effect of medications. One form of plasticity that is unique to the hippocampus and is involved in depression-related behaviors in animal models is adult neurogenesis. While chronic electroconvulsive shock (ECS) strongly promotes neurogenesis, less is known about its acute effects and little is known about the neurogenic effects of other forms of stimulation therapy, such as repetitive transcranial magnetic stimulation (rTMS). Here, we investigated the time course of acute ECS and rTMS effects on markers of cell proliferation and neurogenesis in the adult hippocampus. Mice were subjected to a single session of ECS, 10 Hz rTMS (10-rTMS), or intermittent theta burst stimulation (iTBS). Mice in both TMS groups were injected with BrdU 2 days before stimulation to label immature cells. One, 3, or 7 days later, hippocampi were collected and immunostained for BrdU + cells, actively proliferating PCNA + cells, and immature DCX + neurons. Following ECS, mice displayed a transient increase in cell proliferation at 3 days post-stimulation. At 7 days post-stimulation there was an elevation in the number of proliferating neuronal precursor cells (PCNA + DCX +), specifically in the ventral hippocampus. iTBS and rTMS did not alter the number of BrdU + cells, proliferating cells, or immature neurons at any of the post-stimulation time points. Our results suggest that neurostimulation treatments exert different effects on hippocampal neurogenesis, where ECS may have greater neurogenic potential than iTBS and 10-rTMS.


Assuntos
Proliferação de Células/fisiologia , Eletrochoque , Hipocampo/fisiologia , Animais , Giro Denteado/citologia , Giro Denteado/metabolismo , Giro Denteado/fisiologia , Hipocampo/citologia , Hipocampo/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese/fisiologia , Plasticidade Neuronal , Neuropeptídeos/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo , Estimulação Magnética Transcraniana
17.
Neuropharmacology ; 197: 108706, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34274352

RESUMO

Experimental studies have revealed the involvement of neuroinflammation mediated by activated microglia in the pathophysiology of depression, suggesting a novel target for treatment. The atypical antidepressant Agomelatine (Ago) has an advantage compared to the classical antidepressants due to its chronobiotic activity and unique pharmacological profile as a selective agonist at the melatonin receptors and an antagonist at the 5HT2C receptors. We have recently revealed that Ago can exert a potent antidepressant effect in rats exposed to a chronic constant light (CCL). In the present study, we hypothesized that the anti-inflammatory activity of this melatonin analog on activated neuroglia in specific brain structures might contribute to its antidepressant effect in this model. Chronic Ago treatment (40 mg/kg, i.p. for 21 days) was executed during the last 3 weeks of a 6-week period of CCL exposure in rats. The CCL-vehicle-treated rats showed a profound neuroinflammation characterized by microgliosis and astrogliosis in the hippocampus, basolateral amygdala (BL) and partly in the piriform cortex (Pir) confirmed by immunohistochemistry. With the exception of the Pir, the CCL regime was accompanied by neuronal damage, identified by Nissl staining, in the hippocampus and basolateral amygdala and impaired neurogenesis with reduced dendritic complexity of hippocampal neuroprogenitor cells detected by doublecortin-positive cells in the dentate gyrus (DG) subgranular zone compared to the control group. Ago reversed the gliosis in a region-specific manner and partially restored the suppressed DG neurogenesis. Ago failed to produce neuroprotection in CCL exposed rats. The present results suggest that the beneficial effects of Ago represent an important mechanism underlying its antidepressant effect in models characterized by impaired circadian rhythms.


Assuntos
Acetamidas/farmacologia , Luz , Neurogênese/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/patologia , Animais , Ritmo Circadiano/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Gliose , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Ratos , Ratos Wistar
18.
Exp Mol Med ; 53(7): 1134-1147, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34234278

RESUMO

Calbindin, a major Ca2+ buffer in dentate granule cells (GCs), plays a critical role in shaping Ca2+ signals, yet how it regulates neuronal function remains largely unknown. Here, we found that calbindin knockout (CBKO) mice exhibited dentate GC hyperexcitability and impaired pattern separation, which co-occurred with reduced K+ current due to downregulated surface expression of Kv4.1. Relatedly, manipulation of calbindin expression in HT22 cells led to changes in CaMKII activation and the level of surface localization of Kv4.1 through phosphorylation at serine 555, confirming the mechanism underlying neuronal hyperexcitability in CBKO mice. We also discovered that Ca2+ buffering capacity was significantly reduced in the GCs of Tg2576 mice to the level of CBKO GCs, and this reduction was restored to normal levels by antioxidants, suggesting that calbindin is a target of oxidative stress. Our data suggest that the regulation of CaMKII signaling by Ca2+ buffering is crucial for neuronal excitability regulation.


Assuntos
Calbindinas/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Giro Denteado/metabolismo , Animais , Antioxidantes/farmacologia , Benzilaminas/farmacologia , Calbindinas/genética , Cálcio/metabolismo , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/antagonistas & inibidores , Condicionamento Psicológico , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Medo/fisiologia , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Transporte Proteico , Serina/metabolismo , Sulfonamidas/farmacologia
19.
Sci Rep ; 11(1): 11725, 2021 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-34083623

RESUMO

New neurons continuously arise from neural progenitor cells in the dentate gyrus of the adult hippocampus to support ongoing learning and memory formation. To generate functional adult-born neurons, neural progenitor cells proliferate to expand the precursor cell pool and differentiate into neurons. Newly generated cells then undergo postmitotic maturation to migrate to their final destination and develop elaborate dendritic branching, which allows them to receive input signals. Little is known about factors that regulate neuronal differentiation, migration, and dendrite maturation during adult hippocampal neurogenesis. Here, we show that the transcriptional repressor protein capicua (CIC) exhibits dynamic expression in the adult dentate gyrus. Conditional deletion of Cic from the mouse dentate gyrus compromises the adult neural progenitor cell pool without altering their proliferative potential. We further demonstrate that the loss of Cic impedes neuronal lineage development and disrupts dendritic arborization and migration of adult-born neurons. Our study uncovers a previously unrecognized role of CIC in neurogenesis of the adult dentate gyrus.


Assuntos
Hipocampo/citologia , Neurogênese/genética , Células Piramidais/citologia , Células Piramidais/metabolismo , Proteínas Repressoras/genética , Animais , Diferenciação Celular , Giro Denteado/citologia , Camundongos , Camundongos Knockout , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo
20.
Elife ; 102021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34137370

RESUMO

In adult dentate gyrus neurogenesis, the link between maturation of newborn neurons and their function, such as behavioral pattern separation, has remained puzzling. By analyzing a theoretical model, we show that the switch from excitation to inhibition of the GABAergic input onto maturing newborn cells is crucial for their proper functional integration. When the GABAergic input is excitatory, cooperativity drives the growth of synapses such that newborn cells become sensitive to stimuli similar to those that activate mature cells. When GABAergic input switches to inhibitory, competition pushes the configuration of synapses onto newborn cells toward stimuli that are different from previously stored ones. This enables the maturing newborn cells to code for concepts that are novel, yet similar to familiar ones. Our theory of newborn cell maturation explains both how adult-born dentate granule cells integrate into the preexisting network and why they promote separation of similar but not distinct patterns.


Assuntos
Giro Denteado , Modelos Neurológicos , Neurogênese/fisiologia , Animais , Animais Recém-Nascidos/fisiologia , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Neurônios GABAérgicos/citologia , Neurônios GABAérgicos/fisiologia , Interneurônios/citologia , Interneurônios/fisiologia , Rede Nervosa/citologia , Rede Nervosa/fisiologia , Roedores , Sinapses/fisiologia
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