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1.
Nature ; 610(7933): 713-721, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36198803

RESUMO

RNA is a central and universal mediator of genetic information underlying the diversity of cell types and cell states, which together shape tissue organization and organismal function across species and lifespans. Despite numerous advances in RNA sequencing technologies and the massive accumulation of transcriptome datasets across the life sciences1,2, the dearth of technologies that use RNAs to observe and manipulate cell types remains a bottleneck in biology and medicine. Here we describe CellREADR (Cell access through RNA sensing by Endogenous ADAR), a programmable RNA-sensing technology that leverages RNA editing mediated by ADAR to couple the detection of cell-defining RNAs with the translation of effector proteins. Viral delivery of CellREADR conferred specific cell-type access in mouse and rat brains and in ex vivo human brain tissues. Furthermore, CellREADR enabled the recording and control of specific types of neurons in behaving mice. CellREADR thus highlights the potential for RNA-based monitoring and editing of animal cells in ways that are specific, versatile, simple and generalizable across organ systems and species, with wide applications in biology, biotechnology and programmable RNA medicine.


Assuntos
Edição de RNA , RNA , Animais , Humanos , Camundongos , Ratos , RNA/análise , RNA/genética , RNA/metabolismo , Análise de Sequência de RNA , Transcriptoma/genética , Comportamento Animal , Encéfalo/citologia , Encéfalo/metabolismo , Neurônios , Biossíntese de Proteínas
2.
Nat Commun ; 12(1): 3558, 2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34117238

RESUMO

Hippocampal place cells contribute to mammalian spatial navigation and memory formation. Numerous models have been proposed to explain the location-specific firing of this cognitive representation, but the pattern of excitatory synaptic input leading to place firing is unknown, leaving no synaptic-scale explanation of place coding. Here we used resonant scanning two-photon microscopy to establish the pattern of synaptic glutamate input received by CA1 place cells in behaving mice. During traversals of the somatic place field, we found increased excitatory dendritic input, mainly arising from inputs with spatial tuning overlapping the somatic field, and functional clustering of this input along the dendrites over ~10 µm. These results implicate increases in total excitatory input and co-activation of anatomically clustered synaptic input in place firing. Since they largely inherit their fields from upstream synaptic partners with similar fields, many CA1 place cells appear to be part of multi-brain-region cell assemblies forming representations of specific locations.


Assuntos
Hipocampo/fisiologia , Células de Lugar/fisiologia , Memória Espacial/fisiologia , Sinapses/fisiologia , Potenciais de Ação/fisiologia , Animais , Comportamento Animal , Região CA1 Hipocampal , Dendritos/fisiologia , Ácido Glutâmico , Hipocampo/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Neurológicos , Plasticidade Neuronal/fisiologia , Neurotransmissores
3.
Neuron ; 96(2): 490-504.e5, 2017 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-29024668

RESUMO

Hippocampal place cell ensembles form a cognitive map of space during exposure to novel environments. However, surprisingly little evidence exists to support the idea that synaptic plasticity in place cells is involved in forming new place fields. Here we used high-resolution functional imaging to determine the signaling patterns in CA1 soma, dendrites, and axons associated with place field formation when mice are exposed to novel virtual environments. We found that putative local dendritic spikes often occur prior to somatic place field firing. Subsequently, the first occurrence of somatic place field firing was associated with widespread regenerative dendritic events, which decreased in prevalence with increased novel environment experience. This transient increase in regenerative events was likely facilitated by a reduction in dendritic inhibition. Since regenerative dendritic events can provide the depolarization necessary for Hebbian potentiation, these results suggest that activity-dependent synaptic plasticity underlies the formation of many CA1 place fields.


Assuntos
Potenciais de Ação/fisiologia , Região CA1 Hipocampal/metabolismo , Cálcio/metabolismo , Dendritos/metabolismo , Locomoção/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Região CA1 Hipocampal/química , Região CA1 Hipocampal/citologia , Dendritos/química , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Prevalência
4.
Brain Res ; 1559: 1-10, 2014 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-24594018

RESUMO

Nicotine addiction is associated with the development of tolerance and the emergence of withdrawal symptoms upon cessation of chronic nicotine administration. Changes in cognition, including deficits in learning, are one of the most common withdrawal symptoms reported by smokers. However, the neural substrates of tolerance to the effects of nicotine on learning and the substrates of withdrawal deficits in learning are unknown, and in fact it is unclear whether a common mechanism is involved in both. The present study tested the hypothesis that tolerance and withdrawal are separate processes and that nicotinic acetylcholine receptor (nAChR) upregulation underlies changes in learning associated with withdrawal but not tolerance. C57BL/6 male mice were administered a dose of nicotine (3, 6.3, 12, or 24 mg/kg/d) chronically for varying days and tested for the onset of tolerance to the effects of nicotine on learning. Follow up experiments examined the number of days of chronic nicotine treatment required to produce withdrawal deficits in learning and a significant increase in [(3)H] epibatidine binding in the hippocampus indicative of receptor upregulation. The results indicate that tolerance onset was influenced by dose of chronic nicotine, that tolerance occurred before withdrawal deficits in learning emerged, and that nAChR upregulation in the dorsal hippocampus was associated with withdrawal but not tolerance. This suggests that for the effects of nicotine on learning, tolerance and withdrawal involve different substrates. These findings are discussed in terms of implications for development of therapeutics that target symptoms of nicotine addiction and for theories of addiction.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Síndrome de Abstinência a Substâncias/metabolismo , Tabagismo/metabolismo , Animais , Condicionamento Psicológico/fisiologia , Relação Dose-Resposta a Droga , Tolerância a Medicamentos/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptores Nicotínicos/metabolismo , Fatores de Tempo , Regulação para Cima/efeitos dos fármacos
5.
PLoS One ; 7(6): e39939, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22761932

RESUMO

Nicotine is known to enhance long-term hippocampus dependent learning and memory in both rodents and humans via its activity at nicotinic acetylcholinergic receptors (nAChRs). However, the molecular basis for the nicotinic modulation of learning is incompletely understood. Both the mitogen activated protein kinases (MAPKs) and cAMP response element binding protein (CREB) are known to be integral to the consolidation of long-term memory and the disruption of MAPKs and CREB are known to abrogate some of the cognitive effects of nicotine. In addition, the acquisition of contextual fear conditioning in the presence of nicotine is associated with a ß2-subunit containing nAChR-dependent increase in jnk1 (mapk8) transcription in the hippocampus. In the present study, chromatin immunoprecipitation (ChIP) was used to examine whether learning and nicotine interact to alter transcription factor binding or histone acetylation at the jnk1 promoter region. The acquisition of contextual fear conditioning in the presence of nicotine resulted in an increase in phosphorylated CREB (pCREB) binding to the jnk1 promoter in the hippocampus in a ß2-subunit containing nAChR dependent manner, but had no effect on CREB binding; neither fear conditioning alone nor nicotine administration alone altered transcription factor binding to the jnk1 promoter. In addition, there were no changes in histone H3 or H4 acetylation at the jnk1 promoter following fear conditioning in the presence of nicotine. These results suggest that contextual fear learning and nicotine administration act synergistically to produce a unique pattern of protein activation and gene transcription in the hippocampus that is not individually generated by fear conditioning or nicotine administration alone.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Aprendizagem , Proteína Quinase 8 Ativada por Mitógeno/genética , Nicotina/farmacologia , Regiões Promotoras Genéticas , Sequência de Bases , Imunoprecipitação da Cromatina , Primers do DNA , Eletroforese em Gel de Poliacrilamida , Medo , Hipocampo/metabolismo , Hipocampo/fisiologia , Fosforilação , Reação em Cadeia da Polimerase
6.
Neuropharmacology ; 62(5-6): 2118-25, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22285742

RESUMO

A predominant symptom of nicotine withdrawal is cognitive deficits, yet understanding of the neural basis for these deficits is limited. Withdrawal from chronic nicotine disrupts contextual learning in mice and this deficit is mediated by direct effects of nicotine in the hippocampus. Chronic nicotine treatment upregulates nicotinic acetylcholine receptors (nAChR); however, it is unknown whether upregulation is related to the observed withdrawal-induced cognitive deficits. If a relationship between altered learning and nAChR levels exists, changes in nAChR levels after cessation of nicotine treatment should match the duration of learning deficits. To test this hypothesis, mice were chronically administered 6.3mg/kg/day (freebase) nicotine for 12 days and trained in contextual fear conditioning on day 11 or between 1 to 16 days after withdrawal of treatment. Changes in [(125)I]-epibatidine binding at cytisine-sensitive and cytisine-resistant nAChRs and chronic nicotine-related changes in α4, α7, and ß2 nAChR subunit mRNA expression were assessed. Chronic nicotine had no behavioral effect but withdrawal produced deficits in contextual fear conditioning that lasted 4 days. Nicotine withdrawal did not disrupt cued fear conditioning. Chronic nicotine upregulated hippocampal cytisine-sensitive nAChR binding; upregulation continued after cessation of nicotine administration and the duration of upregulation during withdrawal paralleled the duration of behavioral changes. Changes in binding in cortex and cerebellum did not match behavioral changes. No changes in α4, α7, and ß2 subunit mRNA expression were seen with chronic nicotine. Thus, nicotine withdrawal-related deficits in contextual learning are time-limited changes that are associated with temporal changes in upregulation of high-affinity nAChR binding.


Assuntos
Condicionamento Psicológico/efeitos dos fármacos , Medo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Nicotina/efeitos adversos , Receptores Nicotínicos/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Regulação para Cima/efeitos dos fármacos , Animais , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Hipocampo/metabolismo , Camundongos , Regulação para Cima/fisiologia
7.
Psychopharmacology (Berl) ; 217(3): 353-65, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21487656

RESUMO

RATIONALE: Spatial and novel object recognition learning is different from learning that uses aversive or appetitive stimuli to shape acquisition because no overt contingencies are needed. While this type of learning occurs on a daily basis, little is known about how nicotine administration affects it. OBJECTIVES: To determine the effects of acute, chronic, and withdrawal from chronic nicotine on two related but distinct incidental learning tasks, novel and spatial object recognition. METHODS: In C57BL/6J mice, the effects of acute (0.045-0.18 mg/kg), chronic (6.3 mg/kg/day), and withdrawal from chronic nicotine on novel and spatial object recognition were examined. RESULTS: With a 48-h delay between training and testing, acute nicotine enhanced spatial (difference score, saline = 3.34 s, nicotine = 7.71 s, p = 0.029) but resulted in a deficit in novel object recognition (difference score, saline = 8.76 s, nicotine = 4.48 s, p = 0.033). Chronic nicotine resulted in a strong trend towards a deficit in spatial object recognition (difference score, saline = 4.01 s, nicotine = 1.81 s, p = 0.059) but had no effect on novel object recognition, and withdrawal from chronic nicotine disrupted spatial object recognition (difference score, saline = 3.00 s, nicotine = 0.17 s, p = 0.004) but had no effect on novel object recognition. CONCLUSIONS: The effects of nicotine on spatial object recognition shift from enhancement to deficit as administration changes from acute to chronic and withdrawal. These effects were specific for spatial object recognition, which may be due to differing underlying neural substrates involved in these tasks. Understanding how nicotine alters learning has implications for understanding diseases associated with altered cholinergic function.


Assuntos
Comportamento Exploratório/efeitos dos fármacos , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Reconhecimento Visual de Modelos/efeitos dos fármacos , Comportamento Espacial/efeitos dos fármacos , Animais , Doença Crônica , Condicionamento Clássico , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Bombas de Infusão Implantáveis , Aprendizagem/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Tempo
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