RESUMO
The formation of a long-lasting memory requires a transcription-dependent consolidation period that converts a short-term memory into a long-term memory. Nuclear receptors compose a class of transcription factors that regulate diverse biological processes, and several nuclear receptors have been implicated in memory formation. Here, we examined the potential contribution of nuclear receptors to memory consolidation by measuring the expression of all 49 murine nuclear receptors after learning. We identified 13 nuclear receptors with increased expression after learning, including all 3 members of the Nr4a subfamily. These CREB-regulated Nr4a genes encode ligand-independent "orphan" nuclear receptors. We found that blocking NR4A activity in memory-supporting brain regions impaired long-term memory but did not impact short-term memory in mice. Further, expression of Nr4a genes increased following the memory-enhancing effects of histone deacetylase (HDAC) inhibitors. Blocking NR4A signaling interfered with the ability of HDAC inhibitors to enhance memory. These results demonstrate that the Nr4a gene family contributes to memory formation and is a promising target for improving cognitive function.
Assuntos
Inibidores de Histona Desacetilases/farmacologia , Memória de Longo Prazo/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Nootrópicos/farmacologia , Receptores Nucleares Órfãos/fisiologia , Fatores de Transcrição/fisiologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Eletrochoque , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Genes Dominantes , Hipocampo/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/genética , Transtornos da Memória/prevenção & controle , Memória de Longo Prazo/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas do Tecido Nervoso/agonistas , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Nootrópicos/uso terapêutico , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/deficiência , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Membro 1 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/fisiologia , Receptores Nucleares Órfãos/biossíntese , Receptores Nucleares Órfãos/genética , Fosforilação/efeitos dos fármacos , Processamento de Proteína Pós-Traducional/efeitos dos fármacos , Fatores de Transcrição/agonistasRESUMO
BACKGROUND/AIMS: In terms of blind-person years, the worldwide burden of childhood blindness is second only to cataracts. In many developing countries, 30-72% of childhood blindness is avoidable. The authors conducted this study to determine the causes of childhood blindness and visual impairment (VI) in Botswana, a middle-income country with limited access to ophthalmic care. METHODS: This study was conducted over 4 weeks in eight cities and villages in Botswana. Children were recruited through a radio advertisement and local outreach programmes. Those ≤ 15 years of age with visual acuity <6/18 in either eye were enrolled. The WHO/Prevention of Blindness Eye Examination Record for Children with Blindness and Low Vision was used to record data. RESULTS: The authors enrolled 241 children, 79 with unilateral and 162 with bilateral VI. Of unilateral cases, 89% were avoidable: 23% preventable (83% trauma-related) and 66% treatable (40% refractive error and 31% amblyopia). Of bilateral cases, 63% were avoidable: 5% preventable and 58% treatable (33% refractive error and 31% congenital cataracts). CONCLUSION: Refractive error, which is easily correctable with glasses, is the most common cause of bilateral VI, with cataracts a close second. A nationwide intervention is currently being planned to reduce the burden of avoidable childhood VI in Botswana.
