RESUMO
It is now widely accepted that hippocampal neurogenesis underpins critical cognitive functions, such as learning and memory. To assess the behavioral importance of adult-born neurons, we developed a novel knock-in mouse model that allowed us to specifically and reversibly ablate hippocampal neurons at an immature stage. In these mice, the diphtheria toxin receptor (DTR) is expressed under control of the doublecortin (DCX) promoter, which allows for specific ablation of immature DCX-expressing neurons after administration of diphtheria toxin while leaving the neural precursor pool intact. Using a spatially challenging behavioral test (a modified version of the active place avoidance test), we present direct evidence that immature DCX-expressing neurons are required for successful acquisition of spatial learning, as well as reversal learning, but are not necessary for the retrieval of stored long-term memories. Importantly, the observed learning deficits were rescued as newly generated immature neurons repopulated the granule cell layer upon termination of the toxin treatment. Repeat (or cyclic) depletion of immature neurons reinstated behavioral deficits if the mice were challenged with a novel task. Together, these findings highlight the potential of stimulating neurogenesis as a means to enhance learning.
Assuntos
Aprendizagem da Esquiva/fisiologia , Técnicas de Introdução de Genes/psicologia , Hipocampo/fisiologia , Memória/fisiologia , Proteínas Associadas aos Microtúbulos/fisiologia , Células-Tronco Neurais/fisiologia , Neuropeptídeos/fisiologia , Reversão de Aprendizagem/fisiologia , Animais , Células Cultivadas , Córtex Cerebral , Proteínas do Citoesqueleto/biossíntese , Proteínas do Domínio Duplacortina , Proteína Duplacortina , Técnicas de Introdução de Genes/métodos , Fator de Crescimento Semelhante a EGF de Ligação à Heparina , Peptídeos e Proteínas de Sinalização Intercelular/genética , Masculino , Memória de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/genética , Modelos Animais , Degeneração Neural/genética , Proteínas do Tecido Nervoso/biossíntese , Neurogênese/fisiologia , Neuropeptídeos/genética , Percepção Espacial/fisiologiaRESUMO
RATIONALE: Increased anxiety is a characteristic of the acute ethanol withdrawal syndrome. Repeated exposure of rats to withdrawal from chronic ethanol increases sensitivity to seizures. OBJECTIVES: We investigated whether repeated withdrawal experience increases withdrawal-induced anxiety and stress, and if it changes withdrawal-induced activation of related brain areas. METHODS: Rats were chronically treated with an ethanol-containing liquid diet either for 24 days continuously (single withdrawal, SWD) or interspersed with 2x3-day withdrawal periods (repeated withdrawal, RWD), or with a control diet. Eight hours after ethanol withdrawal, anxiety-like behaviour was tested in the elevated plus-maze, blood corticosterone levels were measured, and expression level of markers of neuronal activity and plasticity, c-fos and zif268, was assessed. RESULTS: Eight hours after ethanol withdrawal, SWD rats showed increased anxiety on the elevated plus-maze relative to control rats. Rats given previous withdrawal experiences did not show further increases in measures of anxiety. Corticosterone levels were elevated during withdrawal in SWD rats but not in RWD rats. RWD resulted in marked increases in c-fos expression in amygdala, hippocampus, nucleus accumbens and dorsolateral periaqueductal grey. In contrast, zif268 expression was not increased after RWD, and in central amygdala the marked increase in zif268 seen after SWD was absent after RWD. CONCLUSIONS: The data suggest increased ability of withdrawal to activate neuronal circuits but reduced plasticity after RWD. We suggest parallels between the consequences of repeated ethanol withdrawal and repeated exposure to stress, and discuss implications of withdrawal for brain plasticity.
Assuntos
Ansiedade/metabolismo , Corticosterona/sangue , Etanol/efeitos adversos , Sistema Límbico/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Ansiedade/induzido quimicamente , Ansiedade/fisiopatologia , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Ratos , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/fisiopatologiaRESUMO
Aggregation of the amyloid ß-protein (Aß) is believed to play a central role in initiating the molecular cascade that culminates in Alzheimer-type dementia (AD), a disease which in its early stage is characterized by synaptic loss and impairment of episodic memory. Here we show that intracerebroventricular injection of Aß-containing water-soluble extracts of AD brain inhibits consolidation of the memory of avoidance learning in the rat and that this effect is highly dependent on the interval between learning and administration. When injected at 1 hour post training extracts from 2 different AD brains significantly impaired recall tested at 48 hours. Ultrastructural examination of hippocampi from animals perfused after 48 hours revealed that Aß-mediated impairment of avoidance memory was associated with lower density of synapses and altered synaptic structure in the dentate gyrus and CA1 fields. These behavioral and ultrastructural data suggest that human brain-derived Aß impairs formation of long-term memory by compromising the structural plasticity essential for consolidation and that Aß targets processes initiated very early in the consolidation pathway.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Memória Episódica , Ratos , Ratos WistarRESUMO
Repeated exposure of rats to withdrawal from chronic ethanol reduces hippocampal long-term potentiation and gives rise to epileptiform-like activity in hippocampus. We investigated whether such withdrawal experience also affects learning in tasks thought to be sensitive to hippocampal damage. Rats fed an ethanol-containing diet for 24 days with two intermediate 3-day withdrawal episodes, resulting in intakes of 13-14 g/kg ethanol per day, showed impaired negative patterning discrimination compared with controls and animals that had continuous 24-day ethanol treatment, but did not differ from these animals in the degree of contextual freezing 24 h after training or in spatial learning in the Barnes maze. Repeatedly withdrawn animals also showed increased numbers of responses in the period immediately before reinforcement became available in an operant task employing a fixed-interval schedule although overall temporal organization of responding was unimpaired. Thus, in our model of repeated withdrawal from ethanol, previously observed changes in hippocampal function did not manifest at the behavioural level in the tests employed. The deficit seen after repeated withdrawal in the negative patterning discrimination and over-responding in the fixed-interval paradigm might be related to the changes in the functioning of the cortex after withdrawal.