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Neuropsychopharmacology ; 44(10): 1762-1768, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30659275


Extinction of a cued-fear memory within the reconsolidation window has been proposed to prevent fear reacquisition by reconsolidation interference. This 'retrieval-extinction' procedure has received interest for its therapeutic potential to reduce the impact of fear memories on behavior. To fully exploit its therapeutic potential, it is critical to understand the mechanisms that underlie the 'retrieval-extinction' effect. If the effect depends upon reconsolidation of the original memory, then it would be predicted that destabilization, induced by prediction error, would be critical for observing the effect. Here, the dependency of the retrieval-extinction effect on memory destabilization or prediction error was investigated in pavlovian cued-fear conditioned adult male rats. The requirement for memory destabilization, and thus reconsolidation, for the retrieval-extinction effect was subsequently investigated using region-specific pharmacological blockade of dopamine D1-receptors. Intra-basolateral amygdala antagonism of dopamine D1-receptors did not prevent the reacquisition of fear associated with the retrieval-extinction procedure. The requirement for prediction error was assessed by using a reinforced or non-reinforced memory retrieval trial before extinction, compared to a no-retrieval, extinction-only control. Both the reinforced (no prediction error) and non-reinforced retrieval sessions led to a decrease in fear reacquisition, suggesting that engagement of prediction error does not influence the occurrence of retrieval-extinction. Together, these data suggest that retrieval-extinction does not require memory destabilization, since behavioral or pharmacological interventions that prevent destabilization did not disrupt any capacity to attenuate fear.

Psychopharmacology (Berl) ; 236(1): 111-132, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30656364


Extinction within the reconsolidation window, or 'retrieval-extinction', has received much research interest as a possible technique for targeting the reconsolidation of maladaptive memories with a behavioural intervention. However, it remains to be determined whether the retrieval-extinction effect-a long-term reduction in fear behaviour, which appears resistant to spontaneous recovery, renewal and reinstatement-depends specifically on destabilisation of the original memory (the 'reconsolidation-update' account) or represents facilitation of an extinction memory (the 'extinction-facilitation' account). We propose that comparing the neurotransmitter systems, receptors and intracellular signalling pathways recruited by reconsolidation, extinction and retrieval-extinction will provide a way of distinguishing between these accounts.

Extinção Psicológica/fisiologia , Medo/fisiologia , Medo/psicologia , Memória/fisiologia , Animais , Humanos , Receptores Dopaminérgicos/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo
Neuroscience ; 370: 112-120, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28736133


Under certain conditions pavlovian memories undergo reconsolidation, whereby the reactivated memory can be disrupted by manipulations such as knockdown of zif268. For instrumental memories, reconsolidation disruption is less well established. Our previous, preliminary data identified that there was an increase in Zif268 in the posterior dorsolateral striatum (pDLS) after expression of an instrumental habit-like 'response' memory, but not an instrumental goal-directed 'place' memory on a T-maze task. Here, the requirement for Zif268 in the reconsolidation of a response memory was tested by knockdown of Zif268, using antisense oligodeoxynucleotide infusion into the pDLS, at memory reactivation. Zif268 knockdown reduced response memory expression 72H, but not 7d later. Western blotting revealed a non-significant increase in Zif268 in the pDLS in rats using response memories, but there was no change in Zif268 expression in the hippocampus following retrieval of a place memory. Zif268 expression increased in the basolateral amygdala after memory reactivation whether a response or place strategy was used during reactivation. We propose that Zif268 expression in the basolateral amygdala may be linked to prediction error, generated by the absence of reward at reactivation. Taken together, these results suggest a complex role for Zif268 in the maintenance of instrumental memories.

Corpo Estriado/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Recompensa , Animais , Condicionamento Clássico/fisiologia , Proteína 1 de Resposta de Crescimento Precoce/genética , Técnicas de Silenciamento de Genes , Hábitos , Masculino , Distribuição Aleatória , Ratos
Brain Struct Funct ; 223(2): 913-923, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29027032


The development of addictive behavior is associated with functional and structural plasticity in the mesocorticolimbic pathway. Increased connectivity upon cocaine administration has been inferred from increases in dendritic spine density, but without observations of presynaptic elements. Recently, we established a method that enables analyses of both dendritic spines and glutamatergic boutons and presented evidence that cocaine induces changes in striatal connectivity. As the pharmacological and behavioral effects of cocaine directly implicate dopaminergic neurons and their afferents, a remaining question is whether dopaminergic striatal innervations also undergo structural plasticity. To address this issue, we generated transgenic mice in which the fluorophore tdTomato is expressed under the promoter of the dopamine transporter gene. In these mice, specific labeling of dopaminergic boutons was observed in the striatum. Of note, the accordance of our results for control mice with previous electron microscopy studies confirms that our method can be used to decipher the spatial organization of boutons in relation to dendritic elements. Following repeated cocaine administration that led to behavioral locomotor sensitization, an increased density of dopaminergic boutons was observed 1 day later in the nucleus accumbens shell specifically, and not in other striatal regions. Combined labeling of dopaminergic boutons and striatal dendrites showed that cocaine significantly increased the percentage of dendritic spines associated with a dopaminergic bouton. Our results show that chronic cocaine administration induces structural plasticity of dopaminergic boutons that could participate in dopamine-dependent neuronal adaptations in the striatum.

Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/citologia , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Dendritos/patologia , Dendritos/ultraestrutura , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Neurônios Dopaminérgicos/ultraestrutura , Imageamento Tridimensional , Técnicas In Vitro , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Terminações Pré-Sinápticas/ultraestrutura , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Estatísticas não Paramétricas , Sinapses/fisiologia , Proteínas Vesiculares de Transporte de Monoamina/metabolismo