Regulation of CREB Phosphorylation in Nucleus Accumbens after Relief Conditioning.

Elaheh Soleimanpour,Dana Mayer,Daniela C Dieterich,Evelyn Dankert,Jorge R Bergado Acosta,Peter Landgraf,Markus Fendt

doi:10.3390/cells10020238

Elaheh Soleimanpour, Dana Mayer + Show 5 more

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https://doi.org/10.3390/cells10020238

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Abstract

Relief learning is the association of environmental cues with the cessation of aversive events. While there is increasing knowledge about the neural circuitry mediating relief learning, the respective molecular pathways are not known. Therefore, the aim of the present study was to examine different putative molecular pathways underlying relief learning. To this purpose, male rats were subjected either to relief conditioning or to a pseudo conditioning procedure. Forty-five minutes or 6 h after conditioning, samples of five different brain regions, namely the prefrontal cortex, nucleus accumbens (NAC), dorsal striatum, dorsal hippocampus, and amygdala, were collected. Using quantitative Western blots, the expression level of CREB, pCREB, ERK1/2, pERK1/2, CaMKIIα, MAP2K, PKA, pPKA, Akt, pAkt, DARPP-32, pDARPP-32, 14-3-3, and neuroligin2 were studied. Our analyses revealed that relief conditioned rats had higher CREB phosphorylation in NAC 6 h after conditioning than pseudo conditioned rats. The data further revealed that this CREB phosphorylation was mainly induced by dopamine D1 receptor-mediated activation of PKA, however, other kinases, downstream of the NMDA receptor, may also contribute. Taken together, the present study suggests that CREB phosphorylation, induced by a combination of different molecular pathways downstream of dopamine D1 and NMDA receptors, is essential for the acquisition and consolidation of relief learning.

Highlights

Relief learning is the association of a cue with the relief from an aversive event and can be observed across species, e.g., in humans, rodents, or flies [1]
Previous studies of our group, in rodents revealed a critical role of coincident activation of dopamine D1 and NMDA receptors within the nucleus accumbens (NAC) in relief learning
The aim of the present study was to decipher the molecular pathways involved in relief learning, by focusing on the signaling pathways underlying NMDA and dopamine D1 receptors

Summary

Introduction

Relief learning is the association of a cue with the relief from an aversive event and can be observed across species, e.g., in humans, rodents, or flies [1]. Since the relief of an aversive event is rewarding [2,3], the associated cue— called conditioned relief stimulus—later induces appetitive behaviors such as approach response or attenuates defensive behavior like the startle response [1]. Studies in humans and rodents identified the nucleus accumbens (NAC) and the mesolimbic dopamine system as critical brain structures for relief learning [2,6,7]. Similar to appetitive instrumental learning [8], relief learning is mediated by a coincident activation of NMDA and dopamine

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