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Cocaine-induced synaptic plasticity in the nucleus accumbens and drug-associated behavior - An unexpected dissociation

dc.contributor.advisorSchlüter, Oliver Dr. Dr.
dc.contributor.authorShukla, Avani
dc.titleCocaine-induced synaptic plasticity in the nucleus accumbens and drug-associated behavior - An unexpected dissociationde
dc.contributor.refereeSchlüter, Oliver Dr. Dr.
dc.description.abstractengDrugs of abuse such as cocaine are known to hijack synaptic plasticity mechanisms of brain circuits underlying motivated behavior. A common mechanism of drugs of abuse is to elevate extracellular dopamine levels in the nucleus accumbens (NAc), a brain region of the ventral striatum that is a central part of the brain’s reward circuit, the mesocorticolimbic dopamine system. NAc synapses are considered as major substrates for neural adaptions underlying drug reward. It has been shown that in vivo cocaine exposure rejuvenates the NAc neural network by generating new ‘silent synapses’. These synapses lack stably integrated AMPA receptors and are hence ‘silent’ or non-transmitting at resting potentials. However, they bear the potential to be integrated into the neural circuit by switching to transmitting synapses, through means of AMPA receptor incorporation. So far, the mechanism with which cocaine exposure induces silent synapses in the NAc remains unknown. My results show that the function of α2δ1, the receptor for synaptogenic astrocyte-secreted proteins called thrombospondins, in the NAc, is essential for the generation of silent synapses in adult mice following in vivo cocaine exposure. This brings to light the potential role of a pathway involving astrocyte-mediated synaptogenesis after cocaine exposure. In this study, I used cocaine-conditioned place preference (cocaine-CPP), a behavioral assay to test the positive association of drug experience in mice. The association of cocaine-induced pleasure with environmental cues, during passive administration of cocaine, was measured as a preference of the mice to stay longer in the cocaine-paired compartment of the CPP apparatus. The long-term retention of this association, after a period of prolonged withdrawal from the drug, was used as a measure of long-term drug-associated memory. This memory was robust and long-lasting as mice retained the preference at least till 45 days of withdrawal from cocaine-CPP. To assess the changes in synaptic plasticity at cellular level, ex vivo electrophysiological measurements from NAc slices of mice were performed at defined time points of withdrawal from cocaine-CPP. My findings indicate that silent synapses are induced in the NAc by cocaine-CPP and mature during long-term withdrawal from cocaine-CPP by gradual incorporation of GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). The association learnt by the mice during the cocaine-CPP paradigm, was required for the accumulation of CP-AMPARs in the NAc synapses. On a molecular level, the function of the DLG-MAGUK proteins - PSD-95 and SAP102 was required for the same. PSD-95 KO mice have a high proportion of immature silent synapses in the NAc, which do NOT accumulate CP-AMPARs during withdrawal from cocaine-CPP. These mice also lack long-term retention of the association learnt from the CPP paradigm. However, the loss of PSD-95 and also SAP102, only from NAc synapses, despite blocking CP-AMPAR accumulation, does NOT impair the long-term retention of drug-associated memory. Therefore contrary to the current understanding, the expression and accumulation of CP-AMAPARs in the NAc synapses was NOT essential for long-term retention of this drug-associated memory. Furthermore, after prolonged withdrawal from cocaine self-administration, the increase in cue-induced cocaine seeking, known as incubation of craving was NOT affected by NAc-restricted loss of PSD-95. Thus accumulation of CP-AMPARs in NAc synapses is a signature of associative memories of drug experience however, it is NOT essential for long-term retention of memory. These results draw attention to the fact that cellular correlates of memory traces pertaining to drug-associated cues may be stored in brain regions of the reward circuit other than the
dc.contributor.coRefereeMoser, Tobias Prof. Dr.
dc.subject.engconditioned place preferencede
dc.subject.engnucelus accumbensde
dc.subject.engsilent synapsesde
dc.affiliation.instituteGöttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB)de
dc.subject.gokfullBiologie (PPN619462639)de

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