AMPA PHOSPHORYLATION · MOLECULAR MECHANISMS OF APPETITIVE ASSOCIATIVE MEMORY

Periodic Report Summary - AMPA PHOSPHORYLATION (Molecular mechanisms of appetitive associative memory)

The overall objective was to assess brain plasticity-related molecular targets in different forms of appetitive / incentive learning and memory, using molecular, systems and behavioural neuroscience approaches. As outlined in the first periodic report, the focus was on two downstream molecular targets of AMPAR and their function in incentive learning; mGluR5 receptor and Darpp-32 - both essential in AMPAR- or IEG regulation underlying synaptic plasticity. Overall, the work has made important advances in determining the critical parameters for behavioural assays of incentive learning in (normal and mutant) mice (leading to three theoretical reviews and a technical report). Our collaborative experiments on mGluR5 have provided important convergent support for precise glutamatergic involvement in select aspects of motivated action (and potentially addiction pathology) and implicate select striatal circuitries. That is, absence of the mGluR5 receptor (e.g. on D1R MSNs) or pharmacological blocking, disrupts neurobiological and psychological processes whereby organisms attribute motivational significant (incentive salience attribution) to (otherwise) neutral cues in the environment. Notably, somewhat preliminary, the experiments using ex vivo analysis of functional (phosphorylated) states of various intracellular signalling molecules, indicate that this involvement of mGluR5 receptor may occur via interactions with AMPA-GluR1 Serine 845 site. These findings highlight how select phosphorylation mechanisms on the AMPA-GluR1 subunit, and their upstream receptor-signalling pathways, modulate specific forms of motivated (reward-based) learning and memory. Finally, the collaborative work is expected to form the basis for a future European Union (EU) grant application. The results on Darpp-32 are some of the first to implicate this molecule in select types of incentive learning and our results identify the central amygdala as the key anatomical site, presumably via interactions with VTA-accumbens dopamine circuitries. Partially completed but on-going studies are assessing the role of Darpp-32 in the effects of drugs of abuse (e.g. cocaine) using ex vivo assays (SDS-PAGE, ICH). Importantly, we have been able to preclude sensory/hedonic processing, overall appetitive learning or even conditioned-secondary reinforcement which are not Darpp-32 dependent. A recently completed study implicates Darpp-32 in frontal regions in inhibitory control and response inhibition over appetitive action. Finally, we have and are exploring the role of Darpp-32 in the interactions between cocaine and incentive learning. The findings reported and follow-up studies directly stemming from the work, offer critical new insights into the cellular-molecular basis of incentive processes critical in learning, motivation and addiction, that will appeal across disciplines, already indicated by the successful published reports in international research journals. Moreover, the work of the PI - now a senior and permanent member of the faculty- on advanced behavioural modelling of complex psychological processes and underlying cellular-molecular substrates, has added an essential new perspective within the School of Psychology at the University of Sussex. Importantly, the work has yielded a number of interesting questions ideally suited for future exploration with novel techniques such as optogenetics.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз