Intrinsically regulated learning is modulated by synaptic dopamine signaling.

Pablo Ripollés,Rosa Maria Antonijoan,Antoni Rodriguez-Fornells,Ernest Mas-Herrero,Helena Alicart,Toemme Noesselt,Alba Gómez-Andrés,Marta Valle,Jordi Riba,Laura Ferreri,Josep Marco-Pallares

doi:10.7554/elife.38113

Abstract

We recently provided evidence that an intrinsic reward-related signal-triggered by successful learning in absence of any external feedback-modulated the entrance of new information into long-term memory via the activation of the dopaminergic midbrain, hippocampus, and ventral striatum (the SN/VTA-Hippocampal loop; Ripollés et al., 2016). Here, we used a double-blind, within-subject randomized pharmacological intervention to test whether this learning process is indeed dopamine-dependent. A group of healthy individuals completed three behavioral sessions of a language-learning task after the intake of different pharmacological treatments: a dopaminergic precursor, a dopamine receptor antagonist or a placebo. Results show that the pharmacological intervention modulated behavioral measures of both learning and pleasantness, inducing memory benefits after 24 hr only for those participants with a high sensitivity to reward. These results provide causal evidence for a dopamine-dependent mechanism instrumental in intrinsically regulated learning and further suggest that subject-specific reward sensitivity drastically alters learning success.

Highlights

By using a double-blind, within-subject randomized pharmacological intervention during a learning task—guided by an intrinsically regulated reward process—known to activate the substantia nigra/ventral tegmental area complex (SN/VTA)-HP loop (Ripolles et al, 2016), we showed that dopamine can modulate the entrance of new information into long-term memory
In a previous study using the same task (Ripolles et al, 2016), we showed that successful learning was in itself associated with increased reward processing and heightened activity within the SN/VTA and the ventral striatum (VS)
We suggested that this intrinsic rewardrelated signal induced a higher release of dopamine in the HP, which resulted in enhanced memory formation due to the well-known role of dopamine in mediating long-term potentiation (LTP) processes

Summary

Introduction

Growing evidence both from animal and human studies support the notion that midbrain dopaminergic neurons of the substantia nigra/ventral tegmental area complex (SN/VTA), along with the ventral striatum (VS) and the hippocampus (HP), form a functional loop (the SN/VTA-HP loop) in the service of learning and memory (Lisman and Grace, 2005; Goto and Grace, 2005; Lisman et al, 2011; Shohamy and Adcock, 2010; Kaminski et al, 2018). In the upward arm of the loop, dopamine is released from the SN/VTA back into the HP, which in turn enhances memory formation and learning through long-term potentiation (LTP) processes (Lisman et al, 2011; Lisman and Grace, 2005; Shohamy and Adcock, 2010) Within this loop, dopamine plays a critical role, as its release promotes the creation of stable memories by allowing LTP to persist over time (Bethus et al, 2010; Frey et al, 1990; Hansen and ManahanVaughan, 2014; Huang and Kandel, 1995; McNamara et al, 2014; Rossato et al, 2009). Several studies have shown that administration of dexamphetamine and methylphenidate (which increase dopamine concentrations in the synapsis by blocking its reuptake; Breitenstein et al, 2004; Whiting et al, 2007; Whiting et al, 2008; Linssen et al, 2014) and specially, levodopa (the immediate precursor of dopamine) can enhance memory and learning in both healthy (Shellshear et al, 2015; Bunzeck et al, 2014; Chowdhury et al, 2012; Knecht et al, 2004) and clinical populations (Berthier et al, 2011)

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