Dopaminergic and cholinergic neuromodulation of novelty encoding in humans. (360G-Wellcome-081259_Z_06_Z)

The ability to memorize preferentially novel stimuli is essential for survivalin a changing environment. The cognitive and neuromodulatory brain mechanisms behind this preference are still unclear. On the basis of our recent work, we take the view that motivation, reinforcement and prediction-errors are key factors in the preferential encoding of novelty. We hypothesize that when a novel stimulus is detected, brain networks specializing in processing motivationally relevant and potentially rewarding stimuli are activated, that includes dopaminergic and cholinergic circuitry. The resulting dopaminergic and cholinergic activation modulates long term plasticity in memory-relevant structures such as the medial temporal lobes. On the basis of these hypotheses, we now aim to identify the mechanisms and cognitive processes through which dopaminergic and cholinergic modulation improve long-term memoryformation for novel stimuli. To that end we will use multimodal pharmacological imaging (functional magnetic resonance imaging and magnetoencephalography) involving dopaminergic and cholinergic drugs in experiments that allow us to contrast the influence of novelty with reinforcement-value and prediction-error, and assess how they interact in memory formation in healthy adults. The results may help in understanding and treating memory impairment associated with neuromodulatory dysfunction in aging and neurodegenerative neurological conditions.