Dopaminergic modulation of neuroplasticity: mechanistic aspects, and transferability to prefrontal functions

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As one of the most important neuromodulators in the brain, dopamine plays a key role in many neural and cognitive functions such as learning and memory. It is also involved in many neurological and psychiatric diseases. The neurophysiological basis of these effects is suggested to be the modulatory effect of dopamine on neural excitability and plasticity, which has been intensively investigated in animal models. It has been proposed that dopamine facilitates learning via enhancing the signal-to-noise ratio of neural network activity, as a result of the balance between distinct regulations of dopaminergic receptor subtypes, particularly D1 and D2. In the previous funding period we have shown such a ‘focusing’ effect of dopamine, both receptor subtype- and dose-dependent, on motor cortical plasticity in healthy humans. In this proposed project, we aim to continue exploring the underlying mechanisms. First, the impact of glutamatergic and GABAergic mechanisms on the dopaminergic impact on plasticity will be investigated, as these have been shown to be prominently and antagonistically altered by dopamine receptor subtype activity. We will furthermore explore specifically the mechanistic basis for the focusing effect of DA on plasticity. Finally, we will explore if, and to which degree, the results obtained in the motor cortex model can be transferred to the prefrontal cortex, which shows gradually different DA receptor compositions, and plays a prominent role in diverse cognitive functions. The results will help us to gain detailed insight in the mechanisms of dopaminergic effects on neuroplasticity of the human brain, and its relevance for cognition.