GABAergic inhibition and disinhibition of midbrain dopaminergic neurons




Lobb, Collin J.

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Midbrain dopaminergic neurons are strongly implicated in Parkinson's disease, drug addiction, and reinforcement learning. Within reinforcement learning, they encode reward prediction error in their firing patterns. They fire bursts of action potentials in response to unexpected rewards or a conditioned stimulus that accurately predicts a future reward. What is the neural mechanism driving burst firing in dopaminergic neurons? Dopaminergic neurons are subject to background NMDA-mediated excitatory inputs and GABAA-mediated inhibitory inputs in vivo. Here we present evidence that phasic changes in the tonic activity of GABAergic afferents are a potential extrinsic mechanism that triggers bursts and pauses in dopaminergic neurons. We show that dopaminergic neurons in slices can be shifted into the high chord conductance state pharmacologically or with NMDA/GABAA conductance application using the dynamic clamp technique. In contrast to NMDAR, application of constant AMPA/GABAA conductances caused the cell to go into depolarization block. Disinhibition bursts have a greater intraburst firing frequency than bursts evoked from phasic excitation alone and occur with shorter latencies. These results support a bidirectional mechanism by which GABAergic inputs, in balance with NMDAR-mediated excitatory inputs, control the firing pattern of dopaminergic neurons. We then demonstrate three functional characteristics of network-based disinhibition that promote high frequency, short latency bursting in dopaminergic neurons. Our results suggest that fast, precisely timed bursts can be evoked by complete and synchronous disinhibition of dopaminergic neurons in the higher conductance state. Consequently, bursts produced by disinhibition may be particularly effective at strengthening corticostriatal synapses and facilitating reward learning.


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Integrative Biology