Burst timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons : a putative cellular substrate for reward learning

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Title: Burst timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons : a putative cellular substrate for reward learning
Author: Harnett, Mark Thomas
Abstract: The neurotransmitter dopamine (DA ) represents a neural substrate for positive motivation as its spatiotemporal distribution across the brain is responsible for goaldirected behavior and learning reward associations . The critical determinant of DA release throughout the brain is the firing pattern of DA -producing neurons . Synchronized bursts of spikes can be triggered by sensory stimuli in these neurons , evoking phasic release of DA in target brain areas to drive reward -based reinforcement learning and behavior . These bursts are generated by NMDA -type glutamate receptors (NMDARs ) . This dissertation reports a novel form of long -term potentiation (LTP ) of NMDARmediated excitatory transmission at DA neurons as a putative cellular substrate for changes in DA neuron firing during reward learning . Patch -clamp electrophysiological recording from DA neurons in acute brain slices from young adult rats demonstrated that synaptic NMDARs exhibit LTP in an associative manner , requiring coordinated pre - and postsynaptic burst firing . Ca2+ signals produced by postsynaptic burst firing needed to be amplified by preceding metabotropic neurotransmitter inputs to effectively drive plasticity . Activation of NMDARs themselves was also necessary . These two coincidence detectors governed the timingdependence of NMDAR plasticity in a manner analogous to the timing rule for cuereward learning paradigms in behaving animals . Further mechanistic study revealed that PKA , but not PKC , activity gated LTP induction by regulating the magnitude of Ca2+ signal amplification via the inositol 1 ,4 ,5 -triphospate (IP3 ) receptor and release of Ca2+ from intracellular stores . Plasticity of NMDARs was input specific and appeared to be expressed postsynaptically , but was not associated with a change in NMDAR subunit stoichiometry . LTP of NDMARs was DA -independent , and was specific for NMDARs : the same induction protocol produced long -term depression of AMPA receptors . NMDARs that had undergone LTP could be depotentiated in a spike -conditional manner , consistent with active unlearning . Finally , repeated , in vivo amphetamine experience dramatically increased facilitation of spike -evoked Ca2+ signals , which in turn drove enhanced plasticity . NMDAR plasticity thus represents a potential neural substrate for conditioned DA neuron burst responses to environmental stimuli acquired during reward -based learning as well a novel therapeutic target for intervention -based therapy of addictive disorders .
URI: http : / /hdl .handle .net /2152 /6871
Date: 2010-02-04

Citation

Burst timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons : a putative cellular substrate for reward learning. Doctoral dissertation, The University of Texas at Austin. Available electronically from http : / /hdl .handle .net /2152 /6871 .

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