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. / text
| Identifer | oai:union.ndltd.org:UTEXAS/oai:repositories.lib.utexas.edu:2152/6871 |
| Date | 04 February 2010 |
| Creators | Harnett, Mark Thomas |
| Source Sets | University of Texas |
| Language | English |
| Detected Language | English |
| Format | electronic |
| Rights | Copyright is held by the author. Presentation of this material on the Libraries' web site by University Libraries, The University of Texas at Austin was made possible under a limited license grant from the author who has retained all copyrights in the works. |
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