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Abstract:
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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 . |