Mesolimbic dopamine neurons play a central role in reward-based reinforcement learning. Recent evidence indicates that a pathological form of reward-based learning contributes to the development of drug addiction. This proposal seeks to define the role of specific calcium signals in regulating the functional output and plasticity of dopamine neurons. It is known that action potential firing of dopamine neurons transitions from tonic single-spike activity to phasic bursts upon presentation of reward-related stimuli. This firing mode transition is thought to be triggered by excitatory glutamatergic inputs predominantly activating NMDA (N-methyl-D-aspartate)-type glutamate receptors. The phasic dopamine release resulting from dopamine neuron bursts acts to promote synaptic plasticity in target brain areas, thereby mediating reinforcement learning and the development of drug addiction. However, recent evidence indicates that plasticity of synapses on dopamine neurons themselves may also be essential for these learning processes. Calcium signals triggered by postsynaptic action potentials are known to play a critical role in the plasticity of synapses in the brain. Therefore, the overarching hypothesis of this proposal is that large calcium transients accompanying bursts of action potentials mediate the induction of long-term potentiation (LTP) of NMDA receptor-mediated transmission onto dopamine neurons. Electrophysiological recording combined with confocal imaging of intracellular calcium and flash photolysis of caged compounds will be performed in acutely prepared brain slices from rats.
The first aim i s to determine the influence of metabotropic neurotransmitter inputs and acute psychostimulant exposure on burst- induced calcium signals.
The second aim i s to test the hypothesis that LTP of NMDA receptor- mediated transmission can be induced in a manner dependent on burst-induced calcium signals boosted by preceding metabotropic neurotransmitter inputs.
The third aim i s to test the hypothesis that repeated psychostimulant exposure in vivo enhances burst-induced calcium signals and the plasticity of NMDA receptor-mediated transmission, which may promote the learning of environmental stimuli associated with drug experience. The results obtained from this project will provide novel information to advance our understanding of the neural mechanisms underlying the development of drug addiction. Experience-dependent changes in the strength of connections between neurons in the brain reward circuit is thought to be one of the key neural mechanisms underlying drug addiction, which can be viewed as a maladaptive form of reward learning. Therefore, understanding the cellular machinery responsible for these changes would help to develop therapeutic strategies for drug addiction. The goal of this project is to determine the critical cellular signals mediating these changes and their regulation by addictive drugs.
Experience-dependent changes in the strength of connections between neurons in the brain reward circuit is thought to be one of the key neural mechanisms underlying drug addiction, which can be viewed as a maladaptive form of reward learning. Therefore, understanding the cellular machinery responsible for these changes would help to develop therapeutic strategies for drug addiction. The goal of this project is to determine the critical cellular signals mediating these changes and their regulation by addictive drugs.
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