Research Summary

We are interested in the molecular machinery for information processing in the dopamine system and in the basal ganglia. By manipulating these molecular pathways using genetic approaches, we want to find out how such information processing is able to support motor control and reward-dependent behavioral modification.

Research Description

The role of dopamine in reward and reward-dependent behavioral modification

Animal behavior can be largely modified by reward/punishment history. The role of dopamine in reward has been well established. However, how the specific aspects of reward are mediated by dopamine remain to be specified. Using both constitutive and inducible dopamine transporter knockdown mice, we found that elevated dopaminergic tone enhanced incentive motivation without altering reinforcement learning. We hypothesize that tonic dopamine release is important for incentive motivation whereas it is the phasic dopamine release that may mediate reinforcement learning. We are generating mice with altered phasic dopamine release to test that hypothesis.

The molecular basis of dopamine-mediated learning/neuroplasticity could be very different from other types of learning. In the striatum/nucleus accumbens, neuroplasticity requires converged input from corticostriatal projections and dopaminergic projections. We are studying candidate molecular pathways that are unique in this system for dopamine-dependent neuroplasticity to take place. We are using genetic approaches to test the significance of these molecular pathways.

The biochemical basis of dopamine neuron degeneration in Parkinson’s disease

Parkinson’s disease is caused by the progressive loss of dopamine neurons. However, the biochemical basis of selective dopamine neuron loss is largely unknown. Both oxidative stress and dysfunction of the ubiquitin-proteasome pathway are implicated. We hypothesize that dopamine itself can cause oxidative stress. Under normal conditions, dopamine neurons are able to handle such cellular stress; in aged animals or in animals with genetic defects, dopamine neurons may die when protective mechanisms are impaired (e.g. defects in transporting dopamine to vesicles, defects in protein folding and protein degradation pathways). We are using in vivo transgenic mouse models to test this hypothesis.

Publications

Pecina S., Cagniard B., Berridge K.C., Aldridge J.W. & Zhuang X. (2003) Hyperdopaminergic mutant mice have higher 'wanting' but not 'liking' for sweet rewards. J. Neurosci. 23, 9395-9402.

Chuhma N., Zhang H., Masson J., Zhuang X., Sulzer D., Hen R. & Rayport S. (2004) Dopamine neurons mediate a fast excitatory signal via their glutamatergic synapses. J. Neurosci. 24, 972-981.

Zhuang X., Masson J., Gingrich J.A., Rayport S. & Hen R. (2005) Targeted gene expression in dopamine and serotonin neurons of the mouse brain. J. Neurosci. Methods. 143, 27-32.

Chen L., Cagniard B., Mathews T., Jones S., Koh H.C., Ding Y., Carvey P.M., Ling Z., Kang U.J. & Zhuang X. (2005) Age-dependent motor deficits and dopaminergic dysfunction in DJ-1 null mice. J. Biol. Chem. 22, 21418-21426.

Cagniard B., Beeler J.A., Britt J.P., McGehee D.S., Marinelli M. & Zhuang X. (2006) Dopamine scales performance in the absence of new learning. Neuron 51, 541-547.

Sanders A.C., Hussain A.J., Hen R., & Zhuang X. (2007) Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward. Neuropsychopharm. 32, 2321-9 7.

Chen L., Ding Y., Cagniard B., Van Laar A.D., Mortimer A., Chi W., Hastings T.G., Kang U.J. & Zhuang X. (2008) Unregulated cytosolic dopamine causes neurodegeneration associated with oxidative stress in mice. J. Neurosci. 28, 425-33

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