Department of Biochemistry

Research

Our group uses genetic techniques to study the role of neuromodulators in the development and function of the mammalian nervous system. Most neuromodulators are polypeptides or amino acid derivatives. They are packaged in synaptic vesicles and released into the synaptic cleft upon neuronal stimulation where they modulate the activity of neurons by binding to membrane receptors coupled to G-protein-linked signaling pathways. Our group has been studying the role of the catecholamines, norepinephrine and dopamine, by making mice in which enzymes required for their biosynthesis have been inactivated.Mice that cannot synthesize dopamine develop normally but they become hypoactive and die of starvation a few weeks after birth. Treatment with L-dopa restores dopamine and restores locomotion and feeding and most other behaviors for about 8 hours. Thus, it is possible to study the same mice in either a dopamine replete and dopamine depleted state. Using this model, we have been examining the roles of dopamine in motivation, reward and learning. We also use viral gene therapy strategies to restore dopamine signaling to particular brain regions to ask where dopamine is needed for particular behaviors. We have begun using genetic techniques to manipulate the activity of dopamine neurons. For example, we have removed NMDA receptors from dopamine neurons to reduce excitatory glutamatergic input and discovered that those mice cannot remember where pleasurable events occur. Next, we will be expressing genes into dopamine neurons that will allow pharmacological activation or inactivation of dopamine neuron activity to allow us more directly assess the role of dopamine neurons in various behaviors.

Another area of interest involves the role of hypothalamic neurons that express a neuropeptide called agouti-related protein (AgRP). This small population of neurons is involved in the regulation of appetite and metabolism. We devised a method to selectively kill these neurons and discovered that mice die of starvation. A few days after killing AgRP neurons, the mice neither initiate feeding voluntarily nor swallow much liquid diet even if it is introduced directly into their mouth. Thus, we believe sudden loss of these AgRP neurons disrupts the normal motivational and consummatory systems that control feeding behavior. In addition to AgRP, these neurons make neuropeptide Y and gamma-amino butyric acid (GABA). We have eliminated AgRP and NPY as being critical players in the starvation phenotype and are currently concentrating on the role of GABA.

Selected Publications

Robinson, S., Rainwater, A.J., Hnasko, T.S. and Palmiter, R.D. (2007) Viral Restoration of dopamine signaling to the dorsal striatum restores instrumental conditioning to dopamine-deficient mice. Psychopharmacology 191, 567-578.

Phillips, C.T. and Palmiter, R. D. (2007) Role of AgRP-expressing neurons in lactation. Endocrinology, in press

Hnasko, T. S., Sotak, B. N and Palmiter, R. D. (2007) Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin. J. Neurosci. 27, 12484-12488.

Hnasko, T.S., Perez, F.A., Scouras, A.D., Stroll, E.A., Gale, S.D., Luquet, S., Phillips, P.E.M., Kremer, E.J. and Palmiter R.D. (2006) Cre recombinase-mediated restoration of nigrostriatal dopamine in dopamine-deficient mice reverses hypophagia and bradykinesia. Proc. Natl. Acad. Sci. USA 103: 8858-8863.

Robinson, S., Sandstrom, S.M., Denenberg, V.H and Palmiter, R.D. (2005) Distinguishing whether dopamine regulates wanting, liking and/or learning about rewards. Beh. Neurosci. 119: 5-15.

Sotak, B.N., Hnasko, T.S., Robinson, S., Kremer, E.J. and Palmiter, R.D. (2005) Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding. Br. Res. 1061: 88-96.

Heusner CL, Palmiter RD (2005) Expression of mutant NMDA receptors in dopamine D1 receptor-containing cells prevents cocaine sensitization and decreases cocaine preference. J Neurosci 25: 6651-6657.

Hnasko TS, Sotak BN, Palmiter RD (2005) Morphine reward in dopamine-deficient mice. Nature 438: 854-857.

Luquet S, Perez FA, Hnasko TS, Palmiter RD (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310: 683-685. Perez FA, Palmiter RD (2005) Parkin-deficient mice are not a robust model of parkinsonism. Proc Natl Acad Sci U S A 102: 2174-2179.

Robinson S, Sandstrom SM, Denenberg VH, Palmiter RD (2005) Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards. Behav Neurosci 119: 5-15.

Sotak BN, Hnasko TS, Robinson S, Kremer EJ, Palmiter RD (2005) Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding. Brain Res 1061: 88-96.

Ste Marie L, Luquet S, Cole TB, Palmiter RD (2005) Modulation of neuropeptide Y expression in adult mice does not affect feeding. Proc Natl Acad Sci U S A.

Cannon CM, Abdallah L, Tecott LH, During MJ, Palmiter RD (2004) Dysregulation of striatal dopamine signaling by amphetamine inhibits feeding by hungry mice. Neuron 44: 509-520.

Hnasko TS, Szczypka MS, Alaynick WA, During MJ, Palmiter RD (2004) A role for dopamine in feeding responses produced by orexigenic agents. Brain Res 1023: 309-318.

Robinson S, Smith DM, Mizumori SJ, Palmiter RD (2004) Firing properties of dopamine neurons in freely moving dopamine-deficient mice: effects of dopamine receptor activation and anesthesia. Proc Natl Acad Sci U S A 101: 13329-13334.

Cannon CM, Palmiter RD (2003) Reward without dopamine. J Neurosci 23: 10827-10831.