News tips from the Journal of Neuroscience

August 26, 2008

1. A New Striatal Microcircuit
Matthew A. Sullivan, Huanmian Chen, and Hitoshi Morikawa

Cholinergic neurons in the striatum generally fire tonically, but stop firing briefly when the animal receives a reward. The physiological mechanisms responsible for these pauses, which are thought to be important for associative learning, are not clear. This week, Sullivan et al. describe a novel striatal microcircuit that may contribute to pausing. Whole-cell recordings from cholinergic neurons in striatal slices revealed that all of these neurons receive polysynaptic inhibition that requires both GABAA receptors and β2-subunit-containing nicotinic acetylcholine receptors (AChRs), but not AMPA receptors, muscarinic AChRs, or D1 or D2 dopamine receptors. Action potentials produced in cholinergic neurons via intracellular stimulation occasionally produced polysynaptic IPSCs in the same and other cholinergic neurons, suggesting that cholinergic neurons are sparsely interconnected via GABAergic interneurons. Although repetitive stimulation of single cholinergic neurons depressed polysynaptic IPSCs, simultaneous, repetitive extracellular stimulation of many cholinergic fibers reliably elicited IPSCs that briefly disrupted tonic firing.

2. Regulation of Neuronal Polarity by Protein Kinase D
Dong-Min Yin, Yan-Hua Huang, Yan-Bing Zhu, and Yun Wang

The transition of a spherical neuroblast into a mature neuron--with a single axon and morphologically and molecularly distinct dendrites--requires polarized trafficking of axonal and dendritic proteins. Trafficking of protein-containing vesicles from the Golgi apparatus to the plasma membrane is regulated in part by the protein kinase D (PKD) family. Yin et al. now report that two members of this family, PKD1 and PKD2, are both required for the development of neuronal polarity. In control hippocampal cultures, the Golgi was likely to be located near the base of the nascent axon, and post-Golgi vesicles moved mainly toward the axon. Blocking either PKD1 or PKD2 using inhibitors, siRNA, or dominant-negative mutants disrupted the polarized trafficking of vesicles and increased the number of axons per cell. Additional experiments suggested that PKD1 and PKD2 do not interact with the cytoskeleton and that they must be present in the Golgi to exert their effects on neuronal polarity.

3. Cognitive and Behavioral Effects of COMT
Francesco Papaleo, Jacqueline N. Crawley, Jian Song, Barbara K. Lipska, Jim Pickel, Daniel R. Weinberger, and Jingshan Chen

Many brain processes require an optimal level of dopamine, with too much or too little dopamine causing impairment. Catechol-O-methyltransferase (COMT) helps regulate dopamine levels, and polymorphisms in human COMT have been implicated in cognitive and emotional dysfunction. A widely studied human variation involves a methionine-to-valine substitution, which increases COMT activity and lowers dopamine levels in the prefrontal cortex and hippocampus. Because human populations have high genetic and behavioral diversity, however, establishing a link between COMT alleles and specific phenotypes is difficult. Therefore, Papaleo et al. expressed the human COMT-Val allele in one line of mice and knocked out COMT expression in another. The mice exhibited all the behavioral traits predicted from human studies--impaired recognition and working memory and reduced pain sensitivity in COMT-Val-expressing mice, and increased startle, stress, and anxiety responses in knock-outs. These data provide compelling evidence for a causal link between COMT activity and these phenotypes.

4. Deep Brain Stimulation for Addiction
Fair M. Vassoler, Heath D. Schmidt, Mary E. Gerard, Katie R. Famous, Domenic A. Ciraulo, Conan Kornetsky, Clifford M. Knapp, and R. Chris Pierce

Cocaine addicts often relapse after detoxification, especially if presented with the drug or stimuli they associate with drug use, and no effective therapy to prevent relapse exists. Using a rat model of relapse, Vassoler et al. have found evidence that deep brain stimulation of the nucleus accumbens shell might reduce relapse. Rats first were trained to press a lever to receive intravenous doses of cocaine. After 3 weeks, saline was administered instead of cocaine, and lever pressing decreased significantly (from ~130 to ~14 presses per 2 h session). Lever pressing was then reinstated by a single noncontingent injection of cocaine, with larger doses causing larger increases in lever pressing. Deep brain stimulation of the nucleus accumbens shell (but not dorsal striatum) greatly reduced the reinstatement of lever pressing. Although implantation of electrodes into the brain is an invasive procedure involving major urgery, these results suggest that deep brain stimulation might be warranted to treat severe, life-threatening cases of cocaine addiction.
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Society for Neuroscience

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