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Published July 9, 2010 | Published + Supplemental Material
Journal Article Open

Altered Neurocircuitry in the Dopamine Transporter Knockout Mouse Brain


The plasma membrane transporters for the monoamine neurotransmitters dopamine, serotonin, and norepinephrine modulate the dynamics of these monoamine neurotransmitters. Thus, activity of these transporters has significant consequences for monoamine activity throughout the brain and for a number of neurological and psychiatric disorders. Gene knockout (KO) mice that reduce or eliminate expression of each of these monoamine transporters have provided a wealth of new information about the function of these proteins at molecular, physiological and behavioral levels. In the present work we use the unique properties of magnetic resonance imaging (MRI) to probe the effects of altered dopaminergic dynamics on meso-scale neuronal circuitry and overall brain morphology, since changes at these levels of organization might help to account for some of the extensive pharmacological and behavioral differences observed in dopamine transporter (DAT) KO mice. Despite the smaller size of these animals, voxel-wise statistical comparison of high resolution structural MR images indicated little morphological change as a consequence of DAT KO. Likewise, proton magnetic resonance spectra recorded in the striatum indicated no significant changes in detectable metabolite concentrations between DAT KO and wild-type (WT) mice. In contrast, alterations in the circuitry from the prefrontal cortex to the mesocortical limbic system, an important brain component intimately tied to function of mesolimbic/mesocortical dopamine reward pathways, were revealed by manganese-enhanced MRI (MEMRI). Analysis of co-registered MEMRI images taken over the 26 hours after introduction of Mn^(2+) into the prefrontal cortex indicated that DAT KO mice have a truncated Mn^(2+) distribution within this circuitry with little accumulation beyond the thalamus or contralateral to the injection site. By contrast, WT littermates exhibit Mn^(2+) transport into more posterior midbrain nuclei and contralateral mesolimbic structures at 26 hr post-injection. Thus, DAT KO mice appear, at this level of anatomic resolution, to have preserved cortico-striatal-thalamic connectivity but diminished robustness of reward-modulating circuitry distal to the thalamus. This is in contradistinction to the state of this circuitry in serotonin transporter KO mice where we observed more robust connectivity in more posterior brain regions using methods identical to those employed here.

Additional Information

© 2010 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Received May 5, 2010; Accepted June 16, 2010; Published July 9, 2010. Editor: Olivier Jacques Manzoni, INSERM U901, France. Funding: The project was funded in part by the Beckman Institute, NINDS RO1 NS062184 and RO1 NS046810 (E.L.B.), NIDA R01DA18184, and NCRR U24 RR021760 Mouse BIRN (R.E.J.) and, in part, by the National Institute on Drug Abuse, Intramural Research Program (G.R.U. and F.S.H.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Mike Tyszka at Caltech for creation and implementation of the DTI routines; Grace Cai and Davit Janvelyan for assistance with image processing; and the Laboratory for NeuroImaging at UCLA for invaluable help with the LONI pipeline and TBM analysis. Author Contributions: Conceived and designed the experiments: REJ. Performed the experiments: XZ ELB BB. Analyzed the data: ELB BB FSH GRU REJ. Contributed reagents/materials/analysis tools: XZ ELB FSH GRU. Wrote the paper: REJ. Revised manuscript critically for important intellectual content: XZ ELB BB FSH GRU.

Attached Files

Published - Zhang2010p10862Plos_One.pdf

Supplemental Material - journal.pone.0011506.s001.tif

Supplemental Material - journal.pone.0011506.s002.mov

Supplemental Material - journal.pone.0011506.s004.mov

Supplemental Material - journal.pone.0011506.s005.mov


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