Altered Reward Circuitry in the Norepinephrine Transporter Knockout Mouse
Synaptic levels of the monoamine neurotransmitters dopamine, serotonin, and norepinephrine are modulated by their respective plasma membrane transporters, albeit with a few exceptions. Monoamine transporters remove monoamines from the synaptic cleft and thus influence the degree and duration of signaling. Abnormal concentrations of these neuronal transmitters are implicated in a number of neurological and psychiatric disorders, including addiction, depression, and attention deficit/hyperactivity disorder. This work concentrates on the norepinephrine transporter (NET), using a battery of in vivo magnetic resonance imaging techniques and histological correlates to probe the effects of genetic deletion of the norepinephrine transporter on brain metabolism, anatomy and functional connectivity. MRS recorded in the striatum of NET knockout mice indicated a lower concentration of NAA that correlates with histological observations of subtle dysmorphisms in the striatum and internal capsule. As with DAT and SERT knockout mice, we detected minimal structural alterations in NET knockout mice by tensor-based morphometric analysis. In contrast, longitudinal imaging after stereotaxic prefrontal cortical injection of manganese, an established neuronal circuitry tracer, revealed that the reward circuit in the NET knockout mouse is biased toward anterior portions of the brain. This is similar to previous results observed for the dopamine transporter (DAT) knockout mouse, but dissimilar from work with serotonin transporter (SERT) knockout mice where Mn2+ tracings extended to more posterior structures than in wildtype animals. These observations correlate with behavioral studies indicating that SERT knockout mice display anxiety-like phenotypes, while NET knockouts and to a lesser extent DAT knockout mice display antidepressant-like phenotypic features. Thus, the mainly anterior activity detected with manganese-enhanced MRI in the DAT and NET knockout mice is likely indicative of more robust connectivity in the frontal portion of the reward circuit of the DAT and NET knockout mice compared to the SERT knockout mice.
Additional Information© 2013 This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication. Received October 16, 2012; Accepted January 22, 2013; Published March 4, 2013. Funding: The project was funded in part by the Beckman Institute, NIH NINDS NS062184, NIMH MH087660, NIMGS P5OGM08273 (ELB), and NIDA R01DA18184 (REJ) and, in part, by the National Institute on Drug Abuse, Intramural Research Program (GRU and FSH), and by the Harvey Family endowment (ELB). 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; Benoit Boulat for implementation of the MRS routines; Grace Cai for imaging processing support; Kathleen Kilpatrick for technical support for histologic preparation and analysis in the Bearer lab; and the Laboratory for NeuroImaging at UCLA for invaluable assistance with LONI pipeline and TBM analysis. Author Contributions: Conceived and designed the experiments: JJG XZ FSH GRU ELB REJ. Performed the experiments: JJG XZ REJ. Analyzed the data: JJG FSH GRU REJ. Contributed reagents/materials/analysis tools: FSH GRU ELB REJ. Wrote the paper: JJG XZ FSH GRU ELB REJ.
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