Reward circuitry is perturbed in the absence of the serotonin transporter
The serotonin transporter (SERT) modulates the entire serotonergic system in the brain and influences both the dopaminergic and norepinephrinergic systems. These three systems are intimately involved in normal physiological functioning of the brain and implicated in numerous pathological conditions. Here we use high-resolution magnetic resonance imaging (MRI) and spectroscopy to elucidate the effects of disruption of the serotonin transporter in an animal model system: the SERT knock-out mouse. Employing manganese-enhanced MRI, we injected Mn^(2+) into the prefrontal cortex and obtained 3D MR images at specific time points in cohorts of SERT and normal mice. Statistical analysis of co-registered datasets demonstrated that active circuitry originating in the prefrontal cortex in the SERT knock-out is dramatically altered, with a bias towards more posterior areas (substantia nigra, ventral tegmental area, and Raphé nuclei) directly involved in the reward circuit. Injection site and tracing were confirmed with traditional track tracers by optical microscopy. In contrast, metabolite levels were essentially normal in the SERT knock-out by in vivo magnetic resonance spectroscopy and little or no anatomical differences between SERT knock-out and normal mice were detected by MRI. These findings point to modulation of the limbic cortical–ventral striatopallidal by disruption of SERT function. Thus, molecular disruptions of SERT that produce behavioral changes also alter the functional anatomy of the reward circuitry in which all the monoamine systems are involved.
Additional Information© 2009 Elsevier Inc. Received 13 October 2008; revised 10 March 2009; accepted 11 March 2009. Available online 20 March 2009. We thank Mike Tyszka at Caltech for creation and implementation of the DTI routines; and Cornelius Hojatkashani, Ilya Eckstein, Boris Gutman, Natasha Lepore, Igor Yanovsky and Mubeena Mirza at the Laboratory for NeuroImaging at UCLA for invaluable assistance with LONI pipeline and TBM analysis. The project was funded in part by the Beckman Institute, NIH NIGMS GM47368, NINDS NS046810, P20 RR018757 (E.L.B.), NIDA R01DA18184, and NCRR U24 RR021760 Mouse BIRN (R.E.J.).
Accepted Version - Bearer2009p72610.1016j.neuroimage.2009.03.026.pdf