title: Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.
abstract: Anxiety and social deficits, often involving communication impairment, are fundamental clinical features of fragile X syndrome. There is growing evidence that dysregulation in reward processing is a contributing factor to the social deficits observed in many psychiatric disorders. Hence, we hypothesized that transgenic fragile X mental retardation 1 gene (fmr1) KO (FX) rats would display alterations in reward processing. To this end, awake control and FX rats were imaged for changes in blood oxygen level dependent (BOLD) signal intensity in response to the odor of almond, a stimulus to elicit the innate reward response. Subjects were 'odor naive' to this evolutionarily conserved stimulus. The resulting changes in brain activity were registered to a three-dimensional segmented, annotated rat atlas delineating 171 brain regions. Both wild-type (WT) and FX rats showed robust brain activation to a rewarding almond odor, though FX rats showed an altered temporal pattern and tended to have a higher number of voxels with negative BOLD signal change from baseline. This pattern of greater negative BOLD was especially apparent in the Papez circuit, critical to emotional processing and the mesolimbic/habenular reward circuit. WT rats showed greater positive BOLD response in the supramammillary area, whereas FX rats showed greater positive BOLD response in the dorsal lateral striatum, and greater negative BOLD response in the retrosplenial cortices, the core of the accumbens and the lateral preoptic area. When tested in a freely behaving odor-investigation paradigm, FX rats failed to show the preference for almond odor which typifies WT rats. However, FX rats showed investigation profiles similar to WT when presented with social odors. These data speak to an altered processing of this highly salient novel odor in the FX phenotype and lend further support to the notion that altered reward systems in the brain may contribute to fragile X syndrome symptomology.
authors.affiliation: The Kinsey Institute, Indiana University, Bloomington, IN, USA.
authors.forename: W M
authors.initials: WM
authors.lastname: Kenkel
authors.affiliation: The Kinsey Institute, Indiana University, Bloomington, IN, USA.|Department of Psychology, Center for Translational NeuroImaging, Northeastern University, Boston, MA, USA.
authors.forename: J R
authors.initials: JR
authors.lastname: Yee
authors.affiliation: Department of Psychology, Center for Translational NeuroImaging, Northeastern University, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Moore
authors.affiliation: Brain Imaging Centre, Douglas Mental Health University Institute, McGill University, Montreal, QC, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Madularu
authors.affiliation: Department of Psychology, Center for Translational NeuroImaging, Northeastern University, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Kulkarni
authors.affiliation: SAGE Labs, St Louis, MO, USA.
authors.forename: K
authors.initials: K
authors.lastname: Gamber
authors.affiliation: Ekam Imaging, Boston, MA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nedelman
authors.affiliation: Department of Psychology, Center for Translational NeuroImaging, Northeastern University, Boston, MA, USA.
authors.forename: C F
authors.initials: CF
authors.lastname: Ferris
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000000981:diagnostic imaging / Q000503:physiopathology*; D059907:Functional Neuroimaging; D019262:Habenula / Q000000981:diagnostic imaging / Q000503:physiopathology; D007031:Hypothalamus / Q000000981:diagnostic imaging / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000000981:diagnostic imaging / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward; D013378:Substantia Nigra / Q000000981:diagnostic imaging / Q000503:physiopathology; D066328:Ventral Striatum / Q000000981:diagnostic imaging / Q000503:physiopathology; D017557:Ventral Tegmental Area / Q000000981:diagnostic imaging / Q000503:physiopathology; D014851:Wakefulness
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1