Functional magnetic resonance imaging in awake transgenic fragile X rats: evidence of dysregulation in reward processing in the mesolimbic/habenular neural circuit.

W M Kenkel,M Nedelman,D Madularu,C F Ferris,K Moore,K Gamber,P Kulkarni,J R Yee

doi:10.1038/tp.2016.15

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.

Highlights

Nearly 30% children with Fragile X syndrome (FXS) meet the diagnostic criteria for autism spectrum disorder (ASD)
FXS is caused by a full mutation in the fragile X mental retardation 1 gene (FMR1)
In a serial dilution study for almond scent, we identified a threshold dilution of 100% benzaldehyde (1/10 000 v/v) that gives a significant and consistent pattern of brain activity

Summary

Introduction

Fragile X syndrome (FXS) is the most commonly inherited cause of intellectual disability and a leading genetic cause of autism.[1,2,3,4] nearly 30% children with FXS meet the diagnostic criteria for autism spectrum disorder (ASD). Individuals with FXS have a mutated FMR1 gene in which the trinucleotide repeat appears over 200 times.[8,9] This expansion leads to hypermethylation of the promoter which silences the gene, inhibiting fmr[1] from producing fragile X mental retardation protein (FMR protein). This protein binds to mRNA and regulates synaptic communication and neural network connectivity.[10,11] Intriguingly, the pathophysiology of FXS can be reversed by the addition of a second mutation that restores translational homeostasis.[12]

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