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Cited by 39Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on Behavior

Functional Magnetic Resonance Imaging in Awake Transgenic Fragile X Rats: Evidence of Dysregulation in Reward Processing in the Mesolimbic/Habenular Neural Circuit

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Kenkel, W M, Yee, J R, Moore, K, Madularu, D, Kulkarni, P, Gamber, K, Nedelman, M, Ferris, C F·2016·Translational Psychiatry
DOI 10.1038/tp.2016.15PMC PMC4872441
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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.

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  • The Fmr1-Δexon 8 rat model is not a null KO of Fmr1; the induced mutation results in a gene product with a loss of exon 8, which encodes the KH1 domain responsible for RNA-binding.

    “Recently, it has been shown that this model is not a null KO of Fmr1, but instead, the induced mutation results in a gene product with a loss of exon 8, which encodes a domain responsible for RNA-binding, named KH1 domain [33].”

    From Brain Cholesterol Biosynthetic Pathway Is Altered in a Preclinical Model of Fragile X Syndrome (2022) · cites this paper as [33]

    The Introduction says that the fmr1-tm1Cgr mouse is not a complete molecular null, but it does not make that statement about the rat model. Searches for exon 8, KH1, and a non-null Fmr1 rat gene product found no passage addressing the claimed mutation or its RNA-binding domain. (LLM, conf=0.75)

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Authors
Kenkel, W. M., Yee, J. R., Moore, K., Madularu, D., Kulkarni, P., Gamber, K., Nedelman, M., & Ferris, C. F.
Affiliations
  • Indiana University Bloomington (US)
  • Northeastern University (US)
  • Douglas Mental Health University Institute (CA)
Corresponding author
Ferris, C F
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2016-03-22
Volume
6
Issue
3
Pages
e763-e763
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2016.15
PMC
PMC4872441
OpenAlex
W2306100596
Cited by
39
References
10
Citations by year
2026: 1 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 5 · 2021: 2 · 2020: 6 · 2019: 4 · 2018: 6 · 2017: 3 · 2016: 1
FWCI
3.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
fragile X syndrome, reward processing, Papez circuit, odor preference, social odors, BOLD signal, accumbens, retrosplenial cortex, lateral preoptic area, social dysfunction, anxiety
MeSH terms
Animals, Brain, Fragile X Syndrome, Hypothalamus, Magnetic Resonance Imaging, Male, Neural Pathways, Nucleus Accumbens, Reward, Substantia Nigra, Wakefulness, Rats, Sprague-Dawley, Ventral Tegmental Area, Habenula, Animals, Genetically Modified, Rats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1, Functional Neuroimaging, Ventral Striatum

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