Diminished Myoinositol in Ventromedial Prefrontal Cortex Modulates the Endophenotype of Impulsivity.
van der Veen, Bastiaan
Barlow, Rebecca L
Nicholson, Janet R
Cerebral cortex (New York, N.Y. : 1991)
Oxford University Press
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Jupp, B., Sawiak, S., van der Veen, B., Lemstra, S., Toschi, C., Barlow, R. L., Pekcec, A., et al. (2020). Diminished Myoinositol in Ventromedial Prefrontal Cortex Modulates the Endophenotype of Impulsivity.. Cerebral cortex (New York, N.Y. : 1991), 30 (5), 3392-3402. https://doi.org/10.1093/cercor/bhz317
Maladaptive impulsivity manifests in a variety of disorders, including attention-deficit/hyperactivity disorder (ADHD), depression and substance use disorder. However, the etiological mechanisms of impulsivity remain poorly understood. In the present study we used in-vivo proton magnetic resonance spectroscopy (1H-MRS) to investigate neurometabolite content in the prefrontal cortex (PFC) and striatum of rats exhibiting low- versus high-impulsive (LI, HI) behavior on a visual attentional task. We validated our 1H-MRS findings using regionally-resolved ex-vivo mass spectroscopy, transcriptomics, and site-directed RNA interference in the ventromedial PFC. We report a significant reduction in myoinositol levels in the PFC but not the striatum of HI rats compared with LI rats. Reduced myoinositol content was localised to the infralimbic (IL) cortex, where significant reductions in transcript levels of key proteins involved in the synthesis and recycling of myoinositol (IMPase1) were also present. Knockdown of IMPase1in the IL cortex increased impulsivity in non-impulsive rats when the demand on inhibitory response control was increased. We conclude that diminished myoinositol levels in ventromedial PFC causally mediate a specific form of impulsivity linked to vulnerability for stimulant addiction in rodents. Myoinositol and related signaling substrates may thus offer novel opportunities for treating neuropsychiatric disorders co-morbid with impulsive symptomology.
MRC Wellcome Trust
Wellcome Trust (093875/Z/10/Z)
MEDICAL RESEARCH COUNCIL (G0001354)
External DOI: https://doi.org/10.1093/cercor/bhz317
This record's URL: https://www.repository.cam.ac.uk/handle/1810/299427
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