Diminished Myoinositol in Ventromedial Prefrontal Cortex Modulates the Endophenotype of Impulsivity

Autor: Trevor W. Robbins, Steve J. Sawiak, Rebecca L Barlow, Anton Pekcec, Suzanne Lemstra, Bianca Jupp, Chiara Toschi, Bastiaan van der Veen, Jeffrey W. Dalley, Tom Bretschneider, Janet R. Nicholson
Přispěvatelé: Sawiak, Stephen [0000-0003-4210-9816], Robbins, Trevor [0000-0003-0642-5977], Dalley, Jeffrey [0000-0002-2282-3660], Apollo - University of Cambridge Repository
Rok vydání: 2020
Předmět:
Male
Endophenotypes
Proton Magnetic Resonance Spectroscopy
Cognitive Neuroscience
medicine.medical_treatment
inositol-triphosphate (IP3)
Ventromedial prefrontal cortex
Prefrontal Cortex
Striatum
Impulsivity
03 medical and health sciences
Cellular and Molecular Neuroscience
0302 clinical medicine
attention-deficit hyperactivity disorder
Cortex (anatomy)
medicine
Animals
Attention deficit hyperactivity disorder
Attention
Intramolecular Lyases
Prefrontal cortex
030304 developmental biology
0303 health sciences
Symporters
business.industry
inositol monophosphatase 1 (IMPA1)
Membrane Proteins
CDP-Diacylglycerol-Inositol 3-Phosphatidyltransferase
medicine.disease
magnetic resonance spectroscopy
Phosphoric Monoester Hydrolases
Rats
Stimulant
medicine.anatomical_structure
Gene Knockdown Techniques
Endophenotype
Impulsive Behavior
Original Article
medicine.symptom
business
Neuroscience
Inositol
030217 neurology & neurosurgery
Zdroj: Cereb Cortex
ISSN: 1460-2199
1047-3211
DOI: 10.1093/cercor/bhz317
Popis: 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 localized 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 nonimpulsive 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 comorbid with impulsive symptomology.
Databáze: OpenAIRE
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