title: Dissociable deficits of executive function caused by gestational adversity are linked to specific transcriptional changes in the prefrontal cortex.
abstract: Poor-quality maternal diet during pregnancy, and subsequent gestational growth disturbances in the offspring, have been implicated in the etiology of multiple neurodevelopmental disorders, including ADHD, schizophrenia, and autism. These disorders are characterized, in part, by abnormalities in responses to reward and errors of executive function. Here, we demonstrate dissociable deficits in reward processing and executive function in male and female mice, solely due to maternal malnutrition via high-fat or low-protein diets. Gestational exposure to a high-fat diet delayed acquisition of a fixed ratio response, and decreased motivation as assessed by progressive ratio. In contrast, offspring of a low-protein diet displayed no deficits in operant learning, but were more prone to assign salience to a cue that predicts reward (sign-tracking) in a Pavlovian-conditioned approach task. In the 5-choice serial reaction time task (5-CSRTT), gestational exposure to a high-fat diet promoted impulsivity, whereas exposure to a low-protein diet led to marked inattention. These dissociable executive function deficits are known to be mediated by the medial prefrontal cortex (PFC), which displays markers of epigenetic dysregulation in neurodevelopmental disorders. Following behavioral characterization, we assayed PFC gene expression using a targeted PCR array and found that both maternal diets increased overall transcription in PFC. Cluster analysis of the relationships between individual transcripts and behavioral outcomes revealed a cluster of primarily epigenetic modulators, whose overexpression was linked to executive function deficits. The overexpression of four genes, DNA methyltransferase 1 (DNMT1), δ-opioid receptor (OPRD1), cannabinoid receptor 1 (CNR1), and catechol-o-methyltransferase (COMT), was strongly associated with overall poor performance. All 5-CSRTT deficits were associated with DNMT1 upregulation, whereas impulsive behavior could be dissociated from inattention by overexpression of OPRD1 or COMT, respectively, as well as a distinct cluster of epigenetic regulators. These data provide molecular support for dissociable domains of executive function.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10-131 Smilow Center for Translational Research, Philadelphia, PA, USA.
authors.forename: Nicola M
authors.initials: NM
authors.lastname: Grissom
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10-131 Smilow Center for Translational Research, Philadelphia, PA, USA.
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Herdt
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10-131 Smilow Center for Translational Research, Philadelphia, PA, USA.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Desilets
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10-131 Smilow Center for Translational Research, Philadelphia, PA, USA.
authors.forename: Jordan
authors.initials: J
authors.lastname: Lidsky-Everson
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 10-131 Smilow Center for Translational Research, Philadelphia, PA, USA.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Reyes
mesh_terms: D000818:Animals; D002394:Catechol O-Methyltransferase / Q000235:genetics / Q000378:metabolism; D003214:Conditioning, Classical / Q000502:physiology; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D018753:Diet, Protein-Restricted / Q000009:adverse effects*; D056344:Executive Function / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D007175:Impulsive Behavior / Q000502:physiology; D008297:Male; D039382:Maternal Nutritional Physiological Phenomena / Q000502:physiology*; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009042:Motivation / Q000502:physiology; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000378:metabolism*; D011597:Psychomotor Performance / Q000502:physiology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000235:genetics / Q000378:metabolism; D012201:Reward
chemical_list: C578453:CNR1 protein, mouse; C470381:DOR-1 protein, mouse; D043884:Receptor, Cannabinoid, CB1; D017465:Receptors, Opioid, delta; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619381:Dnmt1 protein, mouse; C000593198:COMT protein, mouse; D002394:Catechol O-Methyltransferase