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), d-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.

DNA Methylation Signatures of Early Childhood Malnutrition Associated With Impairments in Attention and Cognition

“…These findings significantly extend previous work reporting epigenetic dysregulation after prenatal malnutrition(36, 40–42). Given that DNA and histone methylation landscapes show highly dynamic developmental regulation of neuronal and to some extent also non-neuronal chromatin of human cerebral cortex during infancy and early childhood(43–47), the blood DNA methylation changes as reported here could reflect on epigenetic maladaptations in brain, in analogy to epigenetic changes in the brain and behavioral dysregulation in response to early life adversity(48, 49).…”

Developmental programming by maternal obesity in 2015: Outcomes, mechanisms, and potential interventions

“…The programmed increases in preference for fat and sugar and altered motivation to work for such foods are associated with changes in dopaminergic tone (Naef et al, 2011(Naef et al, , 2013 as well as in expression of key dopaminergic and opioidergic signalling genes (Naef et al, 2011;Ong and Muhlhausler, 2011;Vucetic et al, 2010), with evidence for epigenetic regulation at some loci (Grissom et al, 2014a;Vucetic et al, 2010). In fact, maternal obesity at conception is sufficient to program opioid dysregulation in the offspring (Grissom et al, 2014c). Therefore, maternal obesity may predispose the offspring to DIO via programmed changes in the mesocorticolimbic reward pathway.…”

Long-term consequences of obesity on female fertility and the health of the offspring

“…Interestingly, paternal overweight/obesity was not associated with infant cognitive development. In rodent models, leptin induces excitatory synaptogenesis and promotes dendritic spine formation in the hippocampus, which mediates learning and task functions [84]. In rodent models, leptin induces excitatory synaptogenesis and promotes dendritic spine formation in the hippocampus, which mediates learning and task functions [85].…”