Prenatal Protein Malnutrition in Rats Alters the c-Fos Response of Neurons in the Anterior Cingulate and Medial Prefrontal Region to Behavioral Stress
ABSTRACT Prenatal protein malnutrition affects brain development and behavior despite dietary rehabilitation from birth. Behavioral alterations include abnormal responses to stressors. To explore what brain regions mediate this altered response, we used immunocytochemistry to c-Fos protein, a transcription factor marking neuronal activation. Controls (25% casein diet) and prenatally malnourished (6% casein) adult rats were subjected to 20min of restraint stress or were unstressed. Plasma corticosterone levels were monitored before and after stress. Paired comparisons of corticosterone levels confirmed that both groups showed a significant post-stress increase. Three hours after onset of stress, rats were perfused with paraformaldehyde. Brain sections were immuno-stained together for c-Fos. Since anterior cingulate and medial prefrontal cortex modulate stress responses, labeled neurons in this region were quantified using unbiased stereology. A 2-way ANOVA of neuron numbers demonstrated a strong effect of stress and a stress by nutrition interaction. Post-hoc comparisons showed that stress significantly increased the number of c-Fos labeled neurons in both nutrition groups. Within the stress condition, prenatally malnourished rats showed a significantly greater number of c-Fos positive neurons than well-nourished rats. These results suggest that neurons in anterior cingulate and medial prefrontal regions respond excessively to restraint stress in prenatally malnourished rats.
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ABSTRACT: Globally, over 25% of all children under the age of 5 years experience malnutrition leading to cognitive and emotional impairments that can persist into adulthood and beyond. We use a rodent model to determine the impact of prenatal protein malnutrition on executive functions in an attentional set-shifting task and metabolic activity in prefrontal cortex (PFC) subregions critical to these behaviors. Long-Evans dams were provided with a low (6% casein) or adequate (25% casein) protein diet 5 weeks before mating and during pregnancy. At birth, the litters were culled to 8 pups and fostered to control dams on the 25% casein diet. At postnatal day 90, prenatally malnourished rats were less able to shift attentional set and reverse reward contingencies than controls, demonstrating cognitive rigidity. Naive same-sexed littermates were assessed for regional brain activity using the metabolic marker (14)C-2-deoxyglucose (2DG). The prenatally malnourished rats had lower metabolic activity than controls in prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices, but had comparable activity in the nearby piriform cortex and superior colliculus. This study demonstrates that prenatal protein malnutrition in a well-described animal model produces cognitive deficits in tests of attentional set shifting and reversal learning, similar to findings of cognitive inflexibility reported in humans exposed to early childhood malnutrition. © 2014 S. Karger AG, Basel.Developmental Neuroscience 10/2014; 36(6). DOI:10.1159/000366057 · 2.45 Impact Factor
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ABSTRACT: Objective: To compare neuropsychological profiles of adults who had experienced an episode of moderate to severe protein-energy malnutrition confined to the first year of life with that of a healthy community comparison group. Method: We assessed neuropsychological functioning in a cohort of Barbadian adults, all of whom had birth weight >2268 g. The previously malnourished group (N = 77, mean age = 38 years, 53% male) had been hospitalized during the first year of life for moderate to severe protein energy malnutrition and subsequently enrolled in a program providing nutrition education, home visits and subsidized foods to 12 years of age. They also had documented, adequate nutrition throughout childhood and complete catch-up in growth by the end of adolescence. The healthy comparison group (N = 59, mean age = 38 years, 54% male) were recruited as children from the same classrooms and neighborhoods. Results: Adjusted for effects of standard of living during childhood and adolescence and current intellectual ability level, there were nutrition group differences on measures of cognitive flexibility and concept formation, as well as initiation, verbal fluency, working memory, processing speed, and visuospatial integration. Behavioral and cognitive regulation were not affected. Conclusions: Postnatal malnutrition confined to the first year of life is associated with neurocognitive compromise persisting into midlife. Early malnutrition may have a specific neuropsychological signature, affecting response initiation to a somewhat greater extent than response inhibition. (PsycINFO Database Record (c) 2014 APA, all rights reserved).Neuropsychology 03/2014; 28(4). DOI:10.1037/neu0000058 · 3.43 Impact Factor
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ABSTRACT: Prenatal protein malnutrition (PPM) in rats causes enduring changes in brain and behavior including increased cognitive rigidity and decreased inhibitory control. A preliminary gene microarray screen of PPM rat prefrontal cortex (PFC) identified alterations in KCNJ3 (GIRK1/Kir3.1), a gene important for regulating neuronal excitability. Follow-up with polymerase chain reaction and Western blot showed decreased KCNJ3 expression in the PFC, but not hippocampus or brainstem. To verify localization of the effect to the PFC, baseline regional brain activity was assessed with (14)C-2-deoxyglucose. Results showed decreased activation in the PFC but not hippocampus. Together these findings point to the unique vulnerability of the PFC to the nutritional insult during early brain development, with enduring effects in adulthood on KCNJ3 expression and baseline metabolic activity. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.Neuroscience 11/2014; 286. DOI:10.1016/j.neuroscience.2014.11.005 · 3.33 Impact Factor