Prenatal Malnutrition Leads to Deficits in Attentional Set Shifting and Decreases Metabolic Activity in Prefrontal Subregions that Control Executive Function

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 ¹⁴C-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.

Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex

“…In our group, we have recently reported that PPM rats display cognitive rigidity in tests of attentional set shifting and reversal learning. Same-sex littermates had decreased 2DG uptake in PFC regions critical to these forms of cognitive control (McGaughy et al, 2014). These data support the hypothesis that PPM may selectively diminish activity in the PFC, which then leads to impairments in executive function.…”

“…In the prefrontal cortex (PFC), PPM leads to alterations in neurotransmitter release (Mokler et al, 2007) and in immediate early gene activation in response to stress (Rosene et al, 2004). Behaviorally, PPM rats have decreased inhibitory control and are more cognitively rigid, two behavioral domains that critically depend on PFC circuitry (McGaughy et al, 2014). …”

Neuropsychological outcomes at midlife following moderate to severe malnutrition in infancy.

“…One longitudinal study reported, however, that by 90 days after admission for rehabilitation, the cerebral “shrinkage” was largely reversed, suggesting recovery (Gunston, Burkimsher, Malan, & Sive, 1992). In the rodent models, however, malnutrition can lead to microstructural and neurochemical changes that are not reversed by nutritional rehabilitation (Galler, et al, 1996; Levitsky & Strupp, 1995; McGaughy, et al, 2013; Mokler, et al, 2003; Morgane, et al, 1993), thought to signal impaired synaptic plasticity and responsiveness. Although such changes would not be detected by clinical MRI, neuropathological analysis of the brains of infants who died of malnutrition has in fact documented alterations in dendritic structure (Benítez-Bribiesca, De la Rosa-Alvarez, & Mansilla-Olivares, 1999).…”

“…Although these effects can be partially mitigated by nutritional rehabilitation, the brains of rehabilitated animals show persistent structural, microstructural, and neurochemical changes (Feoli, et al, 2008; Levitsky & Strupp, 1995; Mokler, Galler, & Morgane, 2003; Mokler, Torres, Galler, & Morgane, 2007; Morgane, et al, 1993; Morgane, et al, 2002). Previously malnourished animals also demonstrate long-term changes in cognition and emotionality, with behavioral rigidity a key outcome (Levitsky & Strupp, 1995; McGaughy, et al, 2013; Strupp & Levitsky, 1995; Tonkiss & Galler, 1990). …”

Effects of Metabolic Programming on Juvenile Play Behavior and Gene Expression in the Prefrontal Cortex of Rats

“…Juvenile macaques that were maintained on a low-cholesterol diet after weaning exhibited an increased desire for solidarity and an increased propensity for aggressive behavior when compared to those fed a high-cholesterol diet, which was directly associated with serotonin levels [53]. In addition to the reported changes in the serotonergic system [53], other studies with rats have found that protein malnourishment led to cognitive inflexibility [55] and disrupted the GABA-benzodiazepine system, increasing impulsiveness and decreasing anxiety [56]. This study did not explore neurotransmitter function, but alterations in impulsivity and anxiety could contribute to the dysfunctional play observed in many of our groups.…”