Prenatal protein malnutrition decreases neuron numbers in the parahippocampal region but not prefrontal cortex in adult rats.

OBJECTIVE: Prenatal protein malnutrition produces anatomical and functional changes in the developing brain that persist despite immediate postnatal nutritional rehabilitation. Brain networks of prenatally malnourished animals show diminished activation of prefrontal areas and an increased activation of hippocampal regions during an attentional task [1]. While a reduction in cell number has been documented in hippocampal subfield CA1, nothing is known about changes in neuron numbers in the prefrontal or parahippocampal cortices. METHODS: In the present study, we used unbiased stereology to investigate the effect of prenatal protein malnutrition on the neuron numbers in the medial prefrontal cortex and the cortices of the parahippocampal region that comprise the larger functional network. RESULTS: Results show that prenatal protein malnutrition does not cause changes in the neuronal population in the medial prefrontal cortex of adult rats, indicating that the decrease in functional activation during attentional tasks is not due to a reduction in the number of neurons. Results also show that prenatal protein malnutrition is associated with a reduction in neuron numbers in specific parahippocampal subregions: the medial entorhinal cortex and presubiculum. DISCUSSION: The affected regions along with CA1 comprise a tightly interconnected circuit, suggesting that prenatal malnutrition confers a vulnerability to specific hippocampal circuits. These findings are consistent with the idea that prenatal protein malnutrition produces a reorganization of structural and functional networks, which may underlie observed alterations in attentional processes and capabilities.

The enduring effect of prenatal protein malnutrition on brain anatomy, physiology and behavior.

There is increasing evidence that the maternal environment exerts enduring influences on the fetal brain. In response to certain environmental stimuli such as reduced protein content, the fetus changes the course of its brain development, which leads to specific and programed changes in brain anatomy and physiology. These alterations produce a brain with a fundamentally altered organization, which then translates to alterations in adult cognitive function. The effects on brain and behavior may be linked, such that a prenatal stimulus relays a signal to alter brain development and encourage the selection and development of brain circuits and behaviors that would be beneficial for the environment in which the animal was anticipated to emerge. At the same time, the signal would deselect behaviors unlikely to be adaptive. We draw on evidence from rodent models to suggest that the brain that develops after a reduction in protein during the prenatal phase is not uniformly dysfunctional, but simply different. This perspective has implications for the role of prenatal factors in the production and expression of behavior, and may account for the elevation of risk factors for neurological and psychiatric illnesses.

The neural basis of attentional alterations in prenatally protein malnourished rats.

Protein malnutrition during gestation alters brain development and produces specific behavioral and cognitive changes that persist into adulthood and increase the risks of neuropsychiatric disorders. Given evidence for the role of the prefrontal cortex in such diseases, it is significant that studies in humans and animal models have shown that prenatal protein malnutrition specifically affects functions associated with prefrontal cortex. However, the neural basis underlying these changes is unclear. In the current study, prenatally malnourished and control rats performed a sustained attention task with an unpredictable distractor, a task that depends on intact prefrontal cortical function. Radiolabeled 2-deoxyglucose was used to measure neural and brain network activity during the task. Results confirmed that adult prenatally malnourished rats were more distractible than controls and exhibited lower functional activity in prefrontal cortices. Thus, prefrontal activity was a predictor of task performance in controls but not prenatally malnourished animals. Instead, prenatally malnourished animals relied on different brain networks involving limbic structures such as the hippocampus. These results provide evidence that protein reduction during brain development has more wide-reaching effects on brain networks than previously appreciated, resulting in the formation of brain networks that may reflect compensatory responses in prenatally malnourished brains.

Prenatal protein level impacts homing behavior in Long-Evans rat pups.

OBJECTIVE: This study assessed the effect of varying prenatal protein levels on the development of homing behavior in rat pups. METHODS: Long-Evans rats were fed one of the four isocaloric diets containing 6% (n = 7 litters), 12% (n = 9), 18% (n = 9), or 25% (n = 10) casein prior to mating and throughout pregnancy. At birth, litters were fostered to well-nourished control mothers fed a 25% casein diet during pregnancy, and an adequate protein diet (25% casein) was provided to weaning. On postnatal days 5, 7, 9, 11, and 13, homing behaviors, including activity levels, rate of successful returns to the nest quadrant and latencies to reach the nest over a 3-minute test period were recorded from two starting positions in the home cage. Adult body and brain weights were obtained at sacrifice (postnatal day 130 or 200). RESULTS: Growth was impaired in pups whose mothers were fed a 6% or, to a lesser extent, a 12% casein diet relative to pups whose mothers were fed the 18 and 25% casein diets. The 6 and 12% prenatal protein levels resulted in lower activity levels, with the greatest reduction on postnatal day 13. However, only the 6% pups had reduced success and higher latencies in reaching the nest quadrant when compared with pups from the three other nutrition groups. Latency in reaching the nest quadrant was significantly and negatively associated with adult brain weight. DISCUSSION: Home orientation is a sensitive measure of developmental deficits associated with variations in prenatal protein levels, including levels of protein deficiency that do not lead to overt growth failure.

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

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.