The effects of prenatal malnutrition on the brain of adult rats: a study of anatomical, functional and molecular changes
Silva Amaral, Ana Claudia
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Studies using a rat model of prenatal protein malnutrition (PPM) followed by nutritional rehabilitation show that PPM produces changes in the brain and behavior that endure throughout adulthood. Early studies investigated the vulnerability of the hippocampus, a structure involved in learning and memory, and reported permanent anatomical, physiological, and functional alterations. However, PPM also produces deficits in attentional processes, suggesting vulnerability across a broader cortical network including the parahippocampal region (PHR) and the prefrontal cortex (PFC). This thesis investigates the anatomical, functional, and molecular alterations in these regions resulting from PPM. This was accomplished through 4 studies: 1) A quantitative assessment of the number of neurons in the PHR and in the PFC using design-based stereology; 2) An evaluation of the impact of the PPM on metabolic activity in the PFC using the metabolic marker 2-[14C]deoxyglucose (2DG); 3) The identification of specific neuronal subtypes differentially activated during restraint stress in the PPM network using double-labelling immunohistochemistry; 4) The quantification of mRNA and protein expression of KCNJ3 (GIRK1), a potassium channel involved in regulating neural excitability, using quantitative polymerase chain reaction and Western blot analysis. Results showed that: 1) Neuron number in the PFC is unchanged by PPM, but two subfields of the PHR, the presubiculum and medial entorhinal cortex, exhibit significantly lower numbers in PPM rats; 2) Metabolic activity in specific PFC regions associated with attention including the prelimbic, infralimbic, anterior cingulate, and orbitofrontal cortices was reduced relative to controls while other regions, such as the hippocampus, were unaffected; 3) Exposure to stress evokes a significant increase in the number of inhibitory interneurons that are activated in the PFC of PPM rats which could likely contribute to the observed overall reduction in PFC activity; 4) For the KCNJ3 channel, PPM induces lower levels of mRNA and protein expression in the PFC while levels in the hippocampus and brain stem/basal ganglia are unchanged. Together, these data show that PPM creates permanent anatomical, functional, and molecular alterations selective to specific subfields, cell types, and molecules leading to an imbalance between excitatory and inhibitory processes in the PHR-PFC network of adult rats.