A long-term ketogenic diet in young and aged rats has dissociable effects on prelimbic cortex and CA3 ensemble activity

Abstract

Age-related cognitive decline has been linked to distinct patterns of cellular dysfunction in the prelimbic cortex (PL) and the CA3 subregion of the hippocampus. Because higher cognitive functions require both structures, selectively targeting a neurobiological change in one region, at the expense of the other, is not likely to restore normal behavior in older animals. One change with age that both the PL and CA3 share, however, is a reduced ability to utilize glucose, which can produce aberrant neural activity patterns. The current study used a ketogenic diet (KD) intervention, which reduces the brains reliance on glucose, and has been shown to improve cognition, as a metabolic treatment for restoring neural ensemble dynamics in aged rats. Expression of the immediate-early genes Arc and Homer1a were used to quantify the neural ensembles that were active in the home cage prior to behavior, during a working memory/biconditional association task, and a continuous spatial alternation task. Aged rats on the control diet had increased activity in CA3 and less ensemble overlap in PL between different task conditions than did the young animals. In the PL, the KD was associated with increased activation of neurons in the superficial cortical layers. The KD did not lead to any significant changes in CA3 activity. These observations suggest that the KD does not restore neuron activation patterns in aged animals, but rather the availability of ketone bodies in the frontal cortices may permit the engagement of compensatory mechanisms that produce better cognitive outcomes. Significance StatementThis study extends understanding of how a ketogenic diet (KD) intervention may improve cognitive function in older adults. Young and aged rats were given 3 months of a KD or a calorie-match control diet and then expression of the immediate-early genes Arc and Homer1a were measured to examine neural ensemble dynamics during cognitive testing. The KD diet was associated with increased activation of neurons in the superficial layers of the PL, but there were no changes in CA3. These observations are significant because they suggest that compensatory mechanisms for improving cognition are engaged in the presence of elevated ketone bodies. This metabolic shift away from glycolysis can meet the energetic needs of the frontal cortices when glucose utilization is compromised.