A Ketogenic Diet Improves Cognition and Has Biochemical Effects in Prefrontal Cortex That Are Dissociable From Hippocampus

Abstract

Age-related cognitive decline has been linked to a diverse set of neurobiological mechanisms, including bidirectional changes in proteins critical for neuron function. Importantly, these alterations are not uniform across the brain. For example, the hippocampus (HPC) and prefrontal cortex (PFC) show distinct patterns of dysfunction in advanced age. Because higher cognitive functions require large–scale interactions across prefrontal cortical and hippocampal networks, selectively targeting an alteration within one region may not broadly restore function to improve cognition. One mechanism for decline that the PFC and HPC share, however, is a reduced ability to utilize glucose for energy metabolism. Although this suggests that therapeutic strategies bypassing the need for neuronal glycolysis may be beneficial for treating cognitive aging, this approach has not been empirically tested. Thus, the current study used a ketogenic diet (KD) as a global metabolic strategy for improving brain function in young and aged rats. After 12 weeks, rats were trained to perform a spatial alternation task through an asymmetrical maze, in which one arm was closed and the other was open. Both young and aged KD-fed rats showed resilience against the anxiogenic open arm, training to alternation criterion performance faster than control animals. Following alternation testing, rats were trained to perform a cognitive dual task that required working memory while simultaneously performing a bi-conditional association task (WM/BAT), which requires PFC–HPC interactions. All KD-fed rats also demonstrated improved performance on WM/BAT. At the completion of behavioral testing, tissue punches were collected from the PFC for biochemical analysis. KD-fed rats had biochemical alterations within PFC that were dissociable from previous results in the HPC. Specifically, MCT1 and MCT4, which transport ketone bodies, were significantly increased in KD-fed rats compared to controls. GLUT1, which transports glucose across the blood brain barrier, was decreased in KD-fed rats. Contrary to previous observations within the HPC, the vesicular glutamate transporter (VGLUT1) did not change with age or diet within the PFC. The vesicular GABA transporter (VGAT), however, was increased within PFC similar to HPC. These data suggest that KDs could be optimal for enhancing large-scale network function that is critical for higher cognition.

Sex Differences in Age-related Impairments Vary across Cognitive and Physical Assessments in Rats

“…In this study, we have replicated previous data showing that biconditional association tasks are particularly sensitive behavioral assays for detecting age-related cognitive decline relative to the Morris watermaze [20,35]. Furthermore, we observed that both males and females showed similar performance declines across age on the Similarly, we found no differences in spatial memory recall during Morris watermaze testing and, as previously reported in rats of this strain and age, no age differences either [20].…”

“…Thus, the arms of the maze had an asymmetry, such that only the right arm was enclosed while the animals were relatively more exposed on the middle and left arms. This asymmetry biases rats to alternate towards the closed 'safe' arm [35]. To dampen the influence of extraneous noise on behavior, a white noise machine was used during behavioral training and testing.…”

“…Rats were trained on the working memory/biconditional association task (WM/BAT) as previously described [35] for 12 consecutive days using 2 novel objects.…”

Age and ketogenic diet have dissociable effects on synapse-related gene expression between hippocampal subregions

“…Although cerebral glucose metabolism declines with age, the ability to utilize ketone bodies for energy production does not (Castellano et al, 2015;Cunnane et al, 2016;Lying-Tunell et al, 1981;Ogawa et al, 1996). Therefore, the potential to bypass impaired glycolysis through the elevation of ketone body synthesis and promotion of fat oxidation may alter the expression of hippocampal synaptic signaling-related genes (Hernandez et al, 2018a) to ultimately improve cognitive function (Hernandez et al, 2018b).…”

“…Ketogenic diets have been utilized to alter neuronal signaling patterns in patients with epilepsy for almost a century (Freeman et al, 1998). More recent evidence indicates that it can alter both excitatory and inhibitory signaling-related proteins within young and aged brains (Hernandez et al, 2018a(Hernandez et al, , 2018b.…”