Hernandez Abbi R, Barrett Maya E, Lubke Katelyn N, Maurer Andrew P, Burke Sara N
bioRxiv. 2023 Feb 19:2023.02.18.529095. doi: 10.1101/2023.02.18.529095.
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 brain’s 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 and 1a 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.
This 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 and 1a 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.
与年龄相关的认知衰退与前额叶皮质（PL）和海马体CA3亚区不同的细胞功能障碍模式有关。由于更高的认知功能需要这两个结构，选择性地针对一个区域的神经生物学变化而牺牲另一个区域，不太可能恢复老年动物的正常行为。然而，PL和CA3随着年龄增长共同出现的一个变化是利用葡萄糖的能力下降，这会产生异常的神经活动模式。当前的研究采用生酮饮食（KD）干预，这种干预可减少大脑对葡萄糖的依赖，并且已被证明能改善认知，作为一种代谢疗法来恢复老年大鼠的神经集合动力学。立即早期基因和1a的表达被用于量化在行为前、工作记忆/双条件联想任务期间以及连续空间交替任务期间在饲养笼中活跃的神经集合。与年轻动物相比，对照饮食的老年大鼠在CA3中的活动增加，并且在不同任务条件下PL中的集合重叠较少。在PL中，KD与皮质浅层神经元的激活增加有关。KD并未导致CA3活动的任何显著变化。这些观察结果表明，KD并不能恢复老年动物的神经元激活模式，而是额叶皮质中酮体的可用性可能允许参与产生更好认知结果的代偿机制。
本研究扩展了对生酮饮食（KD）干预如何改善老年人认知功能的理解。给年轻和老年大鼠喂食3个月的KD或热量匹配的对照饮食，然后测量立即早期基因和1a的表达，以检查认知测试期间的神经集合动力学。KD饮食与PL浅层神经元的激活增加有关，但CA3没有变化。这些观察结果很重要，因为它们表明在酮体升高的情况下会参与改善认知的代偿机制。当葡萄糖利用受损时，这种从糖酵解的代谢转变可以满足额叶皮质的能量需求。
