Hernandez Abbi R, Hernandez Caesar M, Truckenbrod Leah M, Campos Keila T, McQuail Joseph A, Bizon Jennifer L, Burke Sara N
Department of Neurosciences, University of Florida, Gainesville, FL, United States.
Department of Physiology, Pharmacology and Neuroscience, University of South Carolina School of Medicine, Columbia, SC, United States.
Front Aging Neurosci. 2019 Sep 13;11:239. doi: 10.3389/fnagi.2019.00239. eCollection 2019.
As the number of individuals living beyond the age of 65 is rapidly increasing, so is the need to develop strategies to combat the age-related cognitive decline that may threaten independent living. Although the link between altered neuronal signaling and age-related cognitive impairments is not completely understood, it is evident that declining cognitive abilities are at least partially due to synaptic dysfunction. Aging is accompanied by well-documented changes in both excitatory and inhibitory synaptic signaling across species. Age-related synaptic alterations are not uniform across the brain, however, with different regions showing unique patterns of vulnerability in advanced age. In the hippocampus, increased activity within the CA3 subregion has been observed across species, and this can be reversed with anti-epileptic medication. In contrast to CA3, the dentate gyrus shows reduced activity with age and declining metabolic activity. Ketogenic diets have been shown to decrease seizure incidence and severity in epilepsy, improve metabolic function in diabetes type II, and improve cognitive function in aged rats. This link between neuronal activity and metabolism suggests that metabolic interventions may be able to ameliorate synaptic signaling deficits accompanying advanced age. We therefore investigated the ability of a dietary regimen capable of inducing nutritional ketosis and improving cognition to alter synapse-related gene expression across the dentate gyrus, CA3 and CA1 subregions of the hippocampus. Following 12 weeks of a ketogenic or calorie-matched standard diet, RTq-PCR was used to quantify expression levels of excitatory and inhibitory synaptic signaling genes within CA1, CA3 and dentate gyrus. While there were no age or diet-related changes in CA1 gene expression, expression levels were significantly altered within CA3 by age and within the dentate gyrus by diet for several genes involved in presynaptic glutamate regulation and postsynaptic excitation and plasticity. These data demonstrate subregion-specific alterations in synaptic signaling with age and the potential for a ketogenic diet to alter these processes in dissociable ways across different brain structures that are uniquely vulnerable in older animals.
随着65岁以上人口数量的迅速增加，开发应对可能威胁独立生活的与年龄相关的认知衰退的策略的需求也在增加。尽管神经元信号改变与年龄相关的认知障碍之间的联系尚未完全明确，但很明显认知能力下降至少部分归因于突触功能障碍。衰老伴随着物种间兴奋性和抑制性突触信号传导方面有充分记录的变化。然而，与年龄相关的突触改变在整个大脑中并不一致，不同区域在老年时表现出独特的易损模式。在海马体中，已观察到跨物种CA3子区域内的活动增加，并且这可以通过抗癫痫药物逆转。与CA3相反，齿状回随着年龄增长活动减少且代谢活性下降。生酮饮食已被证明可降低癫痫发作的发生率和严重程度，改善II型糖尿病的代谢功能，并改善老年大鼠的认知功能。神经元活动与代谢之间的这种联系表明，代谢干预可能能够改善伴随衰老出现的突触信号缺陷。因此，我们研究了一种能够诱导营养性酮症并改善认知的饮食方案改变海马体齿状回、CA3和CA1子区域中与突触相关基因表达的能力。在进行12周的生酮或热量匹配的标准饮食后，使用RTq-PCR定量CA1、CA3和齿状回内兴奋性和抑制性突触信号基因的表达水平。虽然CA1基因表达没有与年龄或饮食相关的变化，但对于参与突触前谷氨酸调节以及突触后兴奋和可塑性的几个基因，CA3内的表达水平因年龄而显著改变，齿状回内的表达水平因饮食而显著改变。这些数据表明，随着年龄增长，突触信号存在区域特异性改变，并且生酮饮食有可能以不同方式改变不同脑结构中这些过程，而这些脑结构在老年动物中具有独特的易损性。
