Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD, USA.
Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD, USA.
Neurobiol Aging. 2020 Jul;91:1-4. doi: 10.1016/j.neurobiolaging.2020.02.019. Epub 2020 Mar 5.
Numerous aging studies have identified a shift in the excitatory/inhibitory (E/I) balance with heightened hippocampal neural activity associated with age-related memory impairment across species, including rats, monkeys, and humans. Neurobiological investigations directed at the hippocampal formation have demonstrated that unimpaired aged rats performing on par with young adult rats in a spatial memory task exhibit gene expression profiles, mechanisms for plasticity, and altered circuit/network function, which are distinct from younger rats. Particularly striking is a convergence of observational evidence that aged unimpaired rats augment recruitment of mechanisms associated with neural inhibition, a finding that may represent an adaptive homeostatic adjustment necessary to maintain neural plasticity and memory function in aging. In this study, we test the effect of limiting inhibition via administration of TB21007, a negative allosteric modulator of the alpha 5 subtype of gamma-aminobutyric acid type A α5 receptor, on a radial arm maze assessment of memory function. Impaired memory performance produced by this intervention in otherwise high-performing aged rats supports an adaptive role for gamma-aminobutyric acid in the functional maintenance of intact cognition in aging.
大量衰老研究已经确定，兴奋性/抑制性（E/I）平衡发生转变，与物种（包括大鼠、猴子和人类）相关的年龄相关性记忆障碍相关的海马神经活动增加。针对海马结构的神经生物学研究表明，在空间记忆任务中表现与年轻成年大鼠相当的未受损老年大鼠表现出基因表达谱、可塑性机制以及改变的回路/网络功能，这些与年轻大鼠不同。特别引人注目的是，观察证据的趋同表明，未受损的老年大鼠增加了与神经抑制相关的机制的募集，这一发现可能代表了维持衰老过程中神经可塑性和记忆功能所必需的适应性平衡调节。在这项研究中，我们通过给予 TB21007（GABAA 型 α5 受体的负变构调节剂）来测试限制抑制的效果，该药物用于评估记忆功能的放射臂迷宫测试。在其他表现出色的老年大鼠中，这种干预措施导致记忆性能受损，支持了γ-氨基丁酸在功能维持完整认知中的适应性作用。
