Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Department of Psychology, University of Alberta, Edmonton, Alberta T6G 2E9, Canada.
Neurobiol Learn Mem. 2020 Feb;168:107151. doi: 10.1016/j.nlm.2019.107151. Epub 2019 Dec 24.
The process of memory consolidation is energy-demanding and brain energy deficits result in memory impairments. Indeed, L-lactate, a preferred neuronal energy substrate, enhances the formation of memory, while blockade of the neuronal uptake of L-lactate by either pharmacological means or using its enantiomer D-lactate, impairs memory. Beyond metabolism, both enantiomers of lactate also have signaling properties through the hydroxycarboxylic acid receptor 1 (HCAR1). Thus far, paradigms testing for an effect of lactate on memory modulation have ignored HCAR1 signaling while also mainly performing manipulations before learning and using intracranial administration techniques. Using an inhibitory avoidance (IA) memory protocol, the present study examined the effects of systemic administration of both L- and D-lactate as well as the specific HCAR1 agonist 3,5-dihydroxybenzoic acid (3,5-DHBA) across pre- and post-training periods. We found that post-training subcutaneous injections of either 3,5-DHBA or D-lactate significantly enhanced memory compared to saline controls, whereas L-lactate had no effect, suggesting that HCAR1 signaling in the absence of lactate metabolism supports memory consolidation processes. When administered 15 minutes prior to training, D-lactate and 3,5-DHBA impaired memory compared to saline controls. In contrast, L-lactate treated rats showed memory enhancements as compared to D-lactate-treated rats. Taken together, these results suggest different roles for lactate at different memory stages. It is likely that a metabolic role is at play during learning while HCAR1 signaling may play a greater role during consolidation.
记忆巩固的过程需要消耗能量,而大脑能量不足会导致记忆损伤。事实上,L-乳酸作为首选的神经元能量底物,可增强记忆的形成,而通过药理学手段或使用其对映体 D-乳酸阻断神经元对 L-乳酸的摄取,则会损害记忆。除了代谢作用之外,两种乳酸对映体还通过羟羧酸受体 1(HCAR1)具有信号转导特性。迄今为止,测试乳酸对记忆调节影响的范式忽略了 HCAR1 信号,同时主要在学习之前进行操作,并使用颅内给药技术。本研究使用抑制回避(IA)记忆协议,在训练前后的不同时期系统给予 L-和 D-乳酸以及特定的 HCAR1 激动剂 3,5-二羟基苯甲酸(3,5-DHBA),考察了它们对记忆的影响。结果发现,与盐水对照组相比,训练后皮下注射 3,5-DHBA 或 D-乳酸均可显著增强记忆,而 L-乳酸则没有作用,这表明在没有乳酸代谢的情况下,HCAR1 信号支持记忆巩固过程。当在训练前 15 分钟给药时,D-乳酸和 3,5-DHBA 与盐水对照组相比,会损害记忆。相比之下,与 D-乳酸处理的大鼠相比,L-乳酸处理的大鼠表现出记忆增强。总的来说,这些结果表明乳酸在不同的记忆阶段发挥不同的作用。在学习过程中,可能是代谢作用在起作用,而在巩固过程中,HCAR1 信号可能发挥更大的作用。