Ménard Caroline, Gaudreau Pierrette, Quirion Rémi
Douglas Mental Health University Institute, McGill University, Perry Pavilion, 6875 LaSalle Boulevard, Montreal, QC, Canada, H4H 1R3.
Handb Exp Pharmacol. 2015;228:59-98. doi: 10.1007/978-3-319-16522-6_3.
Aging is generally associated with a certain cognitive decline. However, individual differences exist. While age-related memory deficits can be observed in humans and rodents in the absence of pathological conditions, some individuals maintain intact cognitive functions up to an advanced age. The mechanisms underlying learning and memory processes involve the recruitment of multiple signaling pathways and gene expression, leading to adaptative neuronal plasticity and long-lasting changes in brain circuitry. This chapter summarizes the current understanding of how these signaling cascades could be modulated by cognition-enhancing agents favoring memory formation and successful aging. It focuses on data obtained in rodents, particularly in the rat as it is the most common animal model studied in this field. First, we will discuss the role of the excitatory neurotransmitter glutamate and its receptors, downstream signaling effectors [e.g., calcium/calmodulin-dependent protein kinase II (CaMKII), protein kinase C (PKC), extracellular signal-regulated kinases (ERK), mammalian target of rapamycin (mTOR), cAMP response element-binding protein (CREB)], associated immediate early gene (e.g., Homer 1a, Arc and Zif268), and growth factors [insulin-like growth factors (IGFs) and brain-derived neurotrophic factor (BDNF)] in synaptic plasticity and memory formation. Second, the impact of the cholinergic system and related modulators on memory will be briefly reviewed. Finally, since dynorphin neuropeptides have recently been associated with memory impairments in aging, it is proposed as an attractive target to develop novel cognition-enhancing agents.
衰老通常与一定程度的认知衰退相关。然而，个体差异是存在的。虽然在无病理状况下，人类和啮齿动物中均可观察到与年龄相关的记忆缺陷，但一些个体直至高龄仍保持完好的认知功能。学习和记忆过程的潜在机制涉及多种信号通路的募集和基因表达，从而导致适应性神经元可塑性以及脑回路的持久变化。本章总结了目前对于这些信号级联如何被促进记忆形成和成功衰老的认知增强剂所调节的理解。它聚焦于在啮齿动物中获得的数据，尤其是大鼠，因为它是该领域研究最常用的动物模型。首先，我们将讨论兴奋性神经递质谷氨酸及其受体、下游信号效应器[如钙/钙调蛋白依赖性蛋白激酶II（CaMKII）、蛋白激酶C（PKC）、细胞外信号调节激酶（ERK）、雷帕霉素靶蛋白（mTOR）、cAMP反应元件结合蛋白（CREB）]、相关的即早基因（如Homer 1a、Arc和Zif268）以及生长因子[胰岛素样生长因子（IGFs）和脑源性神经营养因子（BDNF）]在突触可塑性和记忆形成中的作用。其次，将简要回顾胆碱能系统及相关调节剂对记忆的影响。最后，由于强啡肽神经肽最近被认为与衰老中的记忆损伤有关，它被提议作为开发新型认知增强剂的一个有吸引力的靶点。
