Zhao W Q, Alkon D L
Blanchette Rockefeller Neurosciences Institute, 9601 Medical Center Drive, Johns Hopkins University, Academic & Research Building, 3rd Floor, Rockville, MD 20858, USA.
Mol Cell Endocrinol. 2001 May 25;177(1-2):125-34. doi: 10.1016/s0303-7207(01)00455-5.
As one of the most extensively studied protein hormones, insulin and its receptor have been known to play key roles in a variety of important biological functions. Until recent years, the functions of insulin and insulin receptor (IR) in the central nervous system (CNS) have largely remained unclear. IR is abundantly expressed in several specific brain regions that govern fundamental behaviors such as food intake, reproduction and high cognition. The IR from the periphery and CNS exhibit differences in both structure and function. In addition to that from the peripheral system, locally synthesized insulin in the brain has also been identified. Accumulated evidence has demonstrated that insulin/IR plays important roles in associative learning, as suggested by results from both interventive and correlative studies. Interruption of insulin production and IR activity causes deficits in learning and memory formation. Abnormal insulin/IR levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients. The synaptic bases for the action of insulin/IR include modifying neurotransmitter release processes at various types of presynaptic terminals and modulating the activities of both excitatory and inhibitory postsynaptic receptors such as NMDA and GABA receptors, respectively. At the molecular level, insulin/IR participates in regulation of learning and memory via activation of specific signaling pathways, one of which is shown to be associated with the formation of long-term memory and is composed of intracellular molecules including the shc, Grb-r/SOS, Ras/Raf, and MEK/MAP kinases. Cross-talk with another IR pathway involving IRS1, PI3 kinase, and protein kinase C, as well as with the non-receptor tyrosine kinase pp60c-src, may also be associated with memory processing.
作为研究最为广泛的蛋白质激素之一，胰岛素及其受体在多种重要生物学功能中发挥着关键作用。直到近年来，胰岛素和胰岛素受体（IR）在中枢神经系统（CNS）中的功能在很大程度上仍不明确。IR在几个特定的脑区大量表达，这些脑区控制着诸如食物摄入、生殖和高级认知等基本行为。外周和中枢神经系统的IR在结构和功能上均表现出差异。除了外周系统的IR外，脑内局部合成的胰岛素也已被鉴定出来。越来越多的证据表明，胰岛素/IR在联想学习中发挥重要作用，干预性研究和相关性研究的结果均表明了这一点。胰岛素产生和IR活性的中断会导致学习和记忆形成方面的缺陷。在阿尔茨海默病痴呆患者中可观察到胰岛素/IR水平和活性异常，而给予胰岛素可显著改善这些患者的认知表现。胰岛素/IR作用的突触基础包括在各种类型的突触前终末改变神经递质释放过程，以及分别调节兴奋性和抑制性突触后受体如NMDA和GABA受体的活性。在分子水平上，胰岛素/IR通过激活特定的信号通路参与学习和记忆的调节，其中一条信号通路被证明与长期记忆的形成有关，它由包括shc、Grb-r/SOS、Ras/Raf和MEK/MAP激酶在内的细胞内分子组成。与另一条涉及IRS1、PI3激酶和蛋白激酶C的IR信号通路以及与非受体酪氨酸激酶pp60c-src的相互作用，也可能与记忆加工有关。
