Insulin and the insulin receptor in experimental models of learning and memory

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Abstract

Insulin is best known for its action on peripheral insulin target tissues such as the adipocyte, muscle and liver to regulate glucose homeostasis. In the central nervous system (CNS), insulin and the insulin receptor are found in specific brain regions where they show evidence of participation in a variety of region-specific functions through mechanisms that are different from its direct glucose regulation in the periphery. While the insulin/insulin receptor associated with the hypothalamus plays important roles in regulation of the body energy homeostasis, the hippocampus- and cerebral cortex-distributed insulin/insulin receptor has been shown to be involved in brain cognitive functions. Emerging evidence has suggested that insulin signaling plays a role in synaptic plasticity by modulating activities of excitatory and inhibitory receptors such as glutamate and GABA receptors, and by triggering signal transduction cascades leading to alteration of gene expression that is required for long-term memory consolidation. Furthermore, deterioration of insulin receptor signaling appears to be associated with aging-related brain degeneration such as the Alzheimer's dementia and cognitive impairment in aged subjects suffering type 2 diabetes mellitus.

Introduction

The presence of insulin and insulin receptors in the brain suggests that the brain is a target organ for insulin. However, unlike the classic peripheral insulin target tissues such as adipocyte, muscle and liver, where the primary function of insulin is to regulate glucose homeostasis, insulin in the central nervous system (CNS) exhibits more diverse actions, most of which have not been clearly understood. In addition to its central role in food intake and weight control, a direct role of CNS insulin/insulin receptor signaling in improving cognitive functions, including learning and memory, and the association of insulin receptor deterioration with brain degenerative dementia (e.g., Alzheimer's disease) have attracted increasing interest. Although still at an early stage, efforts in behavioral, electrophysiological and biochemical studies have begun to uncover the cellular and molecular basis for the CNS insulin/insulin receptor action on learning and memory.

Section snippets

Memory-improving effects of insulin

The presence of insulin and insulin receptor in the hippocampus and cerebral cortex suggests a functional involvement in brain cognition phenomena such as learning and memory. Insulin has been shown to exert a memory-enhancing action on both humans and experimental animals. Administration of insulin into the third cerebral ventricles of rats shortly after a passive avoidance training experience resulted in higher memory retention levels compared to rats that received saline and a

The CNS insulin receptor is functionally different from those in classical insulin target tissues. Therefore, memory improvement by insulin/insulin receptor is not due to a direct effect on glucose metabolism

Although glucose is the major nutrient and energy source for brain cells and plays critical role in brain cognitive functions (McNay and Gold, 2002), its uptake, transport and utilization in the majority of brain regions do not depend on insulin. Firstly, the adult brain appears to express two main glucose transporters (GLUTs) that are not insulin-sensitive. While GLUT-1 is expressed in the endothelium of cerebral microvessels and astrocytes, GLUT-3 is predominantly distributed in neurons

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