Insulin-mediated synaptic plasticity in the CNS: Anatomical, functional and temporal contexts

Abstract

For decades the brain was erroneously considered an insulin insensitive organ. Although gaps in our knowledge base remain, conceptual frameworks are starting to emerge to provide insight into the mechanisms through which insulin facilitates critical brain functions like metabolism, cognition, and motivated behaviors. These diverse physiological and behavioral activities highlight the region-specific activities of insulin in the CNS; that is, there is an anatomical context to the activities of insulin in the CNS. Similarly, there is also a temporal context to the activities of insulin in the CNS. Indeed, brain insulin receptor activity can be conceptualized as a continuum in which insulin promotes neuroplasticity from development into adulthood where it is an integral part of healthy brain function. Unfortunately, brain insulin resistance likely contributes to neuroplasticity deficits in obesity and type 2 diabetes mellitus (T2DM). This neuroplasticity continuum can be conceptualized by the mechanisms through which insulin promotes cognitive function through its actions in brain regions like the hippocampus, as well as the ability of insulin to modulate motivated behaviors through actions in brain regions like the nucleus accumbens and the ventral tegmental area. Thus, the goals of this review are to highlight these anatomical, temporal, and functional contexts of insulin activity in these brain regions, and to identify potentially critical time points along this continuum where the transition from enhancement of neuroplasticity to impairment may take place. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders.'

Keywords: Cognition; Glutamate; Hippocampus; Motivation; Nucleus accumbens; Ventral tegmental area.

Fig. 1. Continuum of insulin effects on neuronal plasticity across a temporal/developmental context

While glucose utilization in the CNS is likely to be largely insulin independent, the brain is not an insulin insensitive organ. Rather, insulin promotes neuroplasticity across development in the CNS in a variety of ways ranging from neuronal maturation to behavior. As depicted by the green insulin receptors and arrows in the upper panel, insulin facilitates plasticity at the synaptic level by regulating the expression and phosphorylation of glutamate receptors in the hippocampus and also coordinates the activity of mesolimbic networks. These activities of insulin are proposed to result in enhancement of synaptic transmission, as depicted by the green traces indicating enhancement of excitatory post-synaptic potentials (EPSPs). These activities provide examples of the anatomical and temporal contexts of insulin signaling activity in the CNS. However, insulin resistance will result in decreases in the phosphorylation state of glutamate receptors, as well as decreases in EPSPs, as depicted in red insulin receptors and arrows. Under these conditions, insulin resistance associated with obesity and T2DM impairs the substrate on which synaptic plasticity takes place. In this way, insulin activity in the CNS can be thought of a continuum beginning with the facilitation of neuroplasticity during development into adulthood (as depicted by the green arrows in the bottom panel), which then may be followed by reductions in neuroplasticity resulting from insulin resistance (as depicted in the red arrows in the bottom panel). See text for details.

Fig. 2. Proposed VTA-NAc circuit for insulin regulation of food pursuit

Relatively low concentrations of insulin produce increased glutamate release in the NAc and enhance dopamine release in this region through actions on cholinergic interneurons. As insulin concentrations increase, activation of IGFRs is recruited, causing a reduction in glutamate release. In addition, at these higher concentrations, local dopamine release within the NAc is no longer enhanced, and instead insulin results in LTD of VTA-dopamine neurons. Thus, small anticipatory increases in insulin in response to stimuli associated with food may activate local NAc circuits to promote food pursuit, while larger post-prandial increases in insulin may reduce activity in the VTA and NAc to reduce the pursuit of food and promote feeding cessation.