Insulin and Memory in Invertebrates

Abstract

Insulin and insulin-like peptides (ILP) help to maintain glucose homeostasis, whereas insulin-like growth factor (IGF) promotes the growth and differentiation of cells in both vertebrates and invertebrates. It is sometimes difficult to distinguish between ILP and IGF in invertebrates, however, because in some cases ILP has the same function as IGF. In the present review, therefore, we refer to these peptides as ILP/IGF signaling (IIS) in invertebrates, and discuss the role of IIS in memory formation after classical conditioning in invertebrates. In the arthropod Drosophila melanogaster, IIS is involved in aversive olfactory memory, and in the nematode Caenorhabditis elegans, IIS controls appetitive/aversive response to NaCl depending on the duration of starvation. In the mollusk Lymnaea stagnalis, IIS has a critical role in conditioned taste aversion. Insulin in mammals is also known to play an important role in cognitive function, and many studies in humans have focused on insulin as a potential treatment for Alzheimer's disease. Although analyses of tissue and cellular levels have progressed in mammals, the molecular mechanisms, such as transcriptional and translational levels, of IIS function in cognition have been far advanced in studies using invertebrates. We anticipate that the present review will help to pave the way for studying the effects of insulin, ILPs, and IGFs in cognitive function across phyla.

Keywords: Caenorhabditis elegans; Drosophila; Lymnaea; classical conditioning; insulin; insulin-like growth factor; memory; starvation.

Figure 1

Training protocol for olfactory associative learning in Drosophila. Flies were exposed to odor A with an electric shock and then to odor B with no shock. After training, flies are placed at the choice point of a T maze with odor A or B diffused from both ends. Trained flies avoid the shock-paired odor (i.e., odor A).

Figure 2

Training protocol for salt chemotaxis learning in C. elegans. Worms exhibit positive chemotaxis (attraction behavior) to NaCl under normal conditions, whereas worms subjected to prolonged exposure to NaCl under starvation conditions exhibit negative chemotaxis (avoidance behavior) to NaCl.

Figure 3

Training protocol for conditioned taste aversion (CTA) in Lymnaea. After a sucrose solution (CS) is paired with a KCl solution (US), the sucrose solution does not elicit a feeding response in snails.

Figure 4

Scheme of deduced ILP/IGF signaling cascades for memory enhancement. There are three main pathways: (1) Akt/PKB phosphorylates CREB (e.g., CREB1 in Lymnaea), resulting in gene expression. (2) Akt/PKB phosphorylates FOXO, inducing its secession from DNA. (3) Akt translocates GSV to the membrane, resulting in the expression of GLUT4. The ILP/IGF receptors are called InR in Drosophila, DAF-2/IGFR (insulin/IGF-1 transmembrane receptor) in C. elegans, and MIPR in Lymnaea. Abbreviations: Akt/PKB, Akt/protein kinase B; CREB, cAMP response element-binding protein; FOXO, forkhead box protein O; GLUT4, glucose transporter isoform 4; GSV, GLUT4 storage vesicle; IRS, insulin receptor substrate; PI3K, phosphoinositide-3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10 (i.e., PIP3 phosphatase).