Insulin signaling in the hippocampus and amygdala regulates metabolism and neurobehavior

• Published in: Proceedings of the National Academy of Sciences - PNAS 2019-03, Vol.116 (13), p.6379-6384
• Main Authors: Soto, Marion, Cai, Weikang, Konishi, Masahiro, Kahn, C. Ronald
• Format: Article
• Language: English
• Subjects: Abnormalities; Adipose tissue; Adipose tissue (brown); Adipose Tissue, Brown - metabolism; Amygdala; Animals; Anxiety; Behavior, Animal; Biological Sciences; Brain; Brain Diseases, Metabolic; Central Amygdaloid Nucleus - metabolism; Cognition; Glucose; Glucose - metabolism; Glucose Intolerance; Glucose tolerance; Hippocampus; Hippocampus - metabolism; Homeostasis; Hypothalamus; Insulin; Insulin - metabolism; Insulin receptors; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Intolerance; Liquid oxygen; Memory; Metabolism; Mice; Mice, Knockout; Neural networks; Receptor, IGF Type 1 - metabolism; Receptor, Insulin - metabolism; Receptors; Signal Transduction; Signaling; Spatial discrimination learning; Spatial Learning; Spatial memory; Thermogenesis; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1817391116

Previous studies have shown that insulin and IGF-1 signaling in the brain, especially the hypothalamus, is important for regulation of systemic metabolism. Here, we develop mice in which we have specifically inactivated both insulin receptors (IRs) and IGF-1 receptors (IGF1Rs) in the hippocampus (Hippo-DKO) or central amygdala (CeA-DKO) by stereotaxic delivery of AAV-Cre into IRlox/lox/IGF1Rlox/lox mice. Consequently, both Hippo-DKO and CeA-DKO mice have decreased levels of the GluA1 subunit of glutamate AMPA receptor and display increased anxiety-like behavior, impaired cognition, and metabolic abnormalities, including glucose intolerance. Hippo-DKO mice also display abnormal spatial learning and memory whereas CeA-DKO mice have impaired cold-induced thermogenesis. Thus, insulin/IGF-1 signaling has common roles in the hippocampus and central amygdala, affecting synaptic function, systemic glucose homeostasis, behavior, and cognition. In addition, in the hippocampus, insulin/IGF-1 signaling is important for spatial learning and memory whereas insulin/IGF-1 signaling in the central amygdala controls thermogenesis via regulation of neural circuits innervating interscapular brown adipose tissue.