The role of insulin and the insulin receptor kinase (IR kinase) are poorly understood in the olfactory bulb (OB). What is known, however, is that the IR kinase is expressed in the OB in an activity-dependent manner. Additionally, the voltage-gated potassium channel (Kv1.3) is a major delayed rectifier potassium channel in the OB, and is a substrate for tyrosine phosphorylation by the IR kinase. Post Synaptic Density 95 (PSD-95) is an adaptor protein that is directly involved in synaptic plasticity and long- term potentiation. Kv1.3-null mice show a "super smeller" phenotype; their OB neurons are insensitive to insulin and also show significantly higher levels of PSD-95 in the olfactory bulbs. My preliminary data show a protein-protein interaction between Kv1.3, IR kinase, and PSD-95 in HEK293 cells. To explore this possible native physiological connection, I propose to elaborate the role of insulin in olfactory ability, and the mechanism by which PSD-95 modulates IR kinase in vivo. I will attempt to co-localize IR kinase, Kv1.3, and PSD-95 in native olfactory tissue, show direct evidence for protein-protein interactions, and demonstrate the effects of intranasal insulin administration on the olfactory ability of mice. Intranasal delivery of molecules provides direct access to the central nervous system. Discovering how to optimize delivery of these molecules, and what the effects on physiology and behavior will be, can lay the foundation for new and innovative treatments for stroke, Alzheimer's disease, and many other neurodegenerative diseases. [unreadable] [unreadable] [unreadable] [unreadable]