Project 4- The cognitive functions of the prefrontal cortex (PFC) are impaired early in the aging process, andthere is significant spine loss from the dendrites of aged PFC neurons. Project 4 will examine whether theseage-related changes can be prevented by chronic treatment with the alpha-2A noradrenergic (NE) agonist,guanfacine. We hypothesize that guanfacine will inhibit detrimental cAMP actions in the PFC that lead toweakened connectivity in PFC networks. Electron microscopy (EM) studies of young PFC have shown thatalpha-2A receptors are co-expressed wih HCN (Hyperpolarization-activated Cyclic Nucleotide-gated)channels in the spines of monkey PFC neurons, where they are ideally positioned to gate synaptic events.When the HCN channels are opened by cAMP, they weaken inputs onto the spine. Guanfacine inhibits theproduction of cAMP and strengthens functional connectivity. With advancing age, there is a decrease inalpha-2 receptors, evidence of excessive cAMP signaling, and increased HCN expression. We hypothesizethat disinnibited cAMP actions early in the aging process weakens the functional connectivity of PFCnetworks, contributing to declines in PFC cognitive function. With advancing age, sustained synapticweakness would lead to spine loss.
Aim 1 will test this hypothesis by examining ultrastructural changes indendrites, NE axons, alpha-2A receptors, and HCN channels in the superficial layers of PFC from young,middle aged and aged monkeys. We will use dual immunoEM to visualize the distribution of thesemolecules, and the integrity of dendrites, with particular focus on layer I. We predict that there will bechanges in neuromodulators early in the aging process (e.g. decreased NE axons and alpha-2A receptors inlayer I, increased HCN channels on dendritic spines), followed by architectural decreases in dendritic spineswith advancing age.
Aims 2 and 3 will examine whether chronic stimulation of alpha-2A receptors withguanfacine will reduce functional weakening of synapses and thus prevent spine loss and working memorydecline in aging rats and monkeys. Preliminary results indicate that chronic guanfacine produces enduringimprovements in spine density and working memory abilities. As guanfacine is available for human use, thisresearch is directly relevant to the treatment of age-related cognitive decline. LAY SUM: The research willtest whether chronic treatment with guanfacine will protect brain cells and memory in aged animals.
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