UC San Diego

It is unclear why sleep is required for associative memory. However, this relationship is conserved across evolution, thus supporting the hypothesis that a core function of sleep is to facilitate memory formation. In this thesis, I shed light on this relationship by studying the roles of two established sleep-facilitating genes, DAT and sss, in facilitating gustatory short-term associative memory. First, I show that loss-of-function mutations in DAT and sss reduce this form of memory. Second, I show that DAT mutants require Dop1R1 and Dop1R2 dopamine receptors, whereas sss mutants require Da3 nicotinic acetylcholine receptors, to suppress sleep and associative memory. Third, I show that these receptors appear to function in the same neurons, thus suggesting that hyperdopaminergic signaling by DAT mutants and hypercholinergic signaling by sss mutants converge to suppress sleep and associative memory. Fourth, I show that suppressing hyperdopaminergic signaling restores sleep and memory in animals with hypercholinergic signaling and vice-versa, which suggests that the two pathways have additive effects on a common endpoint in target neurons. Fifth, I show that associative memory can also be disrupted by targeting a particularly pathogenic form of amyloid-beta, a putative causative agent in Alzheimer’s disease, to the same neurons in which Dop1R2 and SSS/Da3 function to facilitate sleep and memory. And sixth, I show that amyloid-beta genetically interacts with and appears to coopt signaling by SSS/Da3 to interfere with associative memory. These last two results may be analogous to the recently published finding that amyloid-beta downregulates the SSS homolog Ly6h, which leads to hypercholinergic signaling in neurons involved in mammalian memory formation.