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GPCR-mediated Postsynaptic Integration of Catecholaminergic Signaling in Learning and Memory
Learning and memory formation are fundamental brain functions essential to everyday survival. However, maladaptive processes such as fear learning hold the potential to result in fear-related disorders. In contrast, extinction learning, the basis of behavioral therapies to treat fear-related disorders such as post-traumatic stress disorder, can counteract these maladaptive fear-memories. While memory formation is affected by many neuronal processes, one important factor that supports stable long-term memories is the release of neuromodulators, especially under emotional conditions such as fear and extinction. While the catecholamines noradrenaline and dopamine are causally linked to the formation of fear and extinction memories, neither the postsynaptic target cells of these substances are known, nor how these target cells integrate and balance the signaling of different neuromodulators, which typically converge on the same postsynaptic signaling pathways via G-protein coupled receptors. On top, sex-related differences in fear and extinction have been reported, but the molecular mechanisms of this dimorphism are not understood. Within the framework of the FOR 5807, this project will fill some of these gaps in our knowledge by investigating catecholamine-mediated second messenger dynamics in postsynaptic target cells, which are pictured as an integration hub for neuromodulatory signaling. By elucidating the net effect of catecholamine release on the dynamics of cAMP, a versatile second messenger essential to memory formation, in different neuronal subpopulations, common motifs of the neuromodulatory mechanisms underlying memory formation will be identified. The first step towards this goal will be the mapping of functional connections between catecholamine release and cAMP dynamics in different target cells. This will be performed in two brain areas related to fear and extinction, and will reveal candidate targets of catecholaminergic signaling for learning and memory. In the second step, a behavioral paradigm for cued fear conditioning and extinction will be established, and the dynamics of neuromodulator release during these processes will be investigated. Building on these experiments, catecholamine-related cAMP dynamics during fear and extinction will then be investigated from the perspective of postsynaptic target cells, comparing male and female mice side by side. In the last step, optogenetic control of G-protein coupled receptors will be used to interfere with natural cAMP dynamics, aiming to modulate memory strength and demonstrate causal roles of cAMP in defined circuit components for learning and memory formation. Taken together, this project will elucidate the mechanisms of catecholamine-mediated cAMP integration across cell types, brain regions, and types of learning in male and female mice, aiming to identify molecular motifs that, in the long run, might serve as entry points for personalized treatments of fear-related disorders.