5-HT1B Autoreceptors: Molecular Mechanisms and Behavioral Implications.

摘要

The serotonergic system is important in modulating a range of emotional behaviors, and disturbances of this system are implicated in psychiatric conditions such as post-traumatic stress disorder, depression, and anxiety. 5-HT 1B autoreceptors are located on serotonergic neurons at the presynaptic nerve terminal and serve to regulate synaptic serotonin levels with precise spatial and temporal control. Spanning both behavioral and molecular work, this dissertation delves into the effects of manipulating 5-HT1B autoreceptor levels on contextual fear conditioning and into the signal transduction pathways underlying 5-HT1B receptor activation. We first describe two novel viral vectors for targeting 5-HT1B autoreceptors: one using the serotonin transporter promoter to drive transgene expression to gain neurochemical specificity, and one using an intersectional method that combines a double-floxed and inverted open reading frame virus with a Cre-expressing virus as a neuroanatomical strategy for targeting a single brain circuit. Second, we apply these tools in the study of fear conditioning in both wild type and 5-HT1B receptor knockout mice and find that overexpression of 5-HT1B autoreceptors in nerve terminals throughout the brain decreases fear expression, while overexpression of 5-HT1B receptors specifically in the dorsal raphe nucleus to amygdala circuit increases fear. We then investigate the molecular mechanisms underlying 5-HT1B signaling, looking in particular at the phosphorylation of ERK1/2 following 5-HT1B receptor activation and the pathway proteins that are involved. Finally, we identify four novel phosphorylation sites in the third intracellular loop of the 5-HT1B receptor and discover that these sites are important for achieving maximal agonist-stimulated activation of phospho-ERK1/2. Taken together, these studies shed light on the intracellular mechanisms by which 5-HT1B receptors function and provide evidence for distinct effects of 5-HT1B receptors on fear behaviors depending on their expression pattern in the brain.