title: A neuronal signaling pathway of CaMKII and Gqα regulates experience-dependent transcription of tph-1.
abstract: Dynamic serotonin biosynthesis is important for serotonin function; however, the mechanisms that underlie experience-dependent transcriptional regulation of the rate-limiting serotonin biosynthetic enzyme tryptophan hydroxylase (TPH) are poorly understood. Here, we characterize the molecular and cellular mechanisms that regulate increased transcription of Caenorhabditis elegans tph-1 in a pair of serotonergic neurons ADF during an aversive experience with pathogenic bacteria, a common environmental peril for worms. Training with pathogenic bacteria induces a learned aversion to the smell of the pathogen, a behavioral plasticity that depends on the serotonin signal from ADF neurons. We demonstrate that pathogen training increases ADF neuronal activity. While activating ADF increases tph-1 transcription, inhibiting ADF activity abolishes the training effect on tph-1, demonstrating the dependence of tph-1 transcriptional regulation on ADF neural activity. At the molecular level, the C. elegans homolog of CaMKII, UNC-43, functions cell-autonomously in ADF neurons to generate training-dependent enhancement in neuronal activity and tph-1 transcription, and this cell-autonomous function of UNC-43 is required for learning. Furthermore, selective expression of an activated form of UNC-43 in ADF neurons is sufficient to increase ADF activity and tph-1 transcription, mimicking the training effect. Upstream of ADF, the Gqα protein EGL-30 facilitates training-dependent induction of tph-1 by functional regulation of olfactory sensory neurons, which underscores the importance of sensory experience. Together, our work elucidates the molecular and cellular mechanisms whereby experience modulates tph-1 transcription.
authors: Department of Organismic and Evolutionary Biology, Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.
authors: Yuqi
authors: Y
authors: Qin
authors: Xiaodong
authors: X
authors: Zhang
authors: Yun
authors: Y
authors: Zhang
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000502:physiology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics* / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics* / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D012701:Serotonin / Q000096:biosynthesis; D015398:Signal Transduction / Q000502:physiology*; D014158:Transcription, Genetic; D014365:Tryptophan Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; C479565:Egl-30 protein, C elegans; D012701:Serotonin; D014365:Tryptophan Hydroxylase; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; C517679:unc-43 protein, C elegans; D043802:GTP-Binding Protein alpha Subunits, Gq-G11