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J Neurosci. 2013 Jan 16;33(3):925-35. doi: 10.1523/JNEUROSCI.2355-12.2013.

A neuronal signaling pathway of CaMKII and Gqα regulates experience-dependent transcription of tph-1.

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Department of Organismic and Evolutionary Biology, Center for Brain Science, Harvard University, Cambridge, Massachusetts 02138, USA.


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.

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