Identification of a CREB-dependent serotonergic pathway and neuronal circuit regulating foraging behavior in Caenorhabditis elegans: a useful model for mental disorders and their treatments?

The cAMP-response element binding protein (CREB)-mediated cell signaling pathway is conserved through evolution and participates in a broad range of complex behaviors of divergent species including man. This study describes the integration of genetic, pharmacologic, and anatomic methods to elucidate a serotonergic signaling pathway by which the CREB homolog CRH-1 controls foraging rate (FR) in the model organism Caenorhabditis elegans, along with the complete neuronal circuit through which this pathway operates. In the anterior afferent arm of the circuit, CRH-1 controls FR by regulating the expression of tph-1, the sole structural gene for tryptophan hydroxylase, in serotonergic sensory (ADF) neurons whose post-synaptic effects are mediated through 5HT(2)-like SER-1 receptors. The posterior afferent limb of the circuit includes an interneuron (RIH) that does not express tph-1 and whose serotonergic phenotype is dependent on the contribution of this neurotransmitter from another source, probably the ADF neurons. The postsynaptic effects of the RIH interneuron are mediated through 5HT(1)-like SER-4 receptors. This model has potential utility for the study of clinical disorders and experimental therapeutics. Furthermore, the discovery of serotonergic neurons that depend on other sources for their neurotransmitter phenotype could provide a mechanism for rapidly altering the number and distribution of serotonergic pathways in developing and adult nervous systems, providing a dimension of functional complexity that has been previously unrecognized.