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?

Abstract

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 C. 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 5HT2-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 5HT1-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.

Dopamine Modulates Acetylcholine Release via Octopamine and CREB Signaling in Caenorhabditis elegans

“…crh-1 also controls the expression of tph-1 , which is required for serotonin synthesis [10], and plays a role in the regulation of aging [11]. We previously showed that CREB was regulated by biogenic amines in C. elegans using the cre::gfp reporter [12], [13], in which a CRE sequence is fused to GFP sequence.…”

Big ideas for small brains: what can psychiatry learn from worms, flies, bees and fish?

“…27 A recent study has revealed the important role that CRH-1, the C. elegans homolog of CREB, has on the worm's foraging rate through regulation of tph-1 (tryptophan hydroxylase), which is necessary for serotonin production. 33 Moreover, the same study showed that the serotonergic phenotype of a certain neuron depends on the contribution of this neurotransmitter from an external source provided by a second neuron. 33 This discovery indicates a mechanism of plasticity for the serotonergic circuit in the developing nervous system that might be of utility in understanding certain aspects of neuropsychiatric disorders.…”

“…33 Moreover, the same study showed that the serotonergic phenotype of a certain neuron depends on the contribution of this neurotransmitter from an external source provided by a second neuron. 33 This discovery indicates a mechanism of plasticity for the serotonergic circuit in the developing nervous system that might be of utility in understanding certain aspects of neuropsychiatric disorders.…”

UsingCaenorhabditis elegansfor antimicrobial drug discovery

“…For example, the use of C. elegans could help to learn more about the mode of action of anesthetics and in the discovery of novel anesthetics [70] . Also, the cAMP-response element binding protein (CREB)-mediated pathway and the complete neuronal circuit which this pathway affects was studied using C. elegans [71] and this model could be used for the study of mental disorders and the discovery of new drugs [72] .…”