Prolonged sensory input and chronic neural activity can lead to several downstream cellular alterations, such as morphological remodeling and changes in gene transcription. The pathways that lead to these changes are often unique in different cell types, and the streamlined nervous system of C. elegans offers a useful system for uncovering genes involved in these processes. To this end, we are investigating cellular changes induced by chronic activity in the main oxygen-sensing neurons URX. The URX neurons are tonically active in the lab with 21% oxygen. Intracellular cGMP levels controlled by the oxygen-sensing guanylyl cyclases GCY-35 and GCY-36 reflect the absolute level of oxygen to which the worms are exposed. These chronically high levels of cGMP open cyclic-nucleotide-gated ion channels which leads to constant calcium influx into the cell. We have identified two cellular consequences of this chronic activity of the URX neurons. First, we have surprisingly found that a transcriptional reporter for the pro-apoptotic gene
egl-1 is expressed in URX in an activity-dependent manner. Animals reared at 1% oxygen have vastly reduced reporter expression when compared to animals raised at 21% oxygen. Similarly, mutations in genes that affect oxygen sensing or signal transduction lead to a loss of
egl-1 reporter expression. Secondly, we have found that the dendritic tips of URX that arborize in the nose grow in length and complexity depending on neuronal activity. Animals raised in 21% oxygen grow extensively elaborated URX dendritic tips by Day 4 of adulthood, while the dendritic tips of animals maintained in 1% oxygen fail to elaborate. Many of the same genes found to control activity-dependent gene expression are also involved in this dendritic growth. To identify genes that influence these phenomena, we performed a forward genetic screen and intriguingly recovered a loss-of-function allele of
crh-1, the worm homolog of the CREB transcription factor. We are currently exploring several avenues for following up on these findings. An activity-dependent pathway for upregulating the pro-apoptotic
egl-1 may shed light on possible activity-dependent cell deaths in C. elegans, and perhaps genes involved in the degeneration of chronically active neurons in other animals. Also, a role for
crh-1 in maintaining sensory endings has not yet been reported, so we are currently working to determine whether
crh-1 is important for dendritic sensory structure in other neurons as well.