Feeding state modulates nociception in C. elegans

Sammanfattning: An important function of the nervous system is to respond to changes in the environment. The nematode C. elegans chemotaxes towards attractants and escapes noxious stimuli. Chemotaxis to salts requires the two ASE neurons ASEL and ASER, and escape responses require the nociceptive ASH neurons. To study the mechanisms underlying these behaviors, we adopted a combination of genetics and in vivo calcium imaging, which allows monitoring of neuronal activity in living animals. Calcium imaging revealed that ASEL and ASER are functionally asymmetric. ASEL is an ON-cell activated by increases NaCl, and ASER is an OFF-cell activated by decreases in NaCl. Activation of ASEL results in forward runs and activation of ASER results in turns. Signal transduction in the ASE neurons involve cGMP signaling, and activation of both neurons require the TAX-2/TAX-4 nucleotide gated channel and the EGL-4 cGMP-dependent kinase. Together ASEL and ASER function to regulate chemotaxis up a concentration gradient (Paper I). To study of neurons in isolation from input to other sensory neurons, we developed a method called Functional Rescue in Single Sensory Cilia (FRISSC). In FRISSC, a null mutation in the RFX transcription factor DAF-19C, which is required for ciliogenesis, is rescued cell-specifically. This allows restoration of cilia and sensory function in individual neurons. We tested if the restored cilia are fully functional by performing calcium imaging in the ASE neurons. Our results show the FRISSC generated fully functional cilia, and that the rescue is cell-specific and cell-autonomous. Thus, FRISSC is a useful method to study sensory neurons in isolation (Paper II). We used FRISSC to study how nociception is modulated by feeding state. We found that the ASH neurons are enhanced by food through dopamine signaling. In a food-rich environment, escape responses to soluble repellents are increased, and the ASH neurons are sensitized. This effect requires input to the dopaminergic neurons and the dopamine receptor DOP-4. Our results indicated that dopamine functions as a food signal to sensitize the ASH neurons and increase escape responses (Paper III). In contrast to dopamine, neuropeptide signaling inhibits nociception in the absence of food. Overexpression analysis revealed that in the absence of food, the FMRFamide-related peptide FLP-8 inhibits responses to soluble repellents. This effect requires the neuropeptide receptor NPR-1, which acts on the ASH neurons to increase adaptation to repellents. These results demonstrate that feeding state modulates nociception through a complex network of bioamine and neuropeptide signaling (Paper IV).