Insights into the selective regulation and function of neuropeptidergic co-transmission

• Applicant: Professor Dr. Alexander Gottschalk, since 11/2025
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells ; General Genetics and Functional Genome Biology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 452359796

Neuropeptides establish orthogonal signaling networks that profoundly influence behavior, either acting alongside or independently of classical small-molecule neurotransmitters, monoamines and gap junctions. Despite many neurons expressing multiple neuropeptides, our understanding of how these signals are coordinated and interact remains limited. My colleagues and I recently demonstrated that two neuropeptides, NLP-10 and FLP-1, released from the same interneuron pair, AVKL/R, have antagonistic effects on locomotion speed in Caenorhabditis elegans. NLP-10 accelerates locomotion by activating the G protein-coupled receptor NPR-35 on premotor interneurons driving forward movement and is crucial for aversive responses to both mechanical and noxious light stimuli. In contrast, AVK-derived FLP-1 slows down locomotion by suppressing the secretion of NLP-10 from AVK through autocrine feedback via its receptor DMSR-7 (Aoki et al, 2024, Nature Communications).To advance our understanding of the selective regulation and function of neuropeptidergic co-transmission, I propose a research project structured along the following five objectives. First, I will determine whether the (1) packaging, trafficking and (2) release of NLP-10 and FLP-1 are differently regulated, by developing optical methodologies to visualize these events in living C. elegans. (3) I will investigate the molecular mechanisms by which FLP-1/DMSR-7 autocrine signaling selectively suppresses the release of NLP-10 but not FLP-1, focusing on the role of Go signaling, downstream of DMSR-7. (4) The functional aspects of co-transmission will also be explored: NLP-10 contributes to locomotion acceleration in response to both mechanical and blue light stimuli, while FLP-1 uniquely suppresses the acceleration after mechanical stimulation. I will identify the neural circuit underlying the blue light response, determine the source of NLP-10 in each context and find out how FLP-1 specifically suppresses mechanical response. (5) Furthermore, I will investigate the neurocircuit mechanisms underlying the multi-sensory integration between blue light and food cues, as NLP-10’s role in blue light response is food-dependent. This integrative study will employ diverse methodologies to unravel the differential regulation of neuropeptide co-transmitters and their broad implications for brain dynamics underlying physiological behavior.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Ichiro Aoki, until 11/2025