De rol van neuropeptiden bij de sturing van CO2 en O2 navigatie in Caenorhabditis Elegans

Animals navigate a complex multisensory environment where adequately responding to changes is crucial for their survival. This adaptability is governed by the coordinated action of neural circuits within the nervous system. These circuits are not static, hardwired structures; instead, they are highly flexible, relying on the integration of sensory input, past experiences, and both internal and behavioral states. A key question in modern neuroscience is how the nervous system processes this information to generate context-appropriate behaviors. While large-scale projects mapping the brain's anatomical connections have provided valuable insights into the structure and architecture of neural circuits, these wiring maps alone are insufficient to explain functionality. It has become increasingly clear that these maps reveal potential synaptic connections between neurons, while other diffusible messengers, such as neuropeptides and monoamines, which can operate outside the synaptic cleft, add a dynamic layer to the anatomical connectome, refining neural activity by allowing changes in neuronal functions to selectively enhance or dampen certain connections. Therefore, this type of extrasynaptic neuromodulatory signaling is crucial for neural signaling and should not be overlooked when examining how nervous systems function. Neuropeptides are an evolutionarily ancient and diverse class of secreted messengers, characterized by distinct release mechanisms and actions, primarily through signaling via G protein-coupled receptors (GPCRs). Recent efforts to map neuropeptide and receptor expression along with peptide-GPCR interactions have uncovered overlapping and highly interconnected neuropeptide signaling networks across animal nervous systems. Despite these emerging wireless maps, the functional logic of these neuromodulatory networks remains poorly understood. An important question that emerges is which of the numerous neuropeptide-receptor pathways expressed in a given circuit are functionally relevant for modulating its activity and corresponding behavior. A systematic analysis of these pathways within the same behavioral circuit could help address this complexity. However, in vertebrates, systematic functional analysis is complicated by the anatomical complexity of the nervous system. In this study, we utilized the CO2-sensing circuit in the nematode Caenorhabditis elegans, a well-characterized and tractable model for sensory-driven navigation, to investigate how neuropeptide systems expressed within specific circuits influence behavior. The CO2-sensing circuit integrates defined sensory inputs and elicits robust behavioral outputs, while being extensively modulated by neuropeptides expressed within the CO2-sensing circuit and in other sensory circuits. Using a reverse genetic screen focused on neuropeptides with receptors expressed in the CO2 navigation circuit, we identified the neuropeptide SNET-1 as a regulator of both CO2 and O2 navigation. This peptide belongs to the ancestral elevenin neuropeptide family that is widely conserved in bilaterians, though appears to have been lost in vertebrates. We discovered that SNET-1 modulates different aspects of the locomotor response to CO2 and O2 stimuli in a context-dependent manner, by modulating turning and speed of forward movement when C. elegans are grown in a high (21%) O2 environment but not when animals are acclimated to low (7%) O2 levels. We find that snet-1 is expressed in neurons of the gas sensing and navigation circuit and acts in distinct neurons to modulate CO2- and O2-evoked locomotor responses. SNET-1 partially acts through the neuropeptide receptor NPR-34 to regulate CO2 and O2 responses, which is the sole ortholog of the elevenin receptor family in C. elegans. Our findings indicate that NPR-34 mediates responses to aversive CO2 and O2, though not to the same extent as SNET-1, suggesting it is not the only SNET-1 receptor. The identity of the other SNET-1 receptor(s) remains unknown. Given the conservation of elevenin neuropeptides and receptors across bilaterians, the findings of this study could illuminate previously unknown functions of elevenin peptides in sensory-driven navigation in other animals. Furthermore, compact neuronal networks frequently reveal fundamental principles of neuronal network function. Consequently, insights derived from these systems can enhance our understanding of how neuromodulatory networks facilitate behavioral flexibility in both anatomically compact and complex nervous systems.