Functional Coding of Neuropeptide Signaling Networks in Learning

Humanity has always been intrigued by the brain’s ceaseless capacity to learn and store experiences. However, the ability to acquire and retrieve learned information is dynamic and regulated by a bewildering variety of chemical messengers. Neuropeptides form the largest and most diverse group of neuromodulators and play important roles in learning. Growing evidence exists showing that they form dense signaling networks, with most neurons expressing many neuropeptides and receptors, but how this complex network is engaged in learning circuits has not been systematically explored in living animals. Our working hypothesis is that the concerted actions and integration of neuropeptide signals mediates flexible control of learning circuits.We will test this hypothesis in the small and well-described nervous system of C. elegans, building on system-wide peptide network maps recently generated by my group. Given their high diversity, such a controlled context for penetrating the complex neuropeptide “language” in learning circuits is preferable. We will first identify the molecular pathways by which C. elegans neuropeptide GPCRs modulate neural activity, as this will provide the foundation to dissect their concerted actions. We will then systematically test how neuropeptide pathways impact short-term aversive learning in defined gustatory and olfactory circuits, study their impact on whole-circuit activity, and determine their temporal dynamics. Pertinent questions we will address include: ‘What are the unique versus redundant effects of neuropeptides in a learning context?’; ‘How do cellular networks encoding aversive experience respond to and integrate neuropeptidergic network activity?’ and ‘When do neuropeptidergic networks act to potentiate or attenuate learned responses?’We expect on the long term, this project will impact our understanding of how neuropeptide networks influence and organize learning, forgetting, and adaptive behavioral responses in general.