NPY/NPF-Related Neuropeptide FLP-34 Signals from Serotonergic Neurons to Modulate Aversive Olfactory Learning in Caenorhabditis elegans.

Aversive learning is fundamental for animals to increase chances of survival. In addition to classical neurotransmitters, neuropeptides have emerged to modulate such complex behaviors. Among them, neuropeptide Y (NPY) is well known to promote aversive memory acquisition in mammals. Here we identify an NPY/neuropeptide F (NPF)-related neuropeptide system in Caenorhabditis elegans and show that this FLP-34/NPR-11 system is required for learning negative associations, a process that is reminiscent of NPY signaling in mammals. The Caenorhabditis elegans NPY/NPF ortholog FLP-34 displays conserved structural hallmarks of bilaterian-wide NPY/NPF neuropeptides. We show that it is required for aversive olfactory learning after pairing diacetyl with the absence of food, but not for appetitive olfactory learning in response to butanone. To mediate diacetyl learning and thus integrate the aversive food context with the diacetyl odor, FLP-34 is released from serotonergic neurons and signals through its evolutionarily conserved NPY/NPF GPCR, NPR-11, in downstream AIA interneurons. NPR-11 activation in the AIA integration center results in avoidance of a previously attractive stimulus. This study opens perspectives for a deeper understanding of stress conditions in which aversive learning results in excessive avoidance.SIGNIFICANCE STATEMENT Aversive learning evolved early in evolution to promote avoidance of dangerous and stressful situations. In addition to classical neurotransmitters, neuropeptides are emerging as modulators of complex behaviors, including learning and memory. Here, we identified the evolutionary ortholog of neuropeptide Y/neuropeptide F in the nematode Caenorhabditis elegans, and we discovered that it is required for olfactory aversive learning. In addition, we elucidated the neural circuit underlying this avoidance behavior, and we discovered a novel coordinated action of Caenorhabditis elegans neuropeptide Y/neuropeptide F and serotonin that could aid in our understanding of the molecular mechanisms underlying stress disorders in which excessive avoidance results in maladaptive behaviors.

Evolutionary conserved peptide and glycoprotein hormone-like neuroendocrine systems in C. elegans.

Peptides and protein hormones form the largest group of secreted signals that mediate intercellular communication and are central regulators of physiology and behavior in all animals. Phylogenetic analyses and biochemical identifications of peptide-receptor systems reveal a broad evolutionary conservation of these signaling systems at the molecular level. Substantial progress has been made in recent years on characterizing the physiological and putative ancestral roles of many peptide systems through comparative studies in invertebrate models. Several peptides and protein hormones are not only molecularly conserved but also have conserved roles across animal phyla. Here, we focus on functional insights gained in the nematode Caenorhabditis elegans that, with its compact and well-described nervous system, provides a powerful model to dissect neuroendocrine signaling networks involved in the control of physiology and behavior. We summarize recent discoveries on the evolutionary conservation and knowledge on the functions of peptide and protein hormone systems in C. elegans.

Neuromodulatory pathways in learning and memory: Lessons from invertebrates.

In an ever-changing environment, animals have to continuously adapt their behaviour. The ability to learn from experience is crucial for animals to increase their chances of survival. It is therefore not surprising that learning and memory evolved early in evolution and are mediated by conserved molecular mechanisms. A broad range of neuromodulators, in particular monoamines and neuropeptides, have been found to influence learning and memory, although our knowledge on their modulatory functions in learning circuits remains fragmentary. Many neuromodulatory systems are evolutionarily ancient and well-conserved between vertebrates and invertebrates. Here, we highlight general principles and mechanistic insights concerning the actions of monoamines and neuropeptides in learning circuits that have emerged from invertebrate studies. Diverse neuromodulators have been shown to influence learning and memory in invertebrates, which can have divergent or convergent actions at different spatiotemporal scales. In addition, neuromodulators can regulate learning dependent on internal and external states, such as food and social context. The strong conservation of neuromodulatory systems, the extensive toolkit and the compact learning circuits in invertebrate models make these powerful systems to further deepen our understanding of neuromodulatory pathways involved in learning and memory.

The role of neuropeptides in learning: Insights from C. elegans.

Learning is critical for survival as it provides the capacity to adapt to a changing environment. At the molecular and cellular level, learning leads to alterations within neural circuits that include synaptic rewiring and synaptic plasticity. These changes are mediated by signalling molecules known as neuromodulators. One such class of neuromodulators are neuropeptides, a diverse group of short peptides that primarily act through G protein-coupled receptors. There has been substantial progress in recent years on dissecting the role of neuropeptides in learning circuits using compact yet powerful invertebrate model systems. We will focus on insights gained using the nematode Caenorhabditis elegans, with its unparalleled genetic tractability, compact nervous system of ∼300 neurons, high level of conservation with mammalian systems and amenability to a suite of behavioural analyses. Specifically, we will summarise recent discoveries in C. elegans on the role of neuropeptides in non-associative and associative learning.