Dissecting neural mechanisms integrating multiple inputs in C. elegans

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Summary Atypical sensory-based behaviors are a common feature of a number of human conditions, including autism spectrum disorder, schizophrenia, etc. Despite this, little is known about how the genes associated with these conditions affect sensory behavior. A complete understanding of this process requires a thorough characterization of the underlying neural circuitry, along with the ability to measure and perturb the activity of these circuits. The nematode, Caenorhabditis elegans, provides a unique opportunity to analyze genes, cells, and circuits regulating complex behaviors, as its nervous system consists of just 302 neurons interconnected via identified synapses that utilize highly conserved synaptic machinery. The Chalasani, Hart, and Pierce labs have shown that loss-of-function mutants in C. elegans homologs of the human autism-associated genes (neurexin (NRX) and neuroligin (NLG)) greatly attenuate aggregation behavior in both wild and lab strains. In addition, the Chalasani and Hart labs have found that NRX is required in specific chemosensory neurons and intact glutamate signaling to modify aggregation behavior. They propose to map the synaptic signaling pathways that are modified by NRX-NLG signaling to regulate aggregation behavior (Aim 1). The Pierce lab has recently found evidence for natural genetic variation that interacts with NRX and NLG to modify aggregation deficits. They propose to identify the relevant genes and validate them using QTL mapping, revealing insights into the NRX-, and NLG-genome interactions critical for animal behavior and intestine physiology (Aim 2). The Chalasani lab has discovered that NRX, but not NLG loss-of-function mutants have leaky intestines. Next, they obtained intestinal-specific transcriptomes to identify candidate genes whose expression is selectively altered in NRX mutants. They propose to use genetic methods to confirm roles for these genes in affecting intestinal integrity. Notably, these signaling pathways, whose mammalian homologs might be relevant to gastrointestinal issues observed in individuals with an ASD diagnosis (Aim 3). These studies will reveal the genes, neurons, synapses, and signaling pathways by which NRX-NLG signaling drives sensory behavior and animal physiology. Importantly, this proposal brings together three labs with complementary expertise to make rapid progress toward revealing the mechanisms underlying the complex NRX-NLG phenotypes.