Understanding how environmental information is integrated into an animal?s behavioral outputs is a central challenge in determining how the brain generates behavior. Newly emerging evidence suggests that disruption of the peripheral nervous system (PNS) has a large contribution to the symptoms of Autism Spectrum Disorders. Investigating causal relationships between sensory input, neuronal circuits, and behavioral outputs requires a highly modifiable experimental system. During development, Drosophila melanogaster larvae exhibit a change in their behavioral response to temperature, suggesting a sensory switch in the regulation of temperature-regulated behaviors.
The aims of this proposal examine the mechanisms of this Thermal Sensory Switch to define the regulation of sensation and behavior.
Aim 1 : Test the requirement of sensory regulators during the Thermal Sensory Switch. The class IV dendritic arbor (cIVda) neurons are PNS neurons that cover the larval body wall, sense preferred ambient temperature (thermotaxis) (Sokabe et al., 2016) and also sense dangerously hot temperatures (thermal nociception) (Tracey et al., 2003). Experimental evidence suggests that cIVda neurons in early-stage vs late- stage larvae elicit different behavioral responses to thermal stimuli (Sokabe et al., 2016; Sokolowski, 2001). To ascertain what contributes to these behavioral differences, I will test whether known sensory factors regulate the Thermal Sensory Switch by: A) determining whether these factors are transcriptionally regulated during this period of development, and B) conduct a gain-of-function screen with a collection of candidate genes to uncover suppressors of the Thermal Sensory Switch.
Aim 2 : Determine the role of ecdysone in regulation of the Thermal Sensory Switch. The steroid hormone ecdysone regulates the major developmental transitions of larvae (Yamanaka et al., 2013a) and the ecdysone receptor (EcR) is required for thermal nociception (McParland et al., 2015). Therefore, increased ecdysone regulation may coincide with the period of development during which the Thermal Sensory Switch is activated. My preliminary data suggest that increased expression of EcR in the cIVda neurons is sufficient to prematurely activate thermal nociception. To determine the mechanism of EcR regulation I will: A) test the ability of altered ecdysone hormone titers to regulate the Thermal Sensory Switch, and B) determine the mechanism and co-factors of EcR transcriptional regulation of the Thermal Sensory Switch.
Aim 3 : Identify steroid hormone regulated genes in cIVda neurons which regulate the Thermal Sensory Switch. To identify novel factors in the Thermal Sensory Switch pathway, I will A) test the suppressor candidate genes as targets of EcR regulation, B) identify novel EcR binding sites in cIVda neurons by ChiP- sequencing, and C) determine which EcR associated genes regulate the Thermal Sensory Switch.
The importance of peripheral nervous system (PNS) development and function in behavioral and disease contexts is becoming increasingly evident. The changing thermal sensory behaviors which occur over the course of Drosophila larval development provide an ideal model to investigate the mechanisms of sensory regulation that shape behavioral development. A greater understanding of the mechanisms of sensory regulation will contribute to more effective treatments for a broad range of diseases, from sensory hypersensitivity in patients with Autism Spectrum Disorders to sensory signaling contributions to hot flashes of perimenopause.
