Neuroendocrine computations underlying an enduring behavioral state - PROJECT SUMMARY Neuroendocrine signaling is central to many aspects of life, but the computational mechanisms underlying the many facets of neuroendocrine biology receive relatively little attention. The cell biology of neuroendocrine signaling differs from that of neuron-to-neuron signaling, and the timescales of regulation are many orders of magnitude longer—implying different computational mechanisms. In responding to stress, behavioral changes that result from neuroendocrine signaling often require sustained or repeated triggers. Once initiated, stress- induced changes in behavior can outlast the triggering stimuli. This implies evidence accumulation and state- persistence. Understanding the computational mechanisms behind these effects would be extremely valuable, as they may explain inter-individual differences in susceptibilities to stressors and disease states in humans. I present a new system for assessing and understanding neuroendocrine computations that determine the entry into, and exit from, a state of stress-induced suppression of ovulation in Drosophila. Our preliminary data implicate conserved hormones under the control of a multi-organ neuroendocrine signaling pathway. Precise genetic access to three anatomical nodes, together with the unparalleled genetic toolbox of Drosophila melanogaster, will allow a detailed investigation of the molecular and electrical mechanisms that measure the amount of stress being experienced and determine the extent and duration of the response. Flies produce insulin-like peptides in a variety of tissues, including 14 brain neurons. We find that stress causes a lasting increase in the activity of the insulinergic neurons, and that the resulting increase in insulin triggers a lasting suppression of ovulation. The brain-derived signal is received through the insulin receptor on an endocrine gland called the corpora cardiaca. We have designed a novel 2-photon fluorescence lifetime imaging paradigm to monitor the activity dynamics of insulin producing cells in response to time spent in stressful situations, and lingering effects in the following days. We will explore the computations underlying the accumulation and dissipation of stress-derived information over time within the insulin producing neurons. A genetic screen targeted to the insulin-receiving cells in the corpora cardiaca indicated cAMP as a critical mediator of resiliency to stress. We will explore the hypothesis that cAMP levels set the threshold that stress levels must cross to trigger entry into the state of suppressed ovulation. Our preliminary data implicate the GnRH homolog Adipokinetic Hormone (AKH), which is produced by the corpora cardiaca, as the readout of this thresholding mechanism. We will work to understand how the insulin signal is translated into an AKH signal, with specific focus on long timescale mechanisms. We will work to understand the signal transduction mechanism downstream of GnRH signaling, which we localize to the adipose tissue of the fly. The result will be an anatomical, electrical, and molecular description of neuroendocrine computations with profound effects on behavior and reproduction.
