Abstract Adaptive control of behavior is critical for survival. Even a simple movement, like extending the arm, requires the activation of many neuronal populations across the nervous system. Our lab has used a combination of anatomical, genetic, optical and behavioral approaches to unravel how animals move, and learn to control movement. However, adaptive responses are not effected only through muscles, but also through other organs. For example, planning to pick an apple will trigger not only muscle activity but also the expectation of food, and the conditioned release of insulin. Hence adaptive behavior requires the coordination of an organism's actions with its physiological internal states. We propose to leverage our expertise to dissect the neural circuits and principles governing the learning and adaptive “motor” control of internal organ function. We will spearhead this new research direction by investigating conditioned insulin release and conditioned immunosuppression, mediated by the innervation of the pancreas and spleen, respectively. We will leverage state of the art viral and RNA-seq approaches to map with high-resolution the first, second and third-order innervation of spleen and pancreas. Our preliminary anatomical mapping of the innervation of these organs revealed that different populations of celiac-mesenteric ganglia sympathetic neurons innervate pancreas versus spleen. Remarkably, most innervation of the thoracic preganglionic spinal cord targeting these organs emerges from the cortex: motor cortex, but also sensory and prefrontal. We therefore hypothesize that learning to select the appropriate responses in internal organs after conditioning is mediated by higher-order brain circuits, and follows principles similar to those used for motor responses. We propose to use both targeted and unbiased approaches to identify and manipulate the activity of descending neural populations responsible for the learned control of spleen and pancreatic function. This new line of research is innovative but trackable with our expertise, and the Pioneer award support will help us attack this novel research area. Importantly, the proposed research has the potential to conceptually position the nervous system as a “smart” regulator of organism homeostasis, and hence impact health in unexpected ways - mental disorders like anxiety and depression, or neurological problems like stroke, are associated with abnormal physiological states likely emerging from these brain-internal organ interactions.

Project Narrative Adaptive control of behavior is critical for survival and requires not only brain control of muscle activity, but also descending control of organism physiology and internal organ function. We will dissect the neural circuits and principles governing the learning and adaptive “motor” control of internal organ function by investigating conditioned insulin release and conditioned immunosuppression, mediated by the innervation of the pancreas and spleen, respectively. We will employ state-of-the art viral tracing methods to map first, second and third- order innervation of spleen and pancreas, RNA sequencing to characterize neuron identity, in vivo calcium imaging to measure neuronal activity in descending circuits, and chemo- and optogenetic tools to causally test how descending circuits impact splenic and pancreatic function.