Dynamic Integration of GPCR Signaling to Control Organ Function and Animal Behavior

Our dynamic world requires continuous adaptation of our physiological states and behavior to changes in the environment over a wide range of time scales. These adaptations typically occur through a complex interplay between the autonomic nervous system (ANS) and the central nervous system (CNS), resulting in changes in cardiac output and alertness that prepare the organism to respond appropriately to the environment. These adaptive processes are mediated by a limited number of transmitters that act on a large number of different G protein-coupled receptors (GPCRs), which in turn activate only four different classes of intracellular G proteins. While the individual actions of most transmitters and the general function of specific signaling cascades are known, our understanding of a number of essential aspects underlying the control of organ function and behavior is limited:

1. the precise effect of a given transmitter on its target organs and animal behavior is difficult to predict: Depending on the expression profile of the GPCR, the same transmitter can exert different - sometimes even opposite - effects in different target tissues.
2. the precise spatiotemporal profiles of transmitter release and clearance have not been studied in detail due to a lack of appropriate tools.
3. the intracellular dynamics of GPCR-mediated signaling cascades need to be better understood.
4. Therefore, we have a limited understanding of the general action of how GPCR signaling controls our organs and ultimately our behavior.

In the FOR5807, we aim to elucidate the fundamental principles of GPCR signaling to understand the general and specific rules of metabotropic control of organ function and behavior. The large number of recently developed optically controlled GPCRs and optical sensors for neuromodulators and intracellular pathways now allow us to overcome the long-standing barriers that have hindered the study of GPCR signaling with high temporal dynamics, spatial precision, and substrate specificity. To elucidate fundamental principles of the integration and balance of GPCR signaling, we will focus on three main aspects:

1. the CNS as the central organ for environmental sensing, signal integration and top-down control of the body
2. the heart as the organ most tightly regulated by the ANS
3. the behavior of intact animals.

We will exploit the new possibilities offered by recently developed optical tools for manipulation and readout of GPCR function to bridge different levels of complexity, ranging from subcellular domains to whole animals and from milliseconds to days. We aim to understand how intracellular signals are precisely controlled and integrated, how different GPCR ligands and GPCR types affect the function of the two excitable organs, heart and brain, and how this relates to appetitive and aversive behavior.