PROJECT SUMMARY: The bone marrow is the major site of hematopoiesis where all blood cells emerge from the regulated differentiation of hematopoietic stem cells (HSCs). Studies from the applicant?s laboratory have uncovered key functions for innervation of the sympathetic nervous system (SNS) in the egress of HSCs from marrow. SNS nerves are required to entrain the circadian release of HSCs and also the circadian recruitment of mature leukocytes to the periphery. In addition, the bone marrow is also innervated by peptidergic sensory fibers whose functions in hematopoiesis remain unclear. In this application, we propose a 3-year experimental plan that will advance our knowledge on the neuroanatomy and neurophysiology of the bone marrow. In Specific Aim 1, we will characterize the functions of sensory nerves in the marrow. We will define the functional neural circuits using immunofluorescence imaging and transneuronal viral tract tracing, and evaluate the interplay of signals between sensory and SNS fibers using pharmacological and genetic model systems. In Specific Aim 2, we will identify the intercellular transduction pathways that relay SNS nerve signals in bone marrow. We will identify the stromal cell types that receive adrenergic signals mediating ROS oscillations which may represent an important link for the propagation of neural signals. Specific Aim 3 will harness endogenous neural circuits to improve hematopoietic regeneration. We will establish selective bone marrow DREADDs using adenoviral transduction that will lead to organ-specific neural activation to enhance regeneration following genotoxic insults such as ionizing irradiation or chemotherapy. Manipulation of endogenous neural circuits may indeed provide a useful future strategy to accelerate hematopoietic regeneration. !