Abstract: The CNS performs extremely complex computations with remarkable efficiency. This is exemplified by the ability to seamlessly execute motor behaviors that necessitate the coordination of multiple muscle groups controlling joints with many degrees of freedom. It is thought that one strategy to simplify motor computations is to adopt a circuit organization that links combinations of motor pools into functional units called “synergies” or “primitives”. Thus, the circuit elements that underlie motor synergies are thought to represent the basic building blocks for orchestrating the neural control of routine motor behaviors. Elegant stimulation and recording experiments from labs working with amphibians, rodents, and primates have found evidence for motor synergy circuits within the spinal cord. The major questions addressed in this grant are: (a) what is the underlying cellular and connectivity organization of lumbar spinal motor synergy circuits, (b) what neuronal subtypes comprise these circuits, and (c) what intrinsic and extrinsic factors shape the formation of these circuits? The laboratory has used trans-synaptic neuronal tracing, optogenetics, and molecular screens to identify a heterogenous (Satb1+, Satb2+, Tcfap2b+, Tcf4+) population of interconnected excitatory and inhibitory pre- motor interneurons within lamina V of the lumbar spinal cord. Based on their properties these lamina V cells are generically referred to as motor synergy encoders (MSE). The hypothesize is that the MSE cell network comprises a major computational node for motor control within the spinal cord. These cells receive inputs from the cortex and sensory neurons such as those that relay proprioceptive information. Thus, MSE neurons are well positioned to mediate coordinated muscle activation patterns arising from command centers for volitional movement as well as reflex pathways activated by sensory feedback locally within the spinal cord. The aims of this grant are designed to unravel the wiring and cellular constituents within motor synergy circuits, and to examine how these circuits form during embryonic development and early postnatal life. Aim 1 will create a cellular atlas and connectivity map of MSE neurons. This will define whether the molecular heterogeneity of MSE neurons corresponds to separate motor pool circuit-modules or physiologically-different classes of neurons used for controlling all motor pools. Aim 2 will define the pattern of propriospinal feedback from muscles onto MSE neurons. Here the goal is to establish whether the MSE circuit is based on simple labeled line pathways or has a more complex input-output relationship. Aim 3 will use transcription factor knockouts to determine whether hardwired intrinsic genetic programs establish the MSE circuitry. Aim 4 will test whether the functional MSE network arises from activity dependent feedback from proprioceptive sensory neurons. Taken together, these aims will provide a detailed molecular-cel...