PROJECT SUMMARY Learning and executing motor skills are crucial functions of the brain and involve the coordinated activity of multiple brain regions. Traditionally, the motor cortex (MCtx), the basal ganglia (BG), and the cerebellum (CB) have been considered key motor control regions of the brain, and plasticity within these regions are known to support motor learning. In addition, neuromodulation, such as from adrenergic neurons in the locus coeruleus (LC), is critical for proper behavior and learning. Despite the key role these regions play in controlling movements and their implication in movement disorders, we are only beginning to understand how motor signals from these regions interact with each other. Anatomically, the thalamus serves as a common target structure for MCtx, BG, and CB, yet conventionally, the thalamus has been viewed as a passive relay station. However, there is emerging evidence that the thalamus can functionally integrate and modulate these diverse motor signals. How thalamic neurons respond to motor inputs, the role of motor thalamus in motor learning, and how adrenergic signaling modulates thalamic activity are largely undefined. My central hypothesis is that the motor thalamus serves as a point of convergence for motor signals from MCtx, BG, and CB, as well as neuromodulatory input from LC, allowing it to functionally integrate these inputs to control movements and promote motor learning. I propose to use a combination of in vivo deep-brain imaging and novel fluorescent sensors for intracellular signaling in mice performing motor tasks, as well as slice electrophysiology, to measure the activity of motor thalamus during movement and determine how such activity is modulated by adrenergic input from LC. These approaches will allow me to define the inputs to motor thalamus and measure thalamic activity during movement and motor learning (Aim 1), determine the functional role of motor thalamus and its inputs in motor control (Aim 2), and determine how adrenergic signaling modulates thalamic activity during motor learning (Aim 3). Results from this study will not only clarify the role of the motor thalamus in motor control and motor learning but also provide an understanding of how adrenergic neuromodulation influences thalamic activity during behavior. This is of critical importance, as abnormal thalamic activity and disrupted adrenergic signaling are characteristic features of motor diseases. The experiments proposed in this study will span the mentored K99 and independent R00 phase of this award, with the K99 phase being focused on defining the activity and role of motor thalamus during motor learning and the R00 phase focused on understanding how adrenergic input to the thalamus modulates motor signals. My proposed training plan builds on my experience in two-photon in vivo imaging and mouse behaviors and will add training in slice electrophysiology. In addition, my expert mentoring team will also provide guidance in ...