Spinal circuits involved in skilled forelimb motor control

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Everyday tasks such as eating and using a mobile phone require complex and precisely controlled arm, hand and finger movements. These movements are coordinated in a process called fine motor control, which involves various parts of our brain, brainstem, and spinal cord. Our general understanding of the various brain and brainstem regions important in fine motor control have been studied for many years. However, the spinal circuitry involved in fine motor control remains poorly understood. This lack of knowledge is largely because, until recently, researchers lacked the tools to experimentally record and control the activity of specific neuronal populations in the spinal cords of adult experimental animals. The long-term goal of my research program is to use advanced genetic and surgical techniques to tease out the spinal circuitry of fine motor control. A requirement of fine motor control is sensory feedback from skin and muscles to the spinal cord. We know this because animals and humans lacking sensory feedback are unable to make smooth and precise movements. Primary afferent depolarization (PAD) is one of the key sensory pathways of the spinal cord. We recently showed that PAD controls whether sensory signals can get to the spinal cord or not (i.e., PAD is the gatekeeper of sensory signaling). Given that fine motor control requires sensory signals, and PAD controls sensory signaling in the spinal cord, the aim of the current proposal is to study the roles of PAD circuitry in fine motor control. To accomplish this, we will use genetically modified adult mice that express optogenetic and chemogenetic proteins specifically in spinal cord neurons (i.e., V3 and GAD2+ neurons) we have shown to be key players in PAD circuity. I will test the hypothesis that PAD neurons are active at specific phases of the SPRGR task (i.e., during reaching, grasping, or retrieval phases) and that blocking V3 of GAD2+ neurons will reduce fine motor control leading to reduced performance in the task. To do this, we will train mice to perform a skilled reaching, grasping, and retrieval called the SPRGR task. Optogenetic reporter proteins expressed in V3 and GAD2+ neurons allow us to record the activity from these cells as animals perform the SPRGR task so that we can understand when these cells are active relative to different parts of the task (e.g., V3s might be ON during reaching, but OFF during grasping). We will then use mice expressing optogenetic actuator or chemogenetic proteins that will allow us to turn ON or OFF V3 and GAD2+ neurons using light (optogenetics) or designer drugs (chemogenetics) as the animals perform the SPRGR task. A drop in performance in the task will indicate that PAD neurons are important for fine motor control. The results from these studies will give us new insights to some of the fundamental principles of the spinal cord neural circuitry of fine motor control and will be highly applicable to understanding human skilled movement.