Cell Biology (Arber)

Imported from Grants Tool 4730055

Imported from Grants Tool 4708224

Imported from Grants Tool 4701374

n.a.

One of the most important tasks of the nervous system is the generation of specific forms of movement as behavioral output, allowing animals or humans to interact with their surroundings appropriately according to motor plans and/or in response to influence from the environment. The motor system is broadly distributed across the nervous system, including areas close to actual motor program execution in the spinal cord, all the way up to regions of the nervous system involved in decision making and planning of motor acts. The brainstem is a key intermediary structure between higher motor centers and spinal circuits, and we have hypothesized that distinct subpopulations of brainstem neurons mediate selective motor programs. The goal of this work is to unravel key defining features of brainstem neurons involved in the regulation of diverse forms of movement, with an emphasis on understanding molecular and genetic underpinnings of brainstem neurons, as well as their plasticity during development and learning. Our project will contribute to uncovering organizational principles of neuronal circuits in the motor output system of mice, as well as the contributions of these circuits to behavioral function.

One of the most important tasks of the nervous system is the generation of specific forms of movement as behavioral output, allowing animals or humans to interact with their surroundings appropriately according to motor plans and/or in response to influence from the environment. The motor system is broadly distributed across the nervous system, including areas close to actual motor program execution in the spinal cord, all the way up to regions of the nervous system involved in decision making and planning of motor acts. The brainstem is a key intermediary structure between higher motor centers and spinal circuits, and we have hypothesized that distinct subpopulations of brainstem neurons mediate selective motor programs. The goal of this work is to unravel key defining features of brainstem neurons involved in the regulation of diverse forms of movement, and to understand how a particular behavior is chosen over others. Our project will contribute to uncovering organizational principles of neuronal circuits in the motor output system of mice, as well as the contributions of these circuits to behavioral function.

Arber, one of the world's most prominent neurobiologists, is a leading figure in the study of neuronal circuitry controlling motor behavior. Her research on the assembly, structure, and function of motor circuits has resulted in fundamental contributions to our understanding of the organizational principles of the motor system including the spinal cord and the brainstem. Arber's early work focused on the molecular mechanisms responsible for the formation of appropriate connections in sensory-motor circuits of the spinal cord. Since then she has turned her attention to the wider circuits of the motor system, with particular emphasis on the functional organization of brainstem nuclei with connections to specific neuronal populations in the spinal cord. Her work combines multiple research approaches, including state-of-the-art mouse genetics, the development and implementation of viral technologies, quantitative behavioral analysis, electrophysiology and gene expression profiling. Some of her lab's most recent research unraveled highly specific bidirectional communication pathways between higher brain centers and the spinal cord. This work demonstrated the existence of molecularly and functionally defined brainstem motor control hubs for diverse actions. Collectively, Arber's work not only reveals the functional organization of circuits at the core of motor control but has the potential to improve recovery in people and animals that have lost or attenuated motor function.

Animals carry out an enormous repertoire of distinct actions, spanning from seemingly simple repetitive tasks, like walking, to more complex movements requiring fine motor skills. The cental nervous system, composed of the brain and spinal cord, integrates information received from the body and coordinates its activity. Within the central nervous system, neurons never function in isolation; they are organized into neuronal circuits, which are at the core of choosing, maintaining, adjusting and terminating distinct motor behaviors to coordinate movement. Over the last decade, Silvia Arber's laboratory has demonstrated that neuronal circuits are oranized into precise modules by functional subdivision at multiple levels of the motor system, including the spinal cord and brainstem. Thus, precisely connected neuronal subpopulations in the motor system align with the distinct behavioral functions, allowing for functional subdivision of labor and diversification of motor programs. This research provides important insights into the mechanisms and organizational principles responsible for the establishment and function of the motor system. Silvia Arber will use the prize money to conduct further reserach on how neuronal circuits regulate the diversification of motor behavioral programs.

The aim of our research is to unravel the organization and function of neuronal circuits controlling motor behavior. Movement is the common behavioral output of all CNS activity, yet how different movement patterns emerge and are regulated at the level of precisely connected neuronal circuits in an animal is currently poorly understood. In the BoE extension of my current SNF grant, we would like to exploit how motor output pathways orchestrate the precise control of motor output regulation in the spinal cord in intact animals, and how this process is influenced by sensory feedback circuits from muscles. This work lays the foundation for a research direction addressing how these identified neuronal circuit elements respond to spinal cord injury. We are convinced that together, these experiments will help to reveal general principles governing neuronal circuit organization at the level of identified neuronal subpopulations involved in motor control, as well as determine the factors influencing motor circuit reorganization after injury.

An important goal in neuroscience is to understand how the assembly of neuronal circuits contributes to the emergence of function controlling dedicated animal behaviors. Motor behavior represents the ultimate output of nearly all nervous system activity. An intricate network of neuronal circuits within the spinal cord communicating bi-directionally with higher centers in the brainstem and brain, as well as integrating sensory feedback from the periphery ensures the accuracy of motor output. Despite its seeming complexity, the final motor output system displays an exquisite degree of organization, and is experimentally accessible at a high degree of specificity, using genetic, molecular, anatomical and physiological analysis linked to a direct behavioral output. The overall goal of our studies will be to extract information on how - at the neuronal circuit level - specificity of connections in the motor system can explain behaviors as complex as motor behavior. Our major focus over the next several years will be to contribute to our understanding of how motor circuits influence and regulate the activity of functionally defined groups of motor neurons in the spinal cord. All experimental approaches described here have the common goal to study how establishment and connectivity of circuits relates to and controls the emergence of motor function. The projects described in the detailed research plan will represent a major effort in my laboratory over the next several years. They are presented in four main sections, but technologies and concepts overarch the entire proposal. (1) Regulation of connectivity and transcription by retrograde NT3 signaling: These studies aim at providing us with an understanding of the mechanisms regulating connectivity and transcription controlled by retrograde NT3 signaling. We will (a) study the distribution of premotor interneuron subpopulations in mice with genetically altered NT3 levels, (b) determine genome-wide transcription profiles of isolated proprioceptive afferents derived from mice with altered NT3 levels, and (c) establish a strategy based on next generation sequencing approaches to identify subpopulation gene expression based on profiles of individual neurons and computational analysis. (2) The role of proprioceptive feedback circuits in assembly and function of motor circuits: The main aim of this project is to reveal the role of the proprioceptive feedback system in motor circuit assembly and function in the spinal cord. We will (a) identify the nature of the signal required for extensor-specific premotor connectivity, (b) establish systems for conditional ablation or alternation of activity patterns in proprioceptors, and (c) determine consequences of proprioceptor ablation at different developmental time points for circuit connectivity and motor behavior. (3) Timing of neurogenesis in motor circuit connectivity and function: This part of the project aims at elucidating the importance and rules of timing of neurogenesis for the establishment of motor circuits. We will (a) address whether individual spinal progenitor cell clones give rise to spinal premotor interneurons with distinct function and elucidate how timing of neurogenesis intersects with the acquisition of transcriptional profiles, and (b) establish whether causality between neuronal birthdating and motor circuit function exists. Together, these experiments will reveal the contribution of neurogenesis timing to the establishment and function of motor circuits. (4) Premotor network analysis of motor neurons of different evolutionary emergence: This project will address the question of whether premotor networks controlling the activation of motor neurons with different evolutionarily standing exhibit distinct or similar spinal distribution patterns. We will categorize which neuronal types of the premotor network are shared or split between ancestrally distinct motor neuron populations. These will include motor neurons innervating axial muscles, body wall muscles, as well as proximal and distal limb muscles, comparing hind- and forelimb patterns; providing insight into different circuit modules and strategies of motor control.