John C. Tuthill, Ph.D. - US grants

A Brain Circuit Program for Understanding the Sensorimotor Basis of Behavior Abstract The Project team's long-term goal is to develop a comprehensive theory of animal behavior that explicitly incorporates neural processes operating across hierarchical levels ? from circuits that regulate the action of individual muscles to those that regulate behavioral sequences and decisions. Our innovative approach is guided by the notion that different brain regions are not linked within a single neuroanatomical tier, but rather constitute a series of hierarchically nested feedback loops. The effort is organized into four Research Projects, each focusing on a different processing stage related to: (1) muscle action, (2) motor patterns, (3) motion guidance, and (4) behavioral sequences. Demonstrating our commitment to team interaction, these Research Projects are not organized according to PIs laboratories, but rather each constitutes a collaborative multi- laboratory effort. The collective expertise of our research team spans the entire nervous system - from the sensory periphery to the motor periphery and was chosen to include experts in every experimental technique we require (molecular genetics, electrophysiology, optical imaging, biomechanics, quantitative behavioral analysis, control theory, and dynamic network theory). We will exploit mathematical approaches ? control theory and dynamic network theory in particular ? that are best suited to model feedback and the flow of information through and among different processing stages in the brain. The four complimentary and integrated Research Projects will focus on ethologically relevant natural behaviors, with an emphasis on recording methods that interrogate the functions of genetically identified neurons in intact, behaving animals ? a rigorous standard that is designed to have the broadest impact on systems neuroscience. Our research exploits a single, experimentally tractable model system (Drosophila melanogaster), in which we can easily study the functions of genetically identified cell classes in ethologically relevant behaviors. Our experiments emphasize methods that interrogate the functions of neurons in intact, behaving animals, a rigorous standard that is designed to have the broadest impact on systems neuroscience. Our research will be supported by an Instrumentation and Software Resource Core that will develop and support novel devices and software, so that we can continue to employ state-of-the-art experimental techniques and data analysis. Collectively, our research program constitutes a systematic attack on the neural basis of behavior that integrates vertically across phenomenological tiers. The result of our effort will be a new synthesis of how a fully embodied brain works to generate behavior.  

Project Summary Proprioception, the sense of self-movement and body position, is critical for the effective control of motor behavior. Humans lacking proprioceptive feedback, such as patients with peripheral nerve damage, are unable to maintain limb posture or coordinate fine-scale movements of the arms and legs. But despite the importance of proprioception to the control of movement in all animals, little is known about the neural computations that underlie limb proprioception in any animal. This gap is due to two basic challenges: (1) identifying specific neuronal-cell types that detect and process proprioceptive signals, and (2) recording neural activity from proprioceptive circuits during natural limb movements. Here, we propose to overcome these challenges by investigating the neural coding of leg proprioception in a genetic model organism: the fruit fly, Drosophila. We have developed new methods to record from genetically-identified neurons in proprioceptive circuits with in vivo electrophysiology and 2-photon imaging, while manipulating leg position and movement with a magnetic control system. In Aim 1, we will use 2-photon calcium imaging to define the spatial organization of proprioceptive neural coding within a population of mechanosensory neurons. In Aim 2, we will use calcium imaging to test the hypothesis that specific parameters of leg proprioception?such as position and movement? are encoded by genetically distinct subtypes of mechanosensory neurons. In Aim 3, we will test the hypothesis that signals from distinct mechanosensory neuron subtypes are integrated by downstream neurons, using optogenetics and whole-cell patch-clamp electrophysiology. Altogether, these studies will elucidate basic mechanisms of proprioceptive neural processing that have not possible to investigate in other systems. Although there are morphological differences between flies and humans, the basic building blocks of invertebrate and vertebrate somatosensory systems share a striking evolutionary conservation. These similarities suggest that the general principles discovered in circuits of the fruit fly will be highly relevant to somatosensory processing in other animals. A deeper understanding of proprioception has the potential to transform the way in which we treat somatosensory disorders.

Project 1: The Neural Basis of Muscle Action Loops Abstract The goal of Project 1 is to identify neural mechanisms of sensorimotor processing within low-level muscle action loops that control walking and flight behavior. Acting at the interface between the nervous system and the body, muscle action loops face a daunting set of demands: they must operate with both speed and precision, while retaining the flexibility and robustness necessary to function in diverse, unpredictable environments. To understand how motor control circuits balance these demands to control adaptive behavior, we will combine cell-type specific genetic tools with electrophysiology, functional imaging, and behavioral analysis in the fly. We will first investigate how activity within diverse populations of motor neurons interacts to produce muscle contraction and complex body movements. We will then ask how proprioceptive feedback signals are integrated with ongoing motor commands to adapt and refine behavioral output. Finally, we will work to understand how low-level muscle action loops interact with descending neuromodulatory signals to generate patterned motor activity. These experimental and theoretical efforts are divided into the following Specific Aims: Specific Aim 1: Investigate how motor neurons robustly control body movement. Specific Aim 2: Determine the role of proprioceptive feedback in fine-tuning precise motor output. Specific Aim 3: Identify origins and mechanisms of sensorimotor neuromodulation that contribute to flexible locomotor behavior.