Julie H. Simpson - US grants

Abstract Animals combine sensory information from their environment with their previous experience and internal state to select among the many different motor behaviors they can perform, but the neural circuits in their brains that enable them to make appropriate choices remain unknown. Our long-term goal is to define the complete neural circuit, from sensory inputs to motor outputs, which governs the sequential selection and execution of the individual cleaning movements that constitute grooming behavior in Drosophila. Here, we identify the combination of sensory inputs that provide the drive to clean, investigate how one motor program is chosen while others are prevented, and define which neurons enable grooming sequence progression. We will use the strengths of our system to map the precise neurons and connections that control this innate motor sequence. Fly grooming behavior provides the opportunity for a detailed interrogation of the neural circuit motifs that form the basic functional units of all nervous systems. Just as a computer is composed of many microprocessors, a brain contains repeated modules of connected neurons, and the ways those neurons connect enables them to perform specific comparisons and logical operations. Our experiments will show how sensory neurons integrate different types of information and compare stimulus strength across space and time. We will determine which neurons constitute the central pattern generators that activate motor neurons in order and how they arbitrate between actions that cannot be performed simultaneously. Inhibitory neurons may impinge anywhere between sensory inputs and motor outputs to establish a hierarchy and ensure that the highest priority action occurs first: we will define the critical processing layers for this regulation. Higher-order neurons that descend from the brain to the ventral nervous system modulate the hierarchy to permit sequence progression; we will map these control circuits. Organizing complex behavioral sequences is a problem common to all animals and defining the neural circuits that accomplish it in a simpler system will provide a template for understanding how these functions are achieved in all brains, and how they are disrupted in diseases ranging from Obsessive Compulsive Disorder to Parkinson's disease.

Abstract Animals collect sensory information from their environment and use it to select among the many behaviors they can perform. The exact neural circuits that enable them to detect, compare, and combine sensory stimuli across space and time to organize motor sequences remain unknown. Grooming behavior in Drosophila is a sensory-driven motor sequence. We propose to use optogenetic tools and behavioral analysis to identify the sensory neurons and circuits relevant for initiation and progression of the fly grooming sequence. Grooming is innate ? the basic capacity to groom is inborn, relying on genetically-specified neural connections, and therefore accessible to dissection by genetic screens. But the sequence of the actions that constitute grooming is flexible: there is a high probability that head sweeps and front leg rubs will occur early and that back leg subroutines to clean the posterior body parts will happen later, but the exact order of these movements is not fixed. Flies use updating sensory cues to modify the trajectory of leg sweeps, the duration of cleaning bouts, and the order of movements to remove different distributions of debris effectively. A deep mechanistic understanding of how the nervous system organizes reliable but adaptive motor sequences will address the larger questions of how animals make use of a flood of sensory data, how they balance the need to exercise a movement precisely with the need to modify it based on context, and how a limited number of neurons produce the diverse array of animal behaviors. Neural circuit motifs form the basic computational units of all nervous systems. Defining the circuits that accomplish sensory comparisons that control a motor sequence in a simpler system such as fly grooming will provide a template for understanding how similar functions are achieved in all brains.

Project Summary Dopamine is a critical neurotransmitter and neuromodulator that governs essential neural circuits and behaviors. It has been implicated in human motor syndromes from Parkinson?s Disease to Obsessive-Compulsive Disorder, but its mechanism of action is not fully understood. Alterations in dopamine signaling affect fly grooming behavior, which is also a complex motor sequence. This discovery opens the door to using the exceptional experimental advantages of this organism to address fundamental open questions. The ability to manipulate small numbers of dopaminergic neurons, measure behavioral consequences, and visualize neural connectivity and activity make fly grooming an excellent model to better understand the action of dopamine at molecular, subcellular, cellular, circuit, and organismal levels. We propose behavioral experiments to determine how dopamine affects the fine structure of an innate, modular motor sequence, where it may enable flexibility based on internal state and changing sensory stimuli. We also propose anatomical characterization of dopaminergic neurons in the ventral nerve cord and their synaptic partners to identify circuit motifs that modify sensory neuron activity. These experiments test the hypothesis that dopamine sustains neural activity in mechanosensory bristle neurons, leading to useful behavioral persistence during grooming. This mechanism may explain more generally how dopamine contributes to motor control and action sequence organization.