Vikas Bhandawat - US grants

A simple task like walking to one's favorite coffee shop involves computation across several timescales. On a short timescale (less than 1 second), one has to move one's legs on an uneven surface and maintain balance; on a medium timescale (a few seconds) one has to walk relatively straight on a sidewalk; on a longer timescale (minutes), one has to follow the street signs or use one's memory to navigate; and on an even longer timescale decisions such as whether or not to drink coffee are made. The mission of the principal investigator's laboratory is to understand neural computations underlying behavior at multiple timescales as they apply to a given task using novel techniques such as creating mathematical models of behavior and developing new methods for probing neural activity as it relates to behavior. The proposed research also has an important educational mission: Most problems in the world require interdisciplinary thinking, which is best taught at an early age. In this project, high school students are directly involved in the investigator's multidisciplinary research program, with the goals of (1) deepening the students' neuroscience education with a focus on engineering, mathematics, and technology, (2) exposing them to interdisciplinary training at a younger and more receptive age, and (3) preparing them well to think holistically about complex scientific problems.

The overarching objective of the principal investigator's research is to understand how sensorimotor transformation unfolds in the brain during the performance of complex behaviors that are part of an animal's natural behavioral repertoire. The gap in understanding of this process exists because attacking this problem requires an integrated, multidisciplinary approach that combines neuroscience techniques, animal behavior, and computational skills- a combination not often found in one investigator. The central hypothesis of the project is that flexible behaviors emerge from a modular organization and can be divided into two neural subtasks: (1) to devise an "action plan" that transforms sensory responses into actions; and (2) to adapt the action plan to current demands and thereby generate behavioral flexibility needed for successful task execution. The project tests this hypothesis in the context of odor-guided locomotion, a complex flexible behavior, in a relatively simple and genetically highly tractable model system, Drosophila. A multidisciplinary approach that includes mathematical modeling, in vivo whole-cell patch clamp recordings, functional imaging, and quantitative behavioral analysis is employed to address the central hypothesis.

1 There is a fundamental gap in our understanding of the circuit mechanisms underlying even simple naturalistic 2 behaviors, such as making a cup of coffee, which proceed through a sequential execution of sub-behaviors. 3 Continued existence of this gap represents an important problem because obtaining a circuit-level understand- 4 ing of complex multi-step behaviors is a necessary step toward unlocking the mysteries of healthy brain func- 5 tion and of disorders. The overarching goal is to obtain a circuit-level understanding of such naturalistic behav- 6 ior. The research objective here is to unravel the logic of sensorimotor transformation in the context of odor- 7 modulation of locomotion in Drosophila. The central hypothesis is that, like many of our own everyday actions, 8 control of odor-modulation of locomotion is hierarchical. A fly?s locomotion is built from simpler elements called 9 locomotor primitives, each of which lasts between 1-3 seconds (or 10-30 steps). Odors, instead of acting on 10 instantaneous locomotor parameters such as speed and angular speed, act on these locomotor primitives and 11 change the probability that the fly spends performing a given locomotor primitive. This hypothesis was formu- 12 lated on the basis of our previous work and preliminary data. The rationale for the proposed research is that 13 understanding odor-guided locomotion?a complex, flexible behavior?in the context of a genetically tractable 14 system will allow a precise delineation of the steps that underlie sensorimotor transformation in the context of a 15 naturalistic behavior. The hypothesis above will be tested by characterizing the circuit basis of modulation of 16 locomotion by food odors using a combination of techniques including imaging, electrophysiology, quantitative 17 behavior and computation. The proposed research has three specific aims. 1) To extract the locomotor primi- 18 tives and test the hypothesis that odors modulate locomotion by changing the time a fly spends performing dif- 19 ferent locomotor primitives. 2) To test the hypothesis that different ORN classes modulate the time spent in 20 distinct locomotor primitives. 3) To elucidate the role of lateral horn in odor modulation of locomotion. The re- 21 search is innovative because it employs sophisticated statistical tool (Hierarchical Hidden Markov model, 22 HHMM) and cutting-edge experimental tools in the context of a genetically tractable model organism to obtain 23 insights into naturalistic behaviors. The proposed research is significant because it will vertical advance our 24 understanding of sensorimotor processes involved in naturalistic behaviors. Insights from multiple fields have 25 all come to the conclusion that behavior is organized into discrete packets or behavioral primitives. Actions un- 26 fold by a sequential recruitment of these discrete packets. A critical barrier to the study of natural behavior is 27 that in most cases there is enough variability in these discrete packets to make them unrecognizable without 28 the help of sophisticated statistical tool. By deploying HHMM, we overcome this critical barrier. Besides repre- 29 senting a vertical advance in our understanding of naturalistic behavior, another possible positive outcome of 30 this study is better diagnosis of neurological conditioning that occur through improper sequencing of actions. 31 32 33

1 Neuromodulators transform the output of neural circuits through their effects on diverse cellular processes and 2 play a particularly important role in the flexible control of behavior. Genetic manipulations of neuromodulators 3 in vivo leave no doubt that they exert a powerful influence on behavior. But it is difficult to pinpoint the role of a 4 given population of neuromodulatory neurons because their overall effect arises through their role on multiple 5 circuits in the brain and spinal cord. In particular, the specific role of neuromodulatory descending neurons 6 (NM-DNs)?neurons whose cell bodies reside in the brain and which send their axons to the spinal cord?in 7 modulating motor outputs is poorly understood. There is an urgent need to fill this gap in our knowledge 8 because NM-DNs are the major source of neuromodulators in the spinal cord and play a crucial role in shaping 9 motor output. The long-term aim of this research is to understand the role of NM-DNs in the context of 10 behaviors that require control over multi-jointed limbs. The overall objective in this proposal is to assess the 11 role of NM-DNs that use aminergic neurotransmitters?dopamine (DA), octopamine (OA) and serotonin 12 (5HT)?in a completely intact animal. The central hypothesis is that NM-DNs are recruited by DNs that mediate 13 sensorimotor transformations, which we refer to as sensory DNs (SDNs), and that SDNs initiate movement 14 while at the same time recruiting NM-DNs through their axon collaterals. NM-DNs do not initiate movement but 15 play a major role in descending motor control by modulating frequency, amplitude and duration of leg 16 movements. The rationale for this study is that a comprehensive understanding of descending 17 neuromodulation in an intact system in the context of multi-jointed limbs is essential to both the basic question 18 of neural control of complex behaviors, and to treatment strategies when such control is affected. The 19 proposed project has three specific aims: 1) To measure the relation between activities in NM-DNs and leg 20 kinematics. 2) To establish the circuit architecture underlying descending neuromodulation. 3) To understand 21 the effect of perturbing neuromodulation on a fly?s movement. Our approach is multidisciplinary: It employs a 22 combination of machine vision techniques to extract leg kinematics, a novel analytical framework for analyzing 23 leg movements, in vivo whole-cell patch clamp recordings to extract the relationship between activities in NM- 24 DNs and leg kinematics, and genetic tools to identify and perturb NM-DNs to establish a causal relationship 25 between NM-DNs and motor output. With regard to outcomes, we expect to elucidate how each of three 26 aminergic neurotransmitters functions individually and together in shaping motor output resulting from multiple 27 multi-jointed limbs. Such results are significant because they are expected to vertically advance understanding 28 of the role of NM-DNs because little is known about the circuit mechanisms by which they function in vivo. 29 Equally importantly, the results will have a positive effect on efforts to ameliorate the loss of motor control 30 during spinal injury by restoring neuromodulators.