Sensory-motor transformations in a neural circuit for object-directed walking

Walking towards a salient object (prey, mate, etc.) is a basic and conserved behavioral motif shared across most terrestrial animals, including humans. Mobility disorders often impact this vital function of goal-directed walking. Despite varied evolutionary histories, both vertebrates and invertebrates have converged on similar leg- kinematics strategies to drive changes in walking speed and direction. Therefore, a mechanistic understanding of goal-directed walking, in any species, is critical and will have broad implications. Certain descending output pathways of the brain that project to the spinal-cord (vertebrates) or ventral-nerve- cord (invertebrates), have been shown to control specific aspects of leg movements required for directed walking. However, how sensory inputs, like those representing a potential mate, engage appropriate combinations of descending pathways to move the animal as intended, remains an open question. This gap is due to two major challenges: 1) defining a clearly resolved sensory-motor neural circuit underlying object-directed walking, and 2) measuring and perturbing combinations of descending pathways that govern the leg movements required for object-directed walking. We propose to overcome these challenges by using the well-established Drosophila model system. In the proposed work, we will evaluate how physiology and connectivity within a defined and genetically accessible, multi-layered neural circuit (the DNp09 input-output circuit) transform object-tracking sensory input into directed-walking output. To enable this, we developed new experimental and modeling approaches, that provide high-fidelity access to this neural circuit at cellular and synaptic resolution. We will first use whole-cell electrophysiological recordings and biophysically detailed full morphology models to examine how synaptic layout of specific visual pathways recruit the DNp09 network during object-directed turning events. We will then use novel calibrated stimulation techniques and connectome-constrained network models to characterize how DNp09 recruits a population of interconnected descending neurons that are poised to control directed walking. Through a combination of modeling and experiments leveraging two-photon holography and high-resolution kinematics analysis, we will then extract how descending neuron population activity states encode directed walking maneuvers. The proposed efforts will determine how sensory-evoked naturalistic activity propagates across a network of interconnected neurons to drive the distributed control of motor outputs required for generating object-directed walking. The long-term objective of this work is to provide cross-species transferable models of how combinations of brain output pathways orchestrate the downstream motor circuits for executing appropriate locomotor outputs, a fundamental problem in understanding how brains control behaviors. Project Number: 1R01NS143970-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Salil Bidaye | Institution: MAX PLANCK FLORIDA CORPORATION, Jupiter, FL | Award Amount: $518,582 | Activity Code: R01 | Study Section: Sensory-Motor Neuroscience Study Section[SMN] View on NIH RePORTER: https://reporter.nih.gov/project-details/11368139