The neural mechanisms underlying temporal integration - Project Summary A central challenge in neuroscience is to understand how the brain performs fundamental computations that allow animals to sense, interpret, and respond to the world. One key computation is temporal integration, the ability to accumulate sensory information over time. This process is essential for behaviors including the vestibulo-ocular reflex (VOR) in humans, which stabilizes vision during head movements, and for maintaining posture and coordinated movement. When temporal integration is disrupted, people can experience gaze instability, nystagmus, imbalance, and other movement disorders. Despite decades of research in vertebrates, many of the cellular and network mechanisms underlying temporal integration remain poorly understood. This proposal leverages the fruit fly Drosophila, which senses angular velocity using specialized sensory organs that function like gyroscopes, called halteres. The haltere-motor system is analogous to vertebrate gaze control circuits but offers unique experimental advantages: the complete wiring diagram is known, individual neurons can be targeted genetically, and neural activity can be recorded and manipulated with precision. We have developed a novel experimental paradigm that delivers controlled rotational stimuli while enabling simultaneous physiological recordings, imaging, and optogenetic manipulations in behaving animals. In Aim 1, we will use connectomics to identify candidate neurons in the haltere-motor pathway that are likely to perform temporal integration, construct genetic driver lines for them, and perform optogenetic manipulations to assess their putative function. In Aim 2, we will establish new preparations for whole-cell recordings of these neurons to determine the molecular, cellular, and network mechanisms that allow them to integrate sensory signals over time. In Aim 3, we will integrate anatomical and physiological data into detailed computational models of the cells and circuits that predicts how neural properties produce temporal integration and guide behavior. This integrative approach combines genetics, physiology, and computational modeling to uncover the principles of temporal integration at multiple levels, from single neurons to circuits. Because similar mechanisms are thought to operate in human gaze and posture control, our work will provide insight into disorders such as gaze- evoked nystagmus, balance impairments, and other conditions caused by neural integrator dysfunction. Beyond human health, these studies will advance fundamental understanding of how nervous systems across species accumulate information over time to drive adaptive behavior, offering a framework for future investigations of sensory-motor computation.
