Shreesh P. Mysore, PhD - US grants

Project Summary Animals are constantly exposed to a barrage of multisensory input from their stimulus-rich environments. They handle this informational complexity by having their behavior guided by the most physically salient (or more generally, the most important) stimulus source in the environment. The identification of the most physically salient stimulus occurs through neural mechanisms of stimulus competition, which must necessarily operate across sensory modalities and across spatial locations. Although the mechanisms of multisensory integration have been studied extensively, the circuit and computational principles underlying competition within and across sensory modalities are largely unknown. Recent evidence from behaving monkeys has revealed the midbrain superior colliculus (SC) as being critical for normal competitive stimulus selection. In parallel, our recent work in the barn owl optic tectum (OT, the avian homolog of the SC) has revealed special neural response properties, namely categorical signaling of the strongest stimulus, that can account for the SC's critical role in selection behavior. Inhibition from a GABAergic midbrain nucleus, the isthmi pars magnocellularis (Imc), is necessary to mediate these response properties. Nonetheless, the computational and mechanistic logic of Imc function in service of competitive stimulus selection remain unknown. Here, we propose to systematically unravel fundamental computations orchestrated by the Imc-OT network for multisensory competition, and to map their implementation explicitly onto circuit elements. Specifically, we first aim to elucidate how the reliable signaling of the strongest stimulus in the presence of noise, i.e, ?robust? signaling, is implemented. Our hypothesis is that special donut-like patterns of spatial inhibition from the Imc to the OT play a central role. Second, we aim to understand if the Imc is an active computational locus for stimulus competition in the OT. Our hypothesis is that competitive interactions within the Imc control the accuracy and strength of categorization by the OT. Third, we ask how the OT resolves competition in cluttered sensory scenes that contain several stimuli. Our hypothesis is that a dynamic inhibitory balance among the multiple competing locations protects OTid responses from being driven to zero and permits network wide decoding of the strongest stimulus. We will test the hypotheses using in vivo electrophysiology and drug iontophoresis in awake, head-fixed barn owls together with computational modeling. In all cases, we will explicitly test whether the hypothesized mechanisms of competition generalize across sensory modalities. Preliminary data from the three aims support our hypotheses. They indicate that results from the proposed experiments have the power to reveal strategic principles of circuit organization for executing the sophisticated computations that subserve multisensory competition and stimulus selection.

PROJECT SUMMARY Attention is the remarkable ability of animals to select and preferentially process the most important, or ?highest priority?, information in complex environments to guide behavior. This dynamic ability is essential for a range of cognitive functions and adaptive behavior, and its dysfunction is found in diverse psychiatric illnesses including ADHD, autism and schizophrenia. Yet, almost nothing is known about the circuit mechanisms by which the brain implements the selection of the highest priority stimulus at any instant. One key factor that has slowed progress has been the nearly exclusive use of primates for the study of attention: the absence of diverse genetic tools for use in primates has precluded the systematic dissection of cell-type specific contributions and neural computations in cortical and subcortical circuits in service of attention control. Another is that rigorous behavioral paradigms to study attention do not currently exist in any other (genetically tractable) mammalian species. To bridge this gap, we propose an innovate alternate approach: to develop parameterized, primate-like behavioral paradigms for visuospatial attention in the mouse so that the full power of genetic techniques offered by the mouse model can be brought to bear to dissect the neural circuitry underlying attention control. Here, we will develop touchscreen-based tasks in freely behaving mice for studying attention. Specifically, in Aim 1, we will develop three parameterized tasks for studying exogenous (bottom-up) control of spatial attention, namely, a Posner discrimination task, a flanker task, and a Posner-cued selection task. In Aim 2, we will develop two parameterized tasks for studying endogenous (top-down) control of spatial attention, namely, a spatial expectation task and a top-down spatially-cued selection task. Additionally, in Aim 3, we will use head and eye-trackers to develop a closed-loop stimulus presentation system that adjusts, in real time, stimulus locations with respect to the gaze direction of the freely behaving mouse. This will permit consistent retinotopic presentation of stimuli across trials in the above tasks, a requirement for future experiments into the functional signatures as well as causal roles of neural circuits in spatial attention control. Preliminary behavioral data support the feasibility of all three proposed aims. This development, for the first time, of rigorous paradigms for spatial attention in a genetically tractable mammalian model will establish a powerful new platform for future work unraveling neural mechanisms of attention control, as well as of neural information processing pathways that are disrupted in attentional dysfunction.

PROJECT SUMMARY The SCid, a sensorimotor hub in the midbrain, plays a fundamental role in stimulus-guided behavior as well as spatial attention control. It encodes a topographic map of stimulus priority, i.e., of physical salience + behavioral relevance of stimuli, as well as a map of relative stimulus priority, which, together, form the basis of SCid's role in behavior. However, the contributions of intrinsic inhibitory cell types to the construction of the SCid's priority map and to behavior are not known. Similarly, how SCid's map of relative stimulus priority, which requires long-range competitive inhibition, is constructed, is unclear. Dissecting the logic of local and long-range competitive inhibition in the SCid, as well as their roles in visually guided behavior necessitates the use of cutting edge technologies for the measurement and perturbation of neural circuits in a cell-type specific manner. The central focus of our future planned R01 is to address these questions in freely behaving mice engaged in visual discrimination tasks, as well in rigorous, primate-like visuospatial attention tasks (that we have developed in the lab). In this R34, we propose to acquire and establish the use of two revolutionary technologies that are indispensable to this endeavor. In Aim 1, using the nVoke system (Inscopix Inc.), we will measure the responses of ensembles of excitatory SCid neurons to visual stimuli in awake, head-fixed mice, without and with optogenetic inactivation of local inhibitory neurons. This unique technology for combined endoscopic calcium imaging and optogenetic perturbation of neurons of different sub-types intermingled within the same brain area will elucidate the role of intrinsic inhibition in the construction of SCid's map of stimulus salience. In Aim 2, using the Quartet system (Neurescence Inc.), we will measure the responses of ensembles of excitatory SCid neurons to competing visual stimuli in awake head-fixed mice, without and with optogenetic inactivation of a group of parvalbumin-positive GABAergic neurons in the midbrain tegmentum called the periparabigeminal lateral tegmental nucleus (pLTN). This unique technology that permits simultaneous endoscopic calcium imaging and optogenetic perturbation of neurons in distinct brain areas will allow us to test the hypothesis, produced by our recent work in barn owls, that the mammalian pLTN generates the long-range competitive inhibition that is essential for competitive representations in SCid, and for the construction of SCid's map of relative stimulus salience. These two aims, coupled with the novel behavioral paradigms that we have developed in the lab for studying spatial attention and visual discrimination in freely behaving mice, will establish the scientific and methodological foundation necessary to pursue our longer-term goals in the planned R01: (a) to dissect the role of local inhibitory circuits of different sub-types in the construction of SCid's map of stimulus priority, as well as in visually-guided behaviors and spatial attention, and (b) to investigate the role of the GABAergic pLTN in the construction of SCid's map of relative stimulus priority, as well as in distracter suppression, target selection and spatial attention. Results have the potential to reveal fundamental mechanistic insights into intrinsic as well as extrinsic inhibitory circuitry that shape SCid function and mediate its role in behavior.