Cristopher M. Niell - US grants

DESCRIPTION (Provided by the applicant) Abstract: During development, cellular processes such as neurite growth and synapse formation sculpt the connectivity of the brain. In the visual cortex, this results in functional neral circuits that allow us to see and understand the world around us. Significant progress has been made in studying neural development and visual processing separately. However, it has been more difficult to link these two aspects into an understanding of how the visual system wires itself up to create the specific receptive field properties that underlie vision. Indeed, we still o not know the developmental mechanisms that create orientation selectivity, the fundamental response property of primary visual cortex. Answering this question requires an approach that can bridge molecular and cellular development with systems visual neuroscience. My previous work demonstrated that the mouse visual cortex is an effective model for studying visual processing, and I have recently established a number of innovative techniques allowing us to study the mouse visual system from single genes and cell types up to visual processing and perception. Here I propose an integrative approach, in which I will apply molecular genetic techniques to manipulate key developmental pathways and neural activity in specific subsets of neurons, use in vivo imaging to assess the impact on both visual response properties and cellular growth and synaptogenesis, and perform behavioral psychophysics to test the effects on visual perception. These studies will provide important insight into the assembly of neural circuits, which underlies both normal brain function as well as numerous developmental disorders. Public Health Relevance: This project addresses the assembly of functional circuits in the visual system, and thus will have direct impact on studies of disease states resulting in blindness or visual impairment. Furthermore, as a general method to elucidate principles of cortical development, our approach should be broadly applicable to a number of developmental disorders, such as dyslexia, autism, and schizophrenia, which are thought to result from aberrant cortical wiring and function.

DESCRIPTION (provided by applicant): The goal of our research is to understand how visual processing is influenced by behavioral demands. The visual thalamus (dorsal lateral geniculate nucleus, LGN) plays a key role in this process, as it provides an intermediate relay between the retina and cortex, where transmission can be dynamically regulated based on multiple modulatory inputs. Although thalamic function has been studied extensively in vitro and under anesthesia, we still do not understand how behavioral state modulates the multiple pathways in LGN during awake visual processing. To address this gap we will study the mouse visual system, in order to take advantage of the range of molecular genetic tools that are available to identify and manipulate the underlying neural circuits. In our first aim, we will delineate the visal pathways present in mouse LGN, both in terms of neural coding and spatial organization, as measured with high-density in vivo electrophysiology. Next, we will determine how information in these pathways is modulated by behavioral state, by measuring the changes in visually-evoked neural activity associated with locomotion in alert subjects. Finally, we will test the role of neuromodulatory inputs in mediating the effects of behavioral state, using optogenetic manipulation of cholinergic circuitry. This work will advance our understanding of the selective gating of information in the brain, which is essential for both visual function and cognitive processes.

DESCRIPTION (provided by applicant): The goal of our research is to understand how visual processing is influenced by behavioral demands. The visual thalamus (dorsal lateral geniculate nucleus, LGN) plays a key role in this process, as it provides an intermediate relay between the retina and cortex, where transmission can be dynamically regulated based on multiple modulatory inputs. Although thalamic function has been studied extensively in vitro and under anesthesia, we still do not understand how behavioral state modulates the multiple pathways in LGN during awake visual processing. To address this gap we will study the mouse visual system, in order to take advantage of the range of molecular genetic tools that are available to identify and manipulate the underlying neural circuits. In our first aim, we will delineate the visal pathways present in mouse LGN, both in terms of neural coding and spatial organization, as measured with high-density in vivo electrophysiology. Next, we will determine how information in these pathways is modulated by behavioral state, by measuring the changes in visually-evoked neural activity associated with locomotion in alert subjects. Finally, we will test the role of neuromodulatory inputs in mediating the effects of behavioral state, using optogenetic manipulation of cholinergic circuitry. This work will advance our understanding of the selective gating of information in the brain, which is essential for both visual function and cognitive processes.

Abstract Development of a functional nervous system is critically dependent on environmental experience, as clearly demonstrated by Hubel and Wiesel?s studies showing disruption of neocortical development by visual deprivation. Despite this knowledge, most studies of visual processing in mice are performed using animals housed in ?standard? conditions optimized for the laboratory setting that likely represent a state of sensory, physical, and social deprivation. Several studies have shown that environmental enrichment of standard laboratory housing can enhance aspects of visual system development and plasticity. However, these individual studies have not quantitatively probed the impact of environmental enrichment across the full extent of visual processing. In order to comprehensively determine the impact of environmental experience on vision, we will measure both visual processing at the level of neural coding and specialization in visual cortex, and visual function through performance on a learned operant task and an innate ethological behavior, prey capture. This work will reveal new avenues for future mechanistic studies of how environmental factors influence a wider range of visual functions, and will enhance the use of mice as a model system for vision.

Abstract Vision is an active sense that we use to explore the world around us. However, studies of visual coding are generally performed in animals that are head-fixed, which constrains the range of visual functions and behaviors that are amenable to study, thereby excluding many ethologically relevant natural behaviors as well as the interaction of visual processing and movement. A fundamental challenge in performing visual physiology in animals that are free to move relates to the fact that the experimenter no longer controls the visual input impinging on the retina, which depends on the animal?s position relative to the stimulus as well as head and eye position. Here we will address this challenge by developing a system to directly determine the visual input the animal receives by using two head-mounted miniature cameras: one to image the visual scene from the animal?s perspective, and one to measure pupil position in order to correct this visual scene for eye movements. In the first aim, we will implement the hardware and data analysis needed to acquire the visual input along with neural activity from an implanted silicon probe. In the second aim, we will apply this system to measure tuning curves and receptive fields in the same neurons across head-fixed and freely moving conditions. In addition to providing a proof-of-principle that the system is successful, the data from this aim will test the hypothesized role for a non-canonical cortical cell type, suppressed-by-contrast neurons, which have been proposed to signal the rapid change in visual input during self-motion. This project will remove a fundamental obstacle in visual physiology, and will provide the necessary foundation for future proposals to study natural behavior and contextual signals in visual processing.

An award is made to the University of Oregon Eugene to support the purchase of a high-throughput fluorescent slide-scanner imaging system. High throughput analysis of biological specimens is increasingly essential for advancing many fields of the life sciences. A key bottleneck, particularly in the study of histological specimens, is the need for manual steps that limit the speed of data acquisition. The new slide scanning microscope will automate many of the manual steps to remove critical bottlenecks and enable high throughput analysis of biological specimens by researchers at the University of Oregon and beyond. The new instrument will be housed in the University of Oregon shared Histology and Genetic Modification Research Core Facility. As part of a core facility, this instrument will enhance training of undergraduate and graduate students and postdoctoral scholars with cutting edge microscopy approaches, advanced image analysis, ?big data?, and other key quantitative skills. The system will further accelerate student research during summer REU programs and will also be used in outreach programs and shared with neighboring institutions.

The new system will be used for a wide range of biological studies, including gene expression, anatomical reconstructions, and tissue analysis, as well as contributing to undergraduate and graduate coursework and training. Two features of this automated instrument will transform the ability of UO researchers to perform these types of studies. First, it automatically images large area specimens, stitching together individual high magnification fields of view into a single high-resolution image. Second, it can automatically process a large number of specimens, with an autoloader capable of processing up to 200 slides in succession. These capabilities will allow researchers to acquire complete datasets that are simply not tractable with manual imaging, thereby opening up new types of biological questions. The instrument has both brightfield and fluorescent capabilities, enabling a wide range of applications including in situ hybridization analysis of gene expression, reconstruction of large-scale neural organization, and quantification of anatomical and cellular structures. Results from these studies will be disseminated in peer-reviewed journals, through presentation at scientific meetings, and as part of public outreach efforts.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

ABSTRACT Cephalopods have large and complex brains, and in particular a highly capable visual system. However, their brains evolved independently from vertebrates, and very little is known about how neural circuits in the cephalopod brain process visual information. In fact, there has never been a direct recording of receptive fields in the central visual system of cephalopods. This study will measure neural activity and visual coding in the optic lobe of Octopus bimaculoides, an emerging model organism for cephalopod research. The first aim will employ two-photon calcium imaging in the optic lobe of juvenile octopuses, combined with controlled visual stimuli, to measure receptive field properties in large ensembles of individual neurons. The second aim will combine this functional imaging with anatomical connectivity, identified via retrograde tracing, to determine how visual information is routed through the visual system and into higher brain regions associated with specific behaviors. The third aim will incorporate these experimental results into computational analysis of the visual features being encoded, and into network models of visual processing. Together, these aims will provide direct insight into the neural coding and functional organization of this unique visual system. This work will be the first to describe neural computations in the central visual system of cephalopods. Examination of a system that is evolutionarily distinct, yet functionally parallel to the vertebrate system, has the potential to illuminate novel ways by which visual processing can be carried out. Likewise, observation of convergence of functional organization in cephalopods, relative to vertebrates and other invertebrates, such as Drosophila, would help identify key features necessary for the function of complex visual systems.

PROJECT SUMMARY Vision facilitates navigation through the world by providing sensory information about the environment, such as the distance to relevant objects. A key feature of visual perception is the active exploration of the visual scene through translation of the eyes, head, and body. Visual cortex has been proposed to combine these self-generated motor signals with visual input to compute information about objects in the environment. While recent studies have shown that a significant fraction of neurons in mouse V1 encode movement information and do not simply act as visual feature detectors, models of V1 function have largely ignored motor efference and sensory reafferent contributions. We aim to elucidate the neural mechanisms underlying active vision by investigating depth perception from motion parallax - a fundamental visual computation that combines observer self-motion and retinal image displacement to calculate the distance to objects in the environment. We will first adapt an ethological, freely-moving gerbil/rat distance estimation task to mice in order to determine the types of visual cues mice use to gauge depth when jumping across a gap. We will then manipulate the activity of visual cortex and its inputs from brain regions conveying movement-related signals, in order to test their roles specifically in distance estimation from motion parallax. The experiments proposed in this R21 application provide the foundation for future studies at the neural circuit level, to determine how visual and movement signals are integrated for computations such as distance estimation, particularly in a natural context.

Project summary Vision plays a key role in our ability to navigate through the environment, from identifying landmarks and obstacles to determining location and heading. While studies of visual cortex have provided an understanding of properties such as orientation selectivity and object recognition, much less is known about how cortical circuitry extracts and processes features from the visual scene to support navigation. In particular, there are two challenges. First, the nature of the visual stimulus is dramatically different in navigation, where the subject's movement through the world creates a complex and dynamic visual input, in contrast to standard synthetic stimuli presented to stationary subjects. Second, the types of visual features and computations that must be performed are different in navigation than in standard detection or discrimination paradigms. Our goal in this proposal is to determine how the brain extracts relevant visual features from the rich, dynamic visual input that typi?es active exploration, and investigate how the neural representation of these features can support visual navigation. We will investigate this through three parallel aims, that build up from the representation of the visual scene in V1 during freely moving navigation, to the computation of speci?c variables needed for navigation. In our ?rst aim, we will measure the visual input in freely moving mice using miniature head-mounted cameras, together with neural activity in V1, to determine how neural dynamics represent the visual scene during natural navigation. In our second aim, we will use large ?eld-of-view two-photon imaging of multiple cortical areas, while mice navigate in a naturalistic open-world virtual reality system, to determine how visual features are represented across visual cortical areas. In our third aim, we will use 2-photon imaging in mice in a rotational arena to determine how visual input is used to dynamically update a key navigational variable: heading direction. Together, this project bridges foundational measurements in freely moving animals with mechanistic circuit investigations, to provide insights into an important aspect of visual system function.

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