Projects funded include:
Dr. Jose Manuel Alonso, SUNY Optometry; Dr. Ji Ung Lee, SUNY College of Nanoscale Science and Engineering
"A novel ultra-thin multielectrode probe for neuronal recordings"
Neuroscience research has benefited tremendously from methods of single unit recordings in awake brains. By introducing microelectrodes in different structures of the brain, researchers have been able to study single neurons and the relation between neuronal activity and behavior. Unfortunately, technical problems still limit the number of well-isolated neurons that can be simultaneously recorded and the systematic exploration of neuronal cell types. Moreover, the available multielectrode arrays are generally quite think (>70 micrometer) and cause considerable tissue damage, which limit their potential use as brain implants. The goal of this proposal is to manufacture and test a novel ultra-thin neural probe that addresses limitations of multielectrodes currently available for brain research. Our long-term goal is to manufacture a probe that has 1000 electrodes densely packed in a volume of 40 x 40 x 2000 microns3 with integrated electronics at the top to amplify, filter and digitize the neuronal signals or to deliver electrical microstimulation. As a first step (current proposal), we will build a passive probe with fewer electrodes to test recording quality and mechanical properties for insertion in the brain. Funding for this first step is crucial to start the collaboration, generate preliminary data, and develop the infrastructure to compete for external funding. The neural probe will be constructed by Dr. Lee at the SUNY College of Nanoscale Science and Engineering, which operates the most advanced nanoelectronics fabrication facility in the world, and will be tested by Dr. Alonso at SUNY Optometry, who has extensive experience performing electrophysiological recordings.
Dr. Helene Benveniste, Stony Brook University
"Role of the Glymphatic Pathway in Glaucoma"
Co- PIs: Dr. Hedok Lee, Stony Brook University; Dr. John Danias, SUNY Downstate Medical Center, Maiken Nedergaard, University of Rochester Medical Center
There have been significant recent breakthroughs in the discovery and understanding of the "glymphatic pathway" that facilitates the clearance of waste products from the brain, in particular during certain states of sleep and anesthesia. In essence, glymphatic clearance of macromolecules and other waste products is driven by a continuous sweeping flow of cerebrospinal fluid (CSF) through the brain via dedicated pathways which drain into lymph vessels of the neck. We have developed a clinically relevant MRI-based imaging platform which allows tracking and mapping of the glymphatic pathway in the rodent brain in real time. The proposed studies will explore the interconnection between the glymphatic pathway of the brain and the subarachnoid space of the optic nerve under normal conditions and conditions of elevated intra-ocular pressure (IOP) which is a major risk factor for development of glaucoma. Paradoxically, glaucoma is associated with reduced CSF pressure although significance of this finding is currently unappreciated. HYPOTHESES: (1) Contrast enhanced MRI can be used to quantify and map synergy between the brain-wide glymphatic pathway and the subarachnoid space of the optic nerve including eye outflow pathways in real time; (2) The brain-wide glymphatic pathway extends and communicates with the outflow pathways of the eye and/or cervical lymph nodes; (3) Elevated IOP is associated with dysfunctional glymphatic system is associated with increased optic neurodegeneration. The aims of our proposal is designed to test the hypothesis and ultimately understand if a decline in glymphatic transport is plays a role in glaucomatous neurodegeneration.
Dr. Stewart Bloomfield, SUNY Optometry
"A Multidisciplinary Approach to the Prevention and Treatment of Myopia"
Co-PIs: Dr. David Troilo, SUNY College of Optometry; Dr. Jose Manuel Alonso, SUNY College of Optometry; Dr. Gary Matthews, Stony Brook University; Dr. Eduardo Solessio, Upstate Medical University
Children's visual experience, such as reduced outdoor activity, can affect eye growth resulting in a significant risk for nearsightedness. This condition, called myopia, currently afflicts 42% of adults in the US and more than 80% of young adults in Asia. Overall, myopia is a leading cause of visual impairment and dramatically increases the risk of other eye diseases that threaten vision. Although myopia is associated with changes to eye structure, it should not be considered simply an ocular disorder. Rather, it likely reflects developmental dysfunction of the nervous system that results in significant changes in retinal function that disrupts processing within the subsequent stages of the visual pathways and light-regulated ocular growth mechanisms. Past myopia research has greatly benefited from a combination of epidemiological tools, animals models and, more recently, genetics. Although these studies have identified risk factors associated with the visual environment, such as near visual tasks such as reading, they have not elucidated the underlying neural mechanisms of myopia. As a result, most current therapies have proved ineffective. Here, we propose to build a multidisciplinary team of SUNY investigators that will develop novel approaches to identify risk factors that drive myopia onset and progression. We will develop novel animal models of myopia in zebrafish and mice that, unlike traditional animal models, will allow for the study of multiple environmental and genetic risk factors. Our long term goal is to combine effective treatments with wearable electronics that can monitor risk and thereby modify visual behavior to prevent or limit the progression of myopia.
Dr. William F. Collins, Stony Brook University
"Integrating high-resolution brain-activity mapping and operant conditioning to improve urinary function"
The goal of this project is to develop and implement new technology for chronic recording and visualization of the brain activity associated with lower urinary tract (LUT) function in awake rats. The team of scientists from SUNY Stony Brook and SUNY Albany/Wadsworth Center will develop and integrate the necessary instrumentation, animal protocols, and data analysis tools. The brain recordings produced by this technology will have high spatial and temporal resolution, and will be combined with simultaneous assessment of LUT function (i.e., bladder pressure, external urethral sphincter activity, and urine output).
These recordings will be submitted to a novel probabilistic signal processing technique that will identify the brain activity associated with specific phases of LUT function (i.e., continence and voiding) on a void-byvoid basis. The methodology will then be used to influence neural control of voiding by pairing reward with specific brain activity patterns. Accomplishment of the aims of this proposal will (1) create a research platform that will be a powerful tool for studying LUT function in awake animals with intact neuraxes and after trauma or neurodegeneration of the brain or spinal cord; (2) demonstrate the feasibility of training based enhancement of LUT function that can form the basis of novel therapeutic approach to treatment of LUT dysfunction; and (3) put the team in a strong position to compete for awards from NIH and other funding sources.
Dr. Robert McPeek, SUNY College of Optometry
"Mapping Superior Colliculus Activity in Naturalistic Contexts: A Neuro-computational Approach"
Co-PIs: Dr. Gregory Zelinsky, Stony Brook University
Saccadic eye movements are crucial for performing everyday tasks. The superior colliculus (SC) is a topographically-organized midbrain structure that plays a key role in saccades. Previous studies mapping saccade-related SC activity have relied upon simple, artificial stimuli, leaving unaddressed the question of how naturalistic stimuli are coded by neuronal populations across the SC map. We propose to map SC activity using real world objects in naturalistic visual scenes. Our novel approach combines neurophysiological recordings with methods from computer vision. Aim 1 uses techniques from computational vision to model the spatiotemporal distribution of SC activity, and consequent saccadic behavior, during search for objects in naturalistic scenes. These predictions are tested by recording SC activity from monkeys performing the identical tasks, with the model informing selection of recording sites. Aim 2 extends this effort to categorical (non-specific) targets to better specify the sources of information used by the SC to code saccades. Here, machine learning techniques are used to extract the visual features used to discriminate targets from non-targets based on the objects that monkeys fixate during categorical search tasks. Combining the previous aims, Aim 3 tests model predictions by recording from monkeys as they search targets, and can a categorical version of the model predict the pattern of SC activity? Answers to these questions will open doors to a new era in brain mapping, one that acknowledges the population of activity elicited by naturalistic stimuli and tasks.
Dr. Lawrence Wrabetz, University at Buffalo School of Medicine and Biomedical Sciences
"Multimodal Functional Brain Mapping for Presymptomatic Diagnosis in Leukodystrophy"
Co-PIs: Dr. Paul Vaska, Stony Brook University; Dr. Randy Carter, University at Buffalo; Dr. Robert Zivadinov, Jacobs Neurological Institute; Dr. Helene Beneveniste, Stony Brook Medicine; Dr. Dimitris Samara, Stony Brook University
New advances in pediatric brain imaging are driving improved diagnosis in neurological disease. Treatments for many leukodystrophies are efficacious only if applied presymptomatically in disease progression. Although newborn screening exists for many of these diseases, the predictive value of enzymatic activity and genotype is limited. Therefore, more sensitive presymptomatic diagnostics are needed. Fractional anisotropy MRI may be an early indicator for Krabbe leukodystrophy, but specifically and sensitivity are limited. We hypothesize that adding simultaneous measurement of metabolism using PET, and perhaps also electrical recordings, together with MRI will constitute a fundamental step forward in the presymptomatic diagnosis of Krabbe leukodystrophy. We propose to study this in a rodent model of the disease in order to develop and validate methods, as a precursor to human studies. To this end, we will establish a unique brain imaging system at the University at Buffalo that combines their state-of-the-art small animal MRI with the novel MR-compatible PET imaging technology developed at Stony Brook University. This hybrid system will allow truly simultaneous PET-MRI imaging at the highest spatial and functional resolution available. The interdisciplinary collaborations, one-of-a-kind imaging technologies, and statistical methods established through this effort will promote future research endeavors in brain science between these institutions, provide preliminary data that can be leveraged to obtain federal and industrial support for this new approach, and facilitate earlier recognition and treatment of new damage in many demyelinating diseases.
Dr. Youping Xiao, SUNY Downstate; Dr. Qasim Zaidi, SUNY Optometry; Dr. Daniel To's SUNY Upstate Medical University
"Mapping neural transformations for context based perceptual adjustments"
Adjusting perception to context is an important dynamic function of the brain, so that estimates of object and material properties are relatively invariant, despite variations in the inputs to the eyes. However, little is understood of how this is done, so understanding the neural transformations underlying perceptual adjustments and how they are driven by environmental properties is a big challenge in neuroscience. We will combine human behavioral measurements, with intrinsic and multi-photon imaging and electrophysiological recordings in areas V1, V2 and V4 of primate cortex, to resolve the neural mechanisms of one important example, the change in perceived color and brightness as a function of surround properties. We will build on psychophysical methods, stimuli, results and models in brightness and color induction to develop a dynamic computational model based on measurements of color-sensitive neurons and their connectivity. We will use these methods with multi-electrode recordings of functional cortical compartments, identified by intrinsic imaging, to do the first critical tests of the locus of color and brightness induction, and use the stimuli to critically tests components of the model. We will then perform novel psychophysical experiments to test hypotheses about the role of image blur, spatial frequency masking, and image junctions that signal 3-D configurations. Based on the results, we will elaborate the model to predict appearance under these ethologically relevant conditions. The elaborated model will then be tested with multi-electrode recordings. Finally, we will test combined dynamic and spatical aspects of the model with high resolution multi-photon imaging of neuronal populations.
Dr. Michael E. Zuber, SUNY Upstate Medical Univeristy
"Membrane-permeable transcriptional regulators for retinal repair"
Co-PIs: Dr. Stephen Fliesler, University at Buffalo; Dr. Jun Qu, University at Buffalo; Dr. Gail M. Seigel, University at Buffalo; Dr. Andrea Viczian, SUNY Upstate Medical University
Understanding and curing neurological diseases will require new technologies designed to generate neural-specific cell types for study and replacement therapies. Pluripotent cells (embryonic and induced pluripotent stem cells) are the obvious starting materials for these efforts. In theory, they have the potential to generate any type of neural cell. The reality, however, is less encouraging ad there are a bewildering number of neural cell types. Current approaches are hindered by an inability to direct cultured pluripotent cells efficiently and reliably to the desired neural subtypes. This is due, in large part, to the relative lack of specificity with which extrinsic factors (e.g., pharmacological agents and signaling ligands) function. In contrast, intrinsic transcription factors can specifically drive cell fate. Therefore, a logical approach is to use transcription factors to drive stem cells to neural cell-specific fates. We have assembled a multi-site, cross-SUNY team of investigators with complimentary expertise and will use the retina as a model to test this approach. Taking advantage of our understanding of the transcription factors required for the conversion of pluripotent cells to retinal progenitor cells, we will use membrane permeable versions of transcription factors to direct mouse and human embroyonic stem cells to retinal progenitor cells. We also will identify the conditions required to maintain retinal progenitor cells in a proliferative, yet multipotent, state. Although this proposal is focused on the generation of retinal neurons, this technology could generate other neural cell classes, thereby providing a powerful new and broadly applicable tool for neuroscience research.