Michael E. Goldberg - US grants

Description (provided by applicant): We live in a complicated world, with far more visual information available to us at any given time than the brain can handle. Attention is the selection process by which the brain chooses certain objects in the world in order to deal more effectively with them. In order to make accurate movements toward or away from attended objects the brain must have a spatially accurate representation of them. The parietal cortex has long been thought to be important in solving both of these problems, describing the visual world in an accurate way for the generation of attention and movement. One area of the parietal cortex, the lateral intraparietal area (LIP) has been described as being important in both the generation of eye movements and the generation of visual attention. We have discovered that LIP describes a spatially accurate salience or priority map which can be used simultaneously by the visual system to describe the locus of attention and by the oculomotor system to choose a goal for a rapid eye movement (saccade) when a saccade is appropriate. Two broad questions arise about this map: 1) what is its coordinate system and 2) how does it remain spatially accurate despite a moving eye? This proposal has three specific aims arising out of recent discoveries in our laboratory, which attack these general questions. Aim 1) when the brain analyzes the visual world it does so in a coordinate frame which can be visual, e.g. the location an object on the retina or in the world, or motor, the amplitude of the saccade necessary to acquire that object. Aim 1 uses the technique of saccadic adaptation, which enables us to separate the amplitude of a saccade from the target which evoked it. One way in which the brain maintains spatial accuracy is by using the metrics of a planned or recently completed saccade to remap the visual representation in LIP areas. We will also use saccadic adaptation to evaluate the metrics of the eye movement vector that shifts the receptive field. Aim 2) The other way that the brain can generate a spatially accurate representation is by actually measuring eye position. We have discovered a proprioceptive representation of eye position in monkey primary somatosensory cortex. However, if this signal is too slow it could not be used for the description of the world for action. Aim 2 is to study the time course of this signal, and see how it relates to eye position signals in LIP. Aim 3) Humans and monkeys can make accurate eye movements to targets which appear and disappear before an intervening eye movement, but they also slightly mislocalize saccade targets flashed immediately around saccades. Aim 3 is to study the spatial and temporal courses of the remapping process and the effects of inactivation of LIP to ascertain if the remapping mechanism can provide the mechanism by which humans can make fairly accurate but not perfect saccades to stimuli which appear and disappear around the time of a saccade. PUBLIC HEALTH RELEVANCE: Spatial processing is impaired in human patients with parietal and frontal lesions. Answering the questions posed in these specific aims will lead to a greater understanding of how the cerebral cortex orders the processes of visual attention and spatial perception. This in turn will lead to insight into the visual and oculomotor deficits that are so devastating in humans with lesions of frontal and parietal cortex, and will aid the designing of diagnostic, prognostic, and rehabilitative strategies.

DESCRIPTION (provided by applicant): The objective of this proposal is to enhance the research capabilities and collaborative efforts of the vision researchers at the Columbia University Medical Center. State-of-the-art vision research often requires the custom fabrication of mechanical instruments to support the research. Support is requested for a single module to renovate and support the machine shop in the Harkness Eye Institute at Columbia University, to be shared primarily between the Department of Ophthalmology and the Mahoney Center for Brain and Behavior. The module will have 10 users, 7 of whom have NEI-funded RO1 grants, and 3 of whom perform research in the area of visual systems neuroscience on grants funded by the NIMH. All of the investigators are also mentors on an NEI-funded training grant. The current systems projects include studies of the neurophysiology and psychophysics of spatial vision, visual attention, early cortical processing, visual emotional association, and visual motion; the cellular and molecular projects include studies of fluid transport across corneal epithelium, retinal axon guidance, ocular wound healing, and the impact of the lipofuscin fluorophores on retinal pigmented epithelial cell function and viability. All of these projects require the development and fabrication of devices primarily designed for a given project. A great number of these can, when perfected, be shared among a number of projects. Examples of such devices include custom-made nanoliter injection devices, recording chambers, multiple-microdrive platforms, dual recording-iontophoretic devices, illumination devices, and recording gdds. The PI has extensive experience collaborating with machinists, and several of the devices in whose development he participated have been marketed commercially. Currently the Department of Ophthalmology has a fully-equipped machine shop the machines of which are all fine old Bridgeport and Hardinge manual machines. This proposal is to upgrade the machine shop, with a computer-controlled lathe and a computer-controlled milling machine, and to support the salary of the machinist who was hired in June, 2003, using university startup funds. The availability of an in-house professionally certified machinist will significantly speed the process of design and fabrication of custom instruments. The use of computer controlled machine tools will facilitate duplication of instruments usable in multiple laboratories.

[unreadable] DESCRIPTION (provided by applicant): We have to know where an object is in visual space relative to the body, in order to look at it, move towards it or away from it, reach out and touch it, grasp it, or even throw something at it. Visual information enters the brain via the retina, but because the retina moves in the orbit, knowing where something is on the retina does not automatically tell the brain where it is in space. In order to calculate where something is in space, the brain must know not only where it is in the retina, but where the retina is in space. The brain knows where the head is in space from signals from the vestibular system in the inner ear, and from sensors in the neck muscles. There are signals in the visual association cortex of the brain that report where the eye is in the orbit, but the source of this eye position information is unknown. One possibility is that the source of the eye position signal arises as a corollary discharge from the motor system, because the signal controlling the muscles that move the eye has a component signaling the position of the eye. We have previously discovered such a corollary signal which reports the dimensions of an impending eye movement to cortical neurons. The other possibility is that sensors in the extraocular muscles send a signal to the brain describing the position of the eye in the orbit. Monkey and human extraocular muscles have many sensors which look like the sensors in the skeletal muscles that signal muscle length. These sensors project through the thalamus to area 3a in primary somatosensory cortex (SI), and to the second somatosensory cortex (Sll). In very preliminary experiments we have found cells in both area 3a and Sll (as identified by magnetic resonance imaging) which describe the position of the eye in the orbit. This proposal has two aims: 1) to characterize the eye position signal, looking at its oculomotor, visual, and attentional properties. 2) to determine by anesthetizing the orbit of one eye, if the signal has a proprioceptive or a corollary origin. These experiments will provide insight into the mechanisms by which the brain analyzes space for perception and action, and will help us understand and design rehabilitative strategies for deficits in spatial behavior such as occur after strokes involving the parietal cortex, of which SI and Sll form a component. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Human performance is not a constant. We all have good days and bad days, times when we work or act efficiently and times when we are inefficient. Motivation has often been studied by changing the amount or the waiting time for reward, but the effect of internal fluctuations of motivation has never been studied in the frontal and parietal cortex of the monkey. Preliminary results from this laboratory indicate that the monkey lateral intraparietal area (LIP) has a signal which, rather than describing what the monkey sees or will do, correlates with the monkey's probability of success on the current trial of a difficult task, and therefore fits the criteria for an arousal or motivational signal rather thana sensoriomotor signal. This signal may be the cortical manifestation of ascending pathways, and if so it should be found in other visual and oculomotor areas, and should have pharmacological properties related to modulatory as opposed to sensorimotor processing. In a difficult visual search task, which begins with the monkey looking at a fixation spot for 500 ms before the search array appears, the baseline activity of neurons in LIP during the fixation period predicts both the monkey's probability of success or failure in the task, and the intensity of the transient visual response to the array onset. The baseline activity correlates inversely, on a trial-by-trial basis, with a recency-weighted index of the monkey's history of success or failure, increasing when the monkey has recently has done poorly and decreasing when the monkey has done well. The baseline does not predict the location of the target in the impending array, and it is unrelated to the monkey's locus of spatial attention as determined by the monkey's response in a cued visual reaction time task. The first aim of this proposal is to verify this signal in LIP, ad then see if it exists in two other visual areas, the frontal eye field (FEF) and prestriate area V4 Further evidence for a behaviorally relevant, spatially non-specific signal in LIP comes from studying noise correlation in a foraging task. Neurons that do not share excitatory receptive fields nonetheless exhibit significant noise correlation, which is maximal during the pretarget fixation period, and also varies inversely with the monkey's history of success and failure. The second aim of this proposal is to verify these findings in the search task and extend them to FEF and V4. The hallmark of a modulatory signal is that it should be modifiable by neurotransmitters associated with ascending pathways. Acetylcholine (ACh) increases the baseline and visual transient signals in LIP, and mecamylamine, an ACh nicotinic receptor antagonist, suppresses the signals, suggesting that nicotinic cholinergic signals are important in modulating sensorimotor activity in LIP. The third aim is to verify these results in LIP, and extend them to FEF and V4. Most behaviorally relevant drugs work on modulatory systems. Understanding the mechanism by which modulatory systems affect visual processing is critical to understanding the mechanism of action of these drugs, and will facilitate the design of new and better agents.

DESCRIPTION (provided by applicant): If you close your eyes you can still image the world around you, and, with your eyes closed point to the spatial location of objects in the world. Patients with lesions of the parietal cortex have deficits in visual memory, and cannot locate objects in the world with their eyes closed. We have discovered that neurons in the lateral intraparietal area, a region in the parietal lobe, maintain a memory of objects in the environment across several trials. When a subject makes a saccade that brings the spatial location of a remembered object into the receptive field of a neuron, the neuron responds as if the object were still there, although with a longer latency and lesser (although still significant) response. The aims of this proposal are to determine the brain areas upon which this environmental memory depends. We will examine the role of three candidates: the frontal eye field, the parahippocampal gyrus, and the eye position region of primary somatosensory cortex. PUBLIC HEALTH RELEVANCE: Normal humans have a detailed visual memory of their environment. With their eyes closed they can point to objects in their environment, or describe familiar places. Patients with lesions of the parietal lobe cannot do this, and the absence of visual memory for action interferes with their rehabilitative potential. This proposal seeks to understand the basic neurophysiology responsible for this environmental memory, in order better to be able to plan rehabilitative strategies.

DESCRIPTION (provided by applicant): Columbia University has a large and vibrant vision research community supported by the National Eye Institute, with 20 qualifying grants. Vision research at Columbia ranges across a huge gamut of topics, from genetic studies of retinal and visual brain development in Drosophila and mice to epidemiological studies of the behavior of patients with eye disease. Computational, neurophysiological, light and electron microscopic, genetic, biochemical, and clinical techniques focus on a range of problems including the development of the eye and the visual brain, the mechanisms of ocular angiogenesis, the systems neuroscience of visual and oculomotor behavior, and the pathophysiology and treatment of retinal diseases such as macular degeneration. To support this vision research we are requesting the establishment of a National Eye Institute supported set of Core Facilities for Vision Research, to provide services that could not be provided by individual research grants. The proposed core will have three modules: a instrumentation fabrication and design module which will be the successor of a similar module which was funded by an NEI program which cannot be renewed; a computer support module which will include offsite data backup, support and maintenance for the hundreds of computers, including an X-grid cluster, used by the vision research community, and a microscopic imaging module which will provide histological and in vivo and fluorescent microscopy services. This core will also facilitate collaboration among members of the Columbia vision research community, and encourage scientists not currently engaged in vision research to use their expertise to solve problems related to vision.

Project Summary/Abstract Columbia University has a large and vibrant vision research community supported by the National Eye Institute, with 25 qualifying R01 grants and 48 vision scientists in all. Vision research at Columbia ranges across a gamut of topics, from genetic studies of retinal and visual brain development in Drosophila and mice to studies of human retinal disease. Computational, neurophysiological, light microscopic, genetic, biochemical, and clinical techniques focus on a range of problems including the development of the eye and the visual brain, the mechanisms of ocular angiogenesis, the systems neuroscience of visual and oculomotor behavior, and the pathophysiology, genetics, and treatment of retinal diseases such as macular degeneration, retinitis pigmentosa, myopia, and glaucoma. To support this vision research, we are applying to renew our National Eye Institute grant P30 EY019007, which will continue to support a set of Core Facilities for Vision Research and enable services that could not be provided by individual research grants. The grant supports three research cores: i) an Instrumentation Fabrication and Design Core that designs and builds custom equipment; ii) a Computer Core that performs support and maintenance for the hundreds of computers, including real-time laboratory computer-based interface used by the vision research community, handles research-specific database design, integrated data storage, management and analysis with the new Genomics Analysis Suite; and iii) an Imaging, Histology and Functional Diagnostics Core, which provides histological, in vivo, fluorescent microscopy, OCT, and ERG services. The grant not only supports currently funded investigators with NEI R01s, but also aids the work of vision scientists supported by other NEI funding mechanisms, other NIH institutes, and, importantly, young investigators gathering data in order to submit their first NEI grants. This grant facilitates collaboration among members of the Columbia vision research community, and encourages scientists not currently engaged in vision research to use their expertise in problems related to vision.

THE ROLE OF THE CEREBELLUM IN VISUAL LEARNING: A major puzzle in understanding the mechanisms of visual behavior is to answer the question of how the brain learns to associate an arbitrary stimulus with an action. There is nothing about a red traffic light that, in itself, demands that a driver slow down and stop the car ? but everyone who drives has learned that association. The cerebellum is a part of the brain that is generally thought to control motor performance. There is a huge amount of cerebellar physiology in animal models from mouse to monkey, studying well- controlled examples of motor performance, for example the change in gain of the vestibuloocular reflex in response to muscular weakening. The cerebellum is also important in classical conditioning of the eye blink, where the unconditioned stimulus is an air puff, and the conditioned stimulus a tone. As expected, the cerebellum is connected to parts of the cerebral cortex involved with movement. However, it is also connected to parts of the cerebral cortex associated with visual perception and cognitive processing. There is a rapidly developing amount of evidence that the cerebellum has a role in cognitive processes as well as motor processes, mostly from clinical correlations, but there is no physiological evidence for cerebellar function in cognitive processes beyond classical conditioning of the eye blink reflex. In our preliminary results we have shown that the cerebellum has a signal that may be important in the visual and cognitive process of visuomotor association, rather than in the shaping of a movement. We trained Rhesus monkeys on a visuomotor association task, in which the monkey learns to associate an arbitrary symbol with a simple movement. The task begins with the monkey?s putting each hand on a different dowel, which brings a fixation point on a screen in front of the monkey, which the monkey looks at. A second later one of two symbols appears replaces the fixation for 200ms. One pattern is associated with a left hand movement and the other with a right hand movement. The monkey?s job is to figure out which symbol is associated with which hand. It usually takes between 20 and 40 trials to solve the problem. We have discovered that the activity of Purkinje cells in the cerebellar cortex tracks the monkey?s process of learning. The movement does not change as the monkey learns, and it is unlikely that the cells we have discovered are controlling the motor aspects of the task. Most cells respond to movements of both hands. Finally the signal is similar when the monkey reports the association left or right using one of two very different movements ? releasing the grasp on the dowel or lifting the hand from a plate. This R21 grant is to firm up our very preliminary results that the cerebellum is involved in visuomotor association as opposed to pure motor control. These results may change the conventional wisdom about the cerebellum, and open a new way of thinking about visual learning.

ABSTRACT Visual learning is critical to the lives of human and non-human primates. Visuomotor association, the assignment of an arbitrary symbol to a particular movement (like a red light to a braking movement), is a well- studied form of visual learning. This proposal tests the hypothesis that the brain accomplishes visuomotor associative learning using an anatomically defined closed-loop network, including the prefrontal cortex, the basal ganglia, and the cerebellum. In our preliminary work we have developed a task that studies how monkeys learn to associate one of two novel fractal symbols with a right hand movement, and the other symbol with a left hand movement. Every experiment begins with the monkeys responding to two overtrained symbols that they have seen hundreds of thousands of times. At an arbitrary time we change the symbols to two fractal symbols that the monkey has never seen. It takes the monkey 40 to 70 trials to learn the new associations. In our preliminary results we have discovered that Purkinje cells in the midlateral cerebellar hemisphere track the monkeys? learning as they as they figure out the required associations. The neurons signal the result of the prior decision. Half of the neurons respond more when the prior decision was correct; the others respond more when the prior decision was wrong. The difference between the activity of these two types of neurons provides a cognitive error signal that is maximal when the monkeys are performing at a chance level, and gradually becomes not different from zero as the monkeys learn the task. The neurons do not predict the result of the impending decision. Although the neurons change their activity dramatically at the symbol switch, the kinematics of the movements do not change at all. This proposal takes this discovery as the starting point for four aims: 1) to use viral transynaptic tract tracing to discover the cortical and basal ganglia regions that project to the cerebellar visuomotor association area. 2) to record from the four nodes of the network as anatomically defined (midlateral cerebellar hemisphere, dentate nucleus, basal ganglia, prefrontal cortex), simultaneously, using multiple single neuron recordings, to see if these areas also have information about the process of visuomotor association 3) to inactivate each node, to see how their inactivation affects the monkey?s ability to learn new associations, and whether the inactivation affects the activity of the neurons at the other nodes. 4) to develop computational methods to analyze the activity of neural activity recorded simultaneously in all four nodes of the network (Aim 2) in the midlateral cerebellar cortex with regard to parameters such as prior outcome and movement, hand, symbol, and the intensity and epoch of the prior cognitive error signal. We will use dimensional reduction techniques to answer questions like whether hand or symbol can be decoded from network activity. We will model how the cerebellum simple spike cognitive error signal might propagate through the network and be used to facilitate visuomotor association learning and the processing of signals in the cerebellum, basal ganglia and cerebral cortex

Summary/Abstract The Administrative Core is critically important for the smooth functioning of the Center Core activities. To ensure consistent functioning of the Research Cores, the Core Staff assign schedules according to the stated priorities of the Core. Scheduling conflicts are handled by the individual Core directors, and if necessary, the Administrative Committee, which consists of the Module Directors, the Contact Principal I Investigator, as well as an outside member. The Grants Manager/Administrator, Ms. Whitney Thomas, will coordinate and manage all grant-related issues including daily management, ordering, financial aspects of equipment maintenance, budget reconciliation, and progress report preparation. She will also administer the iLab program, insuring that the Core participants and Core personnel use the system appropriately. She will generate monthly reports for each Module, for the benefit of the Module Directors in the PI. References Cited Page 1