Richard T. Born - US grants

An important theme that has emerged from studies of the visual system is the tendency for neurons encoding different types of information to become anatomically segregated . The initial segregation of different types of information within an area, and subsequent anatomical divergence and physiological processing of that information, has a clear precedent in the Vl blob-to-V2 stripe organization of the macaque visual cortex. Results from 2-deoxyglucose experiments (Tootell and Born 1990) suggest that this type of parcellation of information continues within the "motion pathway" neurons encoding two different kinds of visual motion (large-field vs. local motion contrast) are clustered in interdigitating columns in area MT. It is proposed to explore the nature and extent of this functional clustering to try to understand how information about visual motion is extracted, organized, and used by subsequent areas. Specific aims of the project are: 1) To study the laminar and horizontal distribution of the receptive field properties in area MT using single unit electrophysiology combined with 2-deoxyglucose functional labelling and cytochrome oxidase histology. 2) To examine the nature of the interaction between center and surround in a subpopulation of surround-inhibited MT neurons. 3) To determine the intrinsic connections within area MT that may lead to the observed receptive field properties, by making tiny injections of horseradish peroxidase into MT. 4) To analyze the outputs of area MT, using conventional tract tracing methods, with respect to its modular organization in order to see how and to what extent different types of motion information remain segregated.

An important theme that has emerged from studies of the visual system is the tendency for neurons encoding different types of information to become anatomically segregated . The initial segregation of different types of information within an area, and subsequent anatomical divergence and physiological processing of that information, has a clear precedent in the Vl blob-to-V2 stripe organization of the macaque visual cortex. Results from 2-deoxyglucose experiments (Tootell and Born 1990) suggest that this type of parcellation of information continues within the "motion pathway" neurons encoding two different kinds of visual motion (large-field vs. local motion contrast) are clustered in interdigitating columns in area MT. It is proposed to explore the nature and extent of this functional clustering to try to understand how information about visual motion is extracted, organized, and used by subsequent areas. Specific aims of the project are: 1) To study the laminar and horizontal distribution of the receptive field properties in area MT using single unit electrophysiology combined with 2-deoxyglucose functional labelling and cytochrome oxidase histology. 2) To examine the nature of the interaction between center and surround in a subpopulation of surround-inhibited MT neurons. 3) To determine the intrinsic connections within area MT that may lead to the observed receptive field properties, by making tiny injections of horseradish peroxidase into MT. 4) To analyze the outputs of area MT, using conventional tract tracing methods, with respect to its modular organization in order to see how and to what extent different types of motion information remain segregated.

DESCRIPTION: The overall goal of this laboratory is to understand the circuitry of the cerebral cortex and how it is related to perception and behavior. Central to this goal is the study of functional architecture, which deals with the way that information represented by the firing patterns of single neurons is anatomically organized into computational structures such as columns and maps. Knowledge of the functional architecture is crucial to an understanding of how the brain works for two major reasons. 1) When combined with knowledge of intrinsic and extrinsic anatomical connections of a cortical area, it yields insights into the nature of the cortical circuitry, how it performs its computations and how it may develop. 2) When combined with behavioral and microstimulation techniques, it can be used to demonstrate causal connections between neural activity and behavior. Understanding these-- relationships is the central goal of neurobiology and a necessary first step in understanding and treating diseases of the brain. An extrastriate visual motion processing area, the middle temporal visual area (area MT), is an excellent place to pursue the issues outlined above. A great deal of information has already been accumulated on the stimulus-response properties of its neurons and its basic connections with other brain areas. Lesion studies and microstimulation experiments have indicated a prominent role in several visual behaviors such as discrimination of direction of motion and visual tracking. The missing element has been an understanding of the functional architecture, which can be used to fit together the many pieces of the puzzle and provide a firm foundation for its relationship to behavior. It will be the goal of this proposal to elucidate the functional architecture of area MT by relating single neuron response properties to the anatomical structure of area MT and then to use microstimulation as a probe to assess the behavioral significance of the functional architecture. SUMMARY: In this well-written and detailed application, Dr. Born requests five years of funding for a comprehensive study of the modular organization of area MT in the macaque monkey. From his preliminary data and previous publications, Dr. Born presents strong evidence that MT is divided up into at least 2 different kinds of columns which he calls bands and interbands. The principal investigator has strong evidence that these bands contain 2 very different kinds of neurons that subserve very different motion tasks: self motion and object motion. In a comprehensive and wide ranging series of experiments he proposes to study the physiology, projection, functional architecture and behavioral function of these cells. The experiments are well designed, and address a critical aspect of this much studied higher cortical area. Given the ample preliminary data there is a high probability of success.

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DESCRIPTION (provided by applicant): We propose to continue a Jointly Sponsored Predoctoral Training Program in Neurosciences that is the major source of support for early year students in the Ph.D. Program in Neurosciences at Harvard University. The goals of this interdepartmental Ph.D. program, established in 1981, are (1) to organize within a single training faculty the neuroscientists at Harvard Medical School, its affiliated hospitals, and Harvard College; and (2) to train research scientists and teachers who are interested in mental health, diseases of the nervous system, and fundamental mechanisms of the brain. The training program is designed to provide trainees with a broad and thorough background in neuroscience and to mentor them in performing original and rigorous research in important areas of neuroscience. In the first 18 months, trainees complete a sequence of core courses ranging from cell and molecular neurobiology to systems neuroscience, as well as collateral courses selected from cell and molecular biology, immunology, statistics, and other subjects appropriate to individual interests. Students rotate through three different laboratories. Following the coursework, laboratory rotations, and a preliminary examination, students begin full time dissertation research. They are also involved in other ongoing training activities including journa clubs, seminars, and data presentation. There are currently 100 graduate students enrolled in the Program in Neuroscience. The total faculty includes 118 members; the 68 faculty who are currently most actively involved in graduate education are training mentors on this proposal. Considerable effort has gone into making this program a highly interactive group with extensive formal and informal contacts between students and faculty. Graduates of this program have a high rate of staying in careers in biomedical research and make substantial contributions to a growing understanding of neuroscience.

? DESCRIPTION (provided by applicant): The ubiquity of cortico-cortical feedback connections argues strongly for their importance, and theoreticians routinely make use of them in models of cortical function. Despite this, next to nothing is known about their function. Previous studies in which feedback has been manipulated have been performed in anesthetized animals, and our recent studies in alert animals have revealed fundamentally different results. Our major finding from the previous cycle is that feedback from V2 exerts minimal effects on the classically defined receptive field center of V1 neurons: orientation tuning and the center's contrast response function are virtually unaffected. However, larger stimuli that engage the receptive field surround and that normally cause suppression, cause much less suppression when V2 is inactivated. We have further discovered that the influence of feedback is on the spatial extent of the surround, rather than on its gain, and that seemingly higher order properties of surround suppression, such as feature- matched suppression, are more strongly influenced by feedback than is basic normalization. All of these observations are consistent with a theoretical framework of predictive coding, which posits a key computational role for the interaction between feedforward and feedback connections. We now propose to examine specific examples ranging from built-in contextual influences in form and motion perception to the nature of changes that underlie the learning of a perceptual task. Our general approach will be to use causal manipulations-reversible inactivation of cortical areas (V2 and/or MT) that feed back to V1-to test the hypothesized role of top-down influences in perceptual inference. Our studies will shed light on the basic mechanisms of cortical function.

DESCRIPTION (provided by applicant): Nineteen neuroscientists within Harvard's Neuroscience Program request continued funding for four pre-doctoral positions in our Training Program in Visual Neuroscience. Training focuses on the study of visual pathways from retina to brain, and of the cellular, molecular and developmental neurobiology of the visual system. These faculty members are distributed throughout the university. Ten faculty members are in basic science departments at the Medical School, six are in hospital-based laboratories, and three are in the Faculty of Arts and Sciences. Over the past two decades, Harvard University has greatly expanded the number faculty members who study the molecular, developmental, and neural-systems approaches to visual science. Students can choose laboratories among a large community of vision researchers, most of who are affiliated with Harvard's NEI Core Grant in Vision research. The goal of the Visual Neuroscience Training Program is to build a large, coherent group of students based in this Harvard-wide vision community, who are trained by its faculty and who have a strong sense of community. The grant will support two students in their second year and two in their third, but students remain actively involved with the program as they advance to later years, creating a large cohort of affiliated students. We train and supervise these students with courses, thesis committees, seminars, symposia, and our Systems-Vision journal club. Thus, trainees interact with the faculty and with each other throughout their graduate careers. Many vision scientists visit Harvard every year to give seminars; trainees at all levels interact with them over lunch and in lab visits. Through these activities, we will help train a new generation of vision scientists whose scientific careers will help us understand all aspects of the visual system: development, information processing, and disease.

Project Summary Current vision research relies on a wide variety of imaging techniques and modalities, ranging from MRI-based imaging of the living brain, to detecting a neuronal tracer, to reconstructing neurons that have been histochemically processed. However, the resources and expertise required for the wide range of such techniques can often lie outside the scope of individual laboratories. The Neural Imaging Module aims to address this need by providing extensive support to investigators using both pre- and post-mortem techniques to visualize brain tissue. Specifically, the Neural Imaging Module (1) supports pre-mortem studies in monkeys, such as fMRI and CT scan-based methods for guiding physiological experiments; (2) assists with post-mortem experiments in rodents and monkeys, including staining for specific neuronal markers, assessment of post- physiology electrode tracks, and testing of new viral-based tracing techniques; and (3) provides tools and services for analysis of histological preparations, including alignment of serial sections, and reconstructions of neurons and projections. In keeping with the diverse nature of these services, the Module has contributed to a wide variety of vision-based investigator projects. Under the experienced direction of Module Director, Dr. Richard Born, and Module staff member Dr. Vladimir Berezovskii, the expertise and services provided by the Neural Imaging Module will continue to play a critical role in advancing Harvard-area vision research.