Barry E. Stein - US grants

The superior colliculus is involved in orienting and attending to visual and somatosensory stimuli. This behavioral role is subserved primarily by intermediate-deep laminae cells. Yet surprisingly, most of the work done on the superior colliculus has focused on superficial lamina visual cells. Thus, we know comparatively little about the manner in which sensory information is processed in the cells that appear critical for the superior colliculus to play its role in orienting to and localizing sensory stimuli. Of primary concern in the present proposal is how the receptive fields and response properties of these intermediate-deep lamina cells are formed from the integration of various ascending and descending inputs. In the past few years, we identified the source of descending (corticotectal) somatosensory input as the anterior ectosylvian sulcus (AES) and the rostral suprasylvian sulcus. A "new" somatosensory cortex in the AES was described and labeled SIV. Both the AES and the rostral supra-sylvian sulcus have also been shown to contain visual cells, and both regions project widely across the intermediate-deep laminae of the superior colliculus. In the proposed experiments, we will conduct an extensive series of experiments to document the normal response and receptive field properties of deep lamina visual, somatosensory and visual-somatosensory (bimodal) cells. We will then determine what contributions are made to these properties by the visual and somatosensory corticotectal afferents received from the areas described above. These data are necessary to (a) give us a comprehensive view of the properties of these intermediate-deep laminae cells, (b) provide insight into how these properties are built from the signals of specific afferents, and (c) afford us the opportunity to compare the properties of visual and somatosensory cells in the same structure that may underlie the same types of behavior. These data are crucial if we are to gain insight into which neuronal properties are essential for which behaviors, and to make progress toward closing the conceptual gap between neurophysiology and behavior.

The literature is rife with striking examples of the powerful influences of nonvisual stimuli on visual behavior and perception, and with speculations about how such multisensory processes develop. For the most part, hypotheses about the development of multisensory integration have had to rely on inferences and extrapolations from overt behaviors and verbal reports because little was known about the development of its neural basis. Indeed, until recently, little was known about the neural mechanisms of multisensory integration in adults. Recently, however, we have developed a robust neural model of multisensory integration. Using the adult deep layer superior colliculus (SC) neuron, specific principles have been found to govern multisensory integration at the single neuron level and these principles have been shown to be applicable across species and across different areas of the neuraxis as well. Because these principles determine the activity of neurons which constitute a major component of the descending output pathways from the SC (which initiate movements of the eyes, ears and head), they have also proven to be predictive of overt visual attentive and orientation behavior. We propose to study deep layer SC neurons for two interrelated purposes: (1) to understand how they develop the response properties through which they mediate attentive and orientation behaviors, and (2) as a model to understand how the brain develops the capacity to integrate information across sensory modalities. The maturation of these neuronal capabilities is essential for the brain to maximize its processing of information about the external world and to ensure that adaptive responses can be initiated when the individual cues associated with a given event are minimal or ambiguous. Understanding their normal developmental course is an essential step in elaborating strategies to deal with developmental anomalies that compromise attentive mechanisms and the overt behaviors that depend upon them.

The environment is rich with ever-changing combinations of sensory stimuli which must be continuously integrated for the brain to produce a comprehensive perception of the world. Although the striking influences of multisensory integration on perception are well documented, the underlying neural bases of these effects are poorly understood. During the funding period of this grant we have found that there are specific principles guiding multisensory integration at the level of the single neuron (the superior colliculus neuron has served as our model), and that these principles are also predictive of overt behavior. It is now necessary to determine how these multisensory properties arise in the superior colliculus, and whether they represent a general set of principles that are applicable to multisensory neurons in regions of the brain (i.e., 'association' cortex) whose inputs, cytoarchitectures and functional roles are quite different. Because of the profound effects induced on a multisensory neuron when two different, sensory stimuli are present, an intriguing question has arisen which we also plan to address: is it possible that the unimodal receptive field properties of these neurons (properties which are responsible for selecting which stimuli gain access to their networks) can be significantly altered in the presence of a stimulus from another modality? If so, this would suggest that receptive field properties can be situation-dependent. Finally, using single neuron recording techniques in behaving animals we will examine how the principles of multisensory integration influence the sequence of events beginning with the processing of sensory inputs, followed by the initiation of premotor discharges, and culminating in the production of an overt response. The information from these experiments is an essential step in the development of a comprehensive understanding of the processes underlying multisensory integration.

DESCRIPTION (provided by applicant): The visual system is opportunistic, incorporating information from non-visual cues whenever possible to enhance its visuomotor control. This dramatically enhances its ability to detect and respond to environmental events and is evident in the response properties of deep layer superior colliculus (SC), a major midbrain visuomotor structure involved in detection, and orientation behavior. Using the visual-auditory SC neuron as a model, we showed that this process of visual multisensory integration must be instantiated during postnatal life based on experience with visual and non-visual (auditory) cues. Surprisingly, this experience is useful only in the presence of inputs from sensory-specific visual and auditory subdivisions of association cortex. In their absence SC neurons will develop the ability to respond to visual and auditory cues independently, but will not be able to integrate these cues to enhance their responses and the visuomotor behaviors that depend on them. But if given appropriate training later in life and in the presence of these cortical influences, they an still acquire this fundamental capability. These findings suggested the presence of substantial adult plasticity, a finding of more than passing interest to those with congenital visual or hearin deficits who have no opportunity to develop V-A multisensory integration until intervention corrects the underlying sensory defect. But, the practical use of this information is limited by poor understanding of the biological constraints and impact of age on this developmental process. We are now poised to determine how these cortical afferents accomplish this task, and what specific information they communicate to their SC target neurons. We posit that these sensory-specific cortical regions must form a functional ensemble with their target SC neuron for this developmental process to take place, and that rather than forming a simple associations, the ensemble encodes their relational statistics and uses this information to tune the properties of the SC neurons that will ultimately integrate this information. But, because of inherent features of the SC (e.g., its sensory topographies) the process is not veridical, but biased toward cross-modal cues in spatial and temporal concordance: those likely derived from the same event and, thus, possible targets of SC-mediated behaviors. Although this process is less rapid and efficient in adulthood, we hypothesize that this is because the circuit becomes less capable of extracting the relevant cross-modal statistics from the ambiguities that characterize normal environments, not because its fundamental mechanisms of plasticity have been compromised We propose to test each of these hypotheses in the current proposal.

[unreadable] DESCRIPTION (provided by applicant): The proposed training program is a natural outgrowth of the ongoing interactions among departmental faculty interested in a broad range of issues, all related to sensory systems. As a program focusing on training predoctoral and postdoctoral students to study questions related to sensory development, organization, processing, perception and especially the ongoing interactions among sensory systems, it provides a unique training environment. Predoctoral students in the Department of Neurobiology and Anatomy and the Interdisciplinary Program in Neuroscience in the Graduate School of Wake Forest University who want to concentrate their graduate studies on an in-depth analysis of one or more sensory systems are eligible for the training program. This training program offers a singular experience in that 1) topics such as neuropharmacology, receptive field organization, and animal behavior which are normally covered in a generic manner in neuroscience courses are addressed in the context of multiple sensory systems, 2) students rotate through laboratories in which they will gain in-depth experience in several sensory systems, 3) all training program students and faculty participate in a seminar series as well as in a journal club that is topic-keyed to the core courses in Sensory Neuroscience, ensuring continuing broad intellectual and collegial interactions among all members of the training program, and 4) students will be exposed to training opportunities that offer exposure to career paths in addition to traditional tenure-track academic positions. The training faculty is a relatively small group of investigators involved in broad collaborative interactions providing a highly cooperative and interactive environment for predoctoral and postdoctoral training. A major focus for the training program continues to be the recruitment of under represented minorities. [unreadable] [unreadable]

Project Summary The brain uses experience with environmental events to construct a framework for integrating the information received from its different senses. The end result is enhanced sensitivity to those cross-modal stimulus configurations that are likely to be derived from the same event. This capacity for 'multisensory integration'optimizes the brain's sensitivity to events of biological significance, and its behavioral responses to those events. It is of obvious survival value. The neural and behavioral manifestations of this process have been studied most extensively in the midbrain superior colliculus (SC), a structure involved in detecting and orienting to external stimuli. However, it is not yet known whether or not once formed during early life, the fundamental spatial and temporal principles that govern multisensory integration are 'fixed'thereafter, or can continue to adapt to changing environmental conditions. Nor is it known whether higher- order cognitive processes can co-opt these midbrain processes so that arbitrary covariant cross-modal features can be accommodated. Based on preliminary observations, we propose that the adult brain retains its sensitivity to the statistics of cross-modal events and is subject to cognitive oversight. Thus, any changes in those cross-modal statistics, or their significance, result in changes in the governing principles of multisensory integration. The present proposal uses multiple approaches and preparations to test these hypotheses. Adult animals will be exposed to systematic alterations in cross-modal statistics and/or their 'significance'via their association with reward. Then, the resultant short-term and long-term neural and behavioral effects of these experiences will be examined. The experiments are also designed to examine where in the neural circuit underlying SC multisensory integration, these experiences are encoded.

DESCRIPTION (provided by applicant): Project Summary The proposed training program is designed to meet the needs of an emerging discipline, and one reflecting the inherent similarities and distinctions among sensory systems. Surprisingly, this rapidly growing discipline of multisensory integration has a paucity of formal training opportunities and the present program offers a unique environment in which to meet this need at both the pre- and postdoctoral levels. Though its curriculum incorporates traditional topics relating to the development, organization, and perception/behavior derived from sensory processing in the different senses, the training program uniquely emphasizes the way in which sensory systems interact to markedly enhance or degrade the physiological salience of external events. Though bound together by common interests in hearing, the faculty provides expertise in each of the senses and, most importantly, has strong expertise in multisensory integration. Students in Neurobiology and Anatomy and the Interdisciplinary Program in Neuroscience are eligible. The training program offers a singular experience in topics such as neuropharmacology, electrophysiology, modern neuroanatomy and immunohistochemistry, computational neuroscience, development, cognition, psychophysics, behavior, and hands-on experience with a variety of laboratory techniques. These are normally covered in a generic manner, but are addressed here in the context of how individual sensory modalities process sensory information and the mechanisms that underlie their synergistic function. Students rotate through laboratories to gain in-depth experience in several sensory systems, but also have mini-courses to give them practical experience in techniques beyond those they may use for a current research project. All students and faculty participate in a seminar series and journal club that is topic-keyed to the core courses in Sensory Neuroscience, ensuring continuing broad intellectual and collegial interactions. Students are exposed to training opportunities and experts that offer advice regarding career paths in addition to traditional tenure-track academic positions. The training faculty is a relatively small group of investigators involved in broad collaborative interactions providing a highly cooperative and rich interactive environment for trainees. A major focus for the training program continues to be the recruitment of underrepresented minorities. PUBLIC HEALTH RELEVANCE: Project Narrative Despite traditional emphasis on individual senses, there is growing appreciation that brains are inherently multisensory, and growing evidence that anomalies of multisensory integration contribute to a host of developmental and age-related disorders. These include, dyslexia, sensory processing disorder, and autism. Multisensory therapeutic regimens may better ameliorate the sensory deficits associated with acute brain trauma (e.g., neglect following stroke), and training programs emphasizing interactions among senses are essential to promote a better understanding of the debilitating effects of disease and the strategies necessary to ameliorate them.

Project Summary The midbrain superior colliculus (SC) typically requires influence from ipsilateral visual cortex to play its critical role in generating visuomotor responses to contralateral cues. Thus, visual cortex lesions eliminate both normal visual feature processing and the visual functions of the ipsilateral SC. The result is a contralateral hemianopia. Although insights from animal models suggest amelioration of this deficit is possible through a number of interventions, none of these offers viable therapeutic options for human patients. However, using an animal model, we have recently demonstrated that a non-invasive rehabilitative training paradigm (using auditory-visual cues) can permanently reinstate vision in animals rendered hemianopic by unilateral removal of all contiguous areas of visual cortex. Unfortunately, we are largely ignorant of the neural changes that induce this reinstatement of vision. Nevertheless, our preliminary data do suggest that cross-modal training produces a functional reorganization in a cortico-SC circuit that involves specific regions of association cortex (i.e., the anterior ectosylvian sulcus, AES). These adaptive changes render SC neurons once again capable of visual responses and of supporting visual behavior in the absence of ipsilateral visual cortex ? presumably via compensatory inputs from AES. Our objective here is to use physiological and behavioral techniques to evaluate the physiological consequences of large visual cortex lesions on the neuronal properties in the AES and SC of hemianopic animals, and to determine how their properties are modified by cross-modal training so that vision is restored. Our overarching hypothesis is that cross-modal training, via Hebbian mechanisms, is able to amplify the normally subthreshold inputs to these regions from sources other than visual cortex. Understanding how the inherent plasticity of this circuit can be harnessed via non-surgical, behavioral training techniques to ameliorate hemineglect will help us understand the latent functional capabilities of this system, and provide invaluable insights to facilitate strategies for dealing with this debilitating condition in human patients.

Project Summary A major issue of ignorance in sensory processing is how the brain develops its remarkable ability to use its senses synergistically, a critical requirement for normal perception. We do know however, that acquiring this capability is a protracted postnatal process, and the ability to use visual and auditory information cooperatively must be learned. This process is best understood in terms of the detection and orientation behaviors mediated by the superior colliculus (SC), a midbrain structure well-endowed with multisensory neurons. After extensive visual-auditory experience, animals show enhanced visual-auditory detection and localization behaviors. Their multisensory SC neurons show similar changes ? now integrating their different sensory inputs to enhance their response and the physiological salience of the initiating events. The brain has come to treat these cross- modal stimuli as a coherent whole rather than as a set of competitive or unrelated cues. These changes are not seen in animals reared in darkness or with masking noise, and chemical lesions preferentially eliminating SC multisensory neurons eliminate the enhanced multisensory detection and orientation behaviors without disrupting responses to their individual component cues. Interestingly, this integrative capacity and its performance benefits in detecting and orienting to external events can be acquired in dark-reared and noise- reared animals by giving them appropriate experience later in life. But, the conceptual and practical use of this information is limited by a poor understanding of the factors underlying its acquisition and operation. We suggest the acquisition of this SC capacity does not depend on forming generic associations between the sensory modalities as is widely believed. Rather, it involves a far more sophisticated form of statistical learning in which the probability that any set of cross-modal inputs derive from the same event is encoded. This information is then used by the circuit to determine how it will later respond to such events. But to be effective in this regard, those cross-modal inputs must access the SC through unisensory projections from association cortex (and be filtered by the SC?s inherent biases). We posit that this natural process can be reproduced artificially by inducing covariant activation of these converging cortico-SC afferents - in the absence of external cues, and without any of the reinforcement contingencies or cognitive factors normally associated with overt behavior. Finally, we hypothesize that NMDA receptors provide the crucial mechanistic basis for encoding this experience by initiating Hebbian-like learning algorithms. The end result is a multisensory system that is extremely sensitive to the particular cross-modal stimulus configurations that were learned to belong to the same events. This gives them preferential access to the neural machinery that will still further enhance their physiological salience and their ability to elicit SC-mediated behavior, ensuring that the system is adapted to the environment in which it was formed, and in which it will likely be used.