Norman M. Weinberger - US grants

This action is provide support for the Fifth Conference on the Neurobiology of Learning and Memory to be held in Irvine, CA on October 22-24, 1992. The general theme of this meeting, "Brain and Memory: Modulation and Mediation of Neuroplasticity" is timely and of high importance to the field. State-of-the-art lectures will be given by internationally recognized investigators highlighting four exciting areas. First, the relationship between emotion and memory will be examined. The findings and theories examined in this session have implications for understanding the role of motivation, emotion and stress in learning and memory. Second, recent findings and theory concerning age-related changes in brain and memory in animals and humans will be explored. The third session will focus on the plasticity in the cerebral cortex, which has received only limited attention to date but has long been recognized as the main processing structure and probably the ultimate forebrain storage site of memories. Finally, the relationship between long-term potentiation and memory will be probed. The format of this conference will insure cross-fertilization of ideas on fundamentally important questions on how we learn and remember. Some of the funds are to used for support of selected graduate and postdoctoral students who might overwise not be able to attend this outstanding conference.***//

Emotional reactions and states, such as fear, are central to adaptive behavior. Inappropriate emotion is a pervasive source and expression of mental and behavioral dysfunction. Although research with non-humans cannot deal directly with mental emotional experience, it can directly elucidate the neurobiological bases of emotional expression and thereby provide a foundation for both preventative and therapeutic approaches to emotional dysfunction in humans. Emotional reactions are based upon an individual's evaluation of his or her sensory experience, yet little is known about the sensory processing of emotion-producing stimuli. Recent studies reveal that when an animal experiences a sound which has fear- producing capabilities, the coding and representation of that fear stimulus is altered; specifically, the auditory cortex becomes "re-tuned" rapidly and in an enduring manner to emphasize the processing of that stimulus. Our long-term objectives are to understand the neural bases of sensory system processing of emotional stimuli and to discover the mechanisms by which emotional stimuli are stored and often resist extinction when reactions to them are inappropriate. The specific goals of this project are to determine how the auditory cortex processes and represents specific information about fear stimuli by neurophysiological determination of frequency receptive fields and basic response area parameters for single cells in the different lamina of the cortex of guinea pigs. Subjects will be trained in two types of tasks, classical conditioning and instrumental avoidance learning, with two types of problems, single toe training and two-tone discrimination training. Thereafter, mechanisms of the fear-based cortical re-tuning will be studied by using microstimulation of an important thalamic input to the cortex, by blockade of NMDA receptors and by a combination of stimulation and NMDA receptor blockade. These findings will provide the firs systematic analysis of how information itself which is specific to fear stimuli is processed and stored in the cerebral cortex.

DESCRIPTION (provided by applicant): Learning and memory are absolutely essential to hearing. In their absence, comprehension would be impossible because no auditory information could be acquired or stored, and the recognition of previously heard sounds would be impossible. The long-term objectives of this research project are to discover the neural mechanisms that enable sounds to acquire meaning. The primary auditory cortex (A1) has been identified as a site for the acquisition and storage of auditory information. In general, encoding of behaviorally relevant sounds is strengthened as part of an overall functional remodeling of acoustic representation. For example, when a tone becomes a signal for rewarding or aversive stimuli, frequency tuning shifts toward or to the signal frequency, strengthening its encoding while weakening that of other frequencies. Tuning shifts can increase the area of signal representation in A1, and the amount of gain is directly proportional to both the cue's level of acquired importance and its memory strength. Such representational plasticity (RP) appears to be a substrate of auditory memory because it has the same attributes as memory itself. Engagement of mAChR's in A1 directly or by pairing tone with stimulation of the cholinergic nucleus basalis (NBstm) is sufficient to (a) produce RP, (b) actually implant specific behavioral auditory memory, and (c) increase neural synchrony (NSync). Further, increased synchrony predicts both RP in A1 and auditory memory. Thus, sounds may gain meaning via increased neural synchrony, which gives them greater effectiveness in communicating with target structures and strengthening their own representations. The specific aims of this project are to determine if increasing NSynch (gamma band oscillations and unit co-variances) during signal presentation can strengthen and increase the specificity of auditory memory, and/or enhance RP. Rats will be trained in auditory fear and reward tasks while a signal tone's induced neural synchronization is boosted via increasing loudness or brief concurrent NBstm. Studies will determine if increasing NSync can enhance memory strength and specificity, using custom designed training protocols that produce a modest level of RP and memory. If these experiments uncover neural synchrony as a mechanism sufficient to strengthen and/or produce specific auditory memory, then this project will have opened a pathway for remediation of auditory comprehension disorders.

DESCRIPTION (Adapted from applicant's abstract): The long-term objective of this research is to understand how the cerebral cortex acquires and stores information, which can lead to neurobiological interventions in maladaptive thought and behavior, and impaired learning in development and aging. Although the cerebral cortex is by far the largest part of the human brain and is a major structure that subserves learning and memory, it has been neglected because of the need for animal models of cortical memory. However, recent studies have established that the auditory cortex develops memory-like changes in the frequency tuning of individual cells during fear learning, termed "receptive field plasticity". This neural plasticity is associative, highly specific, rapidly acquired and retained indefinitely, like major forms of human memory. Cortical control of subcortical fear centers is known but not understood. The specific aims of this project are to determine the nature and extent to which the overall functional organization of the auditory cortex is involved in fear learning and memory. The specific goal of this research project is to provide the first comprehensive investigation of the extent to which learning modifies the spatial representation of behaviorally relevant acoustic frequencies in the primary auditory cortex. Guinea pigs will be trained with pure tones in habituation, sensitization, classical, and instrumental conditioning. Further, the development and long term retention (weeks), and the degree of reversibility of plasticity will be delineated. The neurobiological bases of fear conditioning, which is basic to acquired anxieties, phobias and other behavioral pathologies, requires direct investigation of cellular mechanisms because pharmacological treatments can reduce the elicitation and expression of these emotions but not eliminate their cause.

[unreadable] DESCRIPTION (provided by applicant): The goal of this research project is to determine the involvement of the basolateral amygdala (BLA) in modulating the strength of physiological memory in the cerebral cortex, as indexed by learning-induced receptive field (RF) plasticity in the primary auditory cortex (ACx). The proposed experiments will investigate the role of the BLA in the induction and consolidation of RF plasticity. Moreover, the research will examine the involvement of the cholinergic nucleus basalis (NB) in mediating the BLA effects on cortical plasticity. It is well established that learning produces highly systematic changes in acoustic frequency receptive fields in the primary auditory cortex. Tuning is altered to increase response to and representation of behaviorally important stimuli (e.g., CS in classical conditioning) while reducing responses to other frequencies. RF plasticity has major characteristics of memory: it is associative, highly specific, rapidly induced, long-lasting (months) and exhibits consolidation, that is, increases in strength over hours and days. A central issue addressed by the proposed studies is whether the BLA modulates learning-induced cortical RF plasticity. There is extensive evidence that the BLA modulates the consolidation of memory for various kinds of training and that the modulation involves BLA influences on other brain regions including the caudate nucleus, hippocampus and entorhinal cortex. In view of the extensive evidence that the BLA modulates memory processes in other brain regions, including cortical regions, the proposed experiments will examine the role of the BLA in modulating the induction and consolidation of RF plasticity in the auditory cortex and determine whether the modulatory influences are mediated by activation of the NB. The findings will provide significant new information concerning the pathways and systems mediating the regulating influence of the BLA on memory consolidation and, thus, increase understanding of brain systems modulating the formation of memory for significant experiences.

DESCRIPTION (provided by applicant): Auditory comprehension, as well as auditory analysis, is essential for hearing. The comprehension of sound requires enduring auditory memory, i.e., the storage of the learned meanings of sounds. The rich and complex domain of auditory memory is enabled by the plasticity of the auditory cortex. For example, learning is accompanied by shifts of frequency tuning to emphasize sounds that become behaviorally important, as during associative learning. Although the fact of learning-induced cortical plasticity is now well-established, it alone cannot provide either an adequate understanding of the neural bases of auditory memory or the effective application of basic knowledge to clinical problems in hearing and communication. It is essential to determine the memory functions of cortical plasticity. The goals of this research project are to determine the memory functions of learning-induced cortical plasticity and the role of the cholinergic nucleus basalis as a mechanism mediating those functions. We hypothesize that three main functions of associative auditory plasticity are to enhance auditory memories by (1) making them stronger, (2) preserving their acoustic details and (3) promoting their flexible use to solve new auditory problems. To determine the functions of plasticity, it is necessary to control plasticity. We have already developed two ways to control plasticity: (a) indirectly by guiding learning strategies, (b) directly by stimulating the nucleus basalis. To test these hypotheses and reveal mnemonic functions of associative plasticity we will train rats with microelectrodes chronically implanted in their primary auditory cortex (A1), to bar-press for water in the presence of a tone. We will track the development of behavior and plasticity, and obtain complete functional maps of A1 in a subset of animals, by obtaining repeated profiles of neuronal discharge and local field potential responses to a broad range of pure tone frequency-level combinations. Post-training tests will assess memory strength, memory for details of acoustic experience and the ability to learn an auditory-cued avoidance task compared to appropriate control groups. If the nucleus basalis (NB) can meditate memory functions of A1, then pairing a tone with NB stimulation to induce A1 plasticity and auditory memory should increase the level of memory strength, retention of acoustic details and facilitate avoidance learning. The findings have direct translational implications for the design and implementation of therapeutic interventions, including remediation of phonological processing deficits in children and learning to comprehend speech following cochlear implantation. The optimal design of remediation training will directly benefit from promoting the desired type of specific cortical plasticity (assessed by scalp recordings or functional imaging) that can be custom-designed for each patient to promote strong, specific and flexible auditory memory. PUBLIC HEALTH RELEVANCE: Auditory comprehension, as well as auditory analysis, is essential for hearing as it enables the recognition of all sounds including speech. The results of this project will significantly increase our understanding of how the brain acquires, represents, stores and utilizes auditory experience. The findings will be directly relevant to the design and implementation of therapeutic interventions, to enable and improve general auditory and speech comprehension.