Michael Gabriel - US grants

Studies of human neuropathology have implicated the limbic system in the mediation of learning and memory processes. In accord with this result, our studies of unit activity in behaving animals have shown differentiation of neuronal responses to stimuli with varied associative significance. These effects occur in a triad of reciprocally interconnected limbic structures (the cingulate cortex, anteroventral thalamic nucleus [AVN], and hippocampal formation). Neurons in the deep cingulate cortical layers manifest discriminative firing in the early training stages, but the AVN and the superficial layers do not discriminate until discriminative behavior is well established. Similar relationships hold in the relative prefrontal corticothalamic system, but in this instance, the development of discriminative firing is accelerated, relative to the limbic triad. These results form the basis of a theory in which it is posited that the function of limbic forebrain in learning processes is the encoding and "extraction" of que significance. The sequential character of the developing differential responses provided the rationale for the model's hypotheses about the causal relationships among the involved structures. Recent tests supported the model's hypotheses that the late discriminative code in the upper cortical layers originates in the AVN, and that the hippocampal formation (subiculum) exerts a tonic suppressive influence over neuronal firing in the cingulate cortex. This suppressive control, predicted by the model, provides a mechanisms to account for the behavioral hyperreactivity shown by animals with hippocampal damage. A major breakthrough has been the realization that the structures of the limbic triad produce an "automatic" neural code relevant to the performance of well learned behavior, but not to its original acquisition. The analogous code in the prefrontal system is the "leading edge" code subserving acquisition. Thus our studies identify separate neurobiological substrates for original discriminative acquisition, and for the maintenance of well learned behavior. Most importantly, the recent work indicates that selective removal of afferents yields selective neuronal effects in the recipient structures, and selective behavioral deficits. This general result supports the efficacy of our strategy for the functional analysis of interacting brain systems in relation to ongoing behavior. The proposed studies continue the analytic strategy by investigating the contributions to the significance coding process in the limbic triad made by afferents from the prefrontal system, the noradrenergic and basal forebrain cholinergic projections, the mammillothalamic projection, and possible influences of the pontine reticular formation.

In order to optimize interdisciplinary approaches that capitalize upon new technical and theoretical developments, a Center for the Neurobiology of Learning and Memory is being established at the Beckman Institute (currently under construction) of the University of Illinois at Urbana-Champaign . This center will serve as 1) a Resource Center, providing advanced facilities for the study of the learning and memory process, including optical imaging (for histological studies), multi-electrode array recording (to allow functional patterns of interactions among neurons to be examined), and rapid tissue freezing (for assessment of sub-cellular dynamics); 2) a Research Center that fosters communication and collaboration among scientists pursuing common and related problems of memory and neural plasticity; 3) a Training Center which prepares graduate and postdoctoral investigators for research careers in learning and memory, and 4) a Recruiting Center that to attract outstanding young people to scientific careers. This program of scientific development and interaction is taking advantage of the unusual resources of the Beckman Institute and the University of Illinois Urbana-Champaign campus in neurobiology, interdisciplinary collaboration and cooperation, and strengths of the component disciplines of neural and behavioral sciences. Technical foci of the Center include large array neurophysiological recording facilities, with which the interactions among brain regions during learning are studied; rapid freezing facilities for examining brain slices in vitro, (with which the nature of plasticity at the level of the synapse is studied), and neuroanatomical imaging and analysis facilities (where memory processes are studied at levels ranging from the molecular to the morphological). Several types of learning are being studied, including discriminative conditioning, acquisition of motor skill, acquisition of acoustic discriminative ability, and the traditional psychological animal learning tasks such as mazes. In addition, current "models" of memory (such as long-term potentiation and kindling) are being examined. The function of the Center for the Neurobiology of Learning and Memory is to advance our knowledge of brain substrates of learning and memory from the cellular and molecular to the integrative brain system levels.

This award provides funds to establish an interdisciplinary site REU program in Neuroscience at the University of Illinois Neural and Behavioral Biology (NBB) Program, a Ph.D. granting interdisciplinary program begun in 1970. The common focus is neuroscience, the interdisciplinary field that seeks to understand the function of nerve cells and systems from the molecular and cellular levels to that of behavior. Faculty in the program that demonstrate an extensive history of involvement of undergraduate in laboratory research have been selected as co- Principal Investigators. Collectively, faculty in NBB have sent about 75 undergraduates who worked with them into scientific careers, including faculty positions at Harvard, Yale, Chicago, Stanford, and Pennsylvania. Even greater numbers have gone on to careers in Medicine and other professional Doctorate-level fields. Neuroscience subfields in which research experience will be offered included behavioral neuroscience, neural development and plasticity, molecular, cellular and genetic neuroscience, neurophysiology, neuroanatomy, computational neuroscience, and cognitive neuroscience.

Neuronal pattern analysis (NPA) documents the dynamic brain processes of sensation, perception, learning and cognition by recording the electrical activity of brain neurons. Recent advances in multi-array recording technologies have greatly expanded the rate at which NPA data can be obtained, and these technologies have fostered means not previously available to study the intercorrelations of dynamic activities in neuronal networks. Computational modeling of brain dynamic activity has fostered major increment in the requirements of data processing due to the need to analyze simulated neuronal spike trains and to compare real and simulated neuronal data. These developments call for parallel development of adequate database systems for organization, rapid access, and sharing of NPA data. This project will establish a database system (DBS) for time series neurophysiological data recorded in experiments of members of the University of Illinois Beckman Institute Neuronal Pattern Analysis Group. System design and implementation will be carried out with consultation and guidance of the National center for Supercomputer Applications. This proposed system will foster community-wide sharing of times series and other forms of neural data, proved a model DBS that can generalize to other neuroscience groups, and enhance the research in the involved laboratories.

Neuropsychological studies have established the brain's limbic system as critically important for human learning and memory processes, and limbic system degeneration is centrally involved in the etiology of Alzheimer's and Korsakoff's disease. The highly diffuse character of degenerative change in these conditions has made difficult the discovery of links between specific forms and sites of damage on the one hand and specific mnemonic and behavioral impairments on the other. Knowledge of the specific mnemonic functions and dynamic interactions of limbic brain circuits may prove helpful to the discovery of such links. Yet, little is known of these functions. The overall objective of this project is to specify completely these functions in an animal model. Past work of this project established the critical relevance of limbic circuits in relation to discriminative avoidance learning in rabbits. Studies of the neuronal activity in the behaving animal, selective lesioning, and neurochemical manipulations have fostered substantial progress toward this specification. Of particular value has been multi-channel recording, which allows documentation of learning-related neuronal activity simultaneously in six brain areas. This approach has yielded many unprecedented findings and a theoretical working model of the dynamic interactions of the cerebral cortical and thalamic limbic structures subserving learning. Studies proposed here afford major strides toward the elaboration of a veridical model. These studies will indicate: a) how the convergence of tegmental cholinergic and mammillothalamic afferents brings about training-induced neuronal plasticity in limbic thalamus; b) the pathway whereby cue-driven auditory information that triggers the learned response accesses the sites of critical learning-relevant plasticity in limbic thalamus; c) the functional relevance of training-stage related peaks of learning-relevant plasticity in subdivisions of the anterior thalamus; d) the dynamic interactions of hippocampal with limbic cortical and thalamic circuits that govern the training-stage related peaks of plasticity and suppression of learned behavior in response to unexpected events; e) the pathways whereby learning-relevant plasticity in limbic circuits accesses the motor system to produce output of the learned behavior.

DESCRIPTION (adapted from applicant's abstract): The amygdala and cingulate cortex are importantly involved in the etiology of emotional disturbances such as chronic anxiety, panic attacks and schitzophrenia. Yet, detailed knowledge of how these areas malfunction to bring about emotional disturbance has been elusive. This project approaches these issues, beginning with two fundamental premises. First, an understanding of the etiology of emotional disturbance will require a basic understanding of the role of the involved brain areas in production and control of emotional states. Second, individual brain areas do not influence psychological states in isolation. Instead, neural mediation of emotion and behavior emerges from the interactions of neurons in multiple brain areas that form functional circuits. This project continues an extensive programmatic analysis of the interactions of cingulate cortical and amygdalar neurons, and neurons in related areas, involved in mediation of fear-based learning of discriminative goal-directed behavior. The interactions are studied by recording the activity of neurons simultaneously in multiple brain sites during learning in rabbits. Selective circuit lesions and neurochemical manipulations are used to alter experimentally fear- and behavior-relevant information flow in the circuits. Recent discoveries set the stage for major advances concerning the documentation of specific learning-relevant brain pathways and circuit interactions. The new data demonstrate that amygdala neurons initiate rapidly-developing learning-related discriminative changes in the medial division of the medial geniculate nucleus (Mgm). The changes initiated in the Mgm enhance the sensory transmission of associatively significant stimuli, thereby facilitating behavioral performance. Intriguingly, the initiation process is blocked by briefly inactivating amygdala neurons during early training trials. If this is done, Mgm neurons can no longer develop these changes even after the inactivation is removed. The proposed research defines precisely the training period when the critical initiating events occur. Additional studies: test the hypothesis that amygdalar efferents act via synapses in auditory cortex to initiate the critical changes in the Mgm and establish the particular amygdalar subdivisions involved in the initiation process. The recent data also show that amygdala efferents are essential for the establishment of learning-related changes in the cingulate cortex and limbic thalamus. The changes in these areas are essential for acquisition of the learned behavioral response. Two functionally distinct cingulothalamic circuits exhibit early neuronal changes that mediate the initial stages of behavioral learning and late neuronal changes that mediate the performance of the learned behavior at asymptotic levels. Amygdalar efferents are essential for the early and the late cingulothalamic changes. These two circuits receive input from different amygdalar nuclei. The proposed studies test the hypotheses that neurons in the different nuclei exhibit the early and late forms of learning-related activity respectively and are the specific amygdalar nuclei involved respectively in production of the early and late cingulothalamic activity.

DESCRIPTION (adapted from applicant's abstract): Structures of the brain's limbic system are critically important for processes of attention, memory and cognition, and for the etiology of cognitive and behavioral disturbances such as schizophrenia and attention deficit disorder. Yet, knowledge of the specific malfunctions that bring about attentional and mnemonic disturbance has been elusive. This project approaches these issues, beginning with two fundamental premises. First, an understanding of the etiology of attentional and mnemonic disturbance will require a basic understanding of the involved brain mechanisms in production and control of these processes. Second, individual brain areas do not influence attention and memory in isolation. Instead, these processes emerge from the interactions of neurons in multiple brain areas that form functional circuits. This project continues an extensive programmatic analysis of the interactions of hippocampal, cingulate cortical, limbic diencephalic, amygdalar and striatal neurons involved in mediation of discriminative instrumental learning. The interactions are studied by recording the activity of neurons simultaneously in multiple brain sites during learning in rabbits. Selective circuit lesions and neurochemical manipulations experimentally alter attention- and memory-relevant information flow in the circuits. Recent discoveries set the stage for major advances concerning the documentation of specific learning relevant brain pathways and circuit interactions. The new data demonstrate that contextual information from medial temporal lobe structures (entorhinal cortex, hippocampal formation) modulates distinct associative processes of various other limbic circuit modules to which it is projected. The proposed studies test the following hypotheses, stimulated by these results. Neural transmission (signaling) identifying the learning context, projected from dorsal subiculum, enhances associative attention in cingulate cortex in response to nonsalient, significant cues. Context signaling from entorhinal cortex reduces cingulate cortical associative attention during extinction, however, cingulate cortical attention is preserved during extinction in a novel context. Context-signaling from entorhinal cortex via the ventral subiculum to the nucleus accumbens suppresses behavioral responding during extinction in the presence of novel contextual stimuli. Context signaling from subiculum to the limbic diencephalon induces context-specific topographic retrieval patterns of cue elicited cingulothalamic activation. Disruption of these patterns will impair memory by increasing pro-, and retroactive interference. Flow from entorhinal cortex to amygdala is required to initiate learning-relevant plasticity subserving many or all of the aforementioned effects.

DESCRIPTION (adapted from applicant's abstract): Structures of the brain's limbic system are critically important for processes of attention, memory and cognition, and for the etiology of cognitive and behavioral disturbances such as schizophrenia and attention deficit disorder. Yet, knowledge of the specific malfunctions that bring about attentional and mnemonic disturbance has been elusive. This project approaches these issues, beginning with two fundamental premises. First, an understanding of the etiology of attentional and mnemonic disturbance will require a basic understanding of the involved brain mechanisms in production and control of these processes. Second, individual brain areas do not influence attention and memory in isolation. Instead, these processes emerge from the interactions of neurons in multiple brain areas that form functional circuits. This project continues an extensive programmatic analysis of the interactions of hippocampal, cingulate cortical, limbic diencephalic, amygdalar and striatal neurons involved in mediation of discriminative instrumental learning. The interactions are studied by recording the activity of neurons simultaneously in multiple brain sites during learning in rabbits. Selective circuit lesions and neurochemical manipulations experimentally alter attention- and memory-relevant information flow in the circuits. Recent discoveries set the stage for major advances concerning the documentation of specific learning relevant brain pathways and circuit interactions. The new data demonstrate that contextual information from medial temporal lobe structures (entorhinal cortex, hippocampal formation) modulates distinct associative processes of various other limbic circuit modules to which it is projected. The proposed studies test the following hypotheses, stimulated by these results. Neural transmission (signaling) identifying the learning context, projected from dorsal subiculum, enhances associative attention in cingulate cortex in response to nonsalient, significant cues. Context signaling from entorhinal cortex reduces cingulate cortical associative attention during extinction, however, cingulate cortical attention is preserved during extinction in a novel context. Context-signaling from entorhinal cortex via the ventral subiculum to the nucleus accumbens suppresses behavioral responding during extinction in the presence of novel contextual stimuli. Context signaling from subiculum to the limbic diencephalon induces context-specific topographic retrieval patterns of cue elicited cingulothalamic activation. Disruption of these patterns will impair memory by increasing pro-, and retroactive interference. Flow from entorhinal cortex to amygdala is required to initiate learning-relevant plasticity subserving many or all of the aforementioned effects.

neuroregulation; cingulate gyrus; goal oriented behavior; neural information processing; central neural pathway /tract; amygdala; operant conditionings; association learning; cell cell interaction; brain electrical activity; intercellular connection; avoidance behavior; fear; behavioral /social science research tag; laboratory rabbit; behavior test;