Howard Eichenbaum - US grants

We have developed a prototype of a multichannel electrode system for recording neural spikes and slow wave activity in acute and chronic vertebrate preparations. From the experience of our initial success with problems in cat visual cortex, we propose modifications that will considerably enhance the system's performance. The modified multichannel electrode will have 22 recording sites and 2 lesion site spanning 2.4 mm and spaced at 100 um intervals along its edge. By the use of integrated circuit technology, the electrode will be built in layers of silicon nitride, platinum, and silicon nitride on a molydenum substrate. The total thickness will only be 20 um and the maximum width at the base of its wedge shape will be 135 um. A modified coonnector will be built that will allow quick replacement of damaged electrodes. It will be small enough for moving preparations, and will contain preamplifiers in a hybrid of IC chips. An amplifier array will also be built to process both unit and slow wave activity. Evaluation of the electrode will be performed by standard electrical tests and by extensive use in vivo. The rat hippocampus is a particularly useful test preparation because of its well studied physiology, distinctive lamination of cellular subpopulations, anatomically separated inputs and outputs, and characteristic slow wave pattern and related unitary activity. Recording performance of the multichannel electrode will be compared with that of a conventional metal microelectrode in 3 measures of neural activity. 1) laminar patterns of field potentials evoked by electrical stimulation of known pathways, 2) laminar amplitude and phase relationships of the theta rhythm, and 3) sensitivity and selectivity for unit activity and fixing patterns in relationship to theta cycle. These evaluations will be carried out in both urethane anesthetized and awake, behaving preparations to examine the generality of the system's usefulness as a new tool for the study of local circuit interactions.

When human beings sustain a stroke, traumatic head injury or neurotoxic poisoning, they may suffer from "organic amnesia" -- a form of memory loss resulting from damage to the brain. Clinical studies of these people have increased our understanding of normal memory in two ways. First, we have been able to identify many of the brain structures involved in memory. Second, we are better able to understand some of the basic mechanisms of memory as we learn what causes it's malfunction. Animal models of organic amnesia have furthered our understanding of memory because the conditions leading to such memory deficits can be more carefully controlled. Studies of animal memory often cannot be compared directly to human memory, in part because the information we ask animals to remember may bear but little meaning to their lives. In their recent studies, Drs. Eichenbaum and Cohen have shown that rodents possess exceptionally good abilities in learning about odors. In fact, their olfactory learning capabilities may be as powerful as are visual memories of humans and monkeys. In these studies, Drs. Eichenbaum and Cohen will utilize rodents' striking olfactory learning capacities to: (1) develop new and more powerful memory tasks similar to those used so successfully in monkeys and humans, (2) use these tasks to test whether rats demonstrate amnesia as humans do after damage to specific brain structures, and (3) employ variations of these tasks to clarify how memories are encoded within specific brain regions. The results should indicate whether the qualities of memory are the same in humans and in animals. In addition, their results may help in the search for treatments of memory loss.

Progress in the neurobiology of learning and memory has benefitted recently by the discovery that the hippocampus and associated brain structures play an important role in "working memory," the type of memory that allows us to recall specific recent events. Major successes in creating animal models of working memory have come from the development of the delayed non- match to sample (DNMS) paradigm, a working memory test that involves three sequential phases: A cue phase when the memory cue is presented, a delay phase during which the animal must remember the cue, and a choice phase during which the animal must recognize and reject the memory cue in favor of an alternative. Investigators have shown that damage to the hippocampal system results in severe impairments on performance in DNMS, indicating that this system is critical to information processing for working memory. This research is aimed at determining what role the circuitry of the hippocampus plays in DNMS. Dr. Eichenbaum's strategy is to exploit the rats' striking learning and memory capacities with olfactory and spatial stimuli to describe the neural correlates of memory for these distinct types of information. He is recording the electrophysiological activity of single neurons in the hippocampus as rats perform DNMS tasks using either odors or places as the memory cues. By comparing the firing rates of neurons across the three phases of the task, he will be able to identify which component of memory activates hippocampal circuits, that is, whether the hippocampus is primarily involved in storage (cue phase), in holding (delay phase), or in recognition (choice phase). In addition, by comparing neuronal firing rates across the two categories of memory cues (odor and place), he will be able to determine the general, rather than stimulus-specific, qualities of cues that are processed by the hippocampus.

The broad, long-term objective of this project is to describe the nature of hippocampal neural activity in cognitive functions subserving learning and memory. This knowledge will contribute to our understanding of the neurological basis of memory disorders consequent to hippocampal-system dysfunction in aging and disease. There are two specific aims of the project: 1) to clarify the basic functional correlates of firing in hippocampal principal neurons in rats performing memory tasks, and 2) to describe the topographical organization of those correlates in the hippocampal cortex. The proposed experimental design exploits new methods in chronic unit recording to correlate spike activity with sensory and behavioral events in discrimination learning and spatial navigation tasks for which performance is dependent on hippocampal pathways. Computerized analyses involving physiological and behavioral measures will be used to uncover the optimal correlate of spike activity to key task events. Particular attention will be paid to the degree to which unit activity can be explained by two parameters prominent in previous descriptions of hippocampal units, "behavioral" parameters, including stimuli and responses of learned significance, versus "place" or allocentric spatial position of the animal. Comparison of the firing correlates for the same cell both across parameters within each task, and across separate tasks will be used to infer the higher-order functional attributes common across task variations. Based on neuropsychological data, our working hypothesis is that these higher order attributes will reflect encoding of stimulus configurations by hippocampal neurons. Specific experiments will focus 1) on the identification of functional correlates reflecting configurations of task events, 2) on the development of these correlates during the course of learning, and 3) on their disappearance after disconnection of hippocampal pathways. The proposed experiments involve recording from several single- units simultaneously using two different kinds of multichannel microelectrode. These methods will not only increase the efficiency of data collection, but will also permit an exploration of the anatomical organization of functional correlates within the hippocampus. Analyses will focus on comparisons of the functional correlates among the major hippocampal regions and on comparisons among near and distant neighboring cells recorded simultaneously. These analyses will be used both to generate and to confirm hypotheses about the processing mechanisms reflected in the functional correlates of individual neurons.

biomedical equipment purchase;

PROJECT SUMMARY/ABSTRACT The hippocampus plays a critical role in the organization of memories. Previous studies on the nature of neural representations in the hippocampus have focused on spatial representations by hippocampal neurons, but many studies in humans and animals indicate a broader role for the hippocampus in memory organization. Representational Similarity Analysis, which has been very successful in revealing the organization of neural representations in other domains, will be employed to explore how hippocampal networks organize memories that are distinguished by temporal context and by specific salient cues and rules; and how multiple memory representations are integrated and stabilized over time. These experiments employ a combination of multi- electrode recording in rats, state-of-the-art calcium imaging in behaving mice, and novel neural population analyses, to generate a new understanding of neural network representations. These studies are of high translational potential because cognition dependent on memory organization is impaired in mental disorders including schizophrenia.

The general aim of this project is to characterize age-related alterations in learning and memory capacity and associated changes in neural coding by hippocampal/cortical systems presumed to underlie the cognitive decline. Previous work from this laboratory and elsewhere indicates that the hippocampal system mediates declarative memory and that hippocampal processing central declarative memory is reflected in neuronal activity dependent on conjunctions and/or relations among critical cues in different behavioral paradigms. The proposed experiments are aimed at testing the specific hypothesis that age- related cognitive decline is attributable to a disproportionate deterioration of declarative memory and corresponding loss of conjunctional-relational correlates of hippocampal unit activity, disruption of cortic-limbic coordination, and reduced induction or rapid decay of learning related plasticity in hippocampus and cortex. In a series of empirical studies we propose to test this hypothesis by assessing the behavioral performance of young adult and ages rats in four odor- and spatially-guided learning tasks that impose different kinds of demands on hippocampal processing. We will also characterize the behavioral correlates of single neurons, the relationship between sensory and hippocampal rhythms, and synaptic efficacy of hippocampal and cortical circuitry in rats performing those tasks. Our analyses will focus on comparisons of the data from behaviorally "impaired" and "unimpaired" old rats with that from young mature adults. In parallel computational modeling studies, we propose to develop multiple network models that stimulate hippocampal neural activity and examine the effects of analogues of age-related circuitry changes on processing performance. Our initial studies will compare the effects of aging-like alterations on the processing performance of several simplified models of hippocampal networks. Further studies will involve the development and assessment of the effects of these alterations in more realistic hippocampal models. Our goal is to build models of the hippocampus that stimulate, and therefore can be validated by, the data from recording studies. We will assess the effects of both individual changes that occur in aging and combinations of them to identify the critical determinants of cognitive decline.

The hippocampal region plays a critical role in declarative memory. In addition, there have been significant advances in characterizing several defining features of declarative memory, and in identifying the cortical and hippocampal structures essential to this form of memory. Yet, we have little insight into the nature of the neural coding that underlies declarative representations by the hippocampus or cortex, or into the nature of the essential cortical-hippocampal interactions. The long- term objective of this project is to clarify the hippocampal "memory code" by analyzing firing patterns of single neurons and neuronal ensembles of cortical and hippocampal areas in rats performing different memory tasks, and to identify aspects of cortical memory coding dependent on components of the hippocampal system. Previous anatomical, neuropsychological, and neurophysiological studies have identified the set of cortical structures and pathways by which these structures interact with the hippocampal region, and have provided a preliminary identification of which components of this systems are important to particular features of hippocampal-dependent memory that can be examined in animals: (1) The cortex and parahippocampal region (perirhinal and entorhinal cortex) mediate the sustained retention of memories for single brief experiences. We will examine the nature of cortical representations in this process, and their dependence on the parahippocampal region in sustaining memory representations. (2) Structures of the hippocampal region mediate the organization and the consolidation of cortical memory representations. We will characterize the nature of cortical representations of stimulus- stimulus associations and determine the extent to which the organization of cortical representations depends on hippocampal function. (3) The hippocampus itself may play an especially important role in learning stimulus configurations and episodic information. We will examine the development and scope of the encoding of stimulus configurations in the hippocampus and determine if hippocampal codings are organized to represent episodic memories. The proposed studies will exploit a well established olfactory- hippocampal model system that exploits the superb capacities of rats for odor-guided learning and memory, and is based on well known anatomical and physiological data about olfactory and hippocampal structures and their interactions. Furthermore, the proposed studies will employ recently developed methods for the collection and analysis of neural ensemble recordings in the cortex and hippocampal region. The findings from this work will improve our understanding of 'what the hippocampus does' and what it does within the system of cortical structures with which it interacts in the service of declarative memory.

This project is being funded through the Learning and Intelligent Systems (LIS) Initiative. The project aims to advance understanding of how the brain generates intelligent behavior by examining the capacity to think about sequences of events. Whether cooking an elaborate meal or merely dialing a phone number, multiple events in a specific temporal order must be kept in mind, in a form of working memory that helps in planning complex thoughts and actions. This problem will be studied in the project through an interdisciplinary approach. To directly probe brain mechanisms, neurophysiological experiments will be performed on awake behaving animals. Computer-based experiments with young children will be used to discover how children learn sequential behaviors and to test how to optimize such learning. Behavioral studies will be done on how human infants learn sequences. Cognitive and neural modeling will be used to discover brain designs and mechanisms to link the animal neurophysiological data to the human cognitive data. This interdisciplinary approach promises to produce insights that are beyond the scope of any single approach. Conducting experiments in two different animal species (monkeys and rats), in human infants, and in young children will permit identification of intelligent mechanisms that are preserved across different species. The animal studies will analyse the activity of large groups of single neurons to study how multiple neurons interact to generate intelligent behaviors. Neural modeling will probe the laws that govern these behaviors, and will make predictions that link brain to behavior. Through these analyses of how we learn and remember sequences of events, a foundation will be built for studying the neural basis of high-level cognitive operations such as planning and reasoning; for developing better educational software; and for applying models towards the solution of outstanding technological problems that require algorithms which emulate human intelligence.

The hippocampal region plays a prominent role in learning and memory, particularly in declarative or explicit memory expression and permanent memory consolidation. Yet, despite significant advances in characterizing aspects of memory that are dependent on the hippocampal system, we have little insight into the fundamental cognitive mechanisms, the neural coding schemes, or the cortical-hippocampal interactions that mediate declarative expression and consolidation. This project is aimed to address these issues within an animal model of declarative memory. The three general long-term objectives of this project are 5 grants: (1) Neuropsychological experiments will clarify cognitive aspects memory processing dependent on components of the hippocampal system. (2) Electrophysiological experiments will characterize the firing patterns of single neurons and neuronal ensembles of cortical and hippocampal areas in rats performing tasks that have different cognitive and memory demands, and determine whether cortical memory codings are dependent on hippocampal processing. (3) Aging studies that involve both neuropsychological assessments and electrophysiological recordings will determine what aspects of cognitive function and neural coding in the cortex and hippocampal systems are compromised in normal aging. Together these approaches will provide a broad systems-level analysis of the cortical and hippocampal contributions to declarative memory essential for daily life and compromised in several neurological disorders and normal aging. In collaborative studies the PI will pursue new research career developments, including studies on temporal coding patterns, neural ensemble recording and analyses, aging research, and neurophysiological studies on monkeys. In addition, the PI will increase his mentoring activities with postdoctoral fellows and graduate students, complete writing of graduate level, book-length survey of memory systems in the brain, and develop a program for research opportunities for undergraduates, and particularly for women at Boston University and Wellesely College. The proposed award will release the PI from substantial teaching obligations to pursue these research and other activities.

DESCRIPTION: (Adapted From The Applicant's Abstract) For several years investigators have sought to link mechanisms of long term potentiation (LTP) to memory. These efforts have typically fallen short because they fail to address the issue of how treatments that influence the capacity for synaptic plasticity affect neural firing patterns related to perception, behavior, as well as cognition and memory. This proposal will address that issue by characterizing firing patterns of neurons in the hippocampus and cortical areas of normal mice and mice with deficient capacity for LTP. Our efforts will focus on N- Methyl-D-Aspartate (NMDA) receptor dependent LTP because NMDA receptors are believed critical to induction of an essential form of plasticity while not required for synaptic transmission that mediates information processing in the cortex and hippocampus. The proposed studies will compare the effects of D-2-amino-5-phosphonopentanoate (AP5), a selective blocker of NMDA dependent LTP, and genetic manipulations that inactivate isoforrns of calcium-calmoduline dependent kinase type 11 (CaMKII) and cyclic adenosine monophosphate (cAMP) responsive element binding protein (CREB), two molecules that are critical to the formation of lasting LTP. Our experimental designs will employ recently developed electrophysiological methods for recording the extracellular activity of multiple neurons simultaneously in behaving mice, and several behavioral techniques we have developed to study spatial and olfactory learning and memory. We will examine the extent to which hippocampal and cortical firing patterns not associated with new learning are maintained in animals with a compromised capacity for LTP, with the hypothesis that non-memory sensory and behavior related neural processing, as well as memory processing associated with short term recognition or working memory and that associated with previously well-learned memories, should be intact (sic). We will also characterize lasting changes in neural firing patterns associated with new learning, with the hypothesis that permanent learning-associated changes will be reduced or prevented in animals with compromised LTP capacity. These findings will provide a comprehensive characterization of the effects of drug and genetic manipulations of LTP on different types of sensory, behavioral, and memory related neural processing. The results will strongly test the view that drug and genetic manipulations of NMDA mediated synaptic plasticity selectively affect memory formation, adding useful evidence on the question of whether the form of LTP is essential for memory.

Progress in understanding the nervous system will be enhanced by training scientists with a broad interdisciplinary background including a combination of experimental and computational approaches to the study of the nervous system. To this end we have established at Boston University an independent and interdisciplinary Neuroscience training program that emphasizes this combination of approaches and complements specialized neuroscience training in already existing departmental programs. The Neuroscience Program will be administered by a Steering Committee, who will select the candidates, assign advisors, monitor their progress throughout the pursuit of the degree, and consider the addition of new faculty to the program. The faculty participating in the program is very broad and strong. Departments contributing to the program include Anthropology, Biology, Biomedical Engineering, Cognitive & Neural Systems, Health Sciences, Mathematics, Pharmacology, Physiology, and Psychology. We have instituted five main new training activities: (1) a series of core lecture courses in both experimental and computational neuroscience, (2) a series of core methods courses involving both approaches, (3) a combined computational-experimental lab rotation, (4) an interdisciplinary graduate seminar series, and (5) an annual Neuroscience retreat. As the students focus on their thesis research within a specific discipline, elective courses and other activities are aimed at continuing interdisciplinary exposure throughout their training. The structure of the program will catalyze interactions among neuroscience faculty and students in the various departments at Boston University, fully exploiting the broad range and substantial depth of facilities and resources available at this institution.

Aging is associated with declining function across a broad spectrum of behavioral and biological measures. This component of the program project will pursue a combination of behavioral and neurophysiological studies aimed at characterizing the nature and range of alterations in neuronal representations associated with aging: Specific Aim 1: Exploiting a recent finding of hippocampal neuronal activity patterns closely associated with memory performance in young animals, we will characterize the nature of performance-related abnormalities in hippocampal representation associating with aging. These studies will determine whether memory errors are associated with compromised stability of hippocampal spatial representations, or retrieval of inappropriate memory representations. Specific Aim 2: Extending on findings on the previous funding period, we will examine the development of new hippocampal spatial representations when animals are presented with a novel environment. These studies will examine interference from previous perceptual stimuli and behavioral strategies, and the stability and selectivity of new representations, and the rate and extent to which new representations anchor to salient cues. Parallel studies will determine if the development of new hippocampal representations is impaired in aging, and to what extent the impairment is due to intrusions of existing representations. Specific Aim 3: We will use our well developed paradigm for delayed non-match to sample (DNMS) to examine the nature of memory representations in the prefrontal cortex and perirhinal-entorhinal cortex of aged animals. These studies will determine whether the impairment in DNMS performance in aged rats results from a deficiency in processing of task rules by the prefrontal cortex, or a deficiency in sustaining memory representations in the perirhinal-entorhinal cortex, or both. In addition, these studies will determine whether there are age related abnormalities in interactions among cortical areas and the hippocampus associated with stimulus evaluation and memory. Each of these experiments is designed to test specific hypotheses about the nature of age related cognitive decline: that aging is associated with abnormalities in hippocampal and cortical representations, and age- related memory involves loss of basal forebrain regulation of hippocampal or cortical information processing, and loss of the plasticity of synaptic mechanisms.

This project will examine how neuronal ensembles within the hippocampus, as well as associated[unreadable] parahippocampal cortical areas and prefrontal cortex, represent information in the service of episodic[unreadable] memory for non-spatial information. Our experiments are guided by the hypothesis that information about[unreadable] individual items and spatial context are separately represented in distinct parahippocampal areas, that area[unreadable] CAS encodes items in the context in which they were experienced, and that area CA1 encodes and retrieves[unreadable] the order in which the items were experienced; and our experiments are guided by Hasselmo's models of the[unreadable] mechanisms underlying this scheme. Multi-channel microelectrodes will be used to record the firing patterns[unreadable] of neurons in hippocampal, parahippocampal, and prefrontal areas in rats performing hippocampaldependent[unreadable] tasks that assess rats' ability to remember once-presented sequences of odors and to[unreadable] disambiguate overlapping odor sequences. In the sequence memory paradigm, we will characterize and[unreadable] localize sequence coding, spatial context coding, and coding of item familiarity within this brain system. In[unreadable] the sequence disambiguation paradigm, we will test the hypothesis that overlapping events in two[unreadable] sequences are represented distinctly for each sequence. In both paradigms, we will determine whether[unreadable] there are specific phases of the theta rhythm on which encoding and retrieval of sequence information occur,[unreadable] and whether sequential information from recent experiences persists during a memory delay. For all of[unreadable] these measures we will characterize the extent to which neural firing patterns predict memory performance.[unreadable] The design and focus of these studies is guided by observations of humans performing[unreadable] similar tasks and provides a cellular level analysis not possible in functional imaging studies on humans.[unreadable] These experiments proposed here will be compared with parallel studies on spatial sequence processing, seeking to identify common fundamental mechanisms of non-spatial and spatial sequence[unreadable] representation. The experiments are aimed to test models and to guide the further development[unreadable] of models of hippocampal circuitry that support the temporal organization of episodic memory.

The hippocampus is believed to be necessary for learning sequences and for disambiguation, and computational models predict that different subregions of the hippocampal formation play distinct roles in memory. However, these predictions have not been tested experimentally, and no one has demonstrated a causal relationship between patterns of activity in hippocampus and animal behavior. This project will address both issues in animals performing a delayed non-match to place (DNMP) task in a "T" maze. In Aim 1, we will study the emergence of context-sensitive sequences neural activity in region CA1 of dorsal hippocampus as animals learn the task, and compare activity from the Sample, Delay, and Choice phases of the task in both correct and incorrect trials. Positive results will allow us to develop a stronger tie between electrophysiological and behavioral data. In Aims 2-3, we will extend this approach to region CAS and dorsolateral entorhinal cortex (EC). Computational models predict that CAS neurons should generate queued representations of temporal context, and that separate populations in EC should code for temporal context and and sequences of paths from the current location. In Aim 4, we will test the hypothesis that the period of the theta rhythm can be divided into encoding and retrieval phases. In Aim 5, we will study spatial trends in receptive fields of context-sensitive neurons. In Aim 6, we will test the hypothesis that cells encoding a given temporal context (left-turn vs. right-turn trial) are spatially clustered. In Aim 7, we will stimulate selected hippocampal neurons in an attempt induce "false memories" in the DNMP task. Aim 7 is technically challenging, but if successful, provides direct evidence that manipulation of hippocampal acitivity leads to alterations in episodic-like memory. The long-term goals of the proposed work are to establish a causal relationship between hippocampal activity and behavioral performance in episodic-like tasks, and to understand more completely how memories of relevant episodic experiences are encoded in entorhinal cortex and in regions CA1 and CAS of hippocampus. Such levels of understanding will be of great value in working toward treatments for memory disorders. The value of the planned experiments is not contingent on positive results from the high-risk Aim 7.

Computational models of the hippocampal formation, entorhinal cortex and prefrontal cortex will be used to[unreadable] simulate memory-guided behavior in both rat and human behavioral tasks. These simulations will extend[unreadable] previous modeling work in this laboratory (Hasselmo et al., 2002b; Fransen et al., 2002; Koene et al., 2003;[unreadable] Hasselmo, 2005a; Koene and Hasselmo, 2005; Hasselmo and Eichenbaum, 2005) to generate predictions[unreadable] about physiological data in a range of different memory-guided tasks. Selection of behavioral actions in the[unreadable] model depends on the encoding and context dependent retrieval of sequences of input stimuli (i.e.[unreadable] episodes). The models will generate predictions for specific research projects in the center, including:[unreadable] 1.) generation of predictions about the timing of neuron firing relative to stimuli and hippocampal theta[unreadable] rhythm during performance of the order recognition task with odors in rats, and the[unreadable] magnitude of fMRI activation associated with correct versus incorrect performance of an order recognition[unreadable] task in humans,[unreadable] 2.) generation of predictions about context-dependent properties and theta phase of neuronal firing in the[unreadable] odor sequence disambiguation task, and the magnitude of fMRI activation[unreadable] associated with choice in a disambiguation task in humans,[unreadable] 3.) generation of predictions about the delayed non-match to place (DNMP) task in the T-maze, concerning the timing of splitter cell responses and sequence readout relative to theta rhythm and[unreadable] behavior and the disruption of behavioral responses caused by stimulation at different phases of theta during[unreadable] different task periods.[unreadable] These simulations will use networks of neurons starting with threshold units and building to use of detailed[unreadable] compartmental biophysical simulations, to relate network dynamics to intrinsic currents and subclasses of[unreadable] neurons within the hippocampus and entorhinal cortex. The insights gained from this work will improve our[unreadable] understanding of the normal function of the hippocampus and associated cortex, potentially contributing to[unreadable] treatment of memory impairments in disorders such as Alzheimer's disease or schizophrenia.

[unreadable] DESCRIPTION (provided by applicant): This is an application to establish a Conte Center for Neuroscience Research on the FUNCTIONAL CIRCUITRY OF THE HIPPOCAMPUS. The overall objective is to elucidate the nature of neural processing in the hippocampus and related cortical structures that mediate episodic memory. Our hypothesis is that the hippocampus, together with associated cortical areas, represents sequential events that compose and distinguish episodes. This project provides the first systematic examination of that hypothesis and challenges three prominent alternate views, that memory for order is a reflection of a general associative function of the hippocampus, that the hippocampus is specialized for spatial memory, and that temporal organization of memory is accomplished by other brain areas. Our approach involves different levels of biological organization and combines multiple disciplinary, methodological, and technological perspectives integrated across four projects. Studies on human functional brain imaging will characterize the scope of sequence representation in which the hippocampus is involved, identify interactions between the hippocampus and cortical networks, and distinguish the role of the hippocampus from that of other brain areas involved in sequence representation. Studies on the activity of neural ensembles and rhythmic field potentials in behaving animals will identify neural coding mechanisms for temporal organization of nonspatial and spatial memory in hippocampal and cortical subregions. Computational studies will model behavior and spike timing, revealing basic features of circuit processing and rhythmic activity in the encoding and retrieval of sequential information. The human and animal studies emphasize the strengths of each approach and close parallels in experimental design between species. The experimental and computational projects are highly interactive and co-dependent, designed to provide a circuit level accounting of neural representation and cognitive performance. The combined research is aimed to provide a breakthrough in our understanding of the neural mechanisms of episodic memory and its deterioration associated with aging, brain damage, and disease. [unreadable]

This project will investigate the role of the hippocampus and related medial temporal lobe (MTL) structures in sequence memory. These studies are guided by our recent findings with functional magetic resonance imaging (fMRI) indicating that the human hippocampus is activated in early stages of sequence learning (Schendan et a)., 2003), and also our recent animal and modeling studies that suggest the hippocampus is critical in memory for temporal order (Fortin et al., 2002), and for the disambiguation of overlapping sequences of events in memory (Sohal and Hasselmo, 1998;Agster et al., 2002). The proposed project has three specific aims. The first aim is to use fMRI to explore the scope of hippocampal involvement in sequence learning in humans. Experiments 1 and 2 will examine hippocampal, parahippocampal, prefrontal, and striatal activity during the encoding, delay, and retrieval components of encoding tasks that will contrast learning and memory performance for items, sequences of items, and spatial context information. These event-related fMRI studies directly parallel studies that have been and will be carried out in animal models. Our hypothesis is that the hippocampus is critical not only for associative and contextual learning, but also for remembering the order of events in unique experiences. We further predict that perirhinal activity will relate to item learning, but not contextual or sequence learning. The second aim is to use fMRI to explore the role of the hippocampus in sequence disambiguation. Experiments directly parallel studies in animal models (Agster et al., 2002;Wood, et al, 2000). Exp. 3 will examine hippocampal activation in encoding overlapping versus non-overlapping non-spatial sequences. Exp. 4 is the spatial analog of Exp. 3, and will examine navigation through virtual reality mazes using overlapping and non-overlapping paths. The third aim is to use fMRI to contrast the medial temporal lobe, prefrontal, and striatal systems in sequence learning. Exp. 5 examines implicit sequence learning in a sequence embedded in a "prefrontal" N-back task. Exp. 6 examines learning of first order (FOG) or second order conditional (SOC) sequences in an incidental picture encoding task. The prediction is that FOG sequences will activate the striatum but not the MTL, whereas SOC sequences will activate the MTL. The combined studies will provide a hypothesis-driven examination of episodic sequence learning that closely parallels the studies and models proposed.

computer program /software

Our understanding of the neural mechanisms of memory has been advanced by the characterization of neural activity in behaving animals. The research described in the Projects 2-3 depends crucially on sophisticated devices for simultaneous recording of the activity of multiple neurons and field potentials at multiple sites. For some aims, we require that these devices give us the flexibility to sample hippocampal neurons with regular spacing along the septotemporal axis. For the last aim of Project 3, we require the ability to deliver patterned electrical stimulation to neurons at flexibly chosen sites. Development and fabrication of these devices will be accomplished by establishment of a dedicated facility and personnel who will design and construct multichannel electrode arrays, as well as headstages for preliminary amplification and stimulation of neural activity at multiple sites. The Engineering Core will also serve as a general electronics and mechanics shop for Center personnel and students. Engineering Core personnel will train Center members in safe use of Core equipment and serve as a source of technical advice.

II.D.2.A. Center Administrative Core Unit Description II. D.2.A.a Objective The overarching objective of the Administrative Core is professional and efficient operations and provision of services related to the overall planning, direction, and internal monitoring and review of ACE activities;organization of the annual Advisory Committee meetings and biweekly meetings of Core and project leaders with the Director;fiduciary oversight of the component Core and project budgets;and management and presentation of the "public face" of the Center in all facets of outreach to and interaction with the academic and scientific community as well as other regional, national, and international stakeholder groups, including dissemination of ACE research and general informational materials. In short, the Core's primary purpose and goal is full and proper accountability.

DESCRIPTION (provided by applicant): A fundamental challenge in neuroscience is understanding of how major brain areas operate together as a system to support high level cognitive functions. In particular, one system of great importance to the understanding of mental disorders involves the prefrontal cortex (PFC) and the medial temporal lobe (MTL) that each contribute to high level functions in memory and cognition. In recent years, there has been significant progress in revealing the individual functions of areas within the PFC and MTL, and some successes in showing that these areas work together. However, there is a paucity of knowledge about the mechanisms by which PFC and MTL interact in the service of memory and cognition. Here we bring together a group of investigators who have led research on PFC and MTL, or both, using diverse approaches and different species. We have collaborated to develop an hypothesis of PFC-MTL interactions and aim to integrate our strengths towards revealing the mechanisms of that interaction, and in so doing, pioneer a true systems level understanding of memory and cognition. Our strategy combines theories of PFC and MTL function generated by our group with coordinated experimental analyses that converge on a common behavioral paradigm for exploring encoding and retrieval operations in context-guided associative memory. Experimental projects will examine how PFC and MTL areas contribute individually and interactively, using diverse and intersecting approaches: in humans, using both neuropsychological studies of brain damaged individuals and fMRI on normal human subjects, in monkeys using neurophysiological studies of single neuron activity and local field potentials, in rats using combined neurophysiological and reversible inactivation studies of non-spatial and spatial memory. The findings will be integrated in two key ways, by direct comparison of different data modalities through an Analysis Core and by convergence into a computational model that provides a comprehensive and unified account of PFC-MTL interactions. The Center will also pursue several directly related educational, dissemination, and outreach goals. PUBLIC HEALTH RELEVANCE: PFC and MTL areas are implicated in a broad range of mental disorders. Moreover, it has become increasingly clear that aspects of mental disorders reflect a breakdown of network functions of the PFC-MTL system. Correspondingly, characterization of PFC-MTL interactions is fundamental to understanding the origins of mental disorders and to developing therapies that influence network-level information processing.

PROJECT SUMMARY (See Instructions): This project will employ a combination of recording and reversible inactivation techniques to examine how PFC and MTL areas interact in rats performing a context-guided association task that is formally equivalent to the test used in humans and monkeys in other projects. In this task, on each trial a rat will be move into one of two environmental contexts that conditions associations between odor stimulis and rewards. Using multichannel tetrodes, we will record simultaneously in an MTL area and a PFC area, and test specific hypotheses outlined about the development, nature, timing, and coordination of firing patterns in these areas. These studies will test the generality of our overall hypotheses about information processing in PFC and MTL areas in rats as compared to those in humans and monkeys examined in Projects 1-3. We will also go beyond identifying functional properties of neuronal activity in other experiments by simultaneously recording in one area while reversibly inactivating another area for brief periods during and after learning. Reversible inactivation will be accomplished using florescent muscimoi and by state-of-the-art optical silencing methods that allow millisecond resolution of anatomically identified areas. These experiments will provide tests of whether firing patterns normally observed in one area depend on the other. For example, we will test the hypothesis that, during learning, the development of context general representations in PFC depend on specific MTL areas;whether, within trials following learning, the generation of specific context representations in postrhinal/medial entorhinal cortex depends on PFC;and whether the generation of specific representations of the second element on a conditional association in PFC depends on perirhinal cortex. These and other specific tests will provide evidence on causal relations among areas within PFCMTL circuitry, providing key evidence for computational modeling in Project 6. This project will closely parallel Project 5, which examines the nature of PFC-MTL interactions in rats performing a similar context guided spatial maze task, thus allowing direct comparisons that link the PFC-MTL processing of non-spatial memorties with the large literature on hippocampal spatial memory.

PROJECT SUMMARY/ABSTRACT Episodic memory is characterized by our ability to remember the spatial and temporal context in which events occur. There is substantial evidence that the hippocampal neuronal activity reflects a representation of space but, until recently, little was known about whether or how the hippocampal neurons encode time. However, recent studies by us have shown that hippocampal neuronal activity provides a temporal context signal that contributes to memory. In addition there is now evidence, substantially accumulated in this project, that hippocampal neurons - called time cells - fire during particular moments in a temporally extended experience, similar to hippocampal place cells that fire associated with particular locations in a spatially extended environment. The proposed studies will continue to explore the nature of temporal representation by the hippocampal system and associated brain areas. Experiments so far have focused on time cell activity during a gap between remembered events in order to identify an unambiguous timing signal in the absence of dynamic external events and while holding place and behavior constant. In the next phase of the project we will explore how time cells organize a sequence of events that compose specific episodes. Also, all recordings of hippocampal time cells have so far been examined only in area CA1. We will examine whether temporal coding is limited to CA1 or widespread in the hippocampus and other medial temporal and prefrontal areas. We will also explore whether temporal sequencing is created within intrinsic hippocampal circuits or whether temporal coding within the hippocampus depends on inputs from cortical areas. These studies will challenge the prevalent view that the hippocampal system is dedicated to spatial navigation and advance our understanding of how this system represents events in their spatiotemporal context.