Bruce L. McNaughton - US grants

The objective of this project is to apply a new technique for the isolation of spike trains from several single neurons in behaving rats to the problem of how internal representations of familiar places are maintained upon removal of their initiating cues (i.e. "how does the organism continue to know where it is when the lights go out?"). There are two problems here. The first is to demonstrate beyond question that experimental animals (rats) actually do make use of internal representations to solve spatial problems. The second is to discover the neural basis of this ability. This proposal is based upon O'Keefe's and Nadel's hypothesis that the hippocampal formation acts as a cognitive mapping system. Apart from the lesion literature leading to this notion, its main support is the fact that hippocampal unit activity separates into two clear classes: 'place' cells which carry position and direction information, and 'theta' cells which fire during translational movements. These two types of information could form the elements of a cognitive mapping system. The extension of this theory presented here requires that a) specific stable patterns of neural discharge be set up whenever the animal finds itself in a familiar place, b) these patterns should exhibit hysteresis in that the place specific information required to maintain them should be much less than that required to initiate them (in the limit, all external information should be removable,) and c) learned correspondences between transitions among these neural states and the motor sequences leading to them should result in the ability of the system to reactivate an appropriate series of such place specific states on the basis of the corresponding motor sequences alone (given that some initial state has been set up by externally provided place information). The new recording method to be applied to this problem is based on the principle that cells which are a unique ratio of distances from two closely spaced electrodes will generate spikes with unique ratio of amplitudes on the corresponding recording channels. Evidence is presented that a method based on this principle effectively solves the perennial problems of single unit isolation in the hippocampus where cells are densely packed and may exhibit considerable intrinsic variation in spike amplitude. In addition, it removes some of the selection bias towards large cells, and permits analysis of interactions among spike trains recorded simultaneously from several neurons.

DESCRIPTION (provided by applicant): The mammalian hippocampal formation is crucial to the storage and consolidation of 'episodic'memories: memories for experiences that unfold in space and time. It is now clear that the hippocampus accomplishes its role in memory by generating a unique code reflecting the spatio-temporal context of experiences. This code provides a tag or 'index'that links together components of a given experience stored in a distributed form throughout the neocortex. The long-term goal of this program is to further our understanding of how this unique tag is generated. The generation of the hippocampal code is founded on internal mechanisms for keeping track of spatial location and for appending information about external events onto an internal spatial coordinate system or 'cognitive map'. Sets of neurons in hippocampus are selective for spatial location ('place cells'), neurons in related thalamic and midbrain structures are selective for head orientation in the horizontal plane ('head-direction cells'), and recently discovered cells in medial entorhinal cortex establish a spatial coordinate system ('grid cells'). These neurons are the core of a network that updates its spatial coordinate primarily on the basis of self-motion information ('path-integration'), and then creates and stores a code that is unique to current external and internal events at the current spatial coordinate. This capability appears to depend critically on the generation of precise spike timing relationships relative to the local EEG oscillations (theta rhythm). The project focuses on understanding the mechanisms underlying the grid-like firing patterns of entorhinal neurons and their spike timing dynamics, where the essential linear self-motion information that enables this system to perform path integration comes from, how neuronal firing characteristics of hippocampal cells are synthesized from entorhinal inputs, and how the entorhinal grid-cell network is wired up by a self- organizing process in early post-natal development. We also propose a specific experimental test that can, in principle, distinguish between two leading theoretical models for the mechanism of grid cells. Finally, we will test the hypothesis that a subregion of the hippocampus (the dentate gyrus) adds a temporal tag to episodic memories. In pursuing our long-term goal, we combine computer modeling and theoretical analysis with neurophysiological methods (largely pioneered by the PI) for recording the activity of large ensembles of single neurons in behaving animals. PUBLIC HEALTH RELEVANCE: Impairment of normal hippocampal function is strongly linked to memory impairments associated with normal and pathological aging, brain trauma and disease, developmental disorders and substance abuse. Thus, the neuro-physiological and neuro-computational principles underlying hippocampal function provide a framework for understanding memory processes, which are so important to quality of life, and disorders of which have such a major impact on our health care system. A well characterized and well understood rodent model of hippocampal function will also provide a platform for drug discovery and the development of genetic intervention for treatment of human memory disorder.

DESCRIPTION (Adapted from applicant's abstract): The aim of this project is to understand the mechanisms and computational principles underlying the encoding of memories that depend on a functional hippocampus (HC), and their subsequent consolidation into HC-independent, long-term storage, presumably in the neocortex (NC). This is a prerequisite to ameliorating memory disorders resulting from developmental abnormalities, disease, trauma, aging or drug abuse. The working hypothesis is that the function of long-term memory is to construct, from past experience, internal representations that reflect the statistical regularities of the environment, and which thus permit adaptive generalization and appropriate responses. Such learning requires repeated, interleaved exposure to the items to be stored, with small adjustments to the synapses on each trial. Attempts to store new information all at once in such a memory lead to "catastrophic interference" with items already stored; however, survival often requires adding new items to the existing categorical structure, with only one or a few experiences. It is hypothesized that HC generates and stores compact representations of the spatial contexts of such events, which become associated with the individual components of the events in their respective NC areas at the time of the experience. By spontaneously reactivating these stored contexts, the HC facilitates the reinstatement of the original patterns in a coherent fashion throughout NC, and thus provides the required "training trials" while the system is "off-line". This provides a framework for understanding the phenomenon of temporally graded retrograde amnesia following HC damage, and why and how memory consolidation takes place. Using simultaneous recordings from 50-150 neurons, it has been shown that population-codes for novel environments develop rapidly during exploration, and that traces of recent events and event-sequences can be observed in the collective activity of neurons in both HC and NC during quiet wakefulness and slow-wave sleep. The proposed recording studies address specific aspects of the theory: whether the robustness of off-line reactivation of memory traces is correlated with subsequent performance; whether more remote memories are interleaved with newer ones during off-line periods; whether there is a retrograde gradient of memory reactivation; which behavioral states are most conducive to reactivation; to what extent reactivation also occurs in NC during the off-line periods; whether NC and HC reactivations reflect the same recent experiences; and whether a functional HC is necessary for reactivation of recent memory in NC. Finally, it is proposed to test the theory by imposing distributed patterns of electrical activity in HC using spatially structured electrical stimuli both during acquisition of spatial information and during off-line periods.

DESCRIPTION: (Adapted from the Applicant's Abstract.) Recent neurophysiological and behavioral experiments strongly suggest that the capacity for rapid and effective spatial orientation is based primarily on the interaction between a set of high-order neurons that transmit a representation of spatial location, and an extensive network of neocortical and subcortical neurons which use vestibular, angular-velocity information to compute and transmit a signal reflecting the azimuthal component of the animal's head orientation, relative to an inertial reference framework. Such a system is ideally suited for the computation of relevant behavioral trajectories in an earth-bound environment, first because it enables space to be internally represented and stored economically as a set of landmark- vectors, and second, because it enables the trajectory computation to be carried out by vector subtraction. The latter capacity permits the rapid calculation of novel, direct trajectories to a desired target. Clearly, the fact that this orientation system is based on azimuthal information with respect to the local gravitational field suggests that problems may develop in low or zero-gravity situations. The present proposal for the NeuroLab mission aims to use neurophysiological experiments in freely behaving rodents to address the question of how this crucial system performs and adapts to low gravity conditions. Methods developed in this laboratory have enabled the simultaneous recording from large numbers of neurons involved in the spatial orientation system and which enable the same neuronal ensembles to be studied over periods of up to several weeks. This technology will maximize the amount of relevant neurophysiological data that can be obtained from a small number of rodents (2-4). The investigators realistically expect to be able to obtain well isolated unit recordings from as many as 1000 neocortical, thalamic, and tectal neurons over the course of a single mission, and to study the ensemble interactions of 50-150 cells in any given recording experiment. They also propose to assist and collaborate with other research groups in employing the same technology to address other important neurophysiological questions of relevance to space flight, including possible changes in motor control and sensori-motor integration, sleep-waking cycles, and autonomic control.

Our goal is to develop a computational and empirical framework through which to understand the neuronal dynamics of the mammalian hippocampus and its cortical connections, in relation to spatial representation and memory. This system is crucial for memory formation, and its dysfunction through injury or disease is the major cause of human memory impairment. The project complements ongoing neurophysiological studies of single cell activity in freely behaving animals, spontaneous and evoked synaptic plasticity and modulation in conscious animals, and the micro-physiology of neural interaction using spike-triggered quantal analysis at single synapses in vitro. The wealth of data generated by such studies (from our own and other groups) has created an "embarrassment of riches" crisis. We plan to exacerbate the crisis by developing methods for recording from parallel arrays of "stereotrode" probes to acquire data from interacting populations of about 50 to 100 hippocampal neurons during spatial behavior. We hope to help alleviate the crisis thorough simulations that incorporate enough of the known network, biophysical and unit activity parameters that useful insights into the physiological origins of several important "system-level" phenomena can be derived and tested in physiological experiments. The conceptual starting point for these simulations is the Hebb-Marr formalism for distributed associative memory. Specifically, we address the origins and computational utility of the following phenomena: 1) Hippocampal neurons are exquisitely selective for the animal's location and orientation in space. Such selectivity is present neither at the inputs, nor (surprisingly) at the cortical outputs of the system. Moreover, at least the CA1 region can reconstruct spatial representations when the information transmitted to it from CA3 is drastically degraded (i.e., "pattern completion"). 2) Hippocampal granule cells far outnumber the cortical afferents from which they receive highly convergent input, yet they fire 1:10). Using numerical simulation we will investigate the hypothesis that this organization subserves the orthogonalization or correlated input vectors (c.f. Marr's codon formation). 3). The fascia dentata may also serve in the extraction of novel input features (c.f. the "novelty filter" of Kohonen), an hypothesis based on our observation that net synaptic efficacy increases, yet net excitability is reduced by the acquisition of new information during exploration. To aid in interpreting these phenomena and in the design of future experiments, we will simulate electrically evoked population field potentials in the granule cell network, upon which the theoretical inferences are based, and the possible cellular dynamics that might lead both to these physiological phenomena, and to the proposed novelty extraction effect.

DESCRIPTION (Adapted from applicant's abstract): This is an application for a K05, Senior Scientist Award. Throughout his career, the candidate has pursued the neurobiological and computational basis of memory. In the late 1970's, he provided the first evidence for the biological realization of Hebb's neurophysiological postulate for associative memory, by showing that synaptic long-term potentiation (LTP) in the hippocampus involved the cooperation of converging inputs. Since then, he has made numerous contributions to understanding the process of LTP at both the biophysical and behavioral levels, and contributed significantly to the development of neural network theories of both memory and the neural encoding of spatial information (cognitive maps). Motivated by the idea that memories are properties of neural populations, supported by enhanced mutual connections, the candidate has guided the development of methods that currently routinely enable recording simultaneously from over 100 neurons in the freely behaving rodent. This method has opened an unprecedented window on neuron interactions and has provided strong indirect evidence for the existence of Hebb's "cell assemblies" and "phase sequences" during a process of off-line reprocessing of recent memories in the hippocampus and neocortex. The candidate is currently Director of the Division of Neural Systems, Memory, and Aging, at the University of Arizona, a 9,000 sq. ft. research facility dedicated to memory research. The facility includes dedicated surgical, neuroanatomical and electronics engineering suites, and several specially designed controlled environments for behavioral neurophysiology. The candidate's own research team includes 5 postdoctoral, 6 graduate, and 4 undergraduate research associates, and 5 electronics, computer, and neurophysiological research specialists. The candidate's immediate and long term research goal is to understand the brain dynamics underlying the transformation of episodic memory into categorical knowledge, a process known as memory consolidation. The specific career development plan to be supported by this award is to begin to develop the technology to enable recording from up to 400 cells from the cortex and hippocampus in the behaving primate and to develop new analytical tools for understanding the behavior of cell assemblies in terms of these large populations of recorded units. The specific research projects deal with the questions of the reactivation of memory traces during sleep, how this is orchestrated by the hippocampus, and whether the process itself is truly of behavioral significance.

A fundamental problem in psychology and neuroscience is to understand how the transient memory of an experience becomes stabilized and available as long-term memory. A general theory of memory is that sleep is important to make the memory of an experience stable and resistant to interference. One specific theory has proposed that there are two systems at work during learning, a fast acting system that encodes temporary memories into a brain area called the hippocampus and a slower system that transfer these memories during sleep into a more permanent form in higher-level cortical regions. This process depends on a communicative interaction between the hippocampus and cortex. The present research is the first to directly test the hypothesis of the interleaved interaction between brain regions in the formation of stable more permanent memories from experience. Evidence of this interaction between fast-acting and long-term representations has implications for understanding a number of neurological problems involving memory, for explaining changes in memory with aging, and for the development of new robust computer memory systems. The project provides training opportunities for postdoctoral fellows and data and tools dissemination.

Simultaneous electrical and optical recordings from the hippocampus and neocortex will be made as rodents acquire new memories and consolidate these memories into a stable more permanent form of long-term memory. The project examines patterns of activity in these different brain regions to test the hypothesis that interleaved activity patterns during resting state reflects an interplay of recent and long-term memories. Further, a comparison of brain activity in resting states and task-dependent states will examine the question of whether stable long-term memories are regularized by consolidation to be less detailed and more general. The research will measure patterns in collections of spiking neurons along with global patterns of brain electrical activity to test these hypotheses about the process of memory consolidation.

Project Summary The Training Program in Learning and Memory is based at the University of California - Irvine Center for the Neurobiology of Learning and Memory (CNLM), a research unit established in 1983 by the UC Regents with James L. McGaugh as its Founding Director. The Center?s highly interdisciplinary faculty are working to achieve a complete and integrated understanding of how the brain stores and remembers information across all levels from molecules to mind. Of the Center?s more than 70 active research faculty, 21 will be the core training faculty for this program, representing strengths in molecular, cellular, circuit, systems, cognitive and computational neuroscience of learning and memory. The program?s goal is to train the next generation of innovative leaders in neuroscience by empowering them with the skills, knowledge, and team science core values necessary to comprehensively understand the neural basis of learning and memory. The program is aimed at predoctoral trainees with four slots offered every year and a typical duration of appointment of 2 years. It will feature 10 key components that will provide unique education training in the range of skills required for a successful research career in learning and memory: (1) a new problem-focused seminar course that promotes transdisciplinary and divergent thinking in learning and memory; (2) a new course on neural computation; (3) a new course on research-intensive academic careers (Life Skills for the Academic); (4) a full-day workshop on transdisciplinary research and team science; (5) attending and presenting research at the annual learning and memory conference; (6) attending, presenting at, and taking part in planning a training program fall retreat; (7) networking with visiting experts via the CNLM seminar series, conferences and workshops; (8) attending and presenting in one of the CNLM journal clubs; (9) attending a major conference each year e.g. Society for Neuroscience; and (10) participating in a minimum of three professional development workshops and one certificate program offered by UCI?s Graduate Division. An additional optional component designed for this program is a team science proposal competition that puts into practice many of the principles taught in the team science workshop. The activities fulfill many of the advanced requirements for coursework and will not increase time to degree completion. The overall training program leverages the existing resources and activities in UCI?s graduate training, adds new training components that are unique to trainees of this program, and provides a host of optional activities for professional development. Desired outcomes include successful completion of PhD, published manuscripts, quantified improvement in transdisciplinary thinking and behavior, individual fellowships (e.g. NRSA), successful placement in postdoctoral training, and subsequent career in research-intensive or research-related areas. With a number of value-added components, this training program will successfully prepare our trainees to be future leaders in the neurobiology of learning and memory.

For a given age or level of brain pathology, patients with higher educational status, occupational achievement, bilinguality, and school grades show fewer symptoms of dementia. Such factors have been lumped into a concept called ?Cognitive Reserve? (CR), which is the principal correlate of resilience against dementia and normal, age-related cognitive decline. CR ?may be based on more efficient utilization of brain networks or of enhanced ability to recruit alternate brain networks, or it may reflect intrinsic (innate) brain physiology differences; however, evidence indicates a major role of the degree of knowledge acquisition over the lifespan. But the linkages between enhanced experience and CR, and between CR and neurobiological function, need to be experimentally established. Does enhanced experience actually create CR? What are the neurobiological correlates of CR? Does CR actually preserve neurobiological function, such as the ability to retrieve recent activity patterns or the ability to rearrange synaptic connections, or is it merely a reflection of the complexity of patterns stored before the onset of brain pathology? As an animal proxy for CR, we will exploit a new method for environmental enrichment that we have developed, which produces striking improvements in at least five different tests of memory and cognitive function in normal mice. These improvements are significantly superior to classical environmental enrichment methods, allow for tight control of enrichment parameters and exercise variables, and last at least 6 months. Using advanced optical cellular activity imaging in freely behaving mice and neural ensemble recording methods in a VR apparatus we will assess the neurodynamic effects of EE in the hippocampus of normal mice and in an animal model of Alzheimer's disease (AD). We will study a range of hippocampal neurodynamics that are believed to reflect or to play a key role in memory processes. These parameters include hippocampal oscillations such as theta rhythm and sharp-wave-ripples (SWR), `place' cell population coding of environmental location, rate coding of changes in external inputs at a given location (?rate- remapping?), experience-dependent encoding of sequential experience, representational efficiency (sparse coding, log-normal firing rate distributions) and temporal stability, and post experience reactivation of recent memories during periods of rest. We will compare the effects of running the Enrichment Track with running on an Exercise Control Track. Parallel studies of the effects of Enrichment Track and Control Track on amelioration of cognitive/behavioral deficits in the same, 3xTg AD, mice are being conducted under separate support, which will enable us to assess which neural dynamic parameters best account for behavioral improvements and set the parameters for future within-subject experiments that would enable direct correlation and manipulation. CR is a significant factor not only in protection of cognitive capacity against brain pathology such as AD, but also against the changes that occur in normal, healthy aging. For these reasons, a complete understanding of the neurodynamics basis of CR is of paramount importance.

We propose a circuit-level principal underlying how brains acquire 'episodic' memories and reprocess them into compact, efficient 'schemas': The attributes or 'contents' of experience are represented primarily in the deeper layers of neocortex (NC), whereas the superficial layers are dedicated to encoding the contexts in which the attributes occur. Synaptic associations between superficial context codes and deep attribute codes permit contexts to evoke appropriate attribute output hence enabling memory recall and predictive behavior. The hippocampus (HC) is essential for acquisition of memories and for their reprocessing into efficient, schematic representations of the world. NC exhibits dense local but sparse long-range connectivity, which severely limits its ability to make rapid, long-range associations. HC likely solves this dilemma by merging the totality of the brain's current internal state (i.e., sensory input and internal variables such as hunger, fear, current goals) into a unique, 'index' code that is projected to NC, and associated with its current, distributed, attribute representation. Retrieval of an index code evokes the corresponding attributes. Such HC-orchestrated retrieval may enable the gradual rewiring of NC circuitry in a manner that captures the overall statistics of experience, much the same way as deep, artificial, neural networks learn incrementally by small connection weight adjustments directed by the overall statistics of the input. Our hypothesis on the laminar division of labor in this process is based on the facts that HC output is directed primarily to upper layers of NC, which implements a 'spatial' coding scheme that is lost after HC lesions; and that the deeper layers of NC frequently exhibit more robust responsiveness to and discrimination of sensory inputs than the superficial ones. We propose to record cellular level, neural ensemble activity simultaneously from deep and superficial layers in primary and association cortex, using high-density, electrophysiological recording. First, we attempt to establish the 'attribute vs index' principal by showing that deep cells shift their firing locations with shifts in the relevant sensory attributes, whereas superficial cells do not. Next we test the hypothesis that, as NC accumulates large amounts of diverse experience, attribute representations in deeper layers becomes sparser and more categorically organized, whereas superficial layer coding is relatively unchanged. To accomplish this, we employ a recent chemogenetic advance that enables us to acquire large amounts of resting-state cellular data, in which we expect the predicted changes will be most easily observed. We also explore the statistics of excitatory-inhibitory cell functional connectivity that may underlie such coding statistics changes. The expected advances in understanding cortical memory and schema encoding circuits will ultimately improve clinical assessment of, and intervention in memory and cognitive disorders.