Elizabeth Buffalo - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Memory formation is accomplished through cooperative activity in the hippocampus and the surrounding medial temporal lobe cortex, and the interaction of this complex with neocortex. However, almost nothing is currently known about the neural signals that underlie hippocampal-cortical interaction. Because of its anatomica connectivity, the entorhinal cortex is well-positioned to play a critical role in hippocampal-cortical interaction. The entorhinal cortex is both the main source of cortical input to the hippocampus and the primary target of feedback signals from the hippocampus. Importantly, these connections have laminar specificity such that the superficial layers of the entorhinal cortex project to the hippocampus and the deep layers receive feedback from the hippocampus. The objective of this project has been to to identify the memory-related activity of neurons in superficial and deep layers of the entorhinal cortex. In the past year, we have begun collecting data with a new multi-contact recording electrode. This electrode has 12 contacts, with 300-micron spacing between contacts. Use of this novel technology has allowed us to simultaneously record from all layers of the cortex. Data collected in the past year suggest significant differences in the spectral profile of entorhinal cortex cell layers.

DESCRIPTION (provided by applicant): Impaired memory is an important component of diseases such as Alzheimer?s disease, temporal lobe epilepsy, depression, and schizophrenia that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. The objective of this proposal is to characterize neural signals that support a prototypical form of memory, recognition memory. Recognition memory is the ability to perceive a recently encountered item as familiar. This ability is impaired following lesions of medial temporal lobe structures, including the hippocampus and the underlying perirhinal and entorhinal cortices. Neural signals that may support recognition memory have been described in the perirhinal and entorhinal cortices. However, despite extensive research, there is currently little evidence for the existence of recognition memory signals in the non-rodent hippocampus. This apparent inconsistency between the findings from lesion and physiology studies fuels a current controversy regarding the contribution of the hippocampus to recognition memory and prevents a full understanding of the organization of memory. Based on preliminary data, we hypothesize that single neurons, the local field potential (LFP), and synchronized ensembles of neurons in the hippocampus display modulations in activity that may be used for recognition memory. The experiments proposed here will directly test this hypothesis, using multi-electrode recordings of spiking activity and LFPs during a recognition memory task. We will examine modulations in single-unit firing rates, amplitude and power in the LFP, and spike-field neuronal synchronization with respect to performance on the Visual Preferential Looking Task, which is known to be highly sensitive to lesions of the hippocampus. The proposed experiments have the following potential outcomes: to resolve the apparent inconsistency between lesion and neurophysiological studies regarding the role of the hippocampus in recognition memory;to determine the functional significance of oscillatory activity, including theta-band oscillations, in the hippocampus;and to identify neuronal synchronization as a potential mechanism underlying memory formation. PUBLIC HEALTH RELEVANCE Impaired memory is an important component of diseases such as Alzheimer's disease, temporal lobe epilepsy, depression, and schizophrenia that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. The objective of this proposal is to identify neural mechanisms in the hippocampus and subjacent cortex that may underlie memory formation.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the central goals of the Yerkes National Primate Research Center is to provide educational and training opportunities. The Center is actively involved in training and continuing education activities, including training of graduate students, postdoctoral fellows, and staff. The funds used in this administrative supplement are to extend training opportunities to high school students, high school science teachers and undergraduate students. The objective of this program is to provide a high-quality, translational summer research experience. The project has four core elements: 1) to provide an eight week summer research experience in an out-of-school time setting for high school science teachers and high school students in a participatory learning environment;2) offer stipends and create opportunities for participants to share and present their research and 3) create a collaboration of partners (Yerkes, Center for Behavioral Neuroscience, Gwinnet School of Mathematics, Science and Technology (GSMT), and Georgia Afterschool Investment Council) to maximize the experience and create a powerful forum for sharing results and 4) conduct an evaluation and focus groups to assess impact. An additional goal is to provide science educators with a 'real-world'professional development experience in a scientific research laboratory. This supplement is aligned with the goals of the American Recovery and Reinvestment Act of 2009 by providing summer employment to students and teachers. Further, the activities have the expected outcome of encouraging students to pursue research careers in the health-related sciences as well as providing high school teachers with short-term research experiences in NIH-funded laboratories.[unreadable][unreadable][unreadable][unreadable][unreadable]

DESCRIPTION (provided by applicant): Impaired memory is an important component of diseases such as Alzheimer's disease, temporal lobe epilepsy, depression, and schizophrenia that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. The objective of this proposal is to clarify the role of the hippocampus in relational memory. Relational memory refers to the ability to link together the arbitrary or accidental relations among elements of scenes or events. However, there is currently little evidence for relational memory signals in the primate hippocampus at the level of individual neurons or groups of neurons. Monkeys can be tested on some of the very same relational memory tasks as human subjects, and, therefore, neurophysiological studies of the activity of single units and neuronal networks in the monkey hippocampus will be instrumental in identifying the nature of neuronal representations that underlie relational memory. Based on preliminary data, we hypothesize that single neurons and synchronized ensembles of neurons in the hippocampus display modulations in activity that may be used for relational memory. The experiments proposed here will directly test this hypothesis, using multi-electrode recordings of spiking activity and the local field potential (LFP) in the hippocampus of monkeys engaged in a battery of relational memory tasks, adapted from the human literature. We will examine modulations in single-unit firing rates and spike-field neuronal synchronization with respect to relational memory performance encompassing a variety of domains, e.g., spatial, contextual, and temporal. In addition, to assess whether these hippocampal electrophysiological correlates are critical for relational memory processes or whether these processes could also be supported by medial temporal cortical areas in the absence of a functional hippocampus, we will test the effects of restricted lesions of the hippocampus on these same relational memory tasks. The proposed experiments have the following potential outcomes: 1) to determine the changes in neuronal activity in the primate hippocampus that signal the learning of relational associations, 2) to identify neuronal synchronization as a possible mechanism underlying relational memory performance, and 3) to resolve the apparent inconsistencies among human lesion studies regarding the role of the hippocampus in relational memory. PUBLIC HEALTH RELEVANCE: Impaired memory is an important component of diseases such as temporal lobe epilepsy, depression, schizophrenia, and Alzheimer's disease that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. The objective of this proposal is to identify neural mechanisms in the hippocampus that may underlie relational memory and to determine whether the hippocampus is necessary for relational memory as distinct from memory for individual items.

PROJECT SUMMARY (See instructions): Oxytocin promotes affiliative behaviors and enhances the ability of animals to discriminate between individuals of their own species. The amygdala plays a central role in establishing the social and emotional significance of social stimuli including faces and facial expressions. The central hypothesis of this project is that the oxytocin-induced changes at the behavioral level result from cellular changes in the amygdala, which contains a large concentration of oxytocin receptors. We propose that oxytocin facilitates prosocial behavior by (1) increasing attention directed to social stimuli, particularly the eyes of conspecifics and enhancing the activity of anygdala neurons in response to fixations to the eyes and by (2) enhancing the discrimination of social stimuli through enhanced neural selectivity in the amygdala for face identity and facial expressions. These hypotheses will be tested by recording the activity of multiple single neurons along with the local field potential in the amygdala of monkeys exposed to videos that simulate socio-emotional interactions with other monkeys. It is expected that oxytocin, administered intranasally or by microinjection into the ventricles, will induce behavioral and neural changes that reflect enhanced attention to the eyes and faces, higher individuation of faces, and a processing bias for affiliative stimuli. By examining the effects of oxytocin on neural activity in the amygdala, the proposed experiments will provide a comprehensive test of the hypothesis that oxytocin enhances social cognition via a direct effect on single neurons and networks of neurons in the amygdala. Further, the proposed experiments have the exciting potential outcome of enabling a more detailed and mechanistic understanding of higher cognitive processes involved in primate social behavior, which is critical for the development of better treatments for humans with impairments in social cognition.

DIVISION OF NEUROSCIENCE PROJECT SUMMARY The central aims of the Division of Neuroscience are (i) to advance the nonhuman primate (NHP) model for studies of the nervous system, (ii) to advance understanding of the nervous system in ways that are uniquely supported by the NHP model, (iii) to serve as a focal point for research in systems and translational neuroscience, (iv) to disseminate technical knowledge concerning the NHP model as well as the novel discoveries derived from fundamental neuroscience research in NHPs. The Division consists of six core staff laboratories that represent a broad range of neuroscience spanning motor control, vision, memory, and cognition. The Division boasts productive collaborations with scientists within the WaNPRC, affiliate NHP neuroscience laboratories at the UW, as well as other neuroscientists, both in the US and abroad. The Division of Neuroscience exemplifies NIH and ORIP expectations that the Core Staff and Primate Center serve as a national resource and focal point for a large, vibrant research community. The Division provides an environment in which cutting edge innovative neuroscience thrives. Besides the impressive productivity of each of the individual core staff programs, the division cultivates an atmosphere of interaction, constructive criticism, and support. The environment fosters collaborations with UW faculty from clinical departments, affiliates using the NHP model, and faculty from basic science and clinical departments with expertise in human imaging, human psychophysics, neurology, pathology, engineering, applied math, and theoretical neuroscience. These interactions have led to the development of new techniques, algorithms, web resources, and translational applications. Through service on national review panels, study sections, editorial boards, conference organizing committees, and through teaching and training of students and postdoctoral fellows, the Division of Neuroscience serves as a focal point for a large, vibrant research community.

Project Summary/Abstract The Administrative Core will provide the administrative structure, fiscal expertise, and logistical management to ensure that the goals of this multidisciplinary effort are achieved. The Administrative Core will be responsible for overseeing all aspects of the Program, including providing efficient coordination of the projects and Data Science Core, assuring fiscally and ethically responsible research, and collaborating with the Internal Advisory Board, the External Advisory Board, and the NIH science officers to monitor scientific progress and course- correct, if necessary, to fulfil the scientific aims of the Program. The tasks of the Core include budget oversight and management, coordinating regular meetings of the Internal Advisory Committee and Team members, organizing the annual Team in-person meetings, and working with the Data Science Core to coordinate efforts. Working with the Internal Advisory Board and NIH science staff, the Administrative Core will be responsible for recruiting an External Advisory Board and organizing the site visit in years 2 and 4. The Administrative Core will also be responsible for the preparation and submission of progress reports, as well as other administrative and communications functions including maintenance of the Program website. The Administrative Core serves to bring all Team members together as a common unit, a whole that is greater than the sum of the parts, fostering maximally effective communication, collaboration, and synergy between the collaborating laboratories and institutions, other BRAIN teams, and the broader scientific community.

PROJECT SUMMARY/ABSTRACT The mammalian brain has a remarkable ability to store and retrieve information. Detailed memories can be formed after as little as one exposure, and those memories can be retained for decades. This ability is compromised following damage to structures located in the medial temporal lobe, including the hippocampus and the adjacent cortex. Over the past decade, many studies have highlighted interactions between the hippocampus and neocortex, in particular, the prefrontal cortex (PFC) and posterior parietal cortex (PPC), as having an essential role in memory consolidation. However, the circuit mechanisms that support memory consolidation are not well-understood, particularly in the primate brain. Impaired memory is an important component of diseases such as Alzheimer's disease, temporal lobe epilepsy, depression, and schizophrenia that collectively affect over twenty million Americans. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes, in order to bring us closer to developing new therapies for these disabled patients. Psychological theories and behavioral studies have suggested that rapid, single-trial accumulation of information is facilitated by prior knowledge, a cognitive map or ?mental schema? that provides a framework onto which new information can be assimilated. This concept is relevant for understanding potential hippocampal-neocortical interactions in the service of memory consolidation. The experiments proposed here will directly examine the neural circuits in the hippocampus, PFC, and PPC that support schema development and new learning. The overall goal of this U-19 Program is to develop a comprehensive theory of the circuit mechanisms that support rapid learning. To achieve these goals, we will make use of a multi-laboratory research framework with an ambitious effort that requires multiple areas of expertise, exemplified by our team members. Our team effort is organized around four Research Projects, each supported by Data Science and Administrative Cores. Through parallel projects in monkeys and humans, we will perform large-scale recordings simultaneously across the hippocampus, PFC and PPC to assess modulations in cross-regional connectivity during schema development and new association and categorization learning. Complementary theoretical approaches will integrate large-scale circuit modeling of the human and nonhuman primate brain based on measured mesoscopic connectivity and training recurrent neural networks to perform cognitive tasks. We will test the hypothesis that in the course of schema instantiation, a task structure is encoded in the form of a low-dimensional structure in the space of connection weights, which is reflected in a low- dimensional subspace of neural dynamics. During new learning, the system benefits from the schema to narrow weight parameter search, thereby speeding up learning. We hypothesize that this process is observable at the level of dynamical inter-areal interactions. Taken together, the experiments proposed under this Program will provide a comprehensive, cross-species investigation of the neural mechanisms of rapid learning.

Project Summary/Abstract The ability of the mammalian brain to store and later retrieve information is remarkable. Detailed, complex memories can be formed after as little as one exposure, and those memories can be retained for decades. This ability is compromised following damage to the hippocampus, and interaction between the hippocampus and the neocortex is thought to be critical for systems memory consolidation. Impaired memory is a debilitating consequence of diseases such as temporal lobe epilepsy, Alzheimer's disease, depression, and schizophrenia that collectively affect over twenty-five million Americans. However, our understanding of the circuit mechanisms that support memory consolidation and rapid new learning is incomplete, particularly in the primate brain. Our long-range goal is to contribute to a better understanding of the neural mechanisms that underlie memory processes to bring us closer to developing new therapies for these disabled patients. Psychological theories and behavioral studies have suggested that rapid, single-trial accumulation of information is facilitated by prior knowledge, a ?mental schema? that provides a framework onto which new information can be assimilated. The hippocampus is considered to be critical for extracting and representing regularities that hold across learning episodes, and these regularities constitute the cognitive schema. Determining how the hippocampus supports this cognitive framework will be critical to understanding the hippocampal-neocortical interactions that are necessary for memory consolidation. The experiments proposed here will directly examine hippocampal-cortical interactions during learning and consolidation. We propose to utilize newly available technical developments to advance our understanding of the mechanism that support rapid new learning. Specifically, we propose to perform large-scale recordings from individual neurons throughout the hippocampus, parietal cortex, and prefrontal cortex in monkeys trained to perform a task of object-place association in virtual environments. We will use stable and unstable environments to examine the impact of a schema on association learning and neural activity, and we will track neural activity during learning to investigate the mechanisms that support the formation of a schema. The proposed experiments have the following potential outcomes: 1) to identify the network activity across single units in the hippocampus, parietal and prefrontal cortex in support of object-place association learning, 2) to identify the dynamics of cross- regional communication through synchronized oscillatory activity during schema development and rapid learning, and 3) to identify hippocampal-cortical interaction during sleep and quiet wakefulness and determine how this interaction impacts memory consolidation.

Project Summary/Abstract The hippocampus plays a critical role in the formation of new memories; however, it is not clear how information is structured and processed by the hippocampal network in the service of memory formation. The microcircuitry of the hippocampus is richly interconnected, which produces robust, temporally-structured activity spanning ensembles of neurons. Microcircuit motifs resonate at characteristic frequencies when they become active, recruiting hippocampal neurons into coordinated circuits that can be detected in the rhythmicity of local field potentials (LFP). The hippocampal LFP in primates demonstrates a complex mixture of oscillatory signatures, and there is often no dominant frequency in the signal during memory tasks. This stands in stark contrast to the prominent theta band (6-10 Hz) oscillation that occurs in rodents selectively during exploration and task performance as the animal actively processes incoming information. Theta-rhythmic activity in the rodent hippocampus is coordinated by input from the medial septum, which is a connectional pathway that is conserved across all mammals. Although monkeys lack this sustained archetypal theta-band activity in the LFP, the preservation of anatomy across species suggests the presence of a circuit that would similarly govern hippocampal information processing in primates. In this proposal, we will combine newly available electrophysiological technology with innovative computational approaches to quantify and model complex signals of the primate LFP. Single-unit and LFP activity will be simultaneously recorded from the full extent of the hippocampus using chronically-implanted hyperdrives and linear electrode arrays while monkeys perform a spatial memory task in virtual reality. In addition, we will examine the effects of medial septum stimulation on hippocampal oscillatory dynamics and behavior. We will take advantage of novel spectral analysis techniques to improve interpretation of LFPs characterized by transient and irregular oscillations. The proposed experiments have the following potential outcomes: 1) to determine the relationship of hippocampal oscillatory states to neuronal spiking and memory task events, 2) to develop data-driven computational models that characterize patterns in hippocampal oscillations as they unfold in time and across hippocampal subfields during memory task events, and 3) to identify the extent to which the medial septum drives oscillatory activity mediating active processing in the hippocampus.