Sara N. Burke - US grants

[unreadable] DESCRIPTION (provided by applicant): During the past several decades, the hippocampus has been an empirical focus of age-related memory decline. While this is justified, the extent to which changes in the perirhinal cortex, a region extensively interconnected with the hippocampus, contribute to age-related behavioral deficits is unknown. Humans with lesions of the hippocampus lose the ability to form new memories while humans with lesions of the perirhinal cortex develop semantic dementia, a condition characterized by an insidious and gradual breakdown in semantic knowledge. Thus, while the hippocampus is critical for forming new memories, the perirhinal cortex may be integrally involved in providing content to those memories. Whether the response properties of perirhinal neurons change, and/or there is a decline in perirhinal plasticity during normal aging that contributes to memory impairment, is the major question addressed in the present proposal. To begin to address this, perirhinal function and the mechanisms of recognition memory will be investigated in adult and aged rats using electrophysiological recordings and imaging neural ensembles with cellular compartmental analysis of temporal activity by fluorescence in situ hybridization [unreadable] [unreadable]

? DESCRIPTION (provided by applicant): By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, even in the absence of significant neuropathology, a large proportion of elderly people will experience memory decline that will interfere with their instrumental activities of daiy living. The hippocampus is critical for memory and is subject to dysfunction during aging. Importantly, the dentate gyrus subregion of the hippocampus is one of only two brain regions in which new neurons are born and integrated into existing neural circuits; a process referred to as neurogenesis. Neurogenesis declines with age, but it is not known how this contributes to cognitive impairments. Although neurogenesis could have vital functions for normal memory, there is a fundamental gap in our knowledge of how this process impacts neuronal networks both within the dentate gyrus as well as in the brain regions that receive direct input from this structure. Moreover, to date, there is not a single report of the in vivo physiological characteristics of dentate gyrus neurons in aged animals. The long-term goal of the proposed research plan is to pinpoint disruptions in the neural circuits of old animals that can then be restored through therapeutic or behavioral interventions to reduce cognitive impairments in the elderly. The objective in this particular application is to determine how neurogenesis levels impact hippocampal-dependent behaviors and the dynamics of neural networks within the dentate gyrus and its primary efferent target, CA3. The central hypothesis is that the integration of newborn neurons is critical for dynamic hippocampal representations needed to support complex behaviors. The rationale for the proposed research is that understanding the functional importance of neurogenesis and how dentate gyrus and CA3 cellular activity dynamics are impacted by lower numbers of newborn neurons could direct clinical treatments for cognitive deficits associated with aging that are going to become more prevalent as the number of elderly people in the U.S. continues to grow. The hypothesis will be tested with 2 specific aims: 1) identify how age- related neurogenesis decline impact dentate gyrus circuit dynamics, and 2) quantify the impact of age- associated functional changes in the dentate gyrus on CA3. These aims will be achieved through the use of high-channel count neural recordings that allow single-cell activity to be monitored from up to hundreds of neurons across multiple brain regions simultaneously in behaving rats. This is an innovative approach that optimizes power for detecting neural-behavioral relationships.

Title: Single-Cell Imaging of Functional Connectivity as a Window into Cognitive Aging Sara N. Burke, Ph.D. (P.I.; 20% effort) Assistant Professor, Department of Neuroscience, University of Florida College of Medicine P.O. Box 100244 1149 Newell Drive Gainesville, FL 32611 Phone: 352-294-4979 Email: burkes@ufl.edu Andrew P. Maurer, Ph.D. (co-I.; 15% effort) Assistant Professor, Department of Neuroscience, University of Florida College of Medicine P.O. Box 100244 1149 Newell Drive Gainesville, FL 32611 Email: drewmaurer@ufl.edu Benjamin J. Clark, Ph.D. (co-I.; 15% effort) Assistant Professor, Department of Psychology 1 University of New Mexico MSC03 02 1675 Albuquerque, NM 87131-0001 Phone: 505-277-4121 Fax: 505-277-1394 Email: bnjclark@unm.edu Budget requested: $275,000.00/2 years Abstract: The number of Americans over the age of 65 is projected to reach 55 million within the next decade. With the average annual Medicare cost for the long-term care of an individual exceeding $61k, preserving one?s ability to live independently is imperative for conserving public and private resources as well as maintaining personal dignity. Although a large proportion of elderly experience memory decline that interferes with their quality of life and ability to maintain independence, therapeutic interventions for treating cognitive deficits associated with aging and dementia are limited. Thus, identifying new strategies for mitigating age-related memory loss is critical. Understanding the neurobiology of memory impairments poses a significant challenge, as these processes are distributed throughout the brain and little is known about the orchestrated communication of neural networks in disparate brain areas. Moreover, current tools for evaluating large-scale circuit dysfunction do not have the spatial resolution to identify the specific neuronal populations that are most vulnerable to aging and pathology. The long-term goal of the proposed research is to determine the age-related alterations in interactions between brain regions that underlie cognitive impairments, and how aging and neurodegenerative disease acerbates these effects. The primary objective of the current proposal is to expand the application of a novel method for quantifying functional connectivity among brain regions with single-cell resolution in the context of age-associated behavioral deficits. The central hypothesis that age-related deficits within the perirhinal cortex of the medial temporal lobe lead to a reduced ability of the aged brain to link sensory information with spatial representations will be tested by pursuing the following specific aims: 1) Link reduced neural coordination in hippocampal-projecting perirhinal cortical neurons to behavioral impairments, and 2) Are feedforward and feedback perirhinal cortical projection neurons equally vulnerable to age-related dysfunction. Our rationale is that by enhancing methods for probing circuit function across disparate brain areas, with single-cell resolution, we will be better positioned to identify functional connectivity impairments in aging and Alzheimer?s disease. The proposed research is innovative, because state-of-the-art neuroanatomical measures will be combined with gene expression analysis in behaviorally characterized young and aged rats to probe how local dysfunction manifests as network impairments. This novel single-cell imaging approach has not been possible until recently and has never been applied to animal models of aging and dementia. The significance of successful completion of these experiments will be a powerful tool for quantifying functional connectivity that can be applied to a wide spectrum of research fields. Additionally, these data will provide unprecedented insight into the association between cross- regional communication and cognition that will enable future interventional studies aimed at restoring memory network interactions in the context of aging and neurodegeneration.

? DESCRIPTION (provided by applicant): By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, a large proportion of elderly people experience memory decline that interferes with their quality of life. Understanding the neurobiology of memory impairments in advanced age, however, presents a significant problem, as memory processes are distributed throughout the brain and a fundamental gap exists in our understanding of how these structures interact. The long-term goal of the proposed research is to determine the alterations in network-level interactions that underlie cognitive impairment in advanced age. The primary objective of the current proposal is to identify age-associated changes in medial temporal lobe-prefrontal functional connectivity that contributes to memory deficits. State-of-the-art methodologies in neurophysiology, anatomy and behavioral analysis will be integrated to test the central hypothesis that age-related memory impairments manifest from dysfunction in cross-regional interactions among prefrontal and medial temporal lobe circuits by pursuing the following specific aims: 1) Do deficits in cortical functional connectivity mediate memory impairments, 2) Does age-related perirhinal dysfunction impact activity dynamics within the hippocampus, and 3) Do age-related reductions in prefrontal cortical activity impact functional connectivity in the rhinal cortices. Our rationale is that by elucidating how aging influences systems-level dynamics, we will be better positioned to develop interventions that broadly improve cognition. The proposed research is innovative, because state-of-the-art neuroanatomical measures and neurophysiological techniques will be integrated with measures of behavioral deficits in young and aged rats in order to probe how local dysfunction manifests as network impairments or elicits compensatory mechanisms. The significance of successful completion of these experiments will be to provide an unprecedented understanding of the association between functional connectivity and cognition that will enable future interventional studies aimed at restoring memory network interactions in the context of aging and neurodegeneration.

Title: Interactions of Perirhinal Tau Pathology and Aging in Cognitive Dysfunction Abstract: Intracellular inclusions comprised of tau proteins are among the earliest pathological features of Alzheimer's disease (AD), the most common age-associated neurodegenerative condition. Data show that tau inclusions initially emerge in the transentorhinal subregion (area 35) of perirhinal cortex by the fourth decade of life, twenty years prior to the typical AD diagnosis. The immediate consequences of this early area 35 tau pathology on cognition and disease progression, however, remain poorly understood. The long-term goal of this research is to develop sensitive cognitive assays for humans that provide a reliable index of early AD pathology. The primary objective of the current proposal is to develop a preclinical model that recapitulates many features of early AD using AAV technology to drive pathological tau burden in area 35 of young and aged rats. The secondary goal of this proposal is to establish behavioral assays as a biomarker for early detection and tracking of disease pathology in patient populations. These goals will be attained by testing the hypothesis that aging exacerbates tau burden in area 35 and that progressive pathology in this brain region is associated with performance on sensory discrimination tasks that utilize perceptual gradients to test stimulus discrimination abilities. The rationale for this this work is that because Alzheimer's disease develops against the backdrop of an aging brain, it is critical to elucidate how aging and pathological tau interact to influence disease mechanisms and cognitive outcomes associated with disease progression. This work is innovative because viral vector technology will be used to model the specific anatomical features of early Alzheimer's disease in conjunction with state-of-the-art cognitive assays that are highly sensitive to detecting behavioral dysfunction associated with aging and disease. The significance of the proposed experiments will be to establish the foundation for developing new diagnostic tools for AD that can facilitate early intervention and more effectively evaluate the efficacy of novel therapeutics before widespread neurodegeneration occurs.

Title: Metabolic Interventions for Enhancing Cognitive Resilience in Aging and Alzheimer's Disease Abstract: By the year 2020 the number of Americans over the age of 65 is projected to reach 55 million, occupying a larger portion of our population aging demographics than ever recorded in history. It is therefore imperative that the ability of these individuals to live independently is preserved for reasons of personal dignity as well as the financial and public-health consequences that result from the necessity of long-term care. Unfortunately, a large proportion of elderly people experience memory loss or other types cognitive decline that interfere with quality of life. To date, therapeutic options for mitigating cognitive dysfunction in aging and Alzheimer's disease are limited. A barrier to advancing treatments for cognitive loss in aging it that the brain regions critical for higher cognition show distinct neurobiological mechanisms of dysfunction in old age. One factor that changes ubiquitously across the brain in old age, however, is a reduced ability to use glucose for energy production. The long-term goal of this research program is the implementation of metabolic-based therapies for enhancing cognitive resilience in old age and Alzheimer's disease. The primary objective of this proposal is to investigate the mechanisms by which ketogenic diets restore energy metabolism across the brain to improve cognition in pre-clinical models of aging and Alzheimer's disease. Based on our preliminary data, we will test the central hypothesis that elevated ketone body levels will normalize activity across the prefrontal cortex and medial temporal lobe, and attenuate the progression of tau pathology in a rat model pre-clinical Alzheimer's disease. This hypothesis will be testing with the following specific aims: 1) Determine if a ketogenic diet improves cognition by restoring medial temporal lobe and prefrontal cortical network dynamics in aged rats, 2) Determine biochemical mechanisms of enhanced cognition in aged rats by a ketogenic diet, and 3) Determine the interaction between nutritional ketosis and Alzheimer's disease tau pathology. The proposed research is innovative because behavioral data from a task that is comparable to multi-tasking in humans, will be integrated with cellular imaging and biochemical analysis to test a metabolic intervention in both male and female rats. The rationale for this research is that improving brain energy metabolism may be a mechanism for globally optimizing brain circuits to alleviate cognitive aging. The significance of the successful completion of this work will be the development of broad therapeutic strategies for treating both age- and disease-related cognitive decline.

TITLE: Preclinical Assays of Hippocampal-Prefrontal Cortical Circuit Engagement for Application in Therapeutic Development FOA type: PAR-19-289: Abstract: The high failure rate of translating discovery science to positive clinical outcomes in the treatment of psychiatric diseases demonstrates the necessity of improving the efficiency and rigor of the therapeutic development pipeline. To this end, the critical importance of advancing the discovery of in vivo physiological and behavioral measures of the engagement of specific circuits for normal cognitive function has been acknowledged across funding initiatives. The hippocampus (HPC)-prefrontal cortical (PFC) circuit is critical for affective processing as well as higher cognitive functions and vulnerable in a number of mental health disorders. Although disrupted functional connectivity in the HPC-PFC circuit is a common feature of anxiety, bipolar disorder, schizophrenia, and autism, how local cellular interactions within this circuit manifest as large-scale temporal coordination to support higher cognitive functions remains unknown. Addressing this fundamental gap in our knowledge will establish a foundation for using circuit-based models for therapeutic target discovery and screening tools of novel drug efficacy. The long-term goal of this proposal, in line with the Funding Opportunity Announcement (PAR-19-289), is to enhance the therapeutic development pipeline for mental illness treatment by optimizing, evaluating, and mechanistically testing neurophysiological and behavioral measures of circuit engagement. The primary objective of this proposal, which is the first step towards achieving our goal, is to relate behavioral performance on the rodent analog on the Paired Associates Learning task (PAL), part of human Cambridge Neuropsychological Test Automated Batteries [CANTAB] assessment, and surface EEG recordings to invasive neurophysiological measures of neural coordination in the HPC-PFC circuit. Through an innovative series of experiments that integrate in vivo neurophysiological local field potential (LFP) recordings, circuit manipulation, surface EEG, and behavior, we will optimize, evaluate and mechanistically test novel noninvasive biomarkers of HPC-PFC circuit engagement by pursuing the following specific aims: 1) Optimize behavioral and non-invasive EEG biomarkers for inferring HPC-PFC circuit engagement and temporal coordination, 2) Evaluation of behavioral and non-invasive EEG biomarkers for determining HPC-PFC circuit engagement through pharmacological manipulation, and 3) Mechanistically test HPC-PFC projections as a driver of surface EEG organization. The proposed research is innovative because it integrates a clinically relevant behavioral task, designed to be analogous to human cognitive assessments, with surface EEG measures that translate across mammals. This will enable the optimization, evaluation, and testing of novel and translatable measures of HPC-PFC circuit engagement in the context of higher cognition and global neural organization. The significance of this contribution will be to provide novel diagnostic tools that can be used to enhance the therapeutic development pipeline for treating mental illness.