Michael A. Yassa, Ph.D. - US grants

DESCRIPTION (provided by applicant): The goal of the proposed study is to investigate the neural mechanisms underlying the emotional modulation of hippocampal memory in healthy individuals and how alterations in the amygdala-hippocampal network contribute to the pathophysiology of Major Depressive Disorder (MDD). Major depressive disorder (MDD) is one of the most prevalent lifetime psychiatric disorders with a lifetime prevalence of 16.5%. It is characterized by a cluster of symptoms that range from depressed mood to suicidal ideation and persist for a period of over two weeks. Memory impairment is a core endophenotype of MDD and has been attributed to abnormalities in the hippocampus and amygdala, with both regions exhibiting changes in volume and functional activity. The hippocampus is generally believed to underlie our capacity for learning new declarative memories, while the amygdala is thought to play an important role in the emotional modulation of memories. The hippocampus (particularly the dentate gyrus and CA3 subfield) is critically involved in pattern separation, a computation by which similar or overlapping memories are orthogonalized using distinct neural codes, such that learning is possible despite the potential for interference. Pattern separation provides a robust empirical framework for testing hippocampal function by manipulating mnemonic interference. It can further be used as a platform for testing amygdala modulation of hippocampal memory if stimulus emotionality is included as a parameter. In addition to providing a better understanding of memory network dynamics in healthy brains, this framework can also be used to test hypotheses in depressed individuals and assess the functional integrity of various components of this network. To achieve these goals, we will use powerful high-resolution fMRI (1.5 mm isotropic) methods that are capable of dissociating subfield-specific signals, coupled with a parametric design manipulating interference and emotional content concurrently. We will use this design to examine emotional modulation of memory in the healthy brain, as well as abnormalities in these cognitive processes in MDD. We will also employ cutting-edge ultrahigh-resolution (<1mm) structural and diffusion imaging methods to better understand amygdala-hippocampal abnormalities in MDD. The proposed empirical framework for examining memory and emotion is highly innovative and the application to MDD has never been previously accomplished. Coupled with state-of-the-art neuroimaging techniques, this project will have a high impact on the science of learning, memory, and emotion as well as the neurobiological understanding of MDD. We use a Research Domain Criteria (RDoC) framework to investigate common pathophysiological mechanisms in depression and co-morbid anxiety, which will be assessed along continuous dimensions. Successful completion of this project will shed light on the neural basis of memory and emotional processing in the amygdala-hippocampal network and provide a better understanding of the network changes that occur in depression, paving the way to improving diagnosis and defining novel targets for intervention.

Over five million Americans have Alzheimer?s disease (AD) today. A critical goal of biomedical research is establishing indicators of AD during the preclinical stage (i.e. biomarkers) allowing for early diagnosis and intervention. Currently, the relationship between A? pathology and neuroimaging/cognitive measures during the preclinical stage is not well understood. Our project combines novel high-resolution magnetic resonance imaging (MRI) tools, novel cognitive testing particularly sensitive to hippocampal memory, and assessments of beta-amyloid (A?) pathology in cerebrospinal fluid (CSF) or florbetapir (18F) PET scans to gain a better understanding of the neural basis of preclinical AD and to identify novel mechanistic biomarkers for preclinical AD using non-invasive techniques. The goals of the project are to (1) improve our ability to detect subtle cognitive decline, (2) enhance the sensitivity of standard neuroimaging biomarkers for preclinical AD as well as develop and validate novel biomarkers using ultrahigh-resolution neuroimaging techniques, (3) test the validity of biomarker candidates in two special cohorts as models of early susceptibility (Down syndrome ? DS) and late resistance (nondemented 90+), and (4) deliver a proof of concept high-resolution multimodal neuroimaging platform for the ADRC to build the infrastructure necessary for establishing a high-resolution neuroimaging core. We will recruit and test a total of 90 participants: (a) Longitudinal cohort: 30 healthy nondemented participants (15 A?+ and 15 A?-) and 15 A?+ amnestic MCI participants between the ages of 65 and 85; (b) Down syndrome cohort: 15 A?+ nondemented individuals between the ages of 45 and 65; (c) 90+ cohort: 30 nondemented 90+ participants (15 A?+ and 15 A?-). A? status will be determined for longitudinal cohort via CSF (through ADRC Path Core) and for DS/90+ via florbetapir PET (through synergistic NIH R01?s by Dr. Kawas and Dr. Lott). In Aim 1, we will use a set of newly developed cognitive tests of pattern separation. These tests vary mnemonic interference in the object, spatial and temporal domains. In Aim 2, we will collect high resolution structural MRI (0.55 mm isotropic), resting state fMRI (1.5 mm isotropic) and DTI (0.66 mm inplane) to test hypotheses about changes in neural features related to pathological status (e.g. entorhinal cortical thickness, perforant path integrity, resting state connectivity between the entorhinal cortex and the hippocampus). In Aim 3, we will apply the techniques in Aims 1 and 2 to Down syndrome and 90+ participants to explore resistance and vulnerability to pathology in this brain network. In Aim 4, we will examine relationships between our biomarkers and pre-existing measures in the ADRC database such as genetics, blood/serum markers, and other CSF pathologies (e.g. phospho-tau). In Aim 5, we will build the infrastructure to archive and curate all new imaging data for dissemination to ADRC investigators to provide a proof of concept for a future neuroimaging core at the ADRC. Together, the Aims of this project will allow us to better understand the condition of preclinical AD and develop biomarkers that can be used in future prevention trials.

DESCRIPTION (provided by applicant): Episodic memory loss is one of the hallmarks of aging and is an important risk factor for dementia. Given the rapid rise in the aging population and the increased prevalence of Alzheimer's disease (AD), understanding the neural basis of age-related memory decline is of the utmost importance. The formation of memories is known to depend critically on brain regions within the medial temporal lobes (MTL). Prior aging research has focused on age-related changes in the hippocampus, but changes in extrahippocampal MTL cortices have garnered less attention. These cortices appear to be functionally segregated such that the perirhinal cortex (PRC) is primarily engaged by memory for items or objects, whereas the parahippocampal cortex (PHC) is engaged by memory for spatial configurations or contexts. Animal studies have further demonstrated that that this division of labor extends into the entorhinal cortex (EC), with the lateral portion (LEC) supporting object memory and the medial portion (MEC) supporting spatial memory. We designed a discrimination task taxing both object and spatial memory and used high-resolution functional MRI to not only replicate the dissociation between PRC and PHC, but also critically demonstrated key evidence of a similar object/spatial dissociation between LEC and MEC in humans. Related to these advancements, recent rodent models of neurocognitive aging have identified a selective vulnerability in the PRC/LEC pathway to pathology associated with cognitive decline. The LEC/PRC (transentorhinal) region is also the first to deposit tangle pathology in AD mouse models, which is also clear from postmortem tissue from AD patients (i.e. Braak Stage I). Building on our highly innovative approach to functionally segregate the human PRC/LEC and PHC/MEC networks, we propose a novel series of experiments to characterize the earliest behavioral deficits and functional aberrations in the PRC and LEC in older adults. Furthermore, we intend to probe for specific disruptions in structural connectivity between the hippocampal dentate (DG)/CA3 and upstream PRC/LEC, which project to the DG/CA3 via the lateral perforant path. We have previously reported perforant path degradation in older adults using cutting-edge ultrahigh- resolution diffusion imaging. Here, we will use novel techniques to segment the perforant path into medial and lateral portions and will test the hypothesis that this degradation is more severe in the lateral portion. The proposed project builds on the last five years of work from our lab, which successfully translates decades of animal and computational models to the human aging condition. We have identified aberrant conditions in the DG/CA3 associated with age-related memory loss using multimodal high-resolution MRI techniques. Our proposal here extends this work in an innovative direction both in terms of approach and hypothesis. This project is expected to significantly improve our understanding of the neurobiological bases of memory deficits in aging, and may yield highly selective neural targets for treatments and interventions.

PROJECT SUMMARY Age-related cognitive decline is a significant public health concern as the population over the age of 60 continues to grow sharply. Advances in understanding the mechanisms that underlie this decline will allow for effective interventions and substantially reduce the burden on families as well as government and social programs. We will be faced with 50 trillion dollars in Medicare costs as the baby boomers age, thus magnifying the size of the concern and the significance of our proposed work. Aging is a major risk factor for Alzheimer's disease (AD), which currently affects over five million Americans. If no prevention or treatment is discovered, this number could increase to 16 million by 2050. Establishing early indicators of the disease process during the preclinical stage is a critical goal of biomedical research. Our project goal is to determine the neural features (i.e. biomarkers) associated with amyloid pathology accumulation, and determine objectively how to combine these biomarkers to identify individuals with preclinical AD. We will combine state-of- the-art high-resolution multimodal MRI tools with targeted, innovative cognitive testing approaches and leverage our local UCI Alzheimer's Disease Research Center (ADRC) for (1) recruitment of asymptomatic older adults (Clinical Core), (2) sample enrichment based on ApoE genotype (Pathology Core), (3) detailed cognitive evaluation of all participants (Clinical Core), and (4) development of statistical models to optimally combine imaging and cognitive measures for prediction of cognitive decline (Data Management and Statistics Core). We will recruit asymptomatic older adults (60-85 years old, n=150) from the ADRC and from the local community and will enrich the sample for amyloid positivity via ApoE genotype. We will conduct PET amyloid scans with [18F] AV-45 (florbetapir) on all participants to determine amyloid status (targeting 50% positivity across the whole sample). We will conduct high-resolution multimodal MRI and targeted cognitive examinations in all participants at baseline, and repeat the cognitive examinations contemporaneously with ADRC annual and bi-annual follow-up visits. In Aim 1, we will use a set of newly developed cognitive tests that focus on memory function attributed to medial temporal lobe (MTL) processes, particularly ?pattern separation?. These tests vary mnemonic interference in the object, spatial and temporal domains. In Aim 2, we will use high resolution resting state fMRI (1.5 mm), ultrahigh resolution microstructural diffusion tensor imaging (DTI, 0.66 mm), and high resolution structural MRI (0.55 mm), to assess structure, function and connectivity of the MTL. In Aim 3, we will use statistical prediction modeling to determine the optimal combination of measures that predicts longitudinal cognitive/clinical decline. Collectively, the proposed studies will significantly inform our understanding of cognitive decline in the aging brain in the presence and absence of amyloid pathology and allow us to better define preclinical AD and make recommendations for future intervention trials.

ABSTRACT Neurological and neuropsychiatric illnesses are prevalent and debilitating, affecting more than a quarter of the global population. Learning and memory are implicated in every neurological illness from stroke to Alzheimer?s disease and every neuropsychiatric dysfunction from depression to drug addiction. Understanding the neuroscience of learning and memory, integrating across approaches and methods, is one of the most formidable challenges of the 21st century. While research in these areas has made significant strides in understanding and treating brain disease as well as promoting brain health, progress has been stalled. There are fundamental gaps in our knowledge that stem for lack of integration across approaches and insufficient dialogue among investigators addressing neuroscience questions from different perspectives. Integration across animal and human research as well as basic and clinical research will have substantial impact on facilitating team science, which is essential for successful translation. The 2018 International Conference on Learning and Memory (LEARNMEM2018) covers numerous facets of the neuroscience of learning and memory with an emphasis on integrating across animal and human studies as well as across fundamental and translational science. The 5-day conference that will feature plenary and keynote talks by distinguished neuroscientists, diverse and balanced symposia, short talks, poster sessions, a panel discussion on open science and open publishing, as well as community engagement sessions. Anticipated attendance is ~800 and the conference is open to everyone. AMA PRA Category 1? Continuing Medical Education (CME) credits will be offered to physicians and healthcare professionals. Travel awards for early career scientists will be available, and special emphasis will be placed on multidimensional diversity of contributions across gender, race, seniority, country of origin, and level of analysis. The conference will achieve the following aims (1) Identify knowledge gaps and opportunities for scientists, clinicians, nonprofits, businesses, and community members to share and discuss cutting-edge research in the area of learning and memory; (2) Form collaborative teams among domestic and international investigators, early career and established scientists, animal and human researchers, fundamental and translational scientists, as well as user and developer communities; (3) Disseminate knowledge generated from the meeting through scientific and public venues; and (4) Facilitate engagement between scientists and community members across all levels from schoolchildren to retirees. LEARNMEM2018 will have substantial impact on the field by accelerating the pace of team science and leapfrogging towards a more complete fundamental understanding of learning and memory mechanisms as well as novel therapeutic and preventative approaches to treating brain illness and promoting brain health.

This high-impact Center revised renewal proposal integrates a multidisciplinary group of scientists to investigate the developmental origins of vulnerability to mental illness, with a focus on perturbed environmental / sensory signals impacting brain circuits during sensitive developmental periods. It posits that unpredictable, fragmented sensory signals to the developing brain (FRAG), constitute a previously unrecognized indicator of early-life adversity that impacts brain circuit maturation across species, provoking anhedonia and vulnerability to psychopathology. The overarching goal of the Imaging Core is to enable the Center to use imaging tools to address the as yet unknown mechanistic pathways by which FRAG may lead to anhedonia and other vulnerabilities to psychopathology. The Core will work with Projects 1-4 to conduct translational neuroimaging across species and cohorts, and with the BCDM core it will develop computational and statistical models to provide novel insights into circuit mechanisms that underlie the impact of FRAG on the developing brain. The core will: 1. Acquire, process, analyze, store, and make available all high-resolution structural, functional, and diffusion MRI data on human and rodent cohorts, in support of Projects 1-4 and to address imaging-related hypotheses. 2. Identify aberrant and sex-specific patterns and trajectories in structure, function, and connectivity of pleasure/reward circuitry that link early life FRAG to anhedonia and risk for psychopathology, using innovative multimodal MRI approaches across cohorts, projects, and species. 3. Develop a rich dataset of whole-brain-derived imaging metrics using network connectomics and, working with the BCDM Core, integrate these metrics in statistical models that predict anhedonia and psychopathology from FRAG-associated aberrations in brain circuitry. Whole brain functional and structural connectomes will be created using diffusion and resting state fMRI data to assess dynamic and stable reorganization of circuits as a function of FRAG. Network approaches such as graph theory based on structural and functional connectomes will be used to quantify overall shifts in brain circuits (e.g. rich club and small world networks). The BCDM and Imaging cores, guided by expertise of Center consultant, Prof. Olaf Sporns, will collaborate on employing these methods for integration into models that take into account all other data types to predict anhedonia and psychopathology from FRAG and the associated brain circuitry alterations. These data-driven approaches will additionally allow us to examine alternative and secondary hypotheses.

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.