John Morrison - US grants

DESCRIPTION (Adapted from applicant's abstract): This project outlines a circuit-based approach to fear conditioning and interactive effects of stress that is designed to link the circuits that mediate and/or are affected by these behavioral events to the demonstrated roles of glutamate receptors in these processes. We hypothesize that long-term modifications of the functional attributes of amygdala that are induced by fear conditioning are associated with morphologic and neurochemical changes in the excitatory circuits that mediate this learned response. More precisely, we hypothesize that the glutamate receptor (GluR) profile of the circuits that are coupled through fear conditioning will be modified in a manner that will augment NMDA-mediated transmission and LTP-like events in these circuits. With respect to stress, extensive data are available from hippocampus demonstrating changes in morphology and NMDA receptor-mediated processes that lead to impairment of hippocampal function. Interestingly, while stress has a deleterious effect on hippocampal structure and function, it augments certain functional attributes of the amygdala. We further hypothesize that stress will lead to modifications in the interconnections between medial prefrontal cortex (mPFC) and amygdala that are interactive and in some cases augmentative of the modifications induced by fear conditioning. GluRs will be analyzed in the context of three key sets of circuits that will be targeted in this project: 1) the convergent sensory inputs from the medial geniculate nucleus (MG) and the auditory cortex to pyramidal neurons within lateral amygdala (LA), a set of circuits known to be crucial for fear conditioning; 2) the intra-amygdala projections from LA to the central nucleus (CE), both directly from LA as well as indirectly from LA to Basal (B) and Accessory Basal (AB) nuclei, and then to CE. These are the intra-amygdala circuits that are primarily responsible for linking the key sensory input to the autonomic output from the CE that is linked to the fear response; and 3) The reciprocal connections between mPFC and the amygdala nuclei LA, B, and CE, a set of circuits that may be directly impacted by stress. Our investigations of amygdala circuits will be carried out in close collaboration with Dr. LeDoux's project (Project 1) and the Quantitative Morphology Core. We will assist Dr. McEwen's team (Project 4) in their GluR analyses of hippocampus and carry out Specific Aim 3 of this project in collaboration with McEwen's group.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The primary goal of this Program Project is to investigate interactions between the aging brain and female reproductive senescence. Animal studies have demonstrated clearly that changes in circulating estrogen levels affect cellular and molecular attributes of certain neural circuits and related cognitive functions. However, the link between such observations and the human data on peri- and post-menopausal memory impairment, beneficial neurobehavioral effects of estrogen replacement therapy (ERT) or combined hormone replacement therapy (HRT) and protection against Alzheimer's disease are far from clear. Recent studies from the Women's Health Initiative on potential negative effects of a commonly used combined hormone replacement (HR) regimen have brought these issues to the forefront, and reinforced the need for additional scientific data on which to base therapies that are more physiological and beneficial to women. The Program Project mechanism is ideally suited for a full spectrum analysis of the key issues;from signaling mechanisms of estrogen in the brain to an in-depth structural and functional assessment of the effects of estrogen on the circuits regulating reproductive function (hypothalamus), to the effects of estrogen and aging on cognition and related cortical circuits. Projects 1, 2, and 3 will converge on the rodent model for detailed mechanistic and ultrastructural analyses of estrogen-induced plasticity, interactions with progesterone, and alterations in estrogen-induced plasticity due to aging. Core A and Projects 2, 3, 4, and 5 will converge on the nonhuman primate model (NHP) to study similar systems in NHPs treated with one of several clinically relevant HR regimens involving different schedules of estrogen and progesterone replacement. The aged NHPs will have extensive neuropsychological assessment aimed at determining age, estrogen, and progesterone effects on medial temporal lobe and prefrontal functions. We will investigate the neurobiological effects of multiple HR regimens in young and aged NHPs to reveal key synaptic and cellular reflections of estrogen-induced plasticity as well as effects on neurogenesis, and potential modifications induced by progesterone. In the aged animals, we will illuminate the underlying neurobiological events responsible for cognitive enhancement.

OVERVIEW ABSTRACT The California National Primate Research Center (CNPRC), located at the University of California, Davis, requests funds to renew the base operating grant #P51-OD011107 for the next five year period (May 1, 2018 through April 30, 2023). Currently in the 56th year of operation, the CNPRC serves a range of NIH-supported investigators and industry partners nationwide. From inception through the current year, the CNPRC has been highly responsive to the research community by providing high quality animals, facilities, tools, and services driven by the intellectual infrastructure of the Core Scientists in the service of our Mission: ?To improve human health and quality of life through support of exceptional nonhuman primate research programs?. The goals for the next funding period are reflected in the following Specific Aims: (1) Conduct state-of-the-art research and scientifically contribute to the understanding and treatment of human disease with nonhuman primate models across the age spectrum, (2) Provide exceptional nonhuman primate expertise and services to investigators at the local, regional, and national levels to advance NIH-supported research excellence, (3) Mentor and train the next generation of translational investigators with nonhuman primate expertise, and (4) Ensure the highest standards of responsible conduct of research and animal care. We will continue to emphasize team science aimed at major human health problems across the lifespan, with the goal of moving beyond traditional interdisciplinary efforts to true convergence on the research problems being addressed. Support is requested for Administrative Services (Director's Office, Administration and Operations Services, Information Technology Services, Facilities Improvement), Primate Services (Colony Management and Research Services, National Institute on Aging Colony, Primate Medicine Services, Anatomic and Clinical Pathology Services, Population and Behavioral Health Services, Genetics Management Services), Service Cores (Flow Cytometry, Inhalation Exposure, Multimodal Imaging, Primate Assay Laboratory), Scientific Research Units (Infectious Diseases, Neuroscience and Behavior, Reproductive Sciences and Regenerative Medicine, Respiratory Diseases), and for Outreach, the Pilot Research Program, and NPRC Consortium activities. Our over-arching goal is to achieve translational impact through preclinical programs housed at the CNPRC as well as through collaborative teams that reach out locally, nationally, and globally. We are committed to developing and providing a wide range of research opportunities that maximize use of the nonhuman primate model to improve human health. The institutional commitment from UC Davis to the CNPRC has been reinforced in a manner that will facilitate our role in moving nonhuman primate research into the next era of convergent biomedical research.

Project Summary/Abstract Alzheimer?s disease (AD) is an extremely prevalent and severely disabling disease. Despite several decades of research, AD pathogenesis continues to be poorly understood, and we currently lack reliable biomarkers to spatiotemporally track and predict disease progression. Our overall goal is to address these challenges and develop enhanced biomarkers for diagnosing AD-pathology early and objectively tracking treatments. To that end, this proposal will utilize our highly translational monkey model of the early ?synaptic phase? of AD to assess the merits of in vivo imaging measures (from PET for synaptic density (using 11C-UCB-J) and glucose metabolism (using 18F-FDG), with structural MRI) against postmortem, state-of-the-art microscopic and histologic analysis of brain tissue, in a longitudinal study design. Our hypothesis is that PET measures, as surrogates for quantifying synaptic loss and metabolic dysfunction, will serve as early, independent predictive biomarkers for elevated AD risk and cognitive dysfunction. Our first specific aim will establish the correlation of our in vivo imaging measures with postmortem tissue markers of AD-associated pathologies in our monkey model versus age- and sex-matched control animals. Our second specific aim will map the spatiotemporal patterns of PET synaptic loss versus cerebral glucose metabolism in our monkey model versus control animals over a 12-week period. Completion of both aims will provide novel data to improve our understanding of synaptic neuropathology in AD development. Therefore, this proposal is highly responsive to the PAR-18-760. Positive findings would corroborate recent human studies investigating the role of synaptic dysfunction as a major factor for increased AD risk. Validation of in vivo imaging strategies in a relevant model system will contribute towards (i) optimizing the therapeutic window for future early AD treatments so that their efficacy can be maximized; (ii) testing mechanistic hypotheses associated with the role/blockage of synapse loss; (iii) rapidly evaluating new treatment strategies and their dose-response relationships. In summary, this project has the potential to provide key translational elements that will inform human studies evaluating in vivo markers of synaptic dysfunction.

Project Summary The vast majority of Alzheimer's disease (AD) cases are late-onset and it ss now widely believed that development of late-onset AD is the consequence of accumulated brain damage over many years. This process begins with the generation of abnormal oligomeric proteins (amyloid beta oligomers, A?Os) from misprocessed amyloid precursor protein. A?Os are toxic to synapses, and over time A?O buildup and synaptic damage lead to deposition of amyloid plaques and hyperphosphorylated tau protein causing neurofibrillary tangles and neuronal loss, the hallmarks of AD neuropathology. Despite tremendous resource investment, the translation of this mechanistic understanding of AD pathogenesis into new therapies for AD remains elusive. We propose the development of a nonhuman primate model of early AD pathogenesis based on exogenous administration of A?Os to middle-aged rhesus monkeys. Our extensive preliminary data show that a month of twice-weekly A?O administration causes synapse loss targeted to highly plastic thin dendritic spines, and neuroinflammation, changes that mirror what is thought to occur in the earliest prodromal phase of human AD. This model therefore addresses a key limitation of existing animal models of AD: it is based on the pathogenetic process thought to lead to the vast majority of human late-onset AD cases. Based on the acute effects of A?O administration on synaptic and glial markers in rhesus monkeys, we hypothesize that deficits in cognition and affect mirroring symptoms of AD in humans will develop over time in rhesus monkeys chronically treated with A?Os and relate to synaptic disease observed in postmortem histology. To test our hypothesis, rhesus monkeys treated with A?Os or a scrambled peptide control will complete cognitive and affective tasks sensitive to cortical and subcortical function. Our design provides detailed assessment of the time course of behavioral changes, and we will determine synaptic, neuronal, and glial markers in the brains of these monkeys concurrently with the emergence of behavioral deficits. Behavior will be tested in repeated cycles so that changes over time with increasing cumulative dose of A?Os can be determined. These experiments will provide a multi-faceted behavioral characterization of how synaptic dysfunction caused by A?O treatment impacts cognitive and affective behaviors dependent on multiple cortical and subcortical structures, and will let us develop A?O administration in rhesus monkeys as a model for testing interventions that may derail the progression of pathological cascades before full-blown AD develops, providing a new setting for developing treatments for an urgent public health problem.

Project Summary As the leading cause of age-related disabilities, neurocognitive diseases such as Alzheimer?s disease (AD) and other dementias are poised to significantly impact global health care as the population of people aged 60 and older nearly doubles in the next three decades. One group at a significantly greater risk of age-related neurodegenerative diseases are HIV-infected (HIV+) patients. An estimated 50% of HIV+ patients on antiretroviral therapy (ART) develop mild to severe impairments in brain function with age. Designated as HIV- associated neurocognitive disorders (HAND), this syndrome is expected to increase dramatically in the next decade as more than 70% of Americans with HIV turn 50 and older, and ART becomes more widely available in the developing world. The imminent global impact of HAND underscores the urgent need to understand the mechanistic basis of neurodegeneration in HIV+ patients on ART and devise effective interventions. This proposal is focused on understanding the immune mechanisms underlying age-related neurodegeneration following HIV infection using a robust rhesus model which recapitulates salient aspects of HIV pathophysiology in humans. In Aim 1 of this research project, we will establish the role of monocytes in neurodegeneration; specifically, pro-inflammatory monocytes. In Aim 2, we will determine the role of Th1, and Th17 CD4 T cell subsets in neurodegeneration. Considering that HIV and HIV-associated neuroinflammation interfere with amyloid and tau metabolism, in Aim 3 we will investigate whether pathological AD markers are induced during HIV-associated neuroinflammation. The collective complementary expertise of the investigators and collaborators in tackling the scientific questions posed in the application will facilitate an in-depth understanding of the immune and synaptic mechanisms underlying neurodegeneration. These preclinical studies will establish the mechanistic and experimental foundations to identify predictive biomarkers of HAND and subsequently enable opportunities in a relevant and tractable model for testing novel, targeted interventions as adjunctive therapy to ART. Only by quantifying measures of SIV-induced HAND sequelae in macaques can parameters of intervention be evaluated for efficacy prior to human studies.

Alzheimer?s disease (AD) is a devastating condition that affects more than 5 million Americans, with a total annual cost of more than $300 billion predicted in 2020. Currently there are no effective treatments to counteract or slow the progression of AD, with promising findings in rodents failing to translate into successful therapies for patients. Monkey models may provide a more powerful translational model. The goal of this proposal is to characterize a monkey model of tau pathology in AD. This is responsive to RFA-AG-21-003 requesting proposals that target the ?development, characterization, and validation of suitable new or unconventional mammalian non-murine models of AD that may represent improved translational potential by better replicating pathological features of the disease?. With respect to nonhuman primate (NHP) models of AD, the RFA states explicitly that ?NHP have a very high translational value because of their close relationship to humans in terms of phylogeny, genetics, physiology, cognition, emotion, and social behavior?. In this proposal we describe initial findings in a tau-based monkey model of AD and propose a program to fully develop and validate the model by three PIs who have decades of experience on aging and neurodegeneration in NHP models. We have targeted the highly vulnerable entorhinal cortex (ERC) for unilateral infusions of an adeno-associated virus expressing a double tau mutation known to cause tau-related dementia in humans (AAV-P301L/S320F) and characterized neuropathology at 3 and 6 months after viral injection in NHPs. This causes extensive and progressive neuroinflammation and tau-based neuropathology, including end-stage neurofibrillary tangles, in ERC and in hippocampal and neocortical targets of ERC. Preliminary PET imaging in these monkeys displays robust phospho-tau accumulation in the hippocampus. The progressive time course relative to the time of vector injection is a great strength in terms of using this model for therapeutic development. These early studies demonstrate the potential for this model to replicate pathological features of AD in the monkey brain and to capture aspects of pathology that have not been well-modeled in rodents. We propose to do a full, rigorous characterization of this model, including long-term behavioral assessment, in vivo imaging, fluid biomarker assessment, and microscopic analyses. Full characterization of this model, will provide a platform to test therapeutic agents at different points in the disease process.