Paul E. Gilbert - US grants

The hippocampus has been suggested to support multiple memory processes including pattern separation, working memory, and the formation of arbitrary associations. Therefore, the first aim of the proposed grant will be to develop behavioral paradigms to assess pattern separation, working memory, and the formation of arbitrary associations in rats. Based on computational models and behavioral data, a model of hippocampal function has been proposed in the present grant which localizes particular processes to particular hippocampal subregions. Therefore, the second aim of the proposed grant will be to test the hypothesis that the mechanisms which support processes such as pattern separation, working memory, and the formation of arbitrary associations can be localized to a particular subregions of the hippocampus. Finally, computational models suggest that the hippocampus and its subregions support these processes for spatial and nonspatial information. However, the proposed model suggests that the hippocampus only supports these processes for spatial and temporal information. Therefore, the third aim of this grant will be to test the hypothesis that the subregions of the hippocampus support pattern separation and the formation of arbitrary associations only for spatial and temporal information but not nonspatial and nontemporal information.

DESCRIPTION (provided by applicant): This grant aims to assess odor-place and object-place associative memory, as well as source memory, for olfactory and visual stimuli in the elderly and those at risk for Alzheimer's disease (AD). Problems associated with memory are commonly observed in elderly individuals and characterize dementing diseases such as AD. Studies have reported memory decline for visual and verbal stimuli associated with aging and AD. Verbal memory deficits also have been reported in non-demented individuals with the E4 allele, a genetic risk factor for AD. Studies have shown that the elderly, AD patients, and those at risk for AD show impairments in odor identification and odor recognition memory. Due to the neuropathology associated with aging and AD, associative and source memory for olfactory stimuli also may be particularly impaired in these populations. Numerous studies suggest that the elderly and those at risk for AD show source and associative memory deficits for visual and auditory stimuli; however, more research is needed to examine associative and source memory for olfactory stimuli in these populations. The main aim of this grant will assess memory for odors using novel paradigms that may be very sensitive to the neuropathological changes associated with aging and early AD that affect mnemonic processing. The assessment of olfactory memory in the elderly and those at risk for AD is of great theoretical importance and may be useful in determining who among the elderly may be at risk for AD. Since olfactory loss is often not reported by elderly patients and may not be detected without special measurement, inclusion of olfactory measures into test batteries for AD is important.

[unreadable] DESCRIPTION (provided by applicant): Research in healthy humans over 65 years of age shows greater impairments in learning and memory for olfactory stimuli than visual stimuli. Other studies strongly suggest that problems with remembering and detecting odors may be an early indication of cognitive impairment and Alzheimer's disease. Studies involving aged rats have offered insight into how brain changes associated with aging may result in impaired cognition. However, very little research has examined odor memory in aged rats. The few existing studies investigating odor memory impairments associated with aging in rats have not made direct comparisons with memory for stimuli from a different sensory modality. As a result, it is unknown whether odor memory is any more or less affected by aging than memory for stimuli encoded via other sensory modalities. Therefore, it is unclear whether aging rats are a good model for understanding how age related brain changes might result in impairments in odor memory in older humans. The primary aim of this grant is to investigate the effects of normal aging on memory for olfactory stimuli using an animal model. Specific aim 1 will investigate age- related differences in discrimination and reversal learning for olfactory and visual stimuli. Specific Aim 2 will investigate age-related differences in working memory for olfactory and visual stimuli. Specific Aim 3 will investigate age-related differences in associative learning for olfactory and visual stimuli. The proposed experiments will determine whether odor memory is more affected than visual memory in aged rats. The results of the experiments will offer valuable insight into whether aging has a similar deleterious effect on odor memory in rats and in humans. Furthermore, the findings will suggest whether aged rats are a good animal model for studying the effects of aging on odor memory in older humans. In addition, the results will illustrate how memory for stimuli encoding via different sensory modalities may be differentially affected by aging and how increasing age may differentially affect different types of memory. The findings may have important implications for the selection of memory paradigms for future research studies on aging. The use of an animal model to investigate the effects of aging on odor memory will allow researchers the ability investigate how age-related neuroanatomical and neurochemical changes may result in impaired odor memory. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The characterization of cognitive impairment in older adults, and particularly those at risk for Alzheimer's disease (AD) is critically important. The most widely identified risk factors for AD are increasing age and the presence of the apolipoprotein E epsilon 4 allele. In order to delay age of AD onset and improve quality of life, it is important to identify cognitive changes in older adults as early as possible. The detection of early indicators of AD could reduce the cost of AD care by as much $100 billion per year in the U.S. and interventions that delay AD onset by two years could result in nearly two million fewer cases in 50 years. Therefore, the primary aim of this proposal is to use an innovative, process-oriented approach to examine deficits in specific mnemonic processes in older adults at risk for AD. Impaired episodic memory is regarded as a hallmark deficit in older adults and may serve as an early indicator of AD. The accurate encoding and retrieval of one episodic memory from another may require the function of multiple mnemonic processes to associate the elements of an episodic memory together and also separate the elements from those belonging to a different memory to avoid catastrophic interference. Although episodic memory may involve various cortical regions, there is strong evidence that the hippocampus plays a critical role in supporting specific mnemonic processes such as pattern separation and the formation of arbitrary associations that may enhance episodic memory accuracy. Despite overwhelming evidence suggesting that hippocampal pathology is highly associated with aging, studies have not adequately examined these specific memory processes in older adults at risk for AD. The proposed experiments are highly significant because behavioral tasks that measure these specific mnemonic processes may be powerful and largely unexamined tools for the early detection of age-related cognitive dysfunction. Disruption of these processes may result in impairments in various cognitive functions critical to the execution of daily living skills. The identification of key mnemonic processing deficits may result in behavioral interventions that structure daily living tasks to mitigate interference and enhance memory. Five novel experiments will be used in the proposed studies to provide a highly innovative investigation of specific memory processes in young adults and older adults at risk for AD. The aims of the grant will characterize age-related differences on the proposed experiments (Specific Aim 1), examine relationships between performance on the experiments and standardized neuropsychological tests (Specific Aim 2), and characterize the performance of older adults, with and without the APOE E4 allele on the experiments (Specific Aim 3). If the innovative aims of the present grant are achieved, novel behavioral approaches and methodologies will be developed for future aging studies investigating: 1) episodic memory impairment, 2) hippocampal subregion specific epigenetic and transcriptional changes, 3) structural and functional hippocampal changes using neuroimaging, and 4) the differentiation of preclinical markers of AD from those of normal aging.

Project Summary Abstract This supplement will support the candidate, PhD candidate Makaya Funk-White, to attain her long-term goal of having a career as an independent investigator focused on the intersection of Alzheimer?s disease and related dementias (ADRD) and substance use. To achieve this goal, she needs to learn more about alcohol use among older adults, and how alcohol use may affect cognitive and brain health in aging. Ms. Makaya Funk-White has identified a team of mentors to help her achieve these goals, and together, they have devised a plan of research and career development training activities that will facilitate attainment of her career goals. For this supplement, she will work with her new mentors, Drs. Emilie Reas and Linda McEvoy, on a research project that is examining whether neuroimaging measures of regional cortical thickness or volume, and measures of microstructural integrity differ by amount of alcohol drinking among healthy, community-dwelling older adults. Participating in this project will help her better understand brain anatomy, neuroimaging techniques, statistical methods, and the impact of alcohol on brain aging in older adults. She will also meet regularly with her current mentor Dr. Alison Moore and engage in a series of directed readings to further her understanding of substance use in older adults. These activities will be complimented by other research training activities such as seminars and workshops and presentations including participation in the activities of the San Diego Alzheimer?s Disease Resource Center for Minority Aging Research (ADRCMAR) and the UCSD Alzheimer?s Disease Research Center (ADRC). The parent grant is a collaboration between UCSD and SDSU to provide mentored training of underrepresented scientists in research on Alzheimer?s disease and related dementias. Ms. Funk-White is an underrepresented scientist whose research will examine the effects of alcohol use on brain aging. Moderate drinking has been suggested to protect against the development of Alzheimer?s disease, but how moderate drinking affects the brains of older adults is not well understood. In the context of this research topic, Ms. Funk- White will also learn about neuroanatomy and neuroimaging, receive training in statistical analyses and scientific writing, and will participate in training activities of the San Diego ADRCMAR as well as the UCSD ADRC to broaden her knowledge of Alzheimer?s disease.