Thomas C. Foster - US grants

This is a Shannon Award providing partial support for research projects that fall short of the assigned institute's funding range but are in the margin of excellence. The Shannon award is intended to provide support to test the feasibility of the approach; develop further tests and refine research techniques; perform secondary analysis of available data sets; or conduct discrete projects that can demonstrate the PI's research capabilities or lend additional weight to an already meritorious application. Further scientific data for the CRISP System are unavailable at this time.

DESCRIPTION (Investigator's Abstract): Aging and diseases involving dementia such as Alzheimer's disease are characterized by deficits in memory function. The role of calcium (Ca2+) regulation has been the focus of research on age-related neurodegenerative mechanisms and development of potential treatments for dementia in humans. However, the challenge remains to determine the key elements that link altered Ca2+ homeostasis with cellular changes and memory impairment. Over the past two decades much of the research on neural mechanisms of memory has been directed at the examination of synaptic plasticity. The level of cytosolic free Ca2+ occupies a pivotal position in regulating synaptic plasticity thought to underlie memory. The direction of synaptic modification is believed by many to be determined by the level of intracellular Ca2+. Low levels of calcium influx during low levels of synaptic activity lead to activation of calcium influx increases and Ca2+-dependent kinases are activated resulting in long-term synaptic potentiation (LTP). Previous research has demonstrated that susceptibility to synaptic plasticity is altered during aging. The results suggest the hypothesis that mechanisms regulating synaptic modification are involved in altered synaptic function and memory deficits. Studies are proposed to test the hypothesis that age-related changes in synaptic modification are due to altered synaptic modification thresholds. A model is proposed which links VDCC function with plasticity thresholds. Finally, studies are designed to test the hypothesis that the increased susceptibility to synaptic depression underlies the decrease in CA3-CA1 synaptic strength of aged animals through increased activation of serine/threonine protein phosphatases. The results of these experiments will add significantly to our knowledge of mechanisms for regulation of synaptic function across the life span and provide a basis for understanding the role of synaptic plasticity in cognitive function.

DESCRIPTION (provided by applicant): The long range goal is intervention to delay or prevent cognitive decline associated with unsuccessful aging, in order to improve the health and well-being of older Americans. The incidence of Alzheimer's disease is projected to increase dramatically, with the greatest prevalence in women. Synaptic loss contributes to memory impairments and estrogen (E2) promotes synaptogenesis and memory. Thus, E2 treatment could have a major impact on public health. However, the efficacy of E2 is greatly reduced if therapy occurs several years after the onset of menopause, suggesting a temporally limited therapeutic window. Evidence indicates estrogen receptor (ER) expression and ER polymorphisms contribute to a variety of hormone sensitive diseases, including cognitive decline. We hypothesize that differential expression of ER1 and ER2 interacts with the level of E2 to contribute to 1) the etiology of age-related memory deficits, 2) loss of E2 mediated synaptogenesis, and 3) the closing of the E2 therapeutic window. Aim 1 will combine aging ER1 and ER2 knockout mice with viral vectors to influence ER expression and systematically perform behavioral, molecular, and electrophysiological assays to test the hypothesis. Aim 2 will employ hippocampal viral delivery vectors to increase or decrease ER1 or ER2 in young, middle-age, and aged rats, and will use behavioral and molecular assays to test the hypothesis that shifting the ratio of ER1/ER2 expression rejuvenates hippocampal function. Aim 3 will employ viral vectors to alter the expression of ER1 or ER2, and will test the hypothesis that ER expression contributes to age-related changes in rapid E2 signaling. Knockout mice and viral vector gene delivery provide novel approaches to test the hypothesis that ER expression is a contributing factor for hippocampal aging. Together, these studies will determine whether altering the level of ER1 or ER2 expression is important for age-related memory decline, E2-induced synaptogenesis, and closing of the E2 therapeutic window, and will provide the groundwork for development of therapies to slow or prevent cognitive decline associated with aging and age-related diseases.

DESCRIPTION:(from applicant's abstract) This project developed out of studies on calcium (Ca2+) regulation in age-related neurodegeneration and examination of Ca2+ dependent synaptic plasticity as a neural mechanism for memory. Previous electrophysiological studies in this project found an age-related shift in the balance of synaptic plasticity, long-term potentiation (LTP) and long-term depression (LTD), favoring LTD. The shift in the LTD/LTP balance was associated with Ca2+-dysregulation involving L-type Ca2+ channels and the activity of protein phosphatases and kinases involved in synaptic plasticity. From this work we have proposed the hypothesis that a Ca2+ dependent enhancement of LTD relative to LTP is a major factor in synaptic and cognitive impairment with age. Here we will focus on two main goals: 1) to test the hypothesized link between the LTD/LTP shift and cognitive decline in aging, and 2) to unravel the cellular mechanistic pathways through which age-related altered Ca2+ regulation is linked to the LTD/LTP shift. Specific aims are designed to determine if the age-related shift in LTD/LTP is associated with cognitive decline and determine whether procedures to counteract shift in LTD/LIP also counteracts the memory impairment in aged animals. Other aims will determine whether intracellular Ca2+ stores contribute to altered synaptic plasticity during aging, and identify intermediate linking steps between Ca2+ dysregulation and altered synaptic function (e.g. calcineurin). We believe that the results of our experiments will add significantly to our knowledge of mechanisms for regulation of synaptic function across the life span and provide a basis for understanding the role of synaptic plasticity in cognitive function.

Summary/Abstract Even in the absence of dementia, a dichotomy remains between successful and unsuccessful cognitive aging. The long range goal is to provide interventions to delay, prevent, or treat cognitive decline associated with unsuccessful aging in order to improve the health and well- being of older Americans. The overall hypothesis for the proposed work is that memory consolidation deficits are an early marker of cognitive decline. It is hypothesized that memory deficits result from impaired activation of NMDA receptor (NMDAR) signaling cascades that direct the expression of genes for maintaining hippocampal function. The studies will examine signaling cascades in two fields of the hippocampus (CA1 and the dentate gyrus) of rats at different ages in order to distinguish when and where changes associated with memory deficits first emerge. Specific aim 1 will combine behavioral characterization, in vitro electrophysiology, protein and gene expression analyses to tests the hypothesis that memory consolidation deficits result from a decreased ability to activate signaling cascades that are important for memory. Preliminary data indicates that NMDAR synaptic responses and the activity of ERK is decreased in middle-aged and aged animals with memory consolidation deficits relative to aged-matched, unimpaired rats. Examination of brain tissue supports the idea that deficits are associated with a reduction in experience induced changes in chromatin structure (histone acetylation) and the expression of genes related to synaptic activity. Specific aim 2 will test the hypothesis that neural inflammation contributes to the decline in the signaling cascade and cognitive decline. It is predicted that non-steroidal anti-inflammatory drugs (NSAIDs) will reverse the decrease in NMDAR activated signaling cascade activity and improve memory in aging animals. The same techniques and measures will be used to examine control and NSAID treated naimals. Preliminary data indicates that memory impaired animals exhibit markers of neuroinflammation observed as enhanced expression of cytokines and genes related to cellular stress and memory consolidation deficits associated with neuroinflammation can be reversed by NSAID treatment.

? DESCRIPTION (provided by applicant): The goal of the proposed work is to provide an understanding the role of chronic inflammation in the onset and progression of cognitive decline during aging and Alzheimer's disease. Impaired memory, an early indicator of cognitive decline, is due to impaired synaptic function associated with a redox-mediated hypofunction of N-methyl-D-aspartate receptors (NMDARs). The mechanism involves reactive oxygen species (ROS), possibly from activated microglia, providing a potential link between inflammation and the emergence of impaired memory. Aim 1 will test the hypothesis that the onset of cognitive decline is influenced by an inflammation induced increase in oxidative stress, resulting in a redox-mediated NMDAR hypofunction. Studies employ sensitive behavioral tests for different cognitive processes, and can detect changes in motor function or motivation. Impaired cognitive function will be related to measures of serum and local brain cytokines, glial activation, oxidativ stress, and redox regulation of NMDAR function. We predict that inflammatory markers in the serum are predictive of the emergence of memory deficits and that for specific neural systems, inflammation markers, and impaired NMDAR function is diagnostic of different cognitive impairment phenotypes. Evidence indicates that decreased NMDAR synaptic activity results in transcriptional changes similar to that associated with age-related cognitive decline and Alzheimer's disease suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes. Aim 2 examines brain transcription and cognitive decline due to chronic low-level of systemic inflammation. A systemic inflammation model has been developed and involves muscle expression of interleukin-6 (IL-6), which elevates serum IL-6 and induces brain astrogliosis and microglia activation. We predict that a long-term (3 months) increase in serum cytokines will result in a redox-mediated NMDAR hypofunction and a senescent transcription profile. Aim 3 will examine the idea that region selective upregulation of antioxidant enzymes will have a selective effect in protecting NMDAR function, promoting a youthful transcriptional profile, and rescuing cognition.