Memory loss is prevalent in the aging population and is a key feature of Alzheimer's disease (AD), the most common age-related neurodegenerative disorder. As the global population ages, we must define the mechanisms underlying memory and find effective strategies to prevent memory loss. The roles of astrocytes in memory are poorly understood. The candidate's preliminary findings suggest that G protein-coupled signaling in astrocytes affects long-term memory. In mice, the activation of astrocytic Gs-coupled receptors interfered with long-term memory, while reduction in the expression of an astrocytic Gs-coupled adenosine receptor enhanced long-term memory. The levels of this receptor were found to be increased in postmortem human brain tissue from AD patients. These findings raise the intriguing possibilities that astrocytic Gs-coupled receptors regulate long-term memory and contribute to memory loss. However, it is not known how these astrocytic receptors regulate memory. The main objective of the proposed research is to determine how astrocytic Gs-coupled signaling affects the neural processes underlying memory. By using established transgenic mice and chemogenetic techniques, the proposed studies will determine if astrocytic Gs-coupled receptor signaling influences neuronal immediate early gene expression (Aim 1), neural network oscillations (Aim 2) and neuronal plasticity (Aim 3), all of which have been implicated in the mechanisms that underlie memory. The studies will also define the signaling mechanisms downstream of astrocytic Gs-coupled receptors (Aim 3). These studies promise to reveal novel memory-linked neurobiological processes, advance our understanding of astrocytic functions and uncover new therapeutic strategies for memory loss in aging and disease. Mentored research will enable the candidate to link astrocytic signaling with complex neural processes and determine the effects of astrocytic signaling at the synaptic, cellular and network levels. The short-term goals of the candidate are to 1) obtain additional training related to the mechanisms of memory, 2) obtain career training and secure an independent tenure-track faculty position, and 3) receive funding to support her independent research on the roles of astrocytic receptor signaling in memory. The long-term goals of the candidate are to advance research efforts that elucidate the nature and functions of astrocytic signaling in cognition, brai aging and neurological deficits, and to develop novel therapeutic strategies that target astrocytic receptor signaling mechanisms to modulate disease processes. The proposed research and career training will enable the candidate to develop a strong independent research program focusing on the roles of astrocytic-neuronal interactions in health and disease. The Gladstone Institutes and UCSF will provide an ideal academic environment for carrying out the proposed training. A primary mentor and an advisory committee will provide the candidate with the pertinent expertise, resources and guidance for carrying out the proposed research and becoming an independent investigator.

Public Health Relevance

Memory loss, or forgetting, is prevalent in the elderly and is a key symptom of Alzheimer's disease, the most common neurodegenerative illness. The causes of memory loss are not known and no effective treatments are available. The proposed research will investigate how memory loss is influenced by astrocytes and could be alleviated by targeting astrocytic proteins.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Career Transition Award (K99)
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Neuroscience of Aging Review Committee (NIA)
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Wise, Bradley C
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J. David Gladstone Institutes
San Francisco
United States
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Orr, Anna G; Lo, Iris; Schumacher, Heike et al. (2018) Istradefylline reduces memory deficits in aging mice with amyloid pathology. Neurobiol Dis 110:29-36