Cortical activity underlying cognitive function is classically thought to be exclusively mediated by neurons. In contrast, astrocytes are considered to play solely homeostatic roles, without being directly involved in brain function. Yet, astrocytes are emerging as important cells in brain physiology because they interact with neurons establishing Tripartite Synapses, responding to neurotransmitters with rises in internal calcium levels leading to the release of gliotransmitters that regulate synaptic function. While astrocyte calcium and consequent synaptic regulation has been largely documented at the single cell level, astrocyte network activity and its impact on neuronal network function has been minimally explored. Through the dysregulation of this interaction, astrocytes may be involved in brain pathology, contributing to the cognitive deficits in neurodegenerative diseases such as Alzheimer?s disease (AD). AD is the leading cause of dementia in the United States, and yet the mechanisms contributing to cognitive decline are unclear. The disease progression is associated with depositions of senile plaques of beta-amyloid (A?) aggregates as well as loss or damage of synapses. Beta-amyloid pathology has been shown to disrupt cortical astrocyte calcium homeostasis and desynchronize neuronal networks, however disturbances caused by astrocyte-neuron dysfunctions on evoked cortical activity in AD remain unknown. The overall goal of this proposal is to identify astrocyte cortical activity, its impact on neuronal network function, and beta-amyloid induced dysregulation of astrocyte-neuron interactions in AD. To assess astrocyte impact on neuronal network function, I will monitor astrocyte calcium activity using two-photon microscopy simultaneously with ECoG recordings of neuronal network activity in vivo. While monitoring the somatosensory cortex during hind-paw stimulation, I will test the hypothesis that cortical astrocytes respond to sensory stimulation, they impact neuronal network activity, and astrocyte-neuron interactions are altered in AD. I will begin by identifying cortical astrocyte calcium activity in response to sensory stimulation (Aim 1a). Due to its overexpression of beta-amyloid, I will use the well-established APP/PS1 mouse model of AD to evaluate the impact of A? plaques on cortical astrocyte responsiveness to sensory stimulation (Aim 1b). I will then monitor astrocyte calcium simultaneously with neuronal network function during sensory stimulation to identify coordination of neuron ? astrocyte network activity (Aim 2a). Finally, I will monitor astrocyte calcium and neuronal network activity in the APP/PS1 mouse model to assess alterations in neuron ? astrocyte interactions by beta-amyloid in AD (Aim 2b). This project will aid in the elucidation of novel cellular and network dynamics that are disrupted in Alzheimer?s disease, and provide new potential therapeutic targets for the treatment of Alzheimer?s disease. Astrocyte calcium activity and its relation to neuronal network activity will be examined. I will be trained on a multitude of cutting edge research techniques that I will be able to use and build upon throughout my career as an independent research scientist.

Public Health Relevance

Cortical activity is believed to be exclusively mediated by neurons, however astrocytes are emerging as important elements of brain function because they bidirectionally communicate with neurons. Dysregulation of this interaction may contribute to pathophysiology in neurodegenerative diseases such as Alzheimer?s disease. Using multiphoton calcium fluorescence imaging simultaneously with electrophysiology in vivo, I aim to define astrocyte cortical activity, its impact on neuronal network function, and beta-amyloid induced astrocyte-neuron dysfunction in Alzheimer?s disease.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Wise, Bradley C
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University of Minnesota Twin Cities
Schools of Medicine
United States
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