Browsing by Subject "cortex"

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    Cortical Astrocyte-Neuron Network Interaction in Health and Disease
    (2020-09) Lines, Justin
    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 (Aβ) 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 thesis 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 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 test the hypothesis that cortical astrocytes respond to sensory stimulation, they impact neuronal network activity, and astrocyte – neuronal interactions are altered in an amyloidosis mouse model of AD. I begin by identifying cortical astrocyte calcium activity in response to sensory stimulation. I then monitor astrocyte calcium simultaneously with neuronal network function during sensory stimulation to identify coordination of neuron – astrocyte network activity. With the use of Designers Receptors Exclusively Activated by Designer Drugs (DREADDs), I show astrocytes alter spontaneous and sensory-evoked neuronal activity. Due to its overexpression of beta-amyloid, I use the well-established APPSwe/PS1dE9 (APP/PS1) mouse model of AD to evaluate the impact of Aβ plaques on cortical astrocyte responsiveness to sensory stimulation. Finally, I monitor astrocyte calcium and neuronal network activity in the APP/PS1 mouse model to show alterations in neuron – astrocyte interactions by beta-amyloid in AD. Astrocyte calcium activity and its relation to neuronal network activity is examined. This project aided 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. During my PhD I received training 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.
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    Inducing Neural Plasticity and Modulation Using Multisensory Stimulation: Techniques for Sensory Disorder Treatment
    (2017-06) Gloeckner, Cory Dale
    In this dissertation, we characterized the modulatory and plasticity effects of paired multisensory stimulation on neural firing in sensory systems across the brain. In the auditory system, we discovered that electrical somatosensory stimulation can either suppress or facilitate neural firing in the inferior colliculus (IC) and primary auditory cortex (A1) depending stimulation location. We also tested plasticity effects in A1 in response to paired somatosensory and acoustic stimulation with different inter-stimulus delays in anesthetized guinea pigs, and found that plasticity induced by paired acoustic and right mastoid stimulation was consistently suppressive regardless of delay, but paired acoustic and pinna stimulation was timing-dependent, where one inter-stimulus delay was consistently suppressive while other delays induced random changes. These experiments were repeated in awake animals with paired acoustic and pinna stimulation, and two animal groups of different stress levels were used to assess stress effects on plasticity. We found that in low-stress animals, the same inter-stimulus delay was consistently suppressive and a neighboring delay was consistently facilitative across all animals, which matches previous invasive spike-timing dependent plasticity studies (anesthesia may have affected these trends). Meanwhile, high-stress animal results were not consistent with expected time dependence and exhibited no trends across inter-stimulus delays, indicating that stress can have adverse effects on neuromodulation plasticity outcomes. In all other primary sensory cortices, we found that differential effects can be induced with paired sensory stimulation such that the location, amount, type, and timing of plasticity can be controlled by strategically choosing sensory stimulation parameters for modulation of each sensory cortex. We also investigated the ability to target subpopulations of neurons within a brain region and found that by stimulating at levels near activation thresholds, specific subpopulations of IC neurons can be targeted by varying somatosensory stimulation location. Furthermore, acoustic stimulation can excite or modulate specific areas of somatosensory cortex, and we mapped the guinea pig homunculus to characterize this. Overall, these findings illustrate the immense interconnectivity between sensory systems, and multisensory stimulation may provide a noninvasive neuromodulation approach for inducing controlled plasticity to disrupt pathogenic neural activity in neural sensory disorders, such as tinnitus and pain.