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Thesis Seminars

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The role of microglial β2 adrenergic signaling in Alzheimer's disease pathology - PhD Thesis Proposal

Linh Le - PhD Candidate
Advisors: Ania Majewska, PhD and Kerry O'Banion, MD, PhD

 May 07, 2021 @ 1:00 p.m.

An Investigation of the Genetic Mechanisms Underlying Noise-Induced Hearing Loss in Homozygous Foxo3-knockout Mice - PhD Thesis Defense

Holly Beaulac - PhD Candidate
Advisor: Pat White, PhD

Approximately 16% of global cases of adult-onset hearing loss are attributable to excessive, occupational noise exposure. The prevalence of noise-induced hearing loss (NIHL) continues to increase with limited therapeutic options available. By studying the underlying pathology of NIHL using genetic loss-of-function models, it is possible to identify genes that contribute to hearing loss susceptibility. FOXO3 is a forkhead transcription factor involved in several cellular processes including growth, survival, stress resistance, apoptosis, and longevity. My lab has previously established a role for FOXO3 in preserving outer hair cells (OHCs) and hearing thresholds following a mild noise exposure in mice. I hypothesized that in the absence of FOXO3, reactive oxygen species would accumulate in response to noise exposure and lead to OHC apoptosis. I analyzed the immediate effect of mild noise exposure on wild-type, Foxo3 heterozygous (Foxo+/KO), and Foxo3 knock-out (Foxo3KO/KO) FVB mice. Well-characterized components of noise-induced damage including calcium regulation, oxidative stress, inflammation, apoptosis, necrosis, and parthanatos were examined. In the Foxo3KO/KO mouse, dynamic immunoreactive modulation of the calcium buffer oncomodulin was correlated with OHC loss beginning 4 hours post-noise exposure. Parthanatos was identified as the main cell death pathway for OHCs. In opposition to my hypothesis, oxidative stress response pathways were not significantly altered. Using RNA sequencing I identified differentially expressed genes and examined one whose role in the cochlea has not been described. Glycerophosphodiester Phosphodiesterase Domain Containing 3 (GDPD3) is a possible source of Lysophosphatidic acid (LPA). LPA has been demonstrated to prevent OHC loss after severe noise exposure. When I treated noise-exposed animals with LPA, immediate OHC damage was reduced but no long-term prevention of cell death and hearing loss was observed. These data suggest that FOXO3 acts prior to acoustic insult to maintain cochlear resilience, in part through interaction with GDPD3 to help sustain endogenous LPA levels. Continuing work includes examining FOXO3’s cell-specific importance and recapitulating the NIHL susceptibility linked to human single nucleotide polymorphisms (SNPs) associated with increased FOXO3 levels.

 Apr 26, 2021 @ 10:00 a.m.

Host: Univ. Rochester School of Medicine and Dentistry</br>The Neuroscience Graduate Program

Fluid transport in the brain - PhD Thesis Defense

Humberto Mestre - PhD Candidate
Advisor: Maiken Nedergaard, M.D., D.M.Sc.

Water is the principal component of all biological tissues. The brain is not an exception to this rule and has one of the highest water contents of any tissue type. Normal brain function depends on the precise balance within all the different fluid compartments that include intracellular and extracellular fluid, cerebrospinal fluid (CSF), and cerebral blood volume. When any one of these compartments becomes deranged, such as in cerebral edema, any abnormal accumulation of fluid can lead to herniation and death. The mammalian brain has evolved a global network of fluid conduits surrounding the blood vessels that perfuse it to allow for the rapid exchange of brain fluids. These perivascular spaces serve a multitude of roles in central nervous system physiology and form the basis for the glymphatic system. The flow of CSF through the glymphatic system aids in the clearance of metabolic waste from the parenchyma serving the role of the brain’s lymphatic system. This thesis aimed to understand the mechanisms that regulate flow within the brain. Chapter two of this thesis aimed to determine the anatomical structure and geometry of perivascular spaces in the murine brain. We developed a novel imaging modality to quantify flow within perivascular spaces for the first time. This technique demonstrated that perivascular fluid flow is pumped by arterial pulsations driven by the cardiac cycle and that arterial hypertension disrupts effective pumping slowing the flow. In chapter three, we developed a mesoscopic imaging platform to show that perivascular fluid enters the brain secondary to changes in plasma osmolarity. We then exploited this finding to improve the delivery of a monoclonal antibody targeted against amyloid plaques used in the treatment of Alzheimer’s disease. Astrocytes ensheathe virtually all cerebral blood vessels, forming the outside wall of the perivascular spaces. Their endfeet express high levels of the water channel aquaporin-4 (AQP4) and this unique, polarized distribution increases the influx of CSF to the brain. In chapter four we evaluated the dependence of perivascular transport on AQP4 expression uniting efforts with four independent research groups and using five different AQP4 knockout rodent lines to confirm the dependence of brain fluid transport on AQP4. In chapter five, we leveraged the newly developed imaging modalities from chapter two and three to evaluate how acute cerebrovascular diseases contribute to abnormal fluid flow within the brain. Mainly, we tested how acute ischemic stroke enhanced perivascular inflow of CSF to the brain. This abnormal state of fluid inflow caused the detrimental accumulation of CSF and triggered the onset of edema formation. More importantly, we identified that knocking out AQP4 reduced this effect and protected against edema fluid accumulation after stroke. The results of the present thesis provide novel insights into the principles governing fluid transport in the mammalian brain and developed innovative imaging techniques to further evaluate them. The goal of gaining further insight into these processes is to ultimately use our newly gained understanding to develop novel therapeutic interventions.

 Apr 12, 2021 @ 9:00 a.m.

Host: University of Rochester School of Medicine and Dentistry<br/>The Neuroscience Graduate Program

Task Modulation of Optic Flow Responses: Neural and Neuronal Mechanisms - PhD Thesis Defense

Colin Lockwood - PhD Candidate
Advisor: Charles Duffy, MD, PhD

Self-movement creates a radial pattern of optic flow that tells us where we are going. Navigation-related optic flow perceptual deficits in aging and Alzheimer’s Disease (AD) suggest a combination of visual perceptual deficits and loss of attentional control of visual processing. We have examined these deficits using human evoked potentials to elucidate these deficits and tried to replicate and expand on these mechanisms through recorded monkey evoked potentials.
In our studies of aging and AD, we combined optic flow discrimination with cued spatial attention to assess the effects of shifting attention on optic flow perceptual deficits. We find diminished attentional effects in aging and loss of attentional effects in AD coupled with delayed responses in aging and increased failures of navigation in AD. In addition, aging leads to a loss of coherence in late evoked potentials and an increase in power in early perceptual evoked potentials. However, in AD there is no increase in early evoked potentials leading to decreased responses throughout the task. Thus, aging is associated with increased visual processing and decreased attentional control, while AD is associated with a loss of attentional control and diminished optic flow responses.
Monkeys trained in the same visuo-spatial attentional optic flow discrimination task evoke homologous responses to humans. However, differences in monkey behavior may shed light into different attentional strategies used to complete the task. The monkey that exhibits behavior similar to young people in the task has correspondingly strong attentional evoked potentials. Another monkey who exhibits behavior that suggests a more perceptual strategy has neurophysiological responses similar to those seen in aging. While monkey neurophysiology closely resembles humans, differences between monkeys provide insight into the mechanisms of optic flow deficits in aging and AD.
Despite the differences in species, evoked potentials recorded in both humans and monkeys clearly demonstrate early sensory signals followed closely by cognitive signals that modulate self-movement perception. In aging and in a monkey with a perceptual strategy we see a decrease in the cognitive signals coupled with an increase in the power of sensory signals. In AD the loss of cognitive signals is accompanied by a decrease in the power of the sensory signals, leading to increased failure of optic flow discrimination and navigation.

 Mar 29, 2021 @ 9:00 a.m.

Host: Univ. Rochester School of Medicine and Dentistry<br/>The Neuroscience Graduate Program

Neural dynamics of social processing and underlying perceptual deficits in schizophrenia - PhD Thesis Proposal

Emily Przysinda - PhD Candidate
Advisors: Ed Lalor, PhD and David Dodell-Feder, PhD

Schizophrenia is a chronic and complex disorder with many symptoms, including the hallmark symptoms of hallucinations and delusions that can distort perception of reality. Medications primarily address these positive symptoms, and thus negative symptoms such as anhedonia and social difficulties can cause significant functional impairment for these patients. More research examining how these social difficulties manifest in the brain is needed, especially research utilizing naturalistic stimuli that can mimic real life. Here we use naturalistic paradigms, episodes of TV show, The Office, as our stimuli, because it captures a rich variety of social interactions including some that may be violating social norms. In addition, this experimental design is rich with potential stimulus parameters that we can quantify and relate to the neural signals, including lower-level of perceptual domains such as language and vision. Given that patients with schizophrenia are known to have lower-level perceptual deficits, it will be important to explore how these deficits may impact measures of social cognition. Here, we will use two complementary neuroimaging imaging modalities to examine social brain network differences in patients with schizophrenia and how more basic perceptual deficits may be influencing these measures. Aim 1 will use functional magnetic resonance imaging (fMRI) techniques to characterize neural dynamics of social processing deficits in schizophrenia. We will first explore various lower level perceptual processes during these stimuli utilizing a general linear model approach (GLM). Next, we will utilize GLMs involving social parameters and effective connectivity determined by dynamic causal modeling (DCM) that will allow us to characterize social neural dynamics and explore how these measures may be influenced by lower level sensory processing deficits. Aim 2 will characterize neural dynamics of social processing deficits in schizophrenia using electroencephalography (EEG) across multiple episodes of The Office with various social tasks. We will explore how lower-level features of the stimulus are related to the neural signals using a temporal response function approach. Using the spatially informed models from structural MRI, we will examine social neural dynamics in an analogous way to fMRI with TRFs and DCM analyses. We aim to recruit the same participants for aim one and two, so we can capitalize on the strengths of both methods and examine how these measures may be providing both converging and diverging information about social processing deficits in schizophrenia. We hope that this research can be used to inform future research for biomarkers of mental illness and ultimately improve healthcare outcomes for patients with schizophrenia.

 Mar 04, 2021 @ 9:00 a.m.

Host: Neuroscience Graduate Program