Thesis Seminars

Dominic Bunn - PhD Candidate, Neuroscience Graduate Program

Alzheimer’s Disease (AD) is a progressive neurodegenerative disease characterized by the accumulation of tau and amyloid beta aggregates, reactive astrocytes, activated microglia, and oxidative stress. Tau aggregation is considered a primary driver of the disease, with systematic propagation of tau pathology through the brain in Braak stages. Astrocytes are known to uptake tau, but whether this is beneficial or detrimental is still debated. Mitochondrial reactive oxygen species (ROS) production is one regulator of astrocyte function, as their mitochondria are known to generate an increased amount of ROS compared to other cell types. This mitochondrial ROS production is utilized for signaling that regulates many astrocytic functions. Despite oxidative stress being an early hallmark of AD that has been extensively studied, the specific relationship between astrocytic ROS and tau pathology is unknown. Interestingly, exposure to pathological tau induces mitochondrial dysfunction in astrocytes. Neonatal astrocytes from tauopathy models also adopt abnormal phenotypes, with increased reactivity markers and reduced neurosupportive functions. While no studies have looked at the impact of mitochondrial ROS on astrocytic tau uptake specifically, astrocytic upregulation of BAG3 and transcription factor EB have been shown to increase uptake and have neuroprotective effects in AD. Both proteins are suggested to be regulated by Nrf2 activity, which responds to oxidative stress. These studies suggest mitochondrial ROS is an important regulator of astrocyte function within AD, but the specific relationship has never been directly explored. We hypothesize that increased mitochondrial ROS production will increase tau uptake but impair the ability of the astrocytes to degrade uptaken tau and reduce their neuroprotective functions. To test this hypothesis, we propose to use in vitro approaches that allow for spatially and temporally controlled ROS production. We will generate ROS within the mitochondria of AD model-derived astrocytes. The AD model used is the PS19 mouse model, which expresses human tau with the P301S mutation, known to cause tau pathology in humans, under the mouse prion promoter. While significant tau aggregate pathology is not observed until 6 months in the PS19 model, the prion promoter is active shortly after neurons differentiate. In Aim 1, we will utilize chemogenetics to generate mitochondrial ROS, alongside the ROS biosensor HyPer7, to assess the impact of mitochondrial ROS production on astrocyte mitochondrial health, and neurosupportive functions. The goal of this aim is to understand basal differences in ROS production, ROS sensitivity, and mitochondrial function between PS19 and wild type astrocytes In Aim 2, we will utilize chemogenetic approaches of generating mitochondrial ROS to investigate the effect of ROS on the uptake, degradation, and propagation of tau pathology. The chemogenetic control of ROS production allows for the spatial and temporal control of ROS production independent of metabolism, allowing us to test the cause and effect relationship of ROS generation and tau processing. The experiments proposed are achievable within the lab and will advance our understanding of astrocyte function and oxidative stress in the context of AD.

 Apr 10, 2025 @ 11:00 a.m.

 Medical Center | 2-7534

Host: Advisors: Andrew Wojtovich, PhD and Gail Johnson, PhD

Abigail Alpers - PhD Candidate, Neuroscience Graduate Program

Dystonia is the 3rd most common movement disorder in the US and is characterized by twisting movements or postures that typically worsen with voluntary movements. Generalized dystonia affects the trunk in addition to two other limbs and can be the primary pathology or secondary to another injury, such as a stoke. Current therapies are only partially effective or have side effects. We do not understand the underlying pathophysiology, but evidence suggests dysfunction in the cortico-basal ganglia-thalamo-cortical (CBGTC) circuit. The globus pallidus interna (GPi) and subthalamic nucleus of the basal ganglia are both deep brain stimulation (DBS) targets for dystonia. Both are nuclei in the hyperdirect and indirect pathways, but it is not known which pathways of the CBGTC circuit are involved in the pathophysiology of dystonia, or whether the same pathway underlies different types of dystonia. In this proposal, I will test whether hyperdirect pathway disfunction is related to dystonic motor symptoms. The stop signal task is a measure of reactive inhibition that selectively activates the hyperdirect CBGTC circuit. Participants are instructed to touch a target, but in a subset of trials, they receive a stop cue and must cease their reach quickly.

In Aim 1, I will characterize stop signal (SS) task performance to investigate whether hyperdirect pathway function is impaired in different types of generalized dystonia (primary or secondary). Then, I will analyze local field potential (LFP) recordings from cortex (EEG recordings) and the GPi (DBS recordings) to evaluate neural correlates of this function. I predict that participants with both subtypes of generalized dystonia will have longer latencies to stopping, suggesting abnormal hyperdirect pathway activity, which will correlate with increased beta (13-30 Hz) power in sensorimotor cortex and GPi. Additionally, I predict that participants with both types of generalized dystonia will have more failed stop trials compared to controls, and that failed trials will have greater low frequency (4-12 Hz) power in sensorimotor cortex and GPi.

In Aim 2, I will investigate cortical-subcortical interactions during the stop signal task in dystonia. I predict that there will be increased theta coherence between premotor cortex and GPi during failed trials, and that premotor cortex signaling will lead GPi.

In Aim 3, I will test for LFP biomarkers of dystonia that correlate with dystonia symptom severity as measured by the Burke-Fahn-Marsden dystonia rating scale. Based on prior research and preliminary data collected from subjects at rest, I predict that dystonic symptom severity will positively correlate with low frequency coherence between premotor cortex and the GPi.

Using the LFP data from Aim 1, I predict that coherence in the high gamma band (50-100Hz) will positively correlate with symptom severity during the SS task. Identifying neural activity that corresponds to task behavior as well as biomarkers of dystonia that correlate with symptom severity will improve our understanding of dystonia pathophysiology and lead to the development of more effective therapies, such as adaptive DBS.

 Apr 02, 2025 @ 1:00 p.m.

 Medical Center | SMD Large Auditorium (2-6424)

Host: Advisors: Angela Hewitt, MD, PhD and Manuel Gomez-Ramirez, PhD

Margaux C. Masten - PhD Candidate, Neuroscience Graduate Program

There is a growing body of epidemiological evidence linking air pollution (AP) exposure and increased risk for multiple childhood onset neurodevelopmental disorders (NDDs) including attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). Exposure to AP in the third trimester of pregnancy has been linked with higher odds of ASD diagnosis, as well as, more symptoms of inattention and decreased corpus callosum (CC) volume associated with increased hyperactivity. Ultrafine particulate matter (UFP) is one of the most reactive components of AP, due to its large surface area to volume ratio. Furthermore, UFPs present a unique challenge as their small size allow them to penetrate deep into the lungs and traverse many of the body’s barrier mechanisms such as the placenta and the blood brain barrier, creating a unique challenge for the developing brain during gestation. Previous work from our lab in C57BL/6J mice shows that gestational and early postnatal exposures to ambient UFP from traffic related air pollution trigger unique sex-dependent neurobehavioral outcomes, with ventriculomegaly, alterations in myelination of the CC, persistent CC microglial activation, elevated glutamate in the brain, metal dyshomeostasis, and behavioral deficits including impulsivity, cognitive inflexibility, and altered social interaction. However, the sex-difference and directionality of these effects vary between gestational and post-natal exposures. Due to the altricial brain development at birth in traditional laboratory rodents, we do not know if the differences are due to critical windows of exposure or differential routes of exposure. Unlike C57BL/6J mice, the African Spiny mouse (genus Acomys) is born precocial with neural development more similar to humans at the time of birth. This unique model allows us to test the neurotoxicity of air pollution during late gestation with a more translational pattern of brain development. In addition to their precocial brain development at birth, spiny mice are highly social animals allowing for more expanded social behavioral evaluations. The central hypothesis of this thesis is that late gestational UFP exposure induces neurodevelopmental changes in spiny mice similar to the effects seen in postnatal C57BL/6J UFP exposures, including altered white matter development, cognitive inflexibility, and social behavioral deficits.

Experiments from Aim 1 will use transmission electron microscopy to characterize UFP metal contaminants and particle characteristics across maternal cranial nerves, maternal olfactory bulbs, placenta, and the periventricular region of the fetal brain. We hypothesize that inhaled UFP from the dam will translocate across the placenta and into the pup brain and will show differential bioprocessing in the maternal and fetal brains. In Aim 2 we will use electron microscopy and immunohistochemistry to identify changes in myelination and white matter tracts. We hypothesize that exposure in the spiny mice will lead to white matter damage with decreased corpus collosum size, altered myelin ultrastructure, and enlarged lateral ventricles in a male-biased manner. Experiments from Aim 3 will test social interaction and cognitive flexibility using behavioral paradigms including measures of social interaction and communication as well as the translationally relevant ID/ED shift operant task. We predict there will be sex-dependent deficits in social communication and cognitive flexibility in spiny mice exposed to UFP during the late gestational period in utero. Together these experiments will expand our understanding of how late gestational exposure to air pollution confers risk for multiple neurodevelopmental disorders that share sex-biased prevalence rates and behavioral presentations.

 Mar 07, 2025 @ 12:00 p.m.

 Medical Center | Adolph Lower Aud. (1-7619)

Host: Advisor: Marissa Sobolewski, PhD

Bryan V. Redmond - PhD Candidate, Neuroscience Graduate Program

Cortically induced blindness (CB), which most often results from stroke damage to the primary visual cortex (V1) or its afferents,
leads to binocular loss of conscious visual perception. While motor stroke rehabilitation is well-researched, the visual deficits
faced by CB patients lack effective treatment, with only compensatory therapies like saccadic training and prism lenses
prescribed clinically. CB is considered permanent, offering little hope for visual recovery. However, recent research from the
Huxlin lab and others has challenged this notion, demonstrating the potential for recovering direction discrimination abilities -
among others - within the blind field. In addition, building on the pioneering work of Riddoch and Weiskrantz, Saionz and
colleagues (2020) reported that about 1/3 of naïve, early post-occipital stroke patients retain a range of preserved conscious
simple and complex motion abilities. More rarely, some even retained the ability to discriminate orientation of static targets
within their perimetrically-defined blind fields. Whether with different perimetric tests or psychophysical tasks, evidence is
mounting supporting the heterogeneity of perception inside CB fields. A next step is to identify and understand the natural
history of these abilities, what anatomical structures enable them, and what their presence means for rehabilitation.

The first step in this endeavor is to define the deficit. Humphrey automated perimetry (HAP) is the most common type of clinical
perimetry used in CB. It measures light detection using a small, static stimulus, presented randomly in a grid-like pattern across
the central visual field. However, it does not control fixation during testing as rigorously as the Macular Integrity Assessment
(MAIA) perimeter. We contrasted these two perimeters’ ability to identify visual impairment and assess changes both
spontaneously and following restorative interventions. We concluded that on the sum, HAP performed according to strict test
quality criteria is the most optimal way to quickly but coarsely define the extent and severity of the deficit in CB. Based on HAPdefined
blind-field boundaries, we then proceeded to map motion discrimination in the blind-field. Our standard method for
identifying preservation of such abilities involved repeatedly and densely testing a few, adjacent blind field locations using
random dot stimuli. Although precise, this approach is time-consuming, and oversamples a very small region of visual space
rather than canvassing the entire deficit. This limitation makes it impractical for clinical use, leaving most patients uninformed
about the truly heterogenous nature of their “blind” field.

This thesis addresses this gap, developing an automated, direction discrimination perimetric tool (ADDaPT) able to rapidly and
accurately detect preserved motion discrimination abilities across the HAP-defined blind-field of CB patients. Then, using the
new ADDaPT definition of preservation in concert with computerized, home-based training, we compare the efficacy of training
in preserved and non-preserved CB patients. In addition, we correlated performance outcomes with the progression of
retrograde degeneration affecting the ganglion cell and inner plexiform layers of the retina, measured using optical coherence
tomography at baseline and 12-months post-stroke.

Flyer

 Mar 05, 2025 @ 9:00 a.m.

 Eastman Dental Center | EIOH Farash Auditorium (1st floor EDC)

Host: Advisor: Krystel R. Huxlin, PhD

Dennis Jung, MS - PhD Candidate, Neuroscience Graduate Program

Working memory (WM) enables temporary maintenance and manipulation of task-relevant information. One important role of WM is preventing information loss during distraction. While neural oscillations are known to support WM maintenance and distractor resistance, less is understood about how anticipation influences these processes. This thesis investigated neural oscillations in WM during distractor anticipation. To test this, we recorded local field potentials (LFP) in the lateral prefrontal cortex (LPFC), a key brain area for WM, and scalp electroencephalograms (EEG) from monkeys performing modified memory-guided saccade (MGS) tasks, with varying in distractor timing and item load. The first experiment tested how distractor anticipation influences brain oscillatory dynamics with fixed distractor timing during memory maintenance. We found widespread thetaband (4-8 Hz) EEG activity better encoded the memory item after, rather than before, the anticipated distractor time, regardless of whether the distractor appeared. However, theta-band LFP activity in the LPFC only encoded the item when the distractor was presented. These results suggest large-scale theta oscillations reflect WM dynamics associated with both maintenance and distractor anticipation, while small-scale theta oscillations in the LPFC specifically encode the stored item, ensuring stability. The second experiment varied distractor timing. We found greater behavioral impairment when the distractor appeared towards the end of the task. EEG theta activity continued encoding item—greater towards the end of maintenance, regardless of the presence of the distractor. Similar encoding was observed for the LFP theta activity only when the distractor was shown. These results suggest WM becomes more vulnerable to distraction over prolonged maintenance, but greater encoding of items may reduce deteriorating distractor effects. The third experiment explored effects of increased item load and internal selective attention on distractor anticipation. Selection increased encoding of an attended item in EEG and LFP theta-band activities. Post-cue distractors tended to increase behavioral errors compared to a single-item conditions in the previous experiments, suggesting increased task complexity and variability impairs distractor anticipation. Together, the results of these experiments demonstrate that the distractor anticipation influences the WM dynamics as reflected in both small- and large-scale oscillatory signals.

Event Flyer

 Jan 29, 2025 @ 1:00 p.m.

 Medical Center | Lower Adolph Aud. (1-7619)

Host: Advisor: Adam Snyder, PhD

Andrea Campbell - PhD Candidate, Neuroscience Graduate Program

Visual impairment affects over 2.2 billion people worldwide, with retinal diseases (RDs) like age-related macular degeneration (AMD) and retinitis pigmentosa (RP) as significant contributors to this impairment. These diseases lead to the degeneration of photoreceptor cells, which lack a natural regenerative capacity in humans. Current treatments primarily aim to slow disease progression, underscoring a critical need for regenerative strategies focused on restoring vision. Photoreceptor precursor cells (PRPCs) derived from human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) are promising candidates for cell replacement therapies. However, immune-mediated rejection and inflammation remain significant barriers to their success. To address these challenges without relying on prolonged immune suppression, this study evaluates two complementary strategies: (1) short-term systemic immune suppression and (2) co-transplantation of PRPCs with regulatory T cells (T-regs).

Aim 1 evaluates the efficacy of short-term immune suppression in promoting PRPC survival. Prolonged immune suppression increases risks such as infections and systemic toxicity. Inspired by transient protocols in retinal pigment epithelium (RPE) transplantation, this study hypothesizes that a short-term immunosuppressive regimen can promote PRPC survival while minimizing adverse effects. Advanced adaptive optics scanning laser ophthalmoscopy (AOSLO) will facilitate non-invasive, longitudinal imaging of PRPC survival and host immune responses at cellular resolution.

Meeting ID: 944 0302 2429
Passcode: 903589

Aim 2 examines the co-transplantation of PRPCs with T-regs to locally modulate immune responses. T-regs play a key role in immune tolerance and may provide a localized, cellular alternative to pharmacological immune suppression. By dampening inflammation and inhibiting cytotoxic T-cell activity, T-regs could enhance PRPC survival. Using fluorescent reporters and high-resolution imaging, this study will track immune activity, T-reg function, and PRPC survival in real-time, assessing the potential of T-regs to mitigate rejection.

This research integrates cutting-edge imaging technologies, fluorescent reporters, and an NHP model that closely mimics human retinal anatomy, physiology, and immune responses. By leveraging these innovations, the study seeks to advance regenerative therapies for retinal diseases, providing insights into immune modulation and stem cell-based interventions. Success in these strategies could pave the way for safer and more effective treatments for RD patients, addressing an unmet medical need and establishing a framework for future cell-based therapies in ophthalmology.

 Jan 13, 2025 @ 11:00 a.m.

 Medical Center | K307 (3-6408)

Host: Advisor: Juliette E. McGregor, Ph.D.