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Thesis Seminars

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The role of MKK4 and MKK7 glaucomatous neurodegeneration

Sarah Yablonski - PhD Candidate, Advisor: Rick Libby

Glaucoma is a neurodegenerative disease characterized by death of retinal ganglion cells (RGCs), the output neurons of the retina. The main risk factors for developing glaucoma are age and elevated intraocular pressure (IOP). Current glaucoma therapies are only capable of lowering intraocular pressure, but this does not always halt disease progression. To develop improved therapies, it is important to understand the mechanisms underlying glaucomatous neurodegeneration of RGCs. In glaucoma, an initial insult is thought to occur to the RGC axons as they exit the eye to form the optic nerve. Multiple studies have shown that after this glaucomatous insult, the compartments of RGCs (soma, axon, and dendrites) degenerate via distinct molecular pathways. For example, the transcription factors JUN and DDIT3 were shown to be critical hubs for regulating somal degeneration after glaucomatous insult, but not dendritic or axonal degeneration. Nevertheless, it remains unknown how RGC axonal injury triggers downstream degenerative pathways and whether there may be a common upstream molecular regulator of degeneration for all RGC compartments. The MAP2Ks, MKK4 and MKK7, control activation of JUN and are indirectly capable of activating DDIT3. Therefore, they are ideal candidates for upstream activators controlling degeneration of all RGC compartments. Recent work in our lab using mechanical injury to RGC axons showed that dual deficiency of Mkk4 and Mkk7 protected RGC somas, axons, and dendrites as well as bulk RGC activity following injury. These findings suggest that MKK4 and MKK7 may be the upstream regulators controlling somal, dendritic, and axonal degeneration following a glaucomatous insult. However, it is unknown whether MKK4 and MKK7 are important for synaptic structure, metabolism, and RGC firing rates- all of which are believed to be altered during glaucoma pathogenesis. Additionally, it is unclear whether deficiency of Mkk4 and Mkk7 will provide similar levels of protection in an ocular hypertensive mouse model (which experiences IOP-dependent, age-related, and asynchronous RGC degeneration in a manner that more closely resembles human glaucoma). To address these questions, the importance of MKK4 and MKK7 in maintaining RGC structure and function will be investigated after multiple glaucoma-relevant insults. Specifically, the following specific aims are proposed: 1) determine if dual deficiency of Mkk4 and Mkk7 protects RGC health and function after axonal insult; and 2) determine the role of MKK4 and MKK7 in a mouse model of ocular hypertension. Together, these studies not only will provide additional information about the molecular roles of MKK4 and MKK7 in RGCs, but could also help provide new treatment targets for glaucoma.

 Jul 19, 2022 @ 11:00 a.m.

 Medical Center | Ryan Case Method Room: 1-9576

Zoom Link

Host: Neuroscience Graduate Program

Linking attentional modulation to neuronal feature-selectivity in macaque V1 - PhD Thesis Defense

Shraddha Shah - PhD Candidate, Advisor: Farran Briggs, PhD

Our brains can focus on the most critical information using attentional processes, according us the ability to locate our car keys amidst clutter or hold a conversation in noisy settings.  Accordingly, attention enhances behaviorally relevant information by modulating multiple aspects among groups of neurons.  My thesis research aimed at determining general principles that might dictate attentional modulation of specific neurons and neuronal circuits.

Macaque V1 is an excellent candidate structure in which to ask mechanistic questions about attentional processes because we have a detailed understanding of its structural and functional organization.  We suggest that attentional processes may piggyback onto the feature-specific functional architecture in V1, and hypothesize that the brain can flexibly attend to different features by modulating neuronal activity specifically for neurons tuned for the task-relevant (attended) feature.  In the first study, I demonstrated that robust attentional effects can be measured in the macaque V1, comparable to effect sizes in human neuroimaging studies (Shah et al, 2021), establishing the macaque V1 as a reliable model system for studying neuronal mechanisms of visual attention.

In the second study, I investigated the role of anatomical connectivity in guiding attention-mediated changes of correlated variability.  Our research revealed that attentional modulation of interneuronal variability exhibits strikingly different patterns across neurons with distinct connectivity - 1) attention specifically decorrelated neuronal spikes among neurons monosynaptically connected via an excitatory synapse and encoding task-relevant information, 2) attention led to an increase in interneuronal correlations among neurons monosynaptically connected via an inhibitory synapse, which exhibited high correlated variability independent of attention.

In the third study, I conducted a rigorous test of the hypothesis that attentional modulation of neurons depends on neuronal feature-selectivity, especially for task-relevant features.  Monkeys were trained to perform multiple attention-demanding tasks requiring different visual feature discriminations.  A thorough comparison of the relationships between attentional modulation of neuronal firing rates in each attention task, the task-relevant feature, and the feature-selectivity of neurons was conducted.  Our results so far reveal that different attention tasks recruit distinct functional subpopulations of neurons, diverging in multidimensional feature-selectivity.

 Jul 06, 2022 @ 11:00 a.m.

 Medical Center | Ryan Case Method Rm (1-9576)

Host: The Neuroscience Graduate Program

PhD Thesis Defense: Protective mechanisms in Naked Mole Rat CNS: roles of extracellular matrix and astroglia

Frances (Fara) Tolibzoda Zakusilo - PhD Candidate, Advisors: Vera Gorbunova, PhD and Kerry O'Banion, MD/Phd

The role of extracellular components in the aging phenotype is not well understood. A longliving rodent, Naked Mole Rat (NMR), presents as a salient model of healthy aging. Previous findings in our lab have identified extracellular matrix (ECM) component hyaluronic acid (HA) asan important contributor to the exceptional resilience of NMR to aging associated disease, suchas cancer and degenerative conditions. Our lab designed a high-molecular weight HA (HMW-HA)mouse model (nmrHas2;Cre mice) to mimic the major component of NMR ECM. Pilot data indicated that nmrHas2;Cre mice display significant increase in longevity (~5-15%) and resilienceto oncology. We, however, were not able to see a rescue of memory decline, degeneration, andinflammation associated with aging in these transgenic mice. To test the effect of HMW-HA inAlzheimer’s Disease (AD) we generated nmrHas2;Cre x MAPT/P301S double transgenic mice. These mice failed to show reduction in degeneration and inflammation, but as part of this work,we discovered that HA distribution appears to be distorted in AD as compared to healthy adult(10-months-old, 10mo) and aged (~24mo) mice, which points at HA as an intriguing diagnostictool for this neurodegenerative disease.

Since HA is deposited by multiple cells in the brain, we decided to parse apart the effect of thepolymer for a number of cell types. We purified NMR neurons, OPCs, and astroglia and assessedtheir HA profile. OPCs had the least amount of HA, followed by neurons, with astroglia culturemedia having the greatest abundance of HA. We checked if there was a correlation with resilience to stress and discovered that although astroglia were most resilient to reactive oxidative species (ROS), the correlation did not hold for other cells. That made us question therole of HA in ROS stress, one of the major contributors to aging, and look deeper into what mechanisms underly NMR astroglia’s resilience. In addition to NMR, we optimized astroglial cultures from mice and degus, rodents hypothesized to be a natural model for AD developmentwith age, and obtained human fetal astrocytes to perform a comparative study. Interestingly, human cells showed the greatest susceptibility to ROS stress compared to other species, withNMR showing greatest survival among all four. RNA sequencing analysis helped us uncover metabolism related differences between the species, where human astroglia appeared to bemost dependent on glycolysis compared to others. We have been able to significantly increasesurvival post ROS exposure in human cells by subjecting them to ketogenic and reduced nutrient media, which supports the notion of the importance of metabolic state in resilience tooxidative damage. Taken together, this work suggests that there are cell specific mechanisms inthe NMR CNS that allow for their exceptional resilience to the diseases associated with aging.

 May 25, 2022 @ 11:00 a.m.

 Medical Center | Ryan Case Methods Room (1-9576)

Host: the Neuroscience Graduate Program

PhD Defense: c-Cbl Inhibition in Glioblastoma Multiforme: A Pathway Analysis

Neal Shah, MS - PhD Candidate, Advisor: Mark Noble, PhD

 May 09, 2022 @ 10:00 a.m.

 Medical Center | Ryan Case Method Room

Host: The Neuroscience Graduate Program

PhD Defense: Protein phosphatase 1 isoforms differentially regulate synaptic transmission and plasticity

Karl Foley, MS - PhD Candidate, Advisor: Houhui Xia, MSc, PhD

 Apr 26, 2022 @ 2:00 p.m.

 Medical Center | Ryan Case Method

Host: The Neuroscience Graduate Program

PhD Defense: Amygdala-Prefrontal Circuits Implicated in Expression Perception

Keshov Sharma, MS - PhD Candidate, Mentors: Liz Romanski, PhD; Julie Fudge, MD

Facial and vocal expressions are a fundamental component of communication in primates. Accurate interpretation of an expression is a critical social function that relies on brain networks involved in face and vocal perception, multisensoryintegration, and emotion. In macaques, viewing an expression engages areas within the occipital and temporal lobes, the amygdala, the anterior cingulate cortex (ACC), and ventrolateral prefrontal cortex (VLPFC). While previous studies of macaque facial and auditory processing have focused on the temporal cortex, this thesis expands our understanding of amygdala and prefrontal contributions to expression perception through precise anatomical analysis of amygdala projections to the prefrontal cortex as well as investigation of population level dynamics of VLPFC neuronal responses to naturalistic expressions. As background for the thesis aims, neural tracer injections were made across theACC. The intermediate subdivision of the basal nucleus (Bi) and magnocellular division of the accessory basal nucleus were identified as a specific source of inputs to the ACC from the amygdala. The isolation of the Bi as a specific sourceof amygdala output to the ACC prompted investigation of the specificity of amygdala-prefrontal projections to another location: the VLPFC. In the first thesis aim, combinatorial analysis of retrograde and anterograde projections from the VLPFC and amygdala, respectively, revealed that the Bi is a specific source of amygdala input to the VLPFC, similar to the ACC. These results provide evidence for a direct anatomical pathway underlying the functional coactivation of the amygdala and VLPFC during expression perception. The second aim investigated the role of the VLPFC in the processing of social stimuli using neurophysiology in awake, behaving macaques. Neural activity was recorded from the VLPFC, using multi-electrode arrays, while subjects viewed audiovisual movies of three distinct naturalistic expressions from three different conspecifics. Analysis revealed that single neurons rarely encoded identity or expression independently, typically having complex, non-linear responses to different identity-expression combinations. While ANOVA analysis revealed main effects of expression and identity on single neuron firing rates, decoding of single cell firing rates resulted in low decoding accuracy of expression and identity. Combined as a pseudo-population, decoding accuracy for both variables increased as a function of VLPFC population size, with identity increasing faster than expression. Pseudo-population decoding across the response time resulted in early and sustained identity decoding accuracy compared to expression. Principle component analysis of the mean population response to each stimulus revealed that population responses to the same identity were closer in the response space and followed similar trajectories over time, facilitatingseparation of population responses by identity. These results indicate that VLPFC activity in response to naturalistic expressions is non-linear and temporally dynamic; that information about expression and identity is readily available at the population level during expression perception; and show that identity is the dominant categorical variable in the natural structure of VLPFC neural activity during expression perception.

 Apr 21, 2022 @ 11:00 a.m.

 Medical Center | K-207 (2-6408)

Host: Neuroscience Graduate Program

PhD Defense: Variations in neuronal population activity across behaviors, brain regions, and disease

Uday Chockanathan, MS - PhD Candidate, Mentor: Krishnan Padmanabhan, Ph.D.

Although it is generally accepted that perception, cognition, and behavior arise from the collective activity of groups of neurons in the brain, only recently has it become possible to record from these large populations of neurons in awake behaving animals. As a result of these experimental advances, two critical challenges have emerged: how do we design and perform novel experiments that allow us to study the activity of these populations, and what new analytical and computational methods can be drawn upon to study this activity. To address these questions, I developed novel experimental methods for recording from large populations of neurons and applied cutting edge approaches from statistics and physics to show how this population activity varies across behaviors, brain regions, and disease states. First, I demonstrated that running is associated with an increase in the dimensionality of population activity in the main olfactory bulb (MOB) (Chockanathan and Warner et al. 2021, J. Neurophys.). Second, I showed how the diversity, or entropy, of patterns of population activity in dorsal CA1 hippocampus, was diminished in the APP/PS1 model of amyloid beta (Aβ) pathology (Chockanathan et al. 2020, Sci. Rep.), suggesting a potential truncation of the neural “vocabulary” available to represent memories or percepts in Alzheimer disease (AD). Third, I compared the properties of population activity between dorsal CA1 and ventral CA1 as mice navigated a virtual reality environment and showed that dorsal CA1 had a larger spatial information content of neural populations than ventral CA1 (Chockanathan et al. 2021, eNeuro). Fourth, I showed that population activity in dorsal and ventral CA1 is differentially affected in APP/PS1 mice. While dorsal CA1 patterns are more dominated by pairwise interactions, ventral CA1 patterns are less bound by pairwise interactions, suggesting that effects of Aβ pathology are heterogeneous across different brain regions. Taken together, my work demonstrates novel approaches to analyzing population activity across different brain regions that offer insights into behavior and stimulus representations. These approaches allowed me to link mechanisms of disease pathology to behavior through the intermediary of neural activity.

 Apr 19, 2022 @ 1:00 p.m.

 Medical Center | Ryan Case Method Room (1-9576)

Host: Neuroscience Graduate Program

Thesis Proposal: Secondary insults and the brain: Contribution of peripheral infection to neuropathology in ataxia telangiectasia (AT)

Maleelo Shamambo - PhD Candidate, Advisor: Margot Mayer-Proschel, Ph.D.

 Mar 23, 2022 @ 9:00 a.m.

Virtual

Host: The Neuroscience Graduate Program

PhD Defense: The ins and outs of the primate amygdala: connectivity gradients, development, and early life stress

Alexandra McHale, MS - PhD Candidate, Mentor: Julie Fudge, MD

The amygdala, a heterogeneous collection of nuclei, plays a fundamental role in processing emotions. In primates, the basal amygdala nucleus is massively modulated by the prefrontal cortex and insula, and influences motivated behaviors through its striatal outputs. In Aim 1, I examined the complexity of cortical inputs and striatal outputs of the basal nucleus, and cortical inputs to the amygdalo-recipient ("limbic") striatum. Using tract tracing techniques, I found that cortical cytoarchitecture shaped the strength and complexity of cortical projections into the basal nucleus. Agranular cortical areas formed broad, "foundational" projections throughout the basal nucleus, while increasingly differentiated cortical areas sent more restricted, overlapping inputs to specific basal nucleus subregions. Direct cortical inputs to the "limbic" striatum also followed similar rules, with agranular cortices projecting throughout, and increasingly differentiated cortices overlapping these inputs in restricted regions. Thus, the basal nucleus, and the "limbic" striatum it innervates, receive predictable, "connectivity fingerprints" from the cortex.

The organization of "connectivity fingerprints" in the basal nucleus might have origins in development. In humans, the basal nucleus adds neurons through early life; these neurons are thought to originate in the surrounding paralaminar nucleus (PL), which contains immature, post-mitotic neurons. In Aim 2, I compared numbers of immature (doublecortin, DCX+) and mature (non-DCX+) neurons, and their cellular features, in infant and adolescent primate PL. Infant PL had more immature neurons and fewer mature neurons compared to adolescent PL, suggesting cellular maturation between infancy and adolescence. In Aim 3, I examined effects of maternal deprivation on DCX+ and non-DCX+ PL neurons in infant primates. There were no differences in DCX+ or non-DCX+ PL neuron counts between maternally-deprived and control infants. However, tbr-1 expression (a late-appearing gene transcript in glutamatergic precursors) and mature neuron number were positively correlated across animals, with lower levels in maternally deprived versus control, suggesting cellular growth delay in maternally deprived infant PL. In these studies, I found that connectivity of basal nucleus networks is more complex and highly organized than previously recognized. In addition, development and early life stress influence cellular growth in the surrounding PL/basal nucleus, potentially influencing the construction of neuronal circuits.

 Mar 09, 2022 @ 1:00 p.m.

Host: Neuroscience Graduate Program

PhD Defense: Linking olfaction and locomotion in mice

Emily Warner Crosier, MS - PhD Candidate, Mentor: Krishnan Padmanabhan, Ph.D.

 Feb 28, 2022 @ 1:00 p.m.

Flyer

Host: Neuroscience Graduate Program

PhD Thesis Defense: Redox-Fyn-c-Cbl (RFC) pathway regulates O-2A/OPC cell cycle exit and differentiation by thyroid hormone and negative regulation of the RFC pathway during early OPC development

Yunpeng Pang, MS - PhD Candidate, Mentor: Mark Noble, PhD

Thyroid hormone (TH) plays an important role in the development of the central nervous system (CNS). Inparticular, TH signal is critical for the differentiation of oligodendrocyte precursor cells (O-2A/OPCs) intooligodendrocytes, which myelinate the CNS. Although gene regulations by TH and TH receptors have been thefocus of the field, it is still not clear how does TH drive cell cycle exit in dividing OPCs. Previous work from theNoble laboratory revealed that intracellular redox status is a central regulator of OPC fate decisions between celldivision and differentiation. Here, we report the critical role of c-Cbl, a tumor suppressor protein, in regulating thecell cycle exit of dividing OPCs in response to TH signal via the redox-Fyn-c-Cbl (RFC) pathway. In particular, wefound that treatment of TH in vitro leads to increased intracellular reactive oxygen species (ROS) production andsuperactivation of c-Cbl, downregulation of multiple targets of c-Cbl including PDGFRa, and subsequently leadingto OPC cell cycle exit. We found that c-Cbl is required for TH-driven downregulation of multiple c-Cbl targets andcell cycle proteins, as well as OPC cell cycle exit. Additionally, we found that other glial differentiation signalsincluding TGF-β and BMP4 converge on the activation of the RFC pathway and that they similarly requiregeneration of ROS to drive OPC cell cycle exit. We also found that in vivo injection of TH in a hypothyroid modelresulted in c-Cbl superactivation and led to downregulating of c-Cbl target PDGFRa, suggesting that activation ofthe RFC pathway is relevant in an in vivo setting.
The RFC pathway is also carefully regulated during early development and we uncovered two mechanisms bywhich c-Cbl superactivation can be dampened to allow proliferation of OPCs during development despiteoxidation and ROS signaling by prodifferentation factors. First, growth factors such as NT3 decreased the ability ofROS generation by TH. Secondly, we found that bioactive lipid sphingosine-1 phosphate (S1P) induced inhibitorycomplex formation between c-Cbl and β-pix. Intriguingly, in early embryonic human fetal derived OPCs we foundthe inhibitory complex between c-Cbl and beta-pix exist and prevented TH induced c-Cbl superactivation and cellcycle exit by TH. Here, we investigated whether the c-Cbl/β-pix inhibitory complex is required for embryonichuman OPCs to resist TH-induced c-Cbl superactivation and found that both pharmacological inhibition ofupstream regulators of β-pix and genetic knockdown of β-pix itself released the negative control of c-Cblsuperactivation and allowed embryonic human OPCs to response to TH, leading to cell cycle exit and acceleratedof OL generation. Our findings provide a novel molecular architecture of c-Cbl superactivation via the RFCpathway as well as negative regulation of c-Cbl superactivation. Together these mechanisms help to shed light onthe potentially critical role of c-Cbl in the development of glial progenitors in the CNS.

 Feb 15, 2022 @ 2:00 p.m.

Flyer

Host: Neuroscience Graduate Program

PhD Qualifying Exam: TBA

Caitlin Sharpe - PhD Candidate

ABSTRACT

Schizophrenia is a psychotic disorder that affects millions of people worldwide. Although antipsychotic medications are widely used as an effective treatment for many psychosis symptoms, these medications do little to alleviate the cognitive impairments and visual perceptual distortions commonly found in this population. Long-term aerobic exercise is one intervention that has been shown to improve cognitive abilities in individuals with schizophrenia. However, the impact of aerobic exercise on visual processing in schizophrenia has not yet been studied and the exact extent to which aerobic exercise may improve executive function and visual perception in this population remains unclear. Assessing changes in neural activity during exercise in response to visual stimuli may allow us to simultaneously examine both the therapeutic potential of walking in this population and the neurobiological basis of these effects. The current project will accomplish this using mobile brain/body imaging (MoBI) which allows synchronous collection of electrophysiological, kinematic, and behavioral data. The first aim of this study is to assess whether an acute walking intervention may ameliorate cognitive and visual perceptual deficits in people with schizophrenia. We hypothesize that walking will improve executive function and alleviate visual perceptual abnormalities. Specifically, electrophysiological deficits in visual processing pathways will be reduced in patients while walking and participants with a schizophrenia spectrum disorder will experience more cognitive and perceptual benefits from walking than healthy controls. The second aim of this project is to assess the association between effects of walking on visual perception in individuals with schizophrenia and patients’ psychosis symptoms. We predict that patients reporting greater negative symptoms will demonstrate increased visual processing abnormalities at rest and a greater amelioration of these deficits while walking compared to patients reporting fewer negative symptoms. While the first aim of this study assesses the therapeutic potential of walking in alleviating cognitive and visual perceptual abnormities in schizophrenia, the second aim will allow us to identify sets of patients that may benefit maximally from this treatment.  

 Feb 09, 2022 @ 1:30 p.m.

Zoom Link

Host: Neuroscience Graduate Program