2020 - McGovern Medical School


Transcript of 2020 - McGovern Medical School

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Guillermo Aquino Miranda Postdoctoral Fellow Research Category: Cognition and Behavior Research Analysis Level: Systems The prelimbic prefrontal cortex encodes individual differences in approach-avoidance conflict in rats Aquino-Miranda, G; Fernandez-Leon, JA; Engelke, DS; Do Monte, FH. Neurobiology and Anatomy, McGovern Medical School, The University of Texas Health Science Center, Houston The ability to identify and discriminate cues associated with reward and aversive stimuli allows an organism to select the most appropriate behavioral response. Neurons in the prelimbic subregion of the prefrontal cortex (PL) respond to both reward- and threat-associated cues. However, whether PL activity regulates the animals’ decision to approach or avoid such cues remains unknown. To address this question, male Long-Evans Hooded rats with single-unit recording electrodes implanted in PL were initially trained to press a bar for sucrose during the presentation of audiovisual cues. Next, rats were fear conditioned by pairing a neutral odor with electrical footshocks. During the test session, rats were placed in a rectangular arena comprising two different zones: a food zone where the bar, the sucrose dish, and the odor port were located and an adjacent hidden zone. Rats were exposed to three phases: only audiovisual cues (reward), only odor cues (fear), or both simultaneously (conflict). To search for food during the conflict phase, animals had to leave the hidden zone and approach the conditioned odor presented in the food zone. Our results showed that during the reward phase, animals approached the food zone and pressed the bar immediately after the onset of the food cues. During the fear phase, animals showed stronger defensive behaviors characterized by a reduction in time exploring the food zone and an increase in time spent in the hidden zone. Interestingly, two subpopulations of rats emerged during the conflict phase: rats that continued searching for food (pressers) vs. rats that remained in the hidden area and showed complete suppression of food-seeking responses (non-pressers). PL recordings (n= 367 neurons, 32 rats) during the reward phase revealed a greater number of sustained reward-cue responses in pressers (~45%), when compared to non-pressers (~11%). Notably, the magnitude of reward-cue responses observed during the conflict phase was similar to the reward phase for pressers, but was drastically reduced for non-pressers (Z-score: >2.58 for excitatory and <-1.96 for inhibitory responses). Using a combination of recordings and optogenetics for photoidentification of distinct subtypes of PL neurons in pressers, we found that ~30% of PL glutamatergic (PLGLUT) neurons reduced their spontaneous firing rate during the reward phase, when compared to baseline. Presentation of the conditioned odor during the fear phase disinhibited ~60% of the PLGLUT neurons, whereas the introduction of reward cues during the conflict phase restored the inhibition of PLGLUT neurons to the same levels as the reward phase. In contrast, changes in spontaneous firing rate of PL GABAergic (PLGABA) neurons were similar across the different phases, most likely reflecting the distinct subtypes of

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interneurons described in this region. Moreover, photoactivation of PLGLUT neurons during the onset of the reward-cues reduced reward-seeking responses in pressers, whereas silencing of PLGLUT neurons in non-pressers reduced freezing responses during conflict and biased the animals’ response toward the food area. Our results establish a role for PL in the regulation of approach-avoidance conflict by demonstrating that reduced activity in PLGLUT neurons correlates with increased risky reward-seeking behavior, and bidirectional manipulation of PLGLUT neurons is sufficient to modulate the animal’s drive to search reward during a conflicting situation.

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Christopher Bolden Postdoctoral Fellow Research Category: Novel Methods and Technology Development Research Analysis Level: Cellular Validation of a novel In vitro platform for investigating Traumatic Brain Injury Chris Bolden1, 2 , Max Skibber3 , Scott D. Olson4 , Brijesh S. Gill1 , Charles S. Cox Jr3 ; 1University of Texas Health Science Center at Houston, Surgery; 2University of Texas Health Science Center at Houston, Center for Translational Injury; 3University of Texas Health Science Center at Houston, Pediatric Surgery; 4University of Texas Health Science Center at Houston, Program in Regenerative Medicine, Houston, TX, USA Background and Significance: Traumatic Brain Injury (TBI) remains one of the leading causes of death and disability in the United States in all age groups. TBI is a chronic disorder resulting from a heterogeneous mechanical disruption of brain tissue. This mechanical disruption initiates a biochemical cascade of pathophysiological complications such as edema and neuroinflammation which severely impacts patient outcomes. Current experimental in vitro models attempt to mimic the complex pathophysiology of TBI, but often neglect the hemodynamic parameters that recapitulate in vivo TBI. This occurrence is due to a poor Blood Brain Barrier (BBB) phenotype for experimental investigation. The development of a suitable in vitro TBI model will mimic pathogenesis by sequentially imposing the mechanical, metabolic, and inflammatory insults in a functional BBB in a high-throughput platform. This platform will allow for the independent modulation of the brain and blood compartments’ hydraulic forces, perfusion rates, and biochemical environments that have been neglected in previous models.

Based on these parameters, we engineered a modular, dynamic platform around a Matrigel

coated Transwell membrane seeded with an endothelial cell (EC) monolayer. Our novel TBI platform utilized key BBB cellular components such as brain microvascular endothelial cells, astrocytes and mesenchymal stem cells (pericytes) arranged into either a direct contact coculture or triculture system. Aims and Approach: Cellular layers were exposed to either a combination of Wall Shear Stress (WSS) (average of 4 dyne/cm2), and/or biochemical insult of tumor necrosis factor-alpha (TNF-

, 50 ng/ml) or cytochalasin-D (cD, 2.5 ug/ml). To mimic conditions of TBI, cellular layers were also exposed to an oxygen-glucose depleted environment followed by reperfusion (OGD/R). We utilized transendothelial electrical resistance (TEER), and FITC-Dextran extravasation as validation markers of a BBB phenotype. Results: Our results indicate that the application of shear stress resulted in the enhancement of and maintenance of BBB phenotype through enhanced TEER in comparison to static condition in both the coculture and triculture BBB system. The triculture system achieved favorable BBB characteristics including TEER up to 510 Ω cm2 and a permeability coefficient (Papp) of 2.5 x 10-7 in 15 kDa FITC-dextran. Treatment with inflammatory insults TNF- and cD caused a decrease in TEER over time, confirming the BBB phenotype of paracellular tightness.

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Glucose starvation with oxygen deprivation caused a decrease in TEER of the coculture system at the 2 hr timepoint and eventually recovered 4 hr after this metabolic insult. Conclusion: Our findings suggest that our in vitro TBI platform is capable of initiating and/or enhancing the BBB phenotype over time to relevant in vivo characteristics. The goal in the development of our novel in vitro TBI platform is the potential refinement of current in vivo experiments, as well as the enhanced translation of preclinical results into clinically meaningful neuroprotective strategies for the future. This platform will allow for insight into the molecular investigation of TBI and the cellular interactions between the components of the NVU.

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Jing Cai GSBS Student Research Category: Cognition and Behavior Research Analysis Level: Behavior Identification of a novel neurocircuit of the hedonic pathway in regulating feeding behaviors Jing Cai, GSBS The hypothalamus has long been a major focus for regulating food consumption and recognized as the brain center for homeostatic feeding. However, the therapeutic targets on the hypothalamus have minimal effect for treating eating disorders. Additionally, many recent studies have shown extrahypothalamic regions, which regulate other aspects of feeding rather than inner caloric needs, are also significant for regulating food consumption. Two such extrahypothalamic regions are the diagonal band of broca and the ventral tegmental area. The DBB has been shown to regulate sensory perception and higher brain order functions such as learning and memory. Activation of the DBB glutamatergic neurons and cholinergic neurons reduce food intake, but how the two groups of neurons interact with each other and downstream targets for the DBB in regulating feeding behaviors are still unclear. The ventral tegmental area has been recognized as a major reward behaviors regulator and recent studies show that the VTA modulates hedonic feeding. Acute activation of VTA dopaminergic neurons suppresses food intake, however the key upstream signals orchestrating VTA’s involvement in regulating feeding remain unclear. Previous studies show that DBB glutamatergic neurons send projections to both local cholinergic neurons and the ventral tegmental area (VTA). Behavioral studies also show that DBB cholinergic and VTA dopaminergic neurons are anorexigenic, consistent with the role of DBB glutamatergic neurons in regulating food consumption. Moreover, my preliminary data show that acute activation of DBB glutamatergic projections to the VTA reduces food intake, suggesting DBB-->VTA circuit suppresses feeding. Therefore, my central hypothesis is that DBB glutamatergic neurons suppress feeding behaviors through local projections to cholinergic neurons and long-range projections to VTA dopaminergic neurons. The objective of this proposal is to identify underlying mechanisms of how the DBB and the VTA integratively modulate feeding behaviors by the following two aims. Aim 1. To use monosynaptic tracing, chemogenetic manipulations of neuronal activities to test anatomical connections and functional interaction respectively between DBB glutamatergic neurons and cholinergic neurons. Aim 2. To combine optogenetics and chemogenetics manipulations of neuronal activities to determine the function of the DBB-->VTA in regulating feeding behaviors. This study links two extrahypothalamic regions for their functions in regulating feeding behaviors. Completion of this study may provide a general framework for how eating behaviors are related with sensory perception and reward behaviors and identify potential therapeutic targets for the treatment of eating disorders.

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Renan Costa GSBS Student Research Category: Neural Excitability, Synapses, and Glia: Cellular Mechanisms Research Analysis Level: Systems Analysis of the distributed representation of operant memory in Aplysia californica Renan M. Costa1, 2, Ryota Homma1, Douglas A. Baxter3 and John H. Byrne1, 2 1Department of Neurobiology & Anatomy, McGovern Medical School at UTHealth, Houston, TX, USA; 2MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA; and 3Engineering in Medicine (EnMed), Texas A&M Health Science Center—Houston Reward-related learning (e.g., operant conditioning, OC) underlies both adaptive and maladaptive behaviors. Thus, understanding the neuronal underpinnings of reward learning and memory promises to profoundly benefit human mental health. Gaining insights into the encoding of operant memories has proven challenging, however, for two main reasons. First, operant memories appear to be sparsely distributed among neurons spanning multiple brain regions. Second, in most organisms it is not technically feasible to investigate how specific cellular changes alter population activity and ultimately behavior. Here, we leveraged the advantages of the well-characterized neural circuit that mediates feeding in the marine mollusk Aplysia californica to address these challenges using a two-pronged approach. First, we used population-wide, single-neuron resolution voltage-sensitive dye imaging to examine the reconfiguration of population activity by operant memory. We used an established in vitro analogue of OC, in which stimulation of a nerve that signals reward was made contingent upon occurrences of ingestive motor patterns in the nervous system. Each contingent preparation was paired with a yoked control preparation that received identical, but non-contingent, stimuli. Investigators were blinded during data analysis. Because Aplysia are hermaphroditic, sex-related comparisons could not be made. We observed a greater change in the rate of ingestions in the contingent group (N=10) compared to the yoked group (N=10; p<0.01, Wilcoxon signed-rank test). We simultaneously recorded the activity of ~100 neurons per experiment before and after learning. We used non-negative matrix factorization to decompose population activity into three motor modules consisting of small subpopulations of neurons (<20) that were consistently recruited at specific times during motor patterns. Contingent training altered the activity corresponding to two motor modules, one of which was also affected by yoked training. These findings suggest that subpopulations of neurons encode specific aspects of memory, such as associative (contingent) and non-associative (yoked) components. Second, we used a biologically realistic computational model of the neural circuit that mediates feeding behavior to determine how individual loci of operant memory contribute to population activity and behavior. The model included conductance-based descriptions of 13 identified cells, and their ~100 chemical and electrical synaptic connections. For

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reproducibility, all model parameters are publicly available at ModelDB (accession number: 261489). The model recapitulated the recruitment of cells at specific times during motor patterns, consistent with motor modules observed experimentally. The effects of manipulating all known memory loci were examined in isolation and in combination. We found that each locus altered multiple features of the motor patterns, such as frequency, regularity, and type. Moreover, combinations of plasticity loci exhibited mutual dependence and synergism. These results indicate that the operant memory emerged from the combinatoric engagement of multiple loci of plasticity. Taken together, our results provide insights into the principles underlying encoding of operant reward memories by individual loci and by specific subpopulations of neurons across the nervous system. These insights may lead to more effective treatments for reward-related disorders, such as addiction.

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Camila Nayane de Carvalho Lima Postdoctoral Fellow Research Category: Disorders of the Nervous System Research Analysis Level: Molecular Association between accelerated epigenetic aging and poorer functional status in bipolar disorder Camila Nayane de Carvalho Lima, Jair C. Soares, Consuelo Walss-Bass, Joao Quevedo, Gabriel R. Fries Background: Bipolar disorder (BD) has been previously associated with functional impairment and accelerated epigenetic aging, although the link between these two features has not yet been explored. The present study investigated the relationship between two novel second-generation measures of epigenetic aging acceleration (GrimAge and PhenoAge) and functioning in BD and controls. Methods: Whole blood genome-wide DNA methylation levels were measured in BD patients (n=89) and matched healthy controls (n=39) with the Infinium EPIC BeadChip (Illumina). Epigenetic age estimates were calculated using an online tool (dnamage.genetics.ucla.edu/). Regression modeling was performed with GrimAge or PhenoAge acceleration as dependent variables and group (BD vs. controls) or length of illness as predictors. Separate models were performed while controlling for only age, sex and race (minimally-adjusted model) or also for blood cell count estimates (fully-adjusted model). Spearman correlations tested for associations between aging acceleration and functioning, as measured by the Functioning Assessment Short Test (FAST) and Global Assessment of Functioning (GAF). Results: BD was significantly associated with greater GrimAge acceleration in the unadjusted (β=0.18, p=0.015) and minimally-adjusted (β=2.574, p=0.013) models, but not after controlling for blood cell counts (β=0.823, p=0.345). Greater length of illness significantly predicted GrimAge acceleration in all models (fully adjusted - β=0.205, p=0.03). In contrast, PhenoAge acceleration was not associated with BD or with length of illness. Finally, a significant correlation between GrimAge acceleration and poorer functioning was found with both FAST (rho=0.167, p=0.021) and GAF scores (rho=-0.229, p=0.001). Conclusions: Accelerated epigenetic aging may contribute to functional decline in patients with BD. Funding: This study was funded by the UTHealth Consortium on Aging through the UTHRO Endowment for Healthy Aging Geriatric Studies for Junior Faculty Program and by the Louis A. Faillace, MD Department of Psychiatry and Behavioral Sciences at UTHealth.

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Samantha Debes GSBS Student Research Category: Sensory and Motor Systems Research Analysis Level: Cellular Cortical feedback improves visual stimulus encoding Samantha R. Debes, Xiaoqin Liu, Roger Janz, Valentin Dragoi - UTHealth, Department of Neurobiology and Anatomy Neuronal signals travel the cortex through local, feedforward and feedback projections. Though many studies have examined the function of local and feedforward connections, the role of feedback connections remains poorly understood. Previous work has utilized a variety of methodologies, including pharmacological inactivation, cortical cooling and lesioning, to study feedback. However, these techniques inherently modulate feedforward signals and have poor temporal and spatial resolution. The current literature is slight, but strongly suggests feedback increases the gain, or magnitude, of a response. This effect has only been shown in single cells, and ignores any laminar specific changes and their functional relevance. To address these limitations, we combined electrophysiology and optogenetics to selectively suppress feedback. We injected an inhibitory construct (AAV8-hSyn-Jaws-GFP) in mid-level visual area (V4) of two macaque monkeys. The injected virus expresses throughout the V4 neurons, including their axons which project to the superficial, or supragranular, layers of the primary visual cortex (V1). This allows us to optically stimulate the transfected V4 feedback terminals in V1, without perturbing feedforward processing, while animals view oriented gratings. We hypothesized that feedback alters cortical signaling in a laminar and functionally specific manner. Functional changes in feedback will improve gain responses to relevant stimuli, while responses to irrelevant stimuli are reduced or unchanged. Furthermore, anatomical studies show that feedback projections terminate in the supragranular layers, so we hypothesized that gain changes are strongest in the supragranular layers. We found that suppressing feedback decreases gain at the p¬¬referred orientation for the population (n=190 cells, signed-rank, p=1.19 e-16). Importantly, this decrease in gain is greater in the supragranular layer compared to the granular and infragranular layers (n=27, 28, 21, Kruskal-Wallis, p=2.59 e-5). This suggests that feedback improves signaling for functionally relevant stimuli, and primarily occurs just before signals are sent to hierarchically higher areas through feedforward signaling. Suppressing feedback at the flanking orientations does not change response gain at the population level. However, when separated by laminar position, we found that suppressing feedback increases gain in the supragranular layer (n=27, 28, 21, Kruskal-Wallis, p=1.54 e-8). Decreasing gain at the flanking orientations widens the dynamic signaling range between the preferred and nearby orientations, sharpening the tuning curve and improving stimulus encoding. We found that suppressing feedback at the orthogonal orientation had no effect on the population or any laminar group. As the orthogonal orientation is functionally irrelevant to the cell, feedback has no effect on gain. Control

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experiments confirmed direct suppression of V4 cell bodies (electrode and laser in V4), and no change due to cortical heating (electrode and laser in V1, but separated). Additionally, biopsies from both areas were taken to confirm expression of GFP from the injected construct. These results determine the functional significance of feedback for stimulus encoding in the visual system and inform our basic understanding of a fundamental pathway. Long-term influences will be seen in the design and target location of clinical interventions like visual prosthetics for improved artificial vision.

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Ari Dienel Postdoctoral Fellow Research Category: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homestatic Challenge Research Analysis Level: Molecular 12/15-Lipoxygenase Inhibition Reduces Platelet Activation after Subarachnoid Hemorrhage in Mice Ari Dienel, Peeyush Kumar T, Spiros L. Blackburn, and Devin W. McBride - The Vivian L. Smith Department of Neurosurgery, McGovern Medical School, The University of Texas Health Science Center at Houston Subarachnoid hemorrhage leads to hypercoagulability and induces platelet activation which can promote microthrombi formation within the microvasculature, leading to delayed neurological deficits. Our hypothesis is that inhibition of 12/15-Lipoxygenase reduces platelet activation and aggregation and improves outcome in SAH mice. Mice were randomly assigned into the experimental groups. Neurobehavior was assessed daily for 5 days. Mice were euthanized on day 5 to assess platelet activation and signaling pathways and for microthrombi counting. Inhibition of 12/15-Lipoxygenase in SAH mice improved neurobehavior, increased Cry-1 expression which is responsible for anti-inflammatory cascades and resulted in fewer activated platelets than the vehicle. We are going to inject siRNA to silence 12- and 15-Lipoxygenase to identify which Lipoxygenase is providing the therapeutic benefit. We expect that the siRNA experiment will clarify whether 12- or 15-Lipoxygenase are the main responsible for platelet activation. 12/15-Lipoxygenase may be a therapeutic target for SAH which can promote survival acutely after SAH, especially at the Delay Neurologic Deficit time range.

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Antonio Dono Postdoctoral Fellow Research Category: Disorders of the Nervous System Research Analysis Level: Molecular

The Role of RB1 Alteration and 4q12 Amplification in IDH-WT Glioblastoma

Antonio Dono, M.D., Arvind V. Ramesh, Emily Wang, Mauli Shah, M.S., Nitin Tandon, M.D., Leomar Y. Ballester, M.D., Ph.D., Yoshua Esquenazi, M.D. - Vivian L. Smith Department of Neurosurgery (AD, NT, LYB, YE), Department of Pathology and Laboratory Medicine (AD, MS, LYB), McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, Texas. Center for Precision Health, School of Biomedical Informatics, the University of Texas Health Science Center at Houston, Houston, TX (YE). Rice University, Houston, Texas (AVR, EW). Memorial Hermann Hospital-TMC, Houston, Texas (NT, LYB, YE). Background: Recent studies have identified that glioblastoma IDH-wild-type (GBM IDH-WT) might be comprised of molecular subgroups with distinct prognoses. Aims and Approach: We aim to investigate the correlation between genetic alterations and survival in GBM IDH-WT patients, to identify subgroups with distinct outcomes. We reviewed characteristics of 282 GBM IDH-WT (2009-2019) patients treated at our institution analyzed by next-generation sequencing interrogating 205 genes and 26 rearrangements. Progression-free survival (PFS) and overall survival (OS) were evaluated with the log-rank test and Cox regression models. We validated our results utilizing data from GBM IDH-WT in cBioPortal (MSK-IMPACT dataset, n=551). Results: Multivariable analysis of GBM IDH-WT revealed that treatment with chemoradiation (PFS HR 0.25 p<0.001 and OS HR 0.24 p<0.001) and RB1-mutant status (PFS: HR 0.47, p=0.002 and OS HR 0.49, p=0.016) correlated with improved PFS and OS. In addition, younger age (<55-years) was associated with improved OS. Karnofsky performance status <80 (HR=1.44, p=0.024) and KDR amplification (HR=2.51, p=0.008) were predictors of worse OS. KDR-amplified patients, 7% of GBM IDH-WT cases, frequently harbored coexisting PDGFRA and KIT amplification (p<0.001) and TP53-mutations (p=0.04). KDR, PDGFRA, and KIT are located in the 4q12 chromosome. RB1-mutant patients, 10% of GBM IDH-WT cases, had less frequent CDKN2A/B and EGFR alterations (p<0.001). Conversely, RB1-mutant patients had more frequent TP53 (p<0.001) and SETD2 (p=0.006) mutations. Analysis of the MSK-IMPACT dataset (n=551) validated our results, in which a similar genetic landscape of RB1 mutant and 4q12 amplified GBM IDH-WT were identified. Additionally, the association between RB1 mutations and improved PFS (11.0-months vs. 8.7-months, p=0.009) and OS (34.7-months vs. 21.7-months, p=0.016) was validated in the MSK-IMPACT dataset. Impact: RB1-mutant GBM IDH-WT is a molecular subgroup with improved PFS and OS.

Meanwhile, 4q12 amplification (KDR/PDGFRA/KIT) denoted patients with worse OS.

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Identifying subgroups of GBM IDH-WT with distinct survival is important for optimal clinical

trial design, incorporation of targeted therapies, and personalized neuro-oncological care.

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Brisa Fernandes Postdoctoral Fellow Research Category: Disorders of the Nervous System Research Analysis Level: Molecular The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: a meta-analysis of 101 studies showing a differential pattern between mood disorders and schizophrenia Brisa S Fernandes 1, Alexandre P Diaz 1, João L de Quevedo 1, Jair C Soares 1 - University of Texas Health Science Center at Houston, United States Question Being Addressed: Are the kynurenine pathway and its metabolites differentially expressed between mood disorders and schizophrenia and thus potential targets for molecularly-guided clinical trials? Introduction (Aims): The importance of tryptophan as a precursor for neuroactive compounds has long been acknowledged. The metabolism of tryptophan along the kynurenine pathway and its involvement in mental disorders is an emerging area in psychiatry. We performed a meta-analysis to examine the differences in kynurenine metabolites in major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ). Methods: Electronic databases were searched for studies that assessed metabolites involved in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, quinolinic acid, 3-hydroxykynurenine, and their associate ratios) in people with MDD, SZ, or BD, compared to controls. We computed the difference in metabolite concentrations between people with MDD, BD, or SZ, and controls presented as Hedges’ g with 95% confidence intervals (CI). Results: A total of 101 studies with 10,912 participants were included. Tryptophan and kynurenine are decreased across MDD, BD, and SZ (tryptophan in MDD: g= -0.51, 95% CI= -0.63 to -0.39, p= <0.001; BD: g= -0.56, 95% CI= -0.76 to -0.35, p= <0.001; SZ: g= -0.24, 95% CI= -0.46 to -0.01, p= 0.04. Kynurenine in MDD: g= -0.26, 95% CI= -0.35 to -0.16, p= <0.001; BD: g= -0.34, 95% CI= -0.62 to -0.061, p= 0.02; SZ: g= -0.27, 95% CI= -0.53 to -0.01, p=0.046). Kynurenic acid and the kynurenic acid to quinolinic acid ratio are decreased in mood disorders (i.e., MDD and BD), (kynurenic acid in MDD: g= -0.37, 95% CI= -0.52 to -0.21, p= 0.001; BD: g= -0.44, 95% CI= -0.65 to -0.24, p= <0.001. Kynurenic acid to quinolinic acid ratio in MDD: g= -0.54, 95% CI= -0.82 to -0.27, p= <0.001; BD: g= -0.44, 95% CI= -0.67 to -0.21, p= <0.0001), whereas kynurenic acid is not altered in SZ (g= 0.06, 95% CI= -0.36 to 0.48, p= 0.78). Kynurenic acid to 3-hydroxykynurenine ratio is decreased in MDD (g= -0.42, 95% CI= -0.63 to -0.21, p= <0.001) but not SZ (g= -0.53, 95% CI= -1.11 to 0.05, p= 0.07). Kynurenic acid to kynurenine ratio is decreased in MDD (g= -0.39, 95% CI= -0.73 to -0.04, p= 0.03) and SZ (g= -0.49, 95% CI= -0.85 to -0.12, p= 0.01). Finally, the kynurenine to tryptophan ratio is increased in MDD (g= 0.15, 95% CI= 0.007 to 0.291, p= 0.04) and SZ (g= 0.36, 95% CI= 0.004 to -0.626, p= 0.05). Conclusions: Our results suggest a shift in the tryptophan metabolism from serotonin to the kynurenine pathway across these psychiatric disorders. In addition, a differential pattern exists

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between mood disorders and SZ, with a preferential metabolism of kynurenine to the potentially neurotoxic quinolinic acid instead of the neuroprotective kynurenic acid in mood disorders but not in SZ. Our results suggest that the metabolites of the kynurenine pathway might be promising new targets for clinical trials guided by the specific molecular profile of a sub-group of patients, or molecularly-guided clinical trials, as preconized by precision medicine. Disclosures: The authors report no conflicts of interest for this work.

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Carson Finger Research Scientist Research Category: Disorders of the Nervous System Research Analysis Level: Systems Sex differences in atrial arrhythmogenesis and cardioembolic strokes Carson Finger, Bret Gelinas, Shane Cunha, Diego Morales, Mehmet Enes Inam, Louise D. McCullough, Bharti Manwani - Department of Neurology, University of Texas Health Science Center, McGovern Medical School, Houston, TX Background and aims: Atrial fibrillation (AF) remains the primary cause of large strokes in elderly women. Why females have higher rates of atrial arrhythmias and cardioembolic strokes as they age is unknown. Despite several recent advancements in stroke treatment, there has been limited research on prevention of strokes, especially AF related cardioembolism in women, who bear the major brunt of the disease. The goal of this project is to discern the mechanisms of sexual dichotomy in AF and cardioembolic strokes. Methods: C57BL6 ankyrin B+/- mice were used as models for spontaneous AF. These mice were monitored for AF using implantable telemetry monitors for one day. MRI brain was performed on to assess the number of strokes. Mice were perfused and brains were sliced and stained with Fluor-Jade and NeuN to assess for neuronal death and degeneration. Data was analyzed using Wilcoxon rank sum test in SPSS. Results: The telemetry electrocardiogram recordings for one day in male and female ankyrin B+/- mice were analyzed for AF events using labchart software. Female mice had significantly more AF events vs. males when recorded for one day (male 0.4 ±0.2, females 2.8 ± 0.7, p=0.02, n=5/group). Conclusion: Our preliminary data shows increased spontaneous atrial arrhythmogenesis in females vs. males. Ongoing studies in our lab are targeted to discern the difference in cardioembolic strokes in males vs. females using MRI and histology. Determination of these differences may assist in understanding the mechanisms of cardioembolic strokes in men and women and help in development of sex specific stroke preventative therapies.

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Kiefer Forseth GSBS Student Research Category: Cognition and Behavior Research Analysis Level: Systems Convergent Mappings of Eloquent Cortex: Stimulation, Electrophysiology, and Structural Imaging Forseth KJ, Rollo PS, Tandon N GSBS UT Health Science Center Cortical stimulation mapping (CSM) remains the gold standard methodology for the localization of eloquent cortex in planning resection of neoplasms and seizure foci. The resulting language map is often used in conjunction with structural imaging and intracranial electrophysiology to inform the surgical approach. Here, we combine these functional and structural measures in a large patient population to understand the interplay between the spatially distributed substrates that support language function. We collected data in 214 patients undergoing language mapping (awake craniotomy, n=63, subdural grids, n=49; stereotactic depths, n=102) with CSM (1-10mA, 50Hz, 2s), diffusion tensor imaging (DTI), and/or intracranial electrophysiology. Language function was evaluated with a battery of tasks including visual picture naming and auditory naming to definition. Stimulation-induced depolarization and electrode recording zones were transformed onto the pial surface with a current spread model to generate subject-specific functional map. These were then co-registered with DTI. Gamma (60-120 Hz) power during task performance was strongly predictive of functional classification by CSM. In several regions of interest, we generated distinct volumetric density representations of white matter fibers underlying either positive or negative stimulation sites, as well as either active or quiescent electrodes. Tracts were distilled from the sets of positive and negative fibers using an unsupervised clustering algorithm – DB-SCAN. The resulting subject-specific maps (surface-based) and tracts (volumetric) were projected into a standard atlas space with a nonlinear combined surface-volume transform that maximizes surface-landmark similarity and minimizes volumetric distortion. CSM at the group-level revealed five regions which consistently disrupted both auditory and visual naming function: middle fusiform gyrus, inferior frontal gyrus, dorsomedial prefrontal cortex, superior temporal gyrus, and posterior middle temporal gyrus. These regions were also identified using electrophysiology and are listed in their temporal sequence of engagement. DTI maps in each of these regions of interest revealed strong intra-network connectivity for positive stimulation sites, but diffuse and inconsistent cortical connectivity for negative stimulation sites. This analysis, integrating three essential surgical planning tools, constitutes a significance advance in large-scale multimodal population-level maps of human language. Analyses at the single-subject level will improve understanding of the language network at risk during surgical interventions for tumors and epilepsy.

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Melissa Franch GSBS Student Research Category: Cognition and Behavior Research Analysis Level: Systems Neural representation of learning social interactions in freely moving non-human primates Melissa Franch1, Sudha Yellapantula2, Anthony Wright1, Behnaam Ahzang1,2, Valentin Dragoi1,2 - 1Deparment of Neurobiology & Anatomy, McGovern Medical School, Houston, TX 2Department of Electrical and Computer Engineering, Rice University, Houston, TX The motivation and capacity to be social is necessary for human survival. Especially now, during the COVID-19 pandemic, the world has become increasingly aware of the importance of social interactions. Specifically, visually guided social behavior, such as cooperation, leads to better communication and decision-making. Elucidating the neural representations of cooperation will provide candidate networks for therapeutics in individuals suffering from mental health disorders with social dysfunction, such as autism. Despite this importance, the underlying neural mechanisms of learning advanced social concepts, such as cooperation, are not well understood. Furthermore, cooperation relies heavily on visualizing social cues from the environment, such as the reward for cooperating and the partner’s actions. Therefore, to study which social cues are encoded during learning cooperation and how they influence decision-making, we recorded from hundreds of neurons in a neural network that incorporates two regions- one in the visual pathway (midlevel visual cortex, V4) and one in the social brain (dorsolateral prefrontal cotex, dlPFC). We predicted that learning cooperation will induce changes in 1) the encoding of social variables such as social cues and choice within areas and 2) functional connectivity between areas. To investigate this hypothesis, we developed a novel social experimental paradigm where animals can freely move and visually interact to cooperate for food reward, and we wirelessly recorded animals’ behaviors, gaze location, and neural activity simultaneously as they learned to cooperate. A cross-correlation (CCG) analysis of the timing of animals’ button pushes (choice to cooperate) revealed their responses are coordinated, not random, and their coordination significantly improves during learning. Additionally, other behavioral measures, such as each animal’s conditional probability to cooperate, significantly increased during learning (P<0.0001, Mann Kendall Trend, M-K test). As expected, decoder analysis using dlPFC activity before Monkey M’s choice and his partner’s choice to cooperate revealed that each animal’s decision is encoded in dlPFC and furthermore, correlates with learning cooperation behavior (P<0.01, M-K test). Indeed, decoder accuracy for choice can predict Monkey M’s conditional probability to cooperate in each session (r = 0.83, P<0.0001). Notably, fixation rates on the reward and conspecific are significantly higher within a trial before both animals cooperate than after cooperation (P<0.01, Wilcoxon signed-rank), suggesting these social cues are important for cooperation. In fact, fixations on each social cue can be decoded from neural responses in V4 and dlPFC, and decoder performance significantly improves with learning in each area (P<0.05, M-K test).

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Finally, CCG analysis of spike timing between pairs of V4-dlPFC cells reveals significant connectivity strength between areas before the choice to cooperate, indicating that social information is processed within this network. Moreover, functional connectivity between areas significantly increases during learning (P<0.001, M-K test). Overall, this research provides a novel method and use of analyses to study learning social interactions. This work contributes to our understanding of the social brain by discovering the neural computations of visually guided social interaction, promoting the development of therapies to improve social dysfunction and mental health.

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Chrystine Gallegos GSBS Student Research Category: Disorders of the Nervous System Research Analysis Level: Systems Histological and functional characterization of cervical spinal cord injury after graded contusion Gallegos CM (1,2), Carey MJ (1,2), Zheng YY (1,2), Xue H (1,2), Cao QL (1,2) - 1. The Vivian L Smith Department of Neurosurgery, 2. Center for Stem Cell and Regenerative Medicine, the Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, University of Texas Health Science Center at Houston Most spinal cord injuries (SCIs) are cervical contusions and result in deficits for both locomotion and reaching and grasping functions. Previous studies have characterized histological and functional deficits in locomotion using primarily thoracic contusions, but most patients have cervical injuries. Damage to descending long spinal tracts (dLSTs) is one well-established cause of functional loss after SCI and has been explored in laceration and transection models, but these are not clinically relevant. In this study, we explored the histological and functional deficits after graded cervical hemicontusion SCI and examine the potential contribution of different histological deficits to forelimb function after injury. B6 mice received a clinically relevant cervical hemicontusion graded at either 50, 70, or 90 kDyne force and were then tested weekly in complex horizontal ladder (cHL), rotarod, grooming, and either pellet reaching or pasta handling. Our results showed greater injury severity significantly increased missteps in cHL, reduced stepping time in rotarod, and decreased grooming ability. Histological analyses revealed that injury severity significantly increased the injury area by fibronectin-immunoreactivity (IR) and gray matter loss by MAP2-IR. There was a significant correlation between lesion size and gray matter loss and injury severity. Correlations between histology and behavior outcomes showed a significant correlation between the percentage of missteps in cHL, injury severity, and lesion size. Additionally, both rotarod score and grooming score correlated with injury severity, lesion size, and gray matter loss. This study characterizes a clinically relevant injury model, shows that graded cervical hemicontusions result in degrees of functional and anatomical loss, and serves as a baseline to aid future studies in identifying therapeutic targets to promote functional recovery after cervical SCI and improve the quality of life for patients with SCI.

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Anthony Jennings Medical Student What People Say: A Study of the Predictive Value of Language Use on Cognitive-Behavioral Therapy Outcomes among Individuals with Substance Use Disorders and Posttraumatic Stress Anthony N. Jenningsa, Heather E. Sodera, Margaret C. Wardleab, Joy M. Schmitza, & Anka A.


a Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center

at Houston; 1941 East Road, Houston, TX 77030, United States b Department of Psychology, University of Illinois at Chicago; 603 East Daniel Street,

Champaign, IL 61820, United States c Department of Psychology, University of Houston; 3695 Cullen Boulevard, Houston, TX

77204, United States

Substance use disorders (SUD) commonly co-occur with posttraumatic stress disorder (PTSD) symptoms, and the comorbidity is prevalent and difficult-to-treat. Few studies have objectively analyzed language use in psychotherapy as a predictor of treatment outcomes. We conducted a secondary analysis of patient language use during cognitive-behavioral therapy (CBT) in a randomized clinical trial, comparing a novel, integrated CBT for PTSD/SUD with standard CBT for SUD. Participants included 37 treatment-seeking, predominantly African-American adults with SUD and at least four symptoms of PTSD. We analyzed transcripts of a single, matched session across both treatment conditions, using the Linguistic Inquiry and Word Count (LIWC) program. The program measures language use across multiple categories. Compared to standard CBT for SUD, patients in the novel, integrated CBT for PTSD/SUD used more negative emotion words, partially consistent with our hypothesis, but less positive emotion words. Further, exploratory analyses indicated an association between usage of cognitive processing words and clinician-observed reduction in PTSD symptoms, regardless of treatment condition. Our results suggest that language use during therapy may provide a window into mechanisms active in therapy.

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Charani Kamath Medical Student Interrogation of 511 exomes from patients with myelomeningocele (MM) for relationship to genes involve in nervous system development Charani Kamath 1, Hope Northrup, M.D.2, and Kit Sing Au, Ph.D.2,3 1MD Program - Scholarly Concentration in the Neurosciences, 2Division of Medical Genetics, Department of Pediatrics, 3Neuroscience Research Center, McGovern Medical School Myelomeningocele (MM) is the most severe form of an open neural tube defect (NTD) that is compatible with life. The prevalence of MM in the United States is 1 out of 2,500 live births with the two ethnicities that have the highest occurrence of MM being Mexican American (MexA) and Caucasian American (CauA). Research to date has shown that MM results from a cumulative effect of environmental and genetic factors. Therefore, determining the underlying molecular etiology would be a step towards being able to develop strategies for prevention and treatment. In order to determine which nervous system development genes might be implicated in MM, whole exome sequencing (WES) was conducted on 511 subjects born with MM with 254 subjects from the MexA population and 257 subjects from the CauA population. The data acquired from WES was compared to an ethnically matched control population that was retrieved from publicly available data on Genome Aggregation Database (gnomAD) in order to calculate mutational burdens in the genes of interest. We then analyzed variants that were found in the MM population using Combined Annotation Dependent Depletion (CADD) scores from the database for non-synonymous single nucleotide variant functional predictions (dbNSFP) to identify variants with CADD scores of 20 or above. The variants that meet this criterion represent the top 1% most deleterious variants that potentially pose a genetic risk factor to MM development. We focused on genes with p-value ≤0.05 from Fisher Exact test. A list of 563 genes that are involved in nervous system development was obtained using the Gene Ontology online tool with a database cataloging the molecular function of human genes. Of these 563 genes, higher mutational burden was found in 18 genes (9 in the MexA population, 8 in the CauA population, 1 in both populations). The gene with higher mutational burden common to both the MexA and CauA populations is EP300. EP300 codes for an activator of transcription factors to modulate cell growth that has been shown in case reports to be causative in cases of Rubinstein-Taybi syndrome which are associated with MM. Disruption of EP300 function in animal models leads to neural tube defects. Based on the associations in these cases, EP300 might play a role in the multifactorial causation of MM that involves genetics as well as the environment.

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Sehee Kim Postdoctoral Fellow Research Category: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homestatic Challenge Research Analysis Level: Systems Enhanced stress response is associated with increased inflammation and worse outcomes following ischemic stroke in diabetic condition. Sehee Kim, Eunsu Park, Peng R. Chen, Eunhee Kim - Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston Introduction: Although stroke severity is increased in patients with diabetes (e.g., higher mortality, larger infarcts, and worse neurological deficits), the underlying mechanism(s) of the worse outcomes is not clear. Evidence shows that hypothalamic-pituitary-adrenal (HPA) axis is dysregulated and cortisol levels are increased in diabetes. Based on the role of HPA axis in immunity, we hypothesized that diabetes-enhanced stress response contributes to stroke injury via regulating inflammation. Methods: Diabetes was induced in C57BL/6 mice by feeding a diabetogenic diet and injecting streptozotocin. Mice were subjected to 30 min middle cerebral artery occlusion. Infarct volume and neurological scores were measured at 24h-post stroke. We measured expression of factors related to stress response, plasma corticosterone, c-Fos and corticotropin-releasing factor (CRH) in hypothalamus, and proopiomelanocortin (POMC) and corticotropin-releasing hormone receptor 1 (CRHR1) in pituitary. Inflammatory cytokine levels were also determined in the ischemic brain. Results: Diabetic mice showed hyperglycemia and delayed glucose clearance in blood. At 1d-post stroke, diabetic mice showed larger infarct and worse neurological score. Plasma corticosterone levels were significantly increased in diabetic mice. We also found increased c-Fos in hypothalamus, and CRHR1 and POMC in pituitary. These were accompanied by increased IL-1β, TNF-α, and IL-6 mRNA in the ischemic brain. Conclusion: Our results indicate that stress response is enhanced in diabetic conditions, and associated with increased inflammation in ischemic brain and worse stroke outcomes. It suggests that regulation of stress response may improve stroke outcomes in diabetic conditions.

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Youngran Kim Postdoctoral Fellow Research Category: Disorders of the Nervous System Research Analysis Level: Systems Risk of Intracranial Hemorrhage Associated with Pregnancy in Women with Cerebral Arteriovenous Malformations Youngran Kim, PhD (1), Songmi Lee, MS (2), Babak B. Navi, MD, MS (3), Rania Abdelkhaleq (1), Sergio Salazar-Marioni, MD (1), Spiros Blackburn, MD (4), Arvind B. Bambhroliya, MBBS, MPH, MS (2), Victor Lopez-Rivera, MD (1), Farhaan Vahidy, MBBS, MPH, PhD (5), Sean I. Savitz, MD (1), Annika Medhus, BS (6), Hooman Kamel, MD (3), James C. Grotta, MD (1), Louise McCullough, MD, PhD1, Peng Roc Chen, MD (4), Sunil A. Sheth, MD (1) - (1) Department of Neurology, McGovern School of Medicine, University of Texas Health Science Center at Houston; (2) School of Public Health, University of Texas Health Science Center at Houston; (3) Department of Neurology, Weill Cornell Medical College, New York, NY; (4) Department of Neurosurgery, McGovern School of Medicine, University of Texas Health Science Center at Houston; (5) Center for Outcomes Research, Academic Institute of Houston Methodist; (6) McGovern School of Medicine, University of Texas Health Science Center at Houston Scientific Background: Brain arteriovenous malformations (AVMs) are uncommon but potentially deadly congenital lesions. With the increased usage of non-invasive brain imaging, they are being detected more often prior to rupture and intracranial hemorrhage (ICH). The risk of rupture of an AVM varies considerably based on its angioarchitecture, with some morphologic features associated with a greater risk of ICH. Previous studies examining the effect of pregnancy on ICH risk in women with AVMs have shown inconsistent results, but also have not accounted for AVM morphology and heterogeneity. As such, the aggregation of findings for all women with AVMs may be an inaccurate assessment of true ICH risk. Aims and Approach: We examined the relative risk for ICH during pregnancy and puerperium compared to the prior non-pregnancy period among women with AVMs. To account for the potential heterogeneity of AVM morphology, we used a cohort-crossover design in which each participant was used as her own control in the non-exposure period. Comparisons were made between the exposure period and non-exposure period within a participant instead of comparing two different cohorts of women (pregnant vs non-pregnant women). In this observational cohort study, women who underwent pregnancy and delivery were identified using diagnosis-related group (DRG) codes from the Healthcare Cost and Utilization Project (HCUP) State Inpatient Databases for California (2005-2011), Florida (2005-2014), and New York (2005-2014). Pregnancy was defined as the 40 weeks prior to delivery, and postpartum as 12 weeks after. We defined a non-exposure control period as a 52-week period prior to pregnancy. The presence of AVM and ICH was determined using International Classification of Diseases (ICD) 9 codes. Because AVMs are congenital lesions, we considered a woman to have a brain AVM even if she was ultimately diagnosed after the index pregnancy and delivery. The

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relative risks of ICH during pregnancy against the non-exposure period were estimated using conditional Poisson regression. Results and Impact of the study: Among 4,022,811 women identified with an eligible delivery hospitalization, 568 (0.014%) had an AVM. During the non-pregnancy period, incidence rates of ICH were 1,942 (95% CI 794.4-3089.5) and 2.1 (95% CI 1.7-2.6) per 100,000 person-years for women with AVM and women without AVM respectively. The rates of ICH during pregnancy and puerperium were 6,355.4 (95% CI 4279.4-8431.5) and 14.4 (95% CI 13.3-15.6) per 100,000 person-years for women with and without AVM, respectively. Women with AVM only accounted for 0.014% of the total study population, but 11.5% of ICH incidence during the non-pregnancy period and 5.8% of ICH incidence during pregnancy and puerperium were attributable to AVM. In women with AVMs, the risk of ICH increased 3.27-fold (RR, 95% CI 1.67-6.43) during pregnancy and puerperium compared to a non-pregnant period. Whether the risk of AVM-related ICH is greater during pregnancy and puerperium is an important question, as it can affect a woman’s plan for pregnancy and drive clinical decision making around preventive intervention. In this study, we identified an increased risk of ICH of over 3-fold during pregnancy in women with AVMs. These findings suggest the need for further study on the mechanisms of AVM development and rupture and careful consideration of management strategies in these women.

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Blake McAlpin GSBS Student Research Category: Cognition and Behavior Research Analysis Level: Cellular Doxorubicin treatment induces cognitive dysfunction, microglia alterations and loss of synaptic integrity: Reversal by HDAC6 inhibition Blake McAlpin, MRes., Luis Arroyo, B.Sc., Annemieke Kavelaars, PhD., Cobi J. Heijnen, PhD., -Department of Symptom Research, MD Anderson Cancer Center Background: One in 8 women in the US will be diagnosed with breast cancer. Doxorubicin (DOX) is one of the most effective chemotherapy treatments for breast cancer. Unfortunately, up to 60% of survivors report chemotherapy-induced cognitive dysfunction (CICD) characterized by severe deficits in working memory, processing speed and executive functioning. Currently, no FDA-approved interventions to alleviate CICD exist. Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme whose substrates are involved in protein folding, intracellular transport, and cytoskeletal reorganization. Recently, HDAC6 inhibitors have shown potential in repairing cognitive function in a variety of neurodegenerative disease models. Aims: The aim of this study is to determine whether DOX treatment causes CICD in a therapeutic-dosing model and to determine the potential of ACY-1083, a blood-brain barrier permeable HDAC6 inhibitor, to reverse CICD. We investigated neuroinflammation by evaluating pro-inflammatory cytokine production in the hippocampus. Further, we quantified changes in the morphology of microglia, which regulate the inflammatory profile of the brain and show morphological alterations upon activation. Synaptic protein expression was evaluated to determine synaptic integrity in association with cognitive function tests. Finally, we evaluated whether ACY-1083 can reverse CICD, increased neuroinflammation, and alterations in microglia morphology and synaptic integrity. Methods: Female mice were used exclusively due to the low occurrence of breast cancer in males (1%). Mice were given 5 mg/kg of DOX intraperitoneally per week for 4 weeks followed by 10 mg/kg of ACY-1083 intraperitoneally daily for 2 weeks. Each experimental cohort (n=4) was replicated for a total of n=8 for the following 4 treatment groups: Saline + Vehicle, DOX + Vehicle, Saline + ACY-1083 and DOX + ACY-1083. Behavioral, qPCR and immunofluorescent analyses were blinded in the second cohort. We assessed CICD using the puzzle box and novel object place recognition tests. Hippocampal inflammation was evaluated by qPCR. Microglia morphology was quantified by Iba1+ immunofluorescent staining in 20 µm-thick hippocampal sections that were imaged in a 20-step Z-stack and 3D rendered using the software Imaris. Post-synaptic integrity was analyzed by PSD95+ staining in the hippocampus. Results: DOX-treated mice exhibited cognitive dysfunction in spatial and executive function-based tasks. In the hippocampus, TNF-α, IL-6, and IL-18 were increased following DOX treatment. Microglia morphology was significantly altered in the hippocampus following DOX

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treatment: A decrease in total length and full branch level was observed, and these alterations were further visualized using Sholl analysis. PSD95 expression in the hippocampus was reduced following DOX treatment. All DOX-induced alterations were reversed by ACY-1083. Conclusions: These results suggest that DOX treatment causes CICD and a decrease in post-synaptic integrity. DOX treatment increases neuroinflammation which is associated with a change in the morphology of microglia that can be explained as an activated state. Treatment with the HDAC6 inhibitor ACY-1083 shows promise as a pharmaceutical intervention to reverse the neuro-glia-toxic effects of DOX treatment in association with a reversal of CICD. This study has implications in improving cognitive dysfunction, and therefore the quality of life, in breast cancer survivors globally.

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Emily Mendez GSBS Student Research Category: Disorders of the Nervous System Research Analysis Level: Molecular Differential Regulation of Angiogenic Gene Networks in Postmortem Brains of Opioid Use Disorder Subjects Emily Mendez (1), Haichao Wei (2), Laura Stertz (3), Gabriel Fries (3), Ruifeng Hu (4), Xizi Wu (2), Katherine Najera (3), Karla Moriel (3), Thomas Meyer (3), Zhongming Zhao (4), Jiaqian Wu (2), Consuelo Walss-Bass (3) - (1) The University of Texas Health Science Center At Houston, (2) Institute of Molecular Medicine, The University of Texas Health Science Center At Houston, (3) Department of Psychiatry and Behavioral Sciences, The University of Texas Health Science Center At Houston, (4) Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center At Houston Background: Opioid abuse can cause brain alterations, including neuroinflammation and increased risk for ischemic stroke. Cancer studies show that opioids affect angiogenesis and endothelial cell proliferation. However, human brain studies are scarce, and the molecular mechanisms of opioid-induced neurotoxicity are unclear. This study comprehensively interrogated the transcriptomic and proteomic profiles of the dorsolateral prefrontal cortex (BA9) in subjects with opioid use disorder (OUD), to investigate the molecular effects of opioid abuse in the human brain. Methods: We obtained RNA sequencing (RNAseq) and liquid chromatography mass spectrometry-based proteomics data from the BA9 of 29 OUD subjects and 18 non-psychiatric controls to assess differential expression (DE) of proteins and both coding and long-noncoding (lnc) RNAs. We performed enrichment and pathway analyses on the combined DE genes and proteins to determine convergent gene networks perturbed in OUD. We performed cell type deconvolution (CIBERSORT) to evaluate cell composition effects, and weighted correlation network analysis (WGCNA) to identify hub gene drivers of key gene networks. Results: We found DE of 192 coding and lncRNAs and 213 proteins, enriched in angiogenesis and endothelial cell functions. We also found DE of immediate early genes EGR1, EGR2, ARC, NPAS4, NR4A1, NR4A2, which have previously been indicated as drivers of addiction and angiogenesis as well. DE genes in angiogenic pathways correlated with endothelial/astrocytic cell types. WGCNA identified hub genes involved in endothelial/astrocytic function . Convergent network analysis found perturbation of angiogenic pathways via MAPK/ERK signaling. Postmortem MRI imaging showed markedly increased vascularization in 5 out of 11 imaged OUD subject brains, a finding not seen in any controls. Conclusion/Impact: To our knowledge, this is the first study showing disruption of angiogenic molecular networks in human OUD brain. In addition, we are the first to show qualitative evidence of OUD brain hypervascularization, indicating a likely functional perturbation of these networks that promotes angiogenesis in opioid use. These studies will further our

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understanding of the molecular effects of opioids in human brain, which is of critical importance during the current opioid epidemic.

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Alexis Mobley GSBS Student Research Category: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homestatic Challenge Research Analysis Level: Cellular Group 2 innate lymphoid cells activate microglia to an M2-like phenotype Alexis S Mobley (1,2), J Jesus Bautista Garrido (2), Pedram Honarpisheh (1,2), Joo Eun Jung (2), Louise D McCullough (1,2), and Jaroslaw Aronowski (1,2) - 1 - The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical Sciences; 2 - McGovern Medical School, Department of Neurology Stroke is the fifth leading cause of death in the United States, predominantly affecting aged females. FDA-approved treatments are proving inadequate as many patients are ineligible for these therapies. Moreover, current therapeutics fail to treat secondary brain injury or help in brain repair. One of the most promising treatments for stroke targets immune responses that have roles during all stages of stroke pathobiology. Aging globally suppresses immune function leading to dysregulation of cytokine mediators and increased low-grade inflammation throughout all systems, termed inflammaging. However, understanding the mechanisms of healthy aging can bypass this effect. Two candidate immune cells, (1) microglia, brain-resident macrophages, and (2) innate lymphoid cells, a newly discovered innate immune cell, may control pre- and post-stroke responses in the aged brain. Group 2 innate lymphoid cells (ILC2s) have a unique capacity to promote an anti-inflammatory milieu in peripheral tissues and mitigate age-related cognitive decline centrally. ILC2 effector cytokines [interleukins (IL)-4, IL-5, and IL-13] modulate microglia function, but their source cell has only been alluded to. Moreover, ILC2-microglia interactions under controlled and stressful situations, like aging or ischemia, have not been defined. This project investigates the communication between group 2 innate lymphoid cells (ILC2s) and microglia using aged mice and how this differs in males and females. My preliminary data shows ILC2s are the abundant ILC type present in murine male and female aged brains. Taken together, I hypothesize that ILC2s polarize microglia to a reparative, M2-like phenotype under homeostasis and aging by increasing their quantity and cytokine production to maintain immunologic control of their environment. I aim to determine if (1) ILC2s are still functionally active in aging, and (2) ILC2-secreted factors can polarize microglia in vitro by studying their morphology and gene expression. Thus far, using double-blind studies, I have successfully shown that ILC2s produce more IL-4 in aged brains using flow cytometry, and aged, male ILC2s produce the most IL-4 (n=4). Moreover, after transferring media from activated ILC2s to quiescent microglia, microglia undergo morphology changes to include bigger nuclei, greater cell area, and decreased circularity, indicating they are activated (n=4; one-way analysis of variance). Lastly, media transferred from activated ILC2s can polarize microglia to an anti-inflammatory phenotype by

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increasing transcription of Nrf2 transcripts and its anti-oxidative downstream targets (n=2-4/group; mixed-effects analysis). I will complete these experiments in duplicate to ensure this effect holds true though power analysis confirms these experiments are sufficiently powered. Once this project is complete, these experiments will support the importance of ILC2s in neuroinflammation and understanding immune cell communication in aging. Further investigation can lead to immune therapies that can continue to work through all stages of stroke pathology and provide better treatments for patients.

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Hannah Muniz Castro Resident Research Category: Disorders of the Nervous System Research Analysis Level: Systems Skull Base Thickness in Patients with Pseudotumor Cerebri Hannah Muniz Castro, MD1,2, Matthew Barke, MD3, Alice Z. Chuang, PhD1,2, Thai Do, MD4, Rajan P. Patel, MD5, Kimberly A. Mankiewicz, PhD1,2, Ore-ofe O. Adesina, MD1,2, Karina Richani, MD1,2 - 1 Ruiz Department of Ophthalmology and Visual Science, McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth); 2 Robert Cizik Eye Clinic, Houston, TX; 3 McGovern Medical School at The University of Texas Health Science Center at Houston (UTHealth); 4 Kresge Eye Institute, MI; 5 Department of Diagnostic and Interventional Imaging at The University of Texas Health Science Center at Houston Pseudotumor cerebri (PTC) is a disorder characterized by elevated intracranial pressure (ICP) without secondary causes on neuroimaging. PTC typically occurs in young, obese females and can cause of permanent and irreversible vision loss when severe. The association between skull base thinning in patients with intracranial hypertension and obesity has been previously reported, however no study has reported these findings in pseudotumor cerebri (PTC). The goal of our study is to determine if PTC is independently associated with skull base and calvarium thinning. Methods: A retrospective, matched case-control study was performed. Each patient diagnosed with PTC (case) was matched with a patient diagnosed with headache (control) by age, sex, and race. Patients were included if they underwent CT imaging of the head, maxillofacial or orbits within 3 months of their diagnosis. Exclusion criteria were: history of skull base or frontal bone pathology due to surgery or skull trauma, central nervous system infections, or incomplete radiologic data. Patient demographics, medical history, clinical exam, and skull base, calvarium, and zygoma thickness were recorded. Skull base thickness was measured by the height of the auditory canal in the coronal plane. Calvarium thickness was measured just anterior to the foramen rotundum in the coronal plane. Extracranial zygoma thickness was measured and used as an internal imaging control because the zygoma is not subject to intracranial forces. Results: 128 patients were included in the study, 64 cases with PTC and 64 without PTC. Each group comprised of 62 female patients (97%), 25 (39%) white, 23 (34%) black, 1 (2%) Asian, and 15 (23%) other. The average age was 31.8 ± 8.9 years. PTC patients were more likely to be obese (n=61, 95%) compared to the control group (n=23, 34%, p<0.001). All but one PTC patient underwent lumbar puncture (98%) with an average opening pressure (OP) of 40.5±15.6 cm H2O, while 12 (20%) controls underwent a lumbar puncture with mean OP of 19.5±8.5 cm H2O. There was no statistical difference in mean visual acuity between the PTC and control groups (logMar 0.26 [20/40] ±0.50 versus logMar 0.09 [20/25] ±0.30, p=0.058, respectively).

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Compared to the controls, PTC patients were more likely to have headache (97% vs 74%, p=0.001), pulsatile tinnitus (47% vs 7%, p<0.001), horizontal binocular diplopia (24% vs 4%, p=0.012), confrontational visual field deficit (25% vs 2%, p=0.001), and papilledema (75% vs 0%, p<0.001). Pseudotumor cerebri patients had thinner skull base and calvarium width compared to the controls (mean skull base thickness 4.18±0.93 mm vs 5.06±1.11 mm, p<0.001 and mean calvarium width 1.50±0.50 mm in PTC vs 1.70±0.61 mm in the control group, p<0.027). Zygoma thickness was similar in both groups (mean zygoma thickness 1.18±0.30 mm in PTC vs 1.27±0.36mm in the control group, p=0.082). In a subgroup analysis controlling for obesity (BMI >30 kg/m2), there was no statistically significant difference in skull base, calvarium or zygoma thickness. Conclusions: Patients with PTC were found to have thinner mean skull base and calvarium thickness compared to the controls, while there was no difference in the mean extracranial zygoma thickness. Contrary to previous reports, our study did not find obesity to be associated with skull base or calvarium thinning. These findings suggest that PTC is associated with skull base and calvarium thinning.

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Curtis Neveu Postdoctoral Fellow Research Category: Neural Excitability, Synapses, and Glia: Cellular Mechanisms Research Analysis Level: Cellular Neurophysiological Characterization of Plateau Generating Neurons Curtis L. Neveu, John H. Byrne - Department of Neurobiology and Anatomy, McGovern Medical School at The University of Texas Health Science Center at Houston A fundamental feature across the animal kingdom are switch-like computations mediated in large part by plateau potentials of key neurons. Understanding of the complex neurophysiological underpinnings of plateau potentials in different neuronal subtypes is severely lacking and yet key to understanding the molecular and cellular basis of motor patterns and higher order cognitive processes such as decision making. Our lab took advantage of the tractability of Aplysia californica to examine two plateau generating neurons B51, important for decision-making, and B64, a key motor pattern phase initiator, and B8, an important regularly-spiking motor neuron. Using a combination of two-electrode voltage-clamp and pharmacology we characterized the steady-state and kinetic properties of persistent Na+ (Napp), A-type K+, delayed K+, R-type Ca2+, L-type Ca2+, Ca2+-activated K+, and HCN. The three neurons expressed the same set of channels with the exception that B64 did not express Ca2+-activated K+, a negative feedback of voltage-gated calcium channels, and B51 and B64 did not express the HCN, which mediates the sag potential. Two notable differences in steady-state properties were the Napp half-activation was shifted to the left (more negative) and the A-type K+ half-activation and inactivation was shifted to right in B64 and B8 compared to B51. The differences in Napp and A-type K+ in combination might help explain an observation that B64 had greater tendency to produce plateaus compared to B51. The activation time-constants were typically larger in B8 compared to B51 and B64, however this pattern was not observed for inactivation time constants. Conductance-based models of these neurons were generated to interpret these results. Consistent with observations, the B51 model produced a plateau that self-terminated, but the B64 model produced a plateau that did not self-terminate once it was activated. Adding Ca2+-activated K+ from B51 to B64 produced a plateau in B64 that self-terminated indicating that Ca2+-activated K+ is important in plateau termination. B51 and B64 were regularly spiking neurons when Napp was removed, however the presence of Napp in B8 indicates that plateau generation is more complicated than expression of Napp alone. Moreover, the similarities between B64 and B8 when compared to B51 illustrate the need for detailed understanding of plateau generation in decision making cognitive processes.

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Sreelekha Paladugu Medical Student Research Category: Disorders of the Nervous System Research Analysis Level: Systems The Universal Benefits of Inpatient Rehabilitation in Patients of All Educational Levels Sreelekha Paladugu, Shayandokht Taleb, Mohammad Hossein Rahbar, Resmi Gupta, Amirali Tahanan, Joseph Wozny, ;Sean I Savitz Intro Understanding factors that may affect the benefits of inpatient rehabilitation (IPR) for stroke patients continues to be critical. This study seeks to determine if an association exists between a patient’s education level and their IPR outcomes. Design A retrospective analysis was conducted of a database that collected acute stroke care characteristics and corresponding IPR outcomes across 5 IPR centers in Houston, TX from 4/17-8/19. IPR rehab outcomes include length of stay (LOS), and change in Functional Independence Measure (FIM) scores. Patients’ highest education levels were collected from their electronic medical records and compared to IPR outcomes. These data were analyzed using ordinal logistic regression models. Proportional odds assumption was checked for all the models. A cuboidal polynomial regression was used to predict the LOS on total change in FIM scores with 95% confidence intervals and 95% prediction limits. Statistical significance was evaluated at alpha level of 0.05. Results Among 676 patients, 22% had no high school education, 12% completed high school, 39% had some college education, 10% completed a college education, and 16% patients completed a graduate degree. 72 patients were excluded due to insufficient records. No statistically significant associations were identified between a patient’s highest level of education and IPR outcomes. Patients with no high school education showed the greatest change in FIM scores (29, SD =13). Patients with a high school education showed the lowest change in FIM scores (27, SD =12). Within this same data set, the mean total change in FIM scores was 27. Finally, the findings show a distinct positive correlation between LOS while in IPR and the change in FIM score. Conclusion In conclusion, IPR outcomes did not differ among patients with various educational levels. However, our data suggest that all patients despite educational backgrounds can derive functional gains as shown by the change in FIM score.

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Danny Perez Sierra GSBS Student Research Category: Novel Methods and Technology Development Research Analysis Level: Systems Using Forman curvature geometry to visualize human MEG data Danny Perez Sierra, Iula Veronica Gheorge, Yuri Dabaghian, Ph.D. Usually, networks are judged by their vertices. We are interested in their edges and global properties in the context of brain activity. This is done by computing the Forman curvature of MEG signals in MATLAB. Links between brain regions with a higher curvature are plotted in a darker color. A threshold is arbitrarily set to plot the most 'important' links. This is done to reduce the computational load. Using our algorithm, brain activity can be mapped to potentially predict onset of Alzheimer's or an epileptic episode.

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Cana Quave GSBS Student Research Category: Cognition and Behavior Research Analysis Level: Cellular Repeated morphine administration alters prelimbic cortex activity and increases risk-taking behavior during an approach-avoidance conflict task. C. B. Quave [1], A. M. Vasquez [1,2], E. P. Bora [1], C. L. Chidomere [1,3], D. S. Engelke [1], F. H. Do Monte [1]; - [1] Department of Neurobiology and Anatomy, The University of Texas Health Science Center at Houston, Houston, TX; [2] Department of Neuroscience, Rice University, Houston, TX; [3] Department of Biomedical Engineering, University of Houston, Houston, TX Opioid misuse is associated with impaired risk-related decision making. However, the neural correlates of opioid-induced risky motivated behavior are unclear. Working with the hypothesis that altered prefrontal cortex activity underlies opioid-induced risk taking, we employed an approach-avoidance conflict model using a modified conditioned place preference protocol combined with a fear-inducing predator odor. Adult male Long-Evans rats implanted with single-unit electrodes in the prelimbic cortex (PL) were injected with saline or the opioid drug morphine and placed in the side of the apparatus least preferred at baseline. Conditioning with saline (n=18) or morphine (n=20) occurred on alternating days over a 10-day period. After 72 h of forced abstinence, morphine-treated rats showed increased preference for the drug-paired side when compared to saline controls (p<0.01). Immediately following preference testing, a conflict test began in which a predator odor stimulus (cat saliva) was placed in the previously drug-paired side. During conflict, saline-paired rats demonstrated a clear aversion to the paired side. In contrast, morphine-paired rats continued to enter the paired side despite the presence of predator odor, suggesting an increase in risk-taking behavior. Single-unit recordings from PL neurons revealed a significant suppression in neural activity after acute administration of morphine (22%), but not saline (6%, p<0.05). During the last day of conditioning, PL cells no longer exhibited drug-induced suppression of firing rates, suggesting that repeated morphine administration causes a physiological adaptation in PL activity. During the conflict test, the spontaneous firing rates of most PL cells in the saline group were inhibited (53%) rather than excited (7%; p<0.05), though this pronounced inhibition-to-excitation ratio was not observed in the morphine group (35% inhibited vs. 33% excited; p=1.0). Together, our results indicate that repeated opioid exposure leads to enhanced expression of reward-related memory and a neuronal adaptation to opioid effects in PL. Additionally, repeated administration of opioids increases risk-taking responses during motivational conflict and such behavior correlates with decreased inhibitory tone in PL neurons.

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Iman Sahnoune GSBS Student Research Category: Novel Methods and Technology Development Research Analysis Level: Molecular Targeting oncogenic miR-10b using small molecules in glioblastoma Iman Sahnoune - Department of Translational Molecular Pathology, MD Anderson Cancer Center; Recep Bayraktar - Department of Translational Molecular Pathology, MD Anderson Cancer Center; Lan Pang - Department of Translational Molecular Pathology, MD Anderson Cancer Center; Sanjay Singh - Department of Neurosurgery, MD Anderson Cancer Center; Barbara Czako - Institute of Applied Cancer Science, MD Anderson Cancer Center; George Calin - Department of Translational Molecular Pathology, MD Anderson Cancer Center Scientific Background: Glioblastoma is the most common and aggressive form of primary brain tumor, characterized by a high degree of inter- and intra-tumoral heterogeneity given its variation in cellular composition, genomic profiles and therapy-resistant cancer stem cells. With a multi-faceted therapeutic approach consisting of surgery, radiation therapy, and/or chemotherapy, average survival is only 8 months after diagnosis, with only 5-7% of patients living more than 5 years. Given the heterogeneous nature of this cancer and its dismal prognosis, there is a critical need for the development of more individualized therapies. Oncogenic miRNAs, otherwise called oncomiRs, are a class of small non-coding RNAs that are overexpressed in certain tumor types and have been found to reduce expression of tumor suppressing genes, thereby promoting cancer progression. Recent studies have found miR-10b to be an oncomiR that is linked to the development of cancer in the brain. In the context of the brain microenvironment, studies have found that while miR-10b is expressed elsewhere in the body, it is not seen in detectable amounts in normal brain cells, namely neural progenitor cells, glial progenitor cells, nor mature glia or neurons. It was also not detected in primary cultures of neural stems cells and astrocytes. Its expression in a cancer context makes it a unique and potentially targetable biomarker. The focus of this work is to evaluate the use of novel small molecule therapeutics designed to target oncomiR-10b expression in glioblastoma. Aims and Approach: Our lab has previously shown how high levels of oncomiR-10b can inversely impact the therapeutic efficacy of the small molecule inhibitor linifanib (ABT-869), a common anti-tumor agent that inhibits vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and receptor tyrosine kinases. In this project, we seek to develop an effective chemical derivative of linifanib that specifically targets oncomiR-10b and to assess whether it could yield a positive impact on glioblastoma cell lines. We tested a small molecule library of 50 chemical derivatives of linifanib and identified one compound that yielded the most potent effect, drastically impacting the expression of miR-10b in U251, a glioblastoma cell line, through the use of established in vitro modalities such as RT-PCR of miRNA expression, proliferation assays, protein expression, apoptosis and cell cycle assays via flow cytometry.

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Additionally, we are testing our potential novel therapeutic in a cerebral organoid model. Using human-induced pluripotent stem cells and neural growth factors, approximately 30 organoids of the brain have been cultivated with all major cell types represented, including neurons, oligodendrocytes, microglia and astrocytes. We are in the process of assessing microRNA expression in the endogenous organoids, and co-culturing the glioblastoma cell line to assess where the highest expression of miR-10b occurs, and if there is a preferential cell type for proliferation and invasion. We will then administer our derivative compound in a dose-dependent manner and test whether it is also effective in this cerebral organoid model. Results and Impact: Preliminary results have shown very promising outcomes, with the potential for translational application in glioblastoma and other conditions that have implicated miRNA involvement, such as neurodegenerative diseases.

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Eyad Shihabeddin GSBS Student Research Category: Disorders of the Nervous System Research Analysis Level: Cellular Characterizing Regeneration of Photoreceptor Neurons in a Zebrafish Model of Retinitis Pigmentosa Eyad Shihabeddin1,3, Abirami Santhanam3, Haichao Wei2, Jiaqian Wu2* and John O’Brien3* (1) MD Anderson University of Texas Health Science Center Graduate School of Biomedical Sciences; (2) The Vivian L. Smith Department of Neurosurgery & Center for Stem Cell and Regenerative Medicine, The University of Texas Health Science Center at Houston; (3) Department of Ophthalmology & Visual Science, The University of Texas Health Science Center at Houston Scientific Background: A cellular hallmark of inherited retinal degenerative diseases, such as Retinitis Pigmentosa (RP), is progressive loss of rod and cone photoreceptors until the individual is completely blind. Unlike mammalian models, Zebrafish (Zf) have a remarkable capacity to regenerate neurons following retinal injury or disease, making them a suitable model organism for regenerative studies. Current studies in Zf have indicated that upon detection of retinal insult, Mϋller glial cells (MGCs) are reprogrammed to re-enter the cell cycle, asymmetrically divide, and produce multi-potent progenitor cells. These newly formed progenitor cells rapidly proliferate and re-differentiate to replace lost retinal cells. Several genes, pathways, and transcriptional factors have been shown to play a role in reprogramming MGCs, inducing progenitor cell proliferation, and differentiating these cells into functional inner retinal neurons; however, the mechanisms by which genes work together spatially and temporally in the outer nuclear layer (ONL) where rods are found remain unknown. The purpose of this study is to understand the regeneration mechanism of rod photoreceptors in Zf and identify the master regulatory genes crucial for their lineage trajectory. Aims and Approach: The first aim of this study was to characterize cell turnover and rate of regeneration in Zf with RP. We developed a transgenic Zf model of RP expressing flag-tagged mouse rhodopsin carrying the P23H mutation driven by Zf rhodopsin promoter. Cell turnover and rate of regeneration were assessed by IP injection of BrdU in adult Zf (n=3 per group). Further characterizations were made through the use of immunohistochemistry and TUNEL studies (n=6). The second aim of this study was to identify candidate genes that drive rod photoreceptor regeneration through single-cell transcriptome profiling . Single cell 3’RNA sequencing was performed separately on dissociated wild-type (WT) and P23H Zf retinas (n=3 per group). Cell analysis was performed through Seurat and Monocle3 to generate UMAP clusters and trajectory pathways predicting the genes involved in regeneration. Results and Impact of the study: Adult P23H Zf had 40% as many cells as WT Zf in the ONL and outer segment lengths were greatly reduced. The ONL contained TUNEL positive cells in the P23H Zf suggesting cell death, as well as PCNA positive cells consistent with cell proliferation.

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BrdU pulse-chase labeling revealed approximately 20x more newly born cells in the P23H than in WT Zf. P23H Zf lost 56% of the newly-made cells in one week, while there was no loss of BrdU-labelled cells in WT retina in the same time, indicating cell turnover occurred in 7 days. Single-cell analysis revealed enrichment of a retinal progenitor cluster and rods derived from progenitor cells cluster in the P23H compared to WT. Trajectory analysis revealed trajectories predicting the genes involved in MGCs de-differentiating into progenitor cells, progenitor cells differentiating into rod cells, and rod cell maturation. Cellular reprogramming is a promising approach for vision restoration in individuals with retinal degenerative diseases. The findings of this study will provide a list of candidate genes that will progress the development of genetic therapies to reprogram mammalian cells to undergo productive regenerative responses. Ultimately, our goal is to restore vision to the blind.

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Robert Sickler Medical Student Research Category: Novel Methods and Technology Development Research Analysis Level: Systems Comparison of ROSA and Stealth AutoGuide Robot-Assisted SEEG Implantation Robert Sickler III; Manish N Shah, MD Additional Authors: Joseph S Withrow, MD; Jeremy Lankford, MD; Michael W Watkins, MD; Indira M Kommuru, MD; Leomar Y Ballester, MD, PhD; Meenakshi B Bhattacharjee, MBBS, MD, FRCPath, FCAP; John C Mosher, PhD; Michael E Funke, MD, PhD; Gretchen Von Allmen, MD; David I Sandberg, MD Introduction: Various robot-assisted techniques have been adopted to maximize the safety and efficacy of stereoelectroencephalography (SEEG) implantation. ROSA, a floor-mounted robot, has shown promising results compared to non-robot-guided placement, including decreased operative times without any decrease in safety or precision. The Stealth AutoGuide is a novel miniature head-holder-mounted robot arm, and no investigation has been conducted directly comparing these two systems within a single institution. Methods: We retrospectively reviewed 22 sequential pediatric (age range 4-18) SEEG implantations consisting of 15 ROSA-assisted procedures (5/17-11/19) followed by 7 AutoGuide-assisted procedures (2/20-10/20) at our institution. We determined the mean operative time, mean time per electrode, root mean square (RMS) registration error, and total complications for each robot. 7 additional AutoGuide procedures, 6 laser ablations and 1 biopsy (2/20-10/20) were also reviewed for complications. Results: Mean operating time overall and per electrode were 82.8 and 7.7 minutes for ROSA and 167.0 and 14.1 minutes for AutoGuide (both overall and per electrode p < 0.0001). At registration, RMS error was 0.62 mm for ROSA (range = 0.38 - 0.93) and 0.7 mm for AutoGuide (range = 0.6-0.9) (p = 0.25). No procedures (15 ROSA and 14 AutoGuide) were associated with any complications. Conclusions: Both ROSA and AutoGuide robots were highly accurate with no significant RMS error difference. Neither resulted in any complications such as infection or hemorrhage, the most frequent complications of SEEG placement, revealing no difference in safety as well. Both overall operative time and time per electrode, however, were found to be significantly greater for AutoGuide procedures. We expect improvements in these AutoGuide times as our institution’s experience and familiarity with the novel device grows, potentially eliminating this disparity. Continued comparisons including evaluation of localization and clinical outcomes will further aid in determining the specific advantages of each system.

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Heather Tolcher Medical Student Research Category: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homestatic Challenge Research Analysis Level: Cellular

Evidence of Reduced White Matter Integrity in Veterans with Repetitive Blast-Related Mild Traumatic Brain Injury H. Tolcher, T. Richards, H. Rau, E. Peskind, D. Cross, D. Cook; VA Puget Sound Health Care System, Seattle, WA; University of Washington, Seattle, WA Background: The long-term consequences of blast-related mild traumatic brain injury (mTBI) present a significant and growing health concern among military Veterans and Service members, particularly those deployed to combat zones during Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND). Accumulating evidence suggests repetitive mTBIs increase the risk for degenerative white matter disruption, a topic that warrants further investigations. The purpose of this study was to determine whether similar patterns of white matter changes are observed in Veterans reporting a history of blast-related mTBI. Methods: Participants included 91 Veterans who were deployed during OEF/OIF/OND; 66 reported a history of blast-related mTBI during combat deployment (symptomatic blast exposures ranged from 1-500) and 25 reported no history of TBI (controls). All participants were male; groups were matched for age (range: 22-61, mean: 35.95, SD: 8.19; no between-groups difference, p<0.105). Diffusion imaging data was collected using a 3.0T Philips Acheiva version 5.17 whole body scanner with a 32 channel head coil. Diffusion tensor imaging (DTI) using a state-of-the-art Unscented Kalman Filter two-tensor Tractography model and a Neurite Orientation Dispersion and Density Imaging model (NODDI) was employed to identify areas of disrupted diffusion within axonal bundles. Effects of repetitive blast mTBI on two-tensor based measures of white matter integrity were compared to anatomical regions of interest within the brain. Results: Compared to controls, the mTBI group demonstrated significantly reduced neurite fiber length within the occipital thalamus connection (mean [SD] = 102.52 mm [31.26] for mTBI group, and 94.40 mm [33.47] for controls; p<0.029), and reduced mean diffusivity in the right periaqueductal gray (mean [SD]= 4.09E-4 VOI [2.09E-5] and 3.96E-4 VOI [2.42E-5] VOI average eigenvalue, control and mTBI groups, respectively; p<0.023). NODDI analyses showed significantly increased mean neurite orientation dispersion within the occipital thalamus connection (p<0.012) and posterior cerebellum (p<0.001) within brains of Veterans with a history of symptomatic blast-exposure compared to controls, indicating decreased white matter integrity. Conclusions: Repetitive blast-related mTBI among Veterans is associated with a constellation of chronic structural white matter disturbances in brain regions known to subserve sensorimotor function, pain, and the processing of sensory information.

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This research was funded by The Medical Student Training in Aging Research Program and the National Institute on Aging (T35AG026736

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Rachel Van Drunen GSBS Student Research Category: Integrative Systems: Neuroendocrinology, Neuroimmunology, and Homestatic Challenge Research Analysis Level: Behavior Investigating the role of BMAL1 in the PVN as a central driver for governing diurnal energy balance Rachel Van Drunen, Baharan Fekry, Rafael Bravo Santos, Yuanzhong Xu, Qingchun Tong and Kristin Eckel-Mahan - MD Anderson UTHealth Graduate School of Biomedical Sciences Brown Foundation Institute of Molecular Medicine, Metabolic Disorders and Diseases Department Obesity has reached epic proportions, however, despite the alarming growth of this worldwide pandemic, the current therapeutics are limited in efficacy and the underlying biological mechanisms of obesity are not fully understood. Epidemiological studies on shift workers show that disruption of the natural circadian patterns predisposes individuals to obesity. Rodent models of shift work further reveal widespread desynchrony across peripheral tissue clocks and the central clock. This decoupling suggests body-wide clock desynchrony is involved in the pathogenesis of obesity. To understand rhythmic energy balance my study focuses on the paraventricular nucleus (PVN) of the hypothalamus for its vital function as both integrator and regulator of energy homeostasis. Expression of BMAL1 (Brain and Muscle ARNT-Like1), an essential circadian transcription factor for maintaining robust rhythms in cells across the body, mediates rhythmic PVN function. Inducible knockout of Bmal1, by adenovirus-mediated (AAV)-cre-GFP bilateral injections into the PVN of Bmal1fl/fl mice to produce Bmal1-PVN KO mice. Importantly, Bmal1-PVN KO mice display arrhythmic activity and energy balance while the AAV-GFP injected control mice (which still express Bmal1 in the PVN) remain rhythmic and normal weight. Therefore, we investigate the role of BMAL1 driven mechanisms in the rhythmic PVN as a central driver for governing diurnal energy balance. Towards this end, we first aim to determine whether the PVN is entirely independent or mediated in part by innervation from the light sensitive master clock, the suprachiasmatic nucleus (SCN). Food is a powerful entrainer that is not SCN dependent, thus if the PVN mediates diurnal feeding and metabolism, then restricting feeding to the active phase will restore rhythmicity in the PVN and behaviorally. Lack of restoration indicates the SCN is also disrupted and potentially preventing the restorative effect of time restricted feeding (TRF). In attempt to restore behavioral rhythmicity and reduce weight gain, for one week feeding was restricted to the active phase (12 hours) of arrhythmic Bmal1-PVN KO mice (N=6) and rhythmic AAV-GFP injected control mice (N=6). Mice were continually monitored under infared sensors to capture activity. One way repeated measure ANOVA however reveals no significant difference between active and rest phase activity indicating rhythmicity is not restored in the Bmal1-PVN KO mice. To determine whether this was because the mice did not have enough time to

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entrain to the TRF paradigm, a new group of Bmal1-PVN KO mice (N=4) and AAV-GFP injected control mice (N=3) were tested on a 10 hour feeding window during the active phase for two weeks. My preliminary data suggest this lengthened duration and narrowed window of TRF may partially restore behavioral rhythmicity and reduce body weight gain in the previously arrhythmic Bmal1-PVN KO mice. To assess SCN function, behavioral tests and immunostaining in the arrhythmic Bmal1-PVN KO mice will also be carried out. The restoration of rhythmicity in arrhythmic Bmal1-PVN KO mice would suggest a novel role for the PVN, independent of the SCN, as a rhythmic mediator of feeding and metabolism. Later experiments will also assess the contributing PVN-neuronal subtypes, and the Bmal1 driven molecular mechanisms mediating diurnal PVN function. A complete understanding of the neural mechanisms governing energy homeostasis is necessary to develop effective obesity treatments.

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Vijayasree Vayalanellore Giridharan Postdoctoral Fellow Research Category: Cognition and Behavior Research Analysis Level: Molecular Sepsis induced dysbiosis triggers dementia in Alzheimer's disease mouse model Vijayasree V Giridharan, Pharm PhD1, Jaqueline S Generoso, Pharm PhD2, June Young Lee, PhD1, Fabricia Petronilho, Pharm PhD3, Felipe Dal-Pizzol, Pharm PhD2, Rodrigo Morales, PhD4, Tatiana Barichello, Pharm PhD1 - 1 Translational Psychiatry Program, Faillace Department of Psychiatry and Behavioral Sciences, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX; 2 Laboratory of Experimental Pathophysiology, Graduate Program in Health Sciences, University of Santa Catarina – UNESC, Criciuma, SC, Brazil; 3 Laboratory of Neurobiology of Inflammatory and Metabolic Processes, University of Santa Catarina – UNISUL, Tubarao, SC, Brazil; 4 Department of Neurology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX USA Background: Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to microbial infection that accounts for high mortality and morbidity worldwide. More than 50% of sepsis survivors suffer from severe and long-term cognitive deficits. Also, recent studies affirmed the disruption of gut microbiota at both compositional and functional levels in sepsis patients. However, the impact of microbiota on sepsis outcome has not been investigated. Aims and approach: In this context, we aimed to explore if systemic inflammation triggered by sepsis accelerates or exacerbates Alzheimer's disease pathology using a mouse model. Male, 50-day-old APP/PS1 mice (overexpress the human APP harboring Swedish double mutation and presenilin-1 with delta-E9 mutation) were subjected to a gold standard sepsis model by cecal ligation and perforation (CLP) surgery to sepsis or sham surgery as a control group. Assessment of cognition was performed using novel object recognition (NOR) task at 30 and 120 days after sepsis. Longitudinally, at 3, 30, and 120 days after sepsis or sham surgery, feces were collected for 16S ribosomal RNA sequencing. The brain was harvested to measure inflammatory cytokines using multiplex fluorescent immunoassay in the prefrontal cortex (PFC) and hippocampus region. Results and impacts: We observed decreased alpha diversity (species richness) in the sepsis group at 30 and 120 days after sepsis. Principal coordinates analysis showed a clear separation in beta diversity between sham and sepsis mice at post-sepsis on day 30 and 120. Sepsis mice further demonstrated severe gut dysbiosis at the phylum level compared with sham mice, as reflected by increased Firmicutes to Bacteroidetes ratio. At 30 days, inflammatory cytokines IFN-γ and IL1-α increased and IL-6, IL-13, and IL-17A decreased in PFC; IFN-γ, IL1-α, IL-12 (p40), eotaxin, and TNF- α in the hippocampus were increased. At 120 days, eotaxin, KC, MIP-1, and RANTES in PFC were increased; anti-inflammatory cytokines IL-6, IL-10, and IL-13 were decreased in both PFC and the hippocampus. Further, at 30 and 120 days, the sepsis group

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demonstrated significant memory decline in the NOR task compared to the sham group. Sepsis-induced enteric dysbiosis and increased brain inflammatory cytokines levels negatively regulated the cognition in APP/PS1 mice. Global impact: Gut microbiota can be targeted to improve outcomes from sepsis-related long-term cognitive decline.

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Heather Webber Postdoctoral Fellow Research Category: Cognition and Behavior Research Analysis Level: Systems Posttraumatic stress symptoms increase brain reactivity to drug cues in cocaine users

Heather E. Webber 1, Danielle A. Kessler 2, Emma C. Lathan 1, Joy M. Schmitz 1, Scott D. Lane 1, Francesco Versace 3, Charles E. Green 1, and Anka A. Vujanovic 4; - 1. Faillace Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston 2. Department of Psychological Sciences, Rice University; 3. Department of Behavioral Science, MD Anderson Cancer Center; 4. Department of Psychology, University of Houston

Posttraumatic stress disorder (PTSD) and substance use disorder (SUD) are both characterized by reactivity to salient stimuli (e.g., trauma or drug-related cues). Prior research has demonstrated that exposure to trauma cues can increase craving and cue reactivity in individuals with SUD. However, little attention has been paid to what specific types of PTSD symptoms may increase reactivity to drug cues. The current study investigated differences in brain reactivity to pleasant, unpleasant, neutral and cocaine-related images in 52 trauma-exposed adults with cocaine use disorder. To measure brain reactivity to the cues, we recorded electroencephalogram while the participants viewed a slide show of images. Brain reactivity was defined as the amplitude observed over the occipital cortex immediately following (i.e., 400-800 ms after) the presentation of an image. Participants also completed a diagnostic interview (DSM-5) to assess for PTSD and SUD and self-report questionnaires including the PTSD Checklist and Life Events Questionnaire. The PTSD Checklist assessed four PTSD symptom types: intrusion, avoidance, negative alterations in cognition and mood, and arousal/reactivity. The Life Events Questionnaire was used to assess trauma type. Results indicated that the participants experienced a wide variety of traumas, for example: 82% natural disaster, 71% transportation accident, 63% assault, 42% fire, 23% sexual assault, and 5% combat. Linear mixed modeling revealed that increased negative alterations in cognition and mood was related to increased brain reactivity to cocaine cues (p < .001). Conversely, increased arousal/reactivity was associated with decreased brain reactivity to cocaine cues (p = .007). Intrusion and avoidance were unrelated to reactivity to any images. These results align with motivational theories of addiction suggesting that negative mood is a precipitant of craving and a defining feature of SUD. While it is unclear why increased arousal/reactivity would predict decreased brain reactivity to cocaine cues, it is possible that those with this symptom type are too focused on their trauma and in turn, are less reactive to other salient stimuli. Finally, it is also notable that none of the PTSD symptom types predicted reactivity to unpleasant images. As the sample experienced a variety of traumas, it is possible that the unpleasant images did not match the traumas experienced. Future studies should investigate these relationships in more homogenous samples in order to align the stimuli and trauma experienced. If replicated, these results could have clinical utility. Electroencephalogram

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measures could be used as a potential objective indicator of successful reduction in reactivity to cues in future SUD treatment clinical trials.

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Oscar Woolnough Postdoctoral Fellow Research Category: Cognition and Behavior Research Analysis Level: Systems Spatiotemporal Dynamics of Neural Processing for Reading Aloud Oscar Woolnough, Aidan Curtis, Cristian Donos, Patrick S. Rollo, Zachary J. Roccaforte, Nitin Tandon - Vivian L. Smith Department of Neurosurgery, Texas Institute for Restorative Neurotechnologies Dual stream theories of reading are the most credible models of the neural architecture that enables mapping of a written word to its pronunciation. These models, primarily derived from lesion data, propose a lexico-semantic stream for access to information about known words and a phonological stream for constructing the phonology of novel words. Lesion studies reveal the crucial roles of each route independently of each other but it is unclear how they actually interact in the healthy brain. The lack of temporal resolution in functional imaging and lesional studies has led to an incomplete understanding of the dynamics and interactions of the phonological and lexical streams of reading. We used direct cortical recordings in 44 patients, undergoing implantation of intracranial electrodes for epilepsy localization, to create a spatiotemporal map of reading aloud. Each patient read aloud 80 each of monosyllabic (a) regular words, (b) phonologically irregular exception words (e.g. pint, sew) and (c) novel pseudowords (e.g. meech, virck). Broadband gamma activity (70-150Hz) from electrodes across the left hemisphere (n>3200) was used to index local neural processing. We found that: (i) Response times for regular and exception words were significantly modulated by the frequency of occurrence of the words in natural language, while pseudoword response times were most strongly modulated by orthographic neighbourhood. (ii) Direct contrasts of regular words vs. pseudowords revealed distinctions in mid-fusiform cortex (mFus), anterior inferior frontal gyrus (aIFG) and inferior parietal sulcus (IPS) prior to articulation. (iii) mFus and aIFG were both sensitive to frequency of real words and aIFG was also sensitive to the orthographic neighbourhood of pseudowords. Consistent with our prior work, mFus was the earliest region to show sensitivity to word frequency. (iv) Utilising logistic regression neural decoding, we attained high single trial decoding accuracy between words and pseudowords within the first 500 ms following word presentation. Model coefficients highly weighted activity from mFus and aIFG. By contrast, the model was ineffective at decoding between regular and exception words. In conclusion, we find a strong, early distinction between reading known and novel words, with this effect progressing from mFus to aIFG. Later, the phonological route, via IPS, demonstrates sensitivity to novel words. The lack of distinction between regular and exception words in any of our analyses suggests that, in the healthy brain, known words are processed preferentially through the lexical route, with little distinction made based on atypical phonological mappings. Temporal neural decoding enables the tracking of task-relevant

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information across the cortex without imposing prior assumptions about the data and can give insight into features that distinguish linguistic classes. This study serves to improve our understanding of how our brains process the phonology of the written word, a specific ability disrupted in people with reading disorders such as dyslexia, which affects 5-17% of Americans.

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Xu Zhang GSBS Student Research Category: Cognition and Behavior Research Analysis Level: Systems Paraventricular thalamic CRF neurons integrate reward- and threat-related information to regulate approach-avoidance conflict Zhang, XO1; Engelke, DS1; O’Malley, JJ1; Fernandez-Leon, JA1; Li, S2; Kirouac, GJ2; Beierlein, M1; Do-Monte, FH1. - 1 Dept. of Neurobiology & Anatomy, The University of Texas Health Science Center, Houston, TX; 2 Dept. of Oral Biol., Univ. of Manitoba, Winnipeg, MB, Canada. Balancing food-seeking with threat-avoidance behaviors is crucial for animals to survive, but which neural circuits regulate this motivational conflict remain largely unknown. To answer this question, we designed an ethologically relevant “approach-food vs. avoid-predator threat” conflict test in which rats need to overcome their fear of predator odor to reach food. Animals were initially trained to press a lever for sucrose in the presence of an audiovisual cue. During the conflict test, cat saliva was positioned in the food area adjacent to the lever. Rats exhibited robust defensive behaviors and a clear suppression in food-seeking responses in the presence of the predator odor. Using in situ hybridization, immunohistochemistry and in vivo single-unit recordings from photoidentified cell-types, we identified a subpopulation of neurons in the anterior portion of the paraventricular thalamic nucleus (aPVT) which express the stress neuropeptide corticotrophin-releasing factor (CRF) and are preferentially recruited during conflict. Chemogenetic inactivation of aPVTCRF neurons during conflict reduced defensive responses and restored food-seeking behavior, but had no effect when the predator odor or the food-seeking tasks were carried out independently. Using both anterograde and retrograde viral tracing methods, we characterized the anatomical connectivity between aPVTCRF neurons and brain regions that are implicated in the regulation of food seeking and defensive responses. We observed that aPVTCRF neurons project densely to the nucleus accumbens (NAc), and optogenetic activation of the aPVTCRF-NAc pathway recapitulated the predator odor-induced food-seeking suppression and avoidance responses by mediating target-dependent synaptic transmission in the NAc. In addition, we identified the ventromedial hypothalamus (VMH) as a critical input to aPVTCRF neurons, and demonstrated that aPVT-projecting VMH neurons are activated by predator odor and necessary for the expression of defensive responses during conflict. Together, our findings describe a subpopulation of neurons in a hypothalamic-thalamostriatal circuit that suppresses reward-seeking behavior under the competing demands of avoiding threats.

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The UTHealth Neuroscience Research Center gratefully acknowledges the following:

The Ellwood Foundation UTHealth Graduate School of Biomedical Sciences

Dee S. and Patricia Osborne The Society for Neuroscience


Hyochol Ahn Cizik School of Nursing, UTHealth

Michael Beierlein Department of Neurobiology and Anatomy, UTHealth

Fabricio H. Do Monte Department of Neurobiology and Anatomy, UTHealth

Muhammad Haque Department of Neurology, UTHealth

Vasanthi Jayaraman Department of Biochemistry and Molecular Biology, UTHealth

Ying Liu Department of Neurosurgery, UTHealth

David Marshak Department of Neurobiology and Anatomy, UTHealth

Shin Nagayama Department of Neurobiology and Anatomy, UTHealth

Ponnada A. Narayana Department of Diagnostic and Interventional Imaging, UTHealth

Christophe Ribelayga Department of Ophthalmology And Visual Science, UTHealth

Laura Smith Callahan Department of Neurosurgery, UTHealth

Paul Smolen Department of Neurobiology and Anatomy, UTHealth

Nuray Yozbatiran Department Physical Medicine and Rehabilitation, UTHealth

Sheng Zhang IMM for the Prevention of Human Diseases, UTHealth