Abstract List for 2022 meeting
(Abstracts will only appear after approval by the program committee)
47 abstracts
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Poster
#684: Role of Myrf enhancer in CNS myelination
An, Hongjoo ; Kim, Dongkyeong ; Fan, Chuandong ; Cheli, Veronica ; Hurley, Edward ; Park, Yungki ;
Department of Biochemistry, SUNY University at Buffalo;
In light of the significance of accurate Myrf expression for OL differentiation, we have explored how Myrf expression is triggered in OL lineage cells. Our interdisciplinary research has found two OL enhancers for Myrf (referred as Myrf-E1 and Myrf-E2).
#701: Chemogenetic Manipulation of Astrocyte Reactivity: Implications for Demyelinating Diseases
Angeliu, Christy ; Paez, Pablo ;
Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;
In demyelinating disease, there is extensive damage to the myelin sheath accompanied by neuroinflammation. Astrocytes are glial cells that respond and contribute to this neuroinflammation by becoming reactive. Reactive astrocytes can be both helpful and harmful in demyelinating disease, depending on the level and timing of reactivity. The response of astrocytes is dependent on the activity of ion channel function, which can be modulated by activation of Designer Receptors Exclusively Activated by Designer Drugs (DREADD) with clozapine N-oxide (CNO). Here, we expressed the excitatory hM3Dq and the inhibitory hM4Di DREADD in primary astrocytes cultures and performed calcium imaging and immunocytochemistry in CNO-treated and untreated cells. We found that upon stimulation of the hM3Dq DREADD, there is a robust increase in intracellular calcium levels as well as increased reactivity. Conversely, we find that CNO pretreatment of hM4Di-expressing astrocytes suppresses normal responses to ATP, potassium, glutamate, and acetylcholine. However, CNO treatment does not affect the reactivity of hM4Di-expressing astrocytes. These results show that stimulation of these DREADDs can alter astrocyte physiology in ways that have relevance to demyelinating disease. Using two mouse models of demyelination, future experiments will provide in vivo evidence of how modulation of astrocyte reactivity via these DREADDs affects demyelination, remyelination, and neuroinflammation.
#727: Self-calibrating χ-separation using single-subject (N=1) physics-constrained deep learning
Benslimane, Ilyes A 1; Grabner, Günther 2; Hametner, Simon 3; Jochmann, Thomas 4; Zivadinov, Robert 5; Schweser, Ferdinand 5;
1Buffalo Neuroimaging Analysis Center, SUNY University at Buffalo; 2Department of Medical Engineering, Carinthia University of Applied Sciences, Klagenfurt, Austria ; 3Department of Neuropathology and Neurochemistry, Medical University of Vienna, Austria ; 4Department of Computer Science and Automation, Technische Universität Ilmenau, Germany; 5Buffalo Neuroimaging Analysis Center, Clinical and Translational Science Institute at the University at Buffalo;
χ-separation is a method to separate para- and diamagnetic contributions to tissue magnetic susceptibility. Prior models combine Quantitative Susceptibility Mapping (QSM) with MRI data such as R2* or R2’ given the opposite tissue effects on QSM and assuming known identical a priori proportionality coefficients relating tissue compartments to the MRI metrics. The 1st assumption is problematic when applied to neurological diseases or postmortem tissues, where unknown coefficients may be different between subjects and the 2nd is unverified. This work develops a neural network where subject-specific coefficients are obtained directly from the data. An autoencoder is designed to decompose a set of measured qMRI quantities {si} into biological tissue {cj} and function parameters {pj} that define the functional relationship {cj}→{si} together with biophysical functions defined in the decoder. The network can be trained on data from a single-subject exam without ground truth data for {cj} or {pj}, which are unavailable in vivo. Conventional χ-separation was performed using the model proposed by Dimov et al. in 2022 (r+=r-=87.33 Hz/ppm/T). Self-calibrated χ-separation was performed: (i) Using R2* and QSM with two source compartments (iron and myelin), first-order function families, and unconstrained coefficients, (ii) The same model as in (i) using R1 instead of R2*. (iii) Using R1, R2*, and QSM with second order function families. Corresponding models were trained separately on ex and in vivo quantitative MRI data. Inclusion of both R2* and R1 was required to improve white matter contrast on the iron map and produce a myelin map that resembled ex vivo myelin stains. Our study showed limited performance of conventional χ-separation in estimating tissue, likely due to incomplete information or the pre-determined coefficient r+/-. Self-calibrated χ-separation resulted in more accurate myelin and iron predictions although stains were not used for training or inference.
#679: Central responses in AVP-deficient rats after activating GLP-1R or deprivation-induced drinking
Brakey, Destiny J 1; Schatz, Kelcie C 2; Paul, Matthew J 2; Daniels, Derek 1;
1Biology Department, 2Department of Psychology, SUNY University at Buffalo, College of Arts and Sciences;
Food and water intakes are both behaviorally and physiologically intertwined and the control of these behaviors by glucagon-like peptide-1 (GLP-1) is no exception. In order to determine the degree of overlap and separation in the mechanisms by which GLP-1 controls food and fluid intakes, we employed a rat model that has virtually insatiable thirst, but normal food intake satiety. Specifically, the vasopressin-deficient Brattleboro rat eats similarly to wildtype controls, but drinks approximately five times the amount of water. These differences occur with a greater number of licking bursts, suggesting a deficit in post-ingestive feedback. Brattleboro rats are also hypersensitive to the GLP-1R agonist, exendin-4 (Ex4), but the hypersensitivity is selective to water intake suppression. To test for differences in the brain that may relate to these discrepant behavioral responses, we examined Fos in the nucleus of the solitary tract of wildtype and Brattleboro rats after Ex4 or after water deprivation with and without subsequent drinking. We found an association between Ex4 and Fos in both wildtype and Brattleboro rats. Contrarily, there was an association between Fos and drinking, but only in wildtype rats. Ongoing analyses are testing for differences in other brain regions that are known to participate in the control of thirst- and hunger-related behaviors, but this approach has the potential to reveal key differences in the control of food and water intakes by GLP-1.
#693: Targeting the nociceptor endocytosis AP2 complex affects MIA-Induced Osteoarthritis pain behavior
Cooper, Aubrey J ; Rodriquez, Raider ; Young, Violet ; Bhattacharjee, Arin ;
Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;
Osteoarthritis (OA), is a degenerative condition that leads to chronic pain and a need for pain relief. Pain management for OA pain is fraught with efficacy issues and adverse effects. Although injection of corticosteroids into arthritic joints is a mainstay therapeutic approach to treat arthritic pain, clinical studies raise questions on the efficacy of steroid therapy and have shown treatment caused significantly greater cartilage volume loss (PMID: 28510679). Our previous studies have indicated that inhibition of the nociceptor endocytotic adaptor protein complex 2 (AP2) inhibits neuronal hyperexcitability and inflammatory pain behavior (PMID: 34608164). Here we show the AP2A2 subunit localized to CGRP-containing large dense core vesicles (LDCVs) in human and mouse DRG neurons. We further demonstrate that pain behavior in arthritis is reduced by local pharmacological inhibition of the nociceptor AP2 complex using a lipidated AP2 peptide inhibitor. Monoiodoacetate (MIA) was used to induce knee joint OA in Sprague-Dawley rats. Four days later, upon verification of pain, a one-time intra-articular injection to the arthritic knee of either the AP2 inhibitor peptide or a scrambled peptide control was administered. Joint pain was assessed via a dynamic weight-bearing (DWB) assay. Pain behavior was monitored over the course of 28 days post MIA-induced OA. DWB analyses showed the typical decrease in weight bearing in the group whose arthritic knees were injected with scrambled peptide; however, an increase in weight bearing, persisting up to 24 days, was observed in the AP2 peptide injected group. This data suggests that inhibition joint nociceptor endocytosis can decrease OA pain and pathology.
#729: Persistent Early Life Adversity and Prenatal Ethanol Exposure Induced Cognitive/Behavioral Deficits
Czajka, Kristin 1; Sartori, Mathew 1; Biswas, Srima 2; Wang, An-Li 1; Kelly, Nickesha 2; Hausknecht, Kathryn 1; Ishiwari, Keita 1; Shen, Roh-Yu 1;
1Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences; 2Department of Biological Sciences, SUNY University at Buffalo, College of Arts and Sciences;
Fetal alcohol spectrum disorders (FASD) are a developmental disorder caused by prenatal ethanol exposure. The prevalence rate of FASD is very high (2-5%) in the US. FASD is associated with physical, behavioral, and cognitive deficits. However, how postnatal environment contributes to the severity of these deficits is unclear. The current study is designed to investigate if persistent early life adversity could further exacerbate the sensory processing and habituation deficits of FASD.
#690: Studying the role of autophagy in Krabbe disease pathogenesis
Dhimal, Narayan 1; Aljanahi, Karrar 2; Hurley, Edward 3; Shin, Daesung 4; Wrabetz, Lawrence 3; Feltri, M.Laura 1;
1Department of Biochemistry, 3Department of Neurology, 4Biotechnical and Clinical Laboratory Sciences, SUNY University at Buffalo, School of Medicine and Biomedical Sciences; 2Biology Department, SUNY University at Buffalo;
Krabbe disease (KD) is a lysosomal storage disorder that causes extensive demyelination in the central and peripheral nervous systems. KD is caused by a loss-of-function mutation in lysosomal hydrolase, galactosylceramidase (GALC), which is responsible for breaking down galactosylceramide (GalCer) into galactose and ceramide. Lack of the GALC results in the accumulation of GalCer and its toxic byproduct, psychosine. However, accumulation of these two substrates is not sufficient to explain the severity of the disease. Therefore, using a recently well-characterized Schwann cells (SCs) specific GALC-ablated conditional mouse model that presents with pathologies of KD in the peripheral nervous system, we want to know what cellular mechanisms are altered by the lack of GALC function that further contributes to disease pathogenesis and severity. Based on recent results from electron microscopy, western blotting, and immunohistochemistry, an increase in autophagy regulating proteins were detected in the SCs of pre-symptomatic mutant mice, and autophagosome accumulation, which is shown to be toxic to cells, was observed during pre-symptomatic and symptomatic ages in these mice; Autophagy is a normal cellular process where damaged cell organelles and unused proteins are recycled. The findings led to the hypothesis that autophagy is affected by the lack of GALC and it contributes to disease pathogenesis. To test this, we deleted Atg7 from our KD mouse model and are currently characterizing myelin abnormalities and disease severity by semithin quantification and western blots.
#703: Using human iPSC derived myelinating organoids to study Krabbe Disease
Evans, Lisa Marie P ; Marziali, Leandro N ; Gawron, Joseph ; Feltri, M Laura ;
Department of Biochemistry, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;
Krabbe Disease (KD) is a lysosomal storage disease (LSD) caused by the functional deficiency of the lysosomal enzyme galactosylceramidase (GalC). GalC breaks down galactosylceramide (GalCer). If GalC is deficient and GalCer accumulates, psychosine, a toxin, is produced by another pathway. Maintenance of myelin and myelin turnover is highly important once it is produced. In the central nervous system (CNS), myelin is formed by oligodendrocytes (OLs). Microglia are the resident immune system cell of the CNS and function to shape myelin during development and break down myelin debris after myelin degeneration. At birth, myelin development is normal in KD. Even so, the absence or deficiency of Gal C disrupts myelin turnover and eventually leads to demyelination and neurodegeneration. Myelin disruption results in large amounts of myelin debris that is normally phagocytosed by microglia. In KD, microglia lacks GalC and thus fails to break down myelin debris, resulting in the formation of globoid cells. Globoid cells are cells that contain partly digested myelin sheaths that lead to an inflammatory phenotype. We used induced pluripotent stem cells (iPSCs) from healthy and KD patients to produce myelinating organoids that lack microglia. Our model provides us an opportunity to study KD and the demyelination that occurs, without the inflammatory environment produced by globoid cells. Without the inflammatory environment, we hope to study the effect of lysosomal dysfunction and psychosine accumulation on KD. Initially, we will first characterize both KD and control organoids by looking at development, myelination, and demyelination. Our findings so far show that KD organoids develop seemingly normal with adequate neurogenesis, astrogenesis, and oligodendrogenesis. Curiously, oligodendrogenesis and myelination seem to be accelerated in KD organoids when compared to control organoids, but is later disrupted by demyelination.
#713: Ablation of neuronal galactosylceramidase results in neurodegeneration
Favret, Jacob M ; Shin, Daesung ;
Biotechnical and Clinical Laboratory Science , SUNY University at Buffalo;
Krabbe Disease (KD) is a rare autosomal recessive lysosomal storage disease caused by mutations in the acid hydrolase Galactosylceramidase (Galc). Due to the function GALC serves in hydrolyzing a major myelin membrane component Galactosylceramide (GalCer) the demyelination and neurodegeneration has canonically been associated to the dysfunction of myelinating glia with neuronal pathology following secondarily. However, GALC is expressed ubiquitously in the CNS and recent evidence has shown neuro-axonal degeneration prior to the onset of overt demyelination indicating a neuron specific GALC function. Herein we utilize the constitutively active pan-neuronal Syn1Cre to induce a robust knockout in haplodeficient Galc flox/- mice. Syn1Cre; Galc flox/- mice exhibit neuronal specific expression of Cre recombinase which mediates an efficient loss of neuronal Galc and elicits accumulation of the cytotoxic GALC substrate Psychosine (Psy). Syn1Cre; Galc flox/- mice have reduced bodyweight and impaired locomotion assessed via rotarod compared to control Galc +/- mice; however, there was no impact on overall survival. Electron microscope morphological analysis of Syn1Cre; Galc flox/- mice revealed a significant increase in the number of degenerating and dying neurons; furthermore, G-ratio measurements showed a slightly thinner myelin sheath which was further validated by means of western blot analysis of myelin proteins. Analysis of inflammatory markers, namely GFAP and CD68 revealed a significant increase in astrocytosis and microgliosis respectively. Evidence of Parkinson’s disease pathology such as lipofuscin may provide evidence of the connection between GALC dysfunction and the pathogenic mechanism of other neurodegenerative diseases. The study is the first of its kind to show that neurons are contributors to KD pathology in a cell-autonomous manner and thus require therapeutic intervention for disease management.
#716: Delayed neural processing during working memory in people with Multiple Sclerosis
Haller, Mckenzie L ; Shucard, David W ; Shucard, Janet L ; Covey, Thomas J ;
Department of Neurology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;
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