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Abstract List for 2023 meeting

(Abstracts will only appear after approval by the program committee)

50 abstracts
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Talk

#788: Role of Myrf enhancer in CNS myelination & its upstream regulator

An, Hongjoo 1; Park, Yungki 2;

1Neuroscience Program, 2Department of Biochemistry, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

Myelination of the central nervous system (CNS) by oligodendrocytes (OLs) is indispensable for the function and the development of the CNS. Oligodendrocyte progenitor cells (OPCs) differentiate into OLs that generate myelin in the CNS, highlighting OL differentiation is a key event in CNS myelination. Myrf (myelin regulatory factor, previously known as Mrf or Gm98) is a master regulator of OL differentiation. A distinctive property of Myrf, unparalleled to other OL transcription factors, is that it is expressed in an all-or-nothing pattern in OL lineage cells; its expression is stalled in OPCs, but its expression increases dramatically as OPCs differentiate into OLs. This binary expression pattern suggests that Myrf expression is a critical moment prompting OL differentiation. Therefore, artificial exogenous expression of Myrf in OPCs force their differentiation even in the proliferation condition. Additionally, gene expression analysis of multiple sclerosis lesions revealed that OLs stuck in their differentiation are those that couldn’t upregulate Myrf expression. Considering 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. Epigenome editing analysis revealed that Myrf-E1 and Myrf-E2 are dedicated to Myrf. ATAC-seq and ChIP-seq data show that Myrf-E1 and Myrf-E2 are conserved OL-specific enhancers. We advanced further and searched for Myrf upstream regulators to reveal the Myrf regulatory mechanism and myelination regulatory mechanism. Through these studies, we believe we can present a good therapeutic approach to control Myrf and myelination and treat demyelination diseases and multiple sclerosis.


#776: Clemastine induces OPC depletion and senescence in the context of chronic demyelination

Cooper, James J M1; Muthaiah, Rupadevi 1; Frost, Jon 1; Buck, Gregory 1; Ravichandar, Roopa 1; Gadelkarim, Farah 1; Sim, Fraser 2;

1Department of Pharmacology and Toxicology, 2Neuroscience Program, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

Clemastine has emerged as a promising remyelination-enhancing therapy for the restoration of neurologic function in multiple sclerosis (MS). However, agents investigated for their prodifferentiative effects on oligodendrocyte progenitor cells (OPC), including clemastine, have underperformed in clinical trials. We hypothesized that the efficacy of clemastine is dependent on adequate progenitor recruitment following demyelination, and that the timing of clemastine treatment is critical for meaningful repair. We utilized a rabbit model of demyelination characterized by lower OPC recruitment and chronic demyelination. Oral clemastine was administered either daily for 21 or 56 days (continuous groups), for the first 21 days after lesion induction and then withdrawn (early group) or delayed 35 days and administered for the last 21 days (late group). We found that only continuous administration of clemastine for 56 days resulted in increased oligodendrogenesis vs. vehicle. While short-term treatment induced oligodendrocyte differentiation, this did not increase overall oligodendrocyte density. Furthermore, clemastine significantly reduced OPC proliferation and density. The reduction in OPC density induced by 21-day treatment did not recover following clemastine withdrawal and remained reduced at 56 days. Interestingly, chronically active Sox2+ and senescent p16Ink4a+ OPCs accumulated when clemastine treatment was delayed. Together these findings suggest a double-edged sword for the treatment of MS patients with prodifferentiative agents such as clemastine. Early and prolonged administration of clemastine may be necessary to increase the production of myelinating oligodendrocytes. However, this results in OPC depletion which may impair the potential for future myelin repair and contribute to disease progression.


#789: New insights into the short-range arrangement of rod and cone photoreceptors in the human retina

Ramachandra Rao, Sriganesh ;

Ross Eye Institute, Department of Ophtalmology, SUNY University at Buffalo;

The human retina consists of a cone photoreceptor (PR)-rich fovea responsible for high acuity visual perception. In vivo retinal imaging techniques have demonstrated a rapid decrease in cone PR density and increase in rod PR density outside of the fovea. Cone-rich avian retinas demonstrate a hyperuniform, hexagonal arrangement of cone PRs. The arrangement of rod and cone PRs follow a two-sized disk packing pattern, the understanding of which is sparse. We developed a simple, image analysis technique to describe the short-range arrangement of rod and cone PRs in the human retina. Human donor eyes were harvested, and characterized post-mortem according to the Utah protocol. The anterior segment was carefully removed and fixed in 4% paraformaldehyde for 2 h. Retinal pieces (about 1 cm x 1 cm) were incubated in TBST with phalloidin (for detecting actin cytoskeleton), and Peanut Agglutinin (PNA, for detection of cone PRs). Confocal microscopy was used to image the entire volume of the PR layer, as well as the the actin cytoskeleton at the PR cell cortex. Analysis of the cell cortex revealed that  foveal cone PRs exhibit hyperuniform, hexagonal packing. Cone-cone neighbors occur at high frequency in the peri/parafovea, unlike in the peripheral retina. Outside of the fovea, the arrangement of cone and rod PRs switch to a non-hyperuniform, octagonal packing. In the peripheral retina, cones typically have 9-13 rod PR neighbors. Surprisingly, we observed a novel class of PNA-positive rod PRs. The average radius of cone PRs was about 2.5 microns, and that of rod PRs was about 1.25 microns.  Cone PRs in the fovea exhibit hyperuniform, disordered, hexagonal packing. However, outside the fovea, cone-rod packing switches to non-uniform octagonal packing. We also identified a novel sub-class of rod PRs, primarily characterized by extracellular matrix comparable to that of cones.


#777: Insights in AMD Pathogenesis: Integrative Transcriptomic Analyses of Human Disease-Affected Tissues

Shwani, Treefa 1; Zhang, Charles 2; Barr, Julie L 2; Lillvis, John H 2; Cromwell, Parker 2; Zavala, Rylee A 2; Graves, Elijah C 2; Zhang, Sarah X 2; Farkas, Michael H 2; Allison, Karen M 3; DeAngelis, Margaret M 2;

1Neuroscience Program, 2Ross Eye Institute, Department of Ophthalmology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences; 3Flaum Eye Institute, Department of Ophthalmology, University of Rochester;

Age-related macular degeneration (AMD) is a complex neurodegenerative disease with both intermediate and advanced forms and is the leading cause of visual disability in the aging population. It is only through elucidating its underlying disease mechanism that appropriate therapeutic targets can be identified. Recent studies have explored how splicing diversity and gene expression vary across human traits, implicating aberrant splicing patterns in disease. In the present study, we identified differentially expressed genes (DEGs) and differentially spliced genes (DSGs) across the clinical stages of AMD in disease-affected tissue: the macular retina pigment epithelium (RPE)/choroid and the macular retina within the same eye. We utilized 27 well-characterized donor eyes (recovered within 6 hours postmortem interval time) from Caucasian donors (60-94yrs). Significant findings were validated in an independent set of well-characterized donor eyes (n=85). Ultimately, there was limited overlap between DEGs and DSGs. We compared our DEGs/DSGs to known AMD risk loci and observed tissue-specific patterning of expression, underscoring the importance of tissue specificity. Only significant DEGs/DSGs from the macular RPE/choroid were found to overlap between disease states. STAT1 was validated between the intermediate AMD (iAMD) vs. normal comparison; and AGTPBP1, BBS5, CERKL, FGFBP2, KIFC3, RORα, and ZNF292 were validated in the late stage, neovascular AMD (NEO) vs. normal. These genes have been implicated in Alzheimer’s disease progression, multiple sclerosis, cone-rod dystrophies, and schizophrenia. An intricate regulatory network with transcription factors and miRNAs emerged when looking at these genes together. Our study provides crucial insights into the multifaceted genomic underpinnings of AMD (i.e., tissue-specific gene expression changes and splice variation), which may open new avenues for AMD therapeutics.


#787: Sex-divergent Impact of Polystyrene Microplastics on Metabolism and Feeding Behavior of Rats

Tanvir, Andleeb 1; Demieri, Emily 2; Rideout, Todd 3; Metlicki-Baase, Elizabeth G 3;

1Department of Biological Sciences, 2Exercise and Nutritional Sciences, 3Exercise and Nutrition Sciences, SUNY University at Buffalo;

Microplastics (MPs) are increasingly prevalent in our environment, yet their health impacts remain unclear. Here, we evaluated metabolic and energy balance effects of polystyrene, a common MP in the environment, in rats. Chow-fed rats were given a daily oral gavage of either polystyrene MP solution or control (deionized water) for 3 weeks. Feeding was monitored, and at the end of this time, animals underwent an oral glucose tolerance test (OGTT) to assess glycemic regulation. Minimal effects of MP exposure on feeding were detected, but in OGTT testing, MP-treated males exhibited hyperglycemia while MP-treated females showed a trend (p=0.06) for a lower area under the curve (AUC) suggesting improved glycemic control Then, to assess whether effects of MPs were similar in rats on an obesogenic diet, the same animals were switched to a 60% high-fat diet (HFD) and received an additional 3 weeks of MP or water treatment and underwent similar energy balance and glycemic testing. Later in the HFD-feeding period, MP-treated males showed transient increases in food intake due to increased meal number, whereas MP-treated females had significantly reduced feeding early in the dark phase due to suppressed meal size. During the HFD phase, MP-treated females were hypoglycemic at baseline of the OGTT, whereas no differences were detected in males. At the end of the HFD phase, trunk blood was collected to measure triglycerides. Preliminary analyses showed that MP-treated females had decreased plasma triglycerides compared with water-treated females (p=0.09), with no differences between MP- versus water-treated males, further supporting sex-differential metabolic effects of microplastic exposure. The data suggest that polystyrene MP exposure disrupts glycemic control in a sex-dependent manner in rats, underscoring the significance of investigating the mechanisms underlying these effects and assessing whether other metabolic disruptions may occur in response to MP exposure.


Poster

#761: Microglia and p38 Inhibitors Suppress Mechanical Allodynia in ddC-Induced Neuropathic Pain Model

Alhadlaq, Maryam 1; Masocha, Willias 2;

1Department of Pharmacology and Therapeutics, College of Pharmacy, Kuwait Univeristy; 2Department of Pharmacology and Therapeutics, College of Pharmacy, Kuwait University ;

Microglia activation in the spinal cord play a major role in the pathogenesis of neuropathic pain. The p38 mitogen-activated protein kinase (MAPK) regulates microglia activation. In our previous study, 2′,3′-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor (NRTI), was found to induce mechanical allodynia and microglia activation in the spinal cords of male and female mice. In this study, we investigated the role of spinal microglia and p38 MAPK signaling in the development of mechanical allodynia using immunofluorescence staining and treatment with microglia and p38 MAPK inhibitors in both sexes. Male and female mice (BALB/c strain) treated intraperitoneally once daily with ddC 25 mg/kg for five consecutive days developed mechanical allodynia, assessed using the dynamic plantar aesthesiometer. Treatment with ddC increased microglia markers CD11b and ionized calcium-binding adapter molecule 1 (Iba1) staining intensity in male mice, while only CD11b was increased in female mice. Both sexes had increased phosphorylated p38 MAPK staining intensity. The administration of minocycline, an inhibitor of microglia activation, and adezmapimod, a selective p38 MAPK inhibitor, suppressed mechanical allodynia in both sexes at day 7 after ddC treatment. Therefore, microglia activation and p38 MAPK signaling are important for the development of antiretroviral drug-induced mechanical allodynia.


#754: Chemogenetic Manipulation of Astrocyte Reactivity: Implications for Demyelinating Diseases

Angeliu, Christy G ; Cheli, Veronica T ; Paez, Pablo M ;

Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

In demyelinating diseases such as Multiple Sclerosis (MS), there is extensive damage to the myelin sheath accompanied by neuroinflammation. Astrocytes are glial cells that both respond and contribute to this damage and neuroinflammation by becoming reactive. We hypothesize that in demyelinating disease, activation of astrocytic hM3Dq DREADD will promote reactivity, worsening neuroinflammation and demyelination, while activation of astrocytic hM4Di will have opposing effects. Calcium imaging in primary cortical astrocytes expressing hM4Di showed that CNO-pretreated astrocytes had lowered responses to ATP, potassium, glutamate, and acetylcholine when compared to vehicle-treated cells. Unexpectedly, hM4Di activation seemed to promote proliferation, indicated by a greater number of Ki67+ cells. Next, in vivo experiments in the cuprizone and experimental autoimmune encephalomyelitis (EAE) models of demyelinating disease were performed utilizing mice that express hM4Di in astrocytes. During EAE, hM4Di-expressing mice were treated with vehicle or CNO during the acute phase of the disease. CNO-treated mice showed better motor function and lower clinical scores at disease peak than vehicle-treated mice. Tissues were collected at the peak and chronic phase of the disease for analysis of demyelination, astrocyte reactivity, and neuroinflammation. In a mild model of cuprizone demyelination, there seems to be some protection of myelin, along with increased GFAP expression. We have demonstrated that hM4Di is functional in astrocytes and that activation alters calcium signaling. Preliminary experiments suggest that this is relevant in vivo. Presumably through suppression of calcium signaling, reduction of reactivity, and proliferation of astrocytes, hM4Di activation in astrocytes seems to be able to attenuate the severity of demyelinating disease.


#780: Neuronal Circuits Encoding Methamphetamine Seeking Behavior

Avelar, Alicia ; Dominguez-Lopez, Sergio ;

Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

The reinforcing effects of methamphetamine (METH) are modulated by the dopamine mesolimbic system. However, METH chronic users develop deficiencies in dopamine-related brain functions that become more severe with increased exposure to the drug. In addition, postmortem studies in heavy users reported indications of neurodegeneration and brain damage. How and whether these findings contribute to the the persistent use of methamphetamine is not completely known.  In our lab, we train mice in operant chambers to self-administer intravenous infusions of METH for several weeks to months. We used electrophysiological techniques to assess functional changes in dopamine neuronal firing activity. Using in vivo single-unit extracellular recordings in anesthetized mice, we corroborated a decrease in firing and burst activity of dopamine neurons recorded in the ventral tegmental area (VTA) after METH self-administration exposure. We also observed a decrease in dopamine neuron firing and increased cell excitability in whole-cell patch clamp recordings in VTA slices from mice with a METH-self-administration story. However, it is not clear yet how these changes in dopamine physiology contribute to drug-seeking behavior. To investigate if prolonged methamphetamine self-administration exposure could lead to neurodegeneration of dopamine circuitry in mice, our current research efforts have focused on developing a methodology to visualize changes in brain dopaminergic circuits in the whole mouse brain. For this, we combined the use of tissue-clearing procedures and light sheet microscopy, tyrosine hydroxylase immunolabeling, and genetic tagging of neuronal circuits activated during methamphetamine-seeking behavior. Our preliminary results indicated that mice exposed to methamphetamine self-administration for several weeks recruited brain circuits outside the midbrain during methamphetamine seeking.


#763: Effects of reducing neuroinflammation to ameliorate prenatal ethanol exposure induced addiction risk

Barve, Maitreyee ; Czajka, Kristin ; Wang, An-Li ; Hausknecht, Kathryn ; Haj-Dahmane, Samir ; Shen, Roh-Yu ;

Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences;

Alcohol consumed during pregnancy can disrupt the brain development of the fetus. Prenatal ethanol exposure can lead to an increased risk of addiction to psychostimulant drugs. A possible neuronal mechanism for this is neuroinflammation, mediated by microglial activation. We are investigating if chronic minocycline treatment, which is known to reduce microglial activation, can ameliorate addiction risk. The addiction risk is measured by the amphetamine self-administration paradigm in rats. We expect to observe reduced amphetamine self-administration after minocycline treatment in prenatal ethanol exposed rats. We will also perform immunohistochemistry studies to compare the morphology of the microglia in the ventral tegmental area of control and minocycline treated rats. These results will support the hypothesis that reducing neuroinflammation rescues increased addiction risk after prenatal ethanol exposure.


#775: Sex differences in sensation/novelty seeking in a large cohort of young adult outbred rats

Bruno, Christian R 1; Ishiwari, Keita 2; Aktar, Fahmida 2; Bool, Heather M 1; George, Anthony M 3; Khalil, Andrew 2; Kwarteng, Francis 2; Martin, Connor D 3; Ramsoomair, Deryn 2; Sherwood, Laura J 2; Smith-Peters, William A 2; Turk, Marisa C 2; Solberg-Woods, Leah C 4; Polesskaya, Oksana 5; Palmer, Abraham A 5; Richards, Jerry B 2; Dietz, David M 2;

1Neuroscience Program, 3Research Institute on Addictions, SUNY University at Buffalo; 2Department of Pharmacology and Toxicology, SUNY University at Buffalo, School of Medicine and Biomedical Sciences; 4Department of Molecular Medicine, Wake Forest University School of Medicine; 5Department of Psychiatry, University of California San Diego;

High sensation/novelty seeking (SNS) is linked to maladaptive behaviors such as drug abuse and gambling addiction, especially in adolescents and young adults. In humans, men generally display higher SNS than women, while this difference may partially reflect culturally transmitted social norms. In rodents, past studies that examined sex differences in SNS using various behavioral paradigms show mixed results. Here, we examined sex differences in SNS in a large cohort (M: N=1,407, F: N=1,406) of young adult outbred rats using two tasks designed to measure partially overlapping but different aspects of SNS. In the first, locomotor response to novelty test, rats were allowed to explore a novel chamber for 18 min. In the second, operant sensation seeking test, which measures voluntary operant responding for a purely sensory stimulus (light), rats were placed in a dark operant chamber with two snout-poke holes and lights for 18 min/session. In the first habituation phase (6 sessions), pokes into either hole had no consequences. In the second light reinforcement phase (6 sessions), pokes into one of the holes (active hole) produced a 5-s light onset according to a variable-interval 1 min schedule, while pokes into the other inactive hole had no consequences. In the locomotor response to novelty test, female rats reacted to the novel chamber more than males. In the operant sensation seeking test, during habituation, females poked more into both holes in the dark chamber than males, again suggesting that females had greater reactivity to novelty. With the response-contingent light stimulus in the next phase, females made more active responses than males, but females also made more inactive responses, and there was no sex difference in the relative preference for light. Our results indicate that, while female rats have greater reactivity to novelty than males, the sexes may not differ in some other aspects of SNS such as their propensity to seek purely sensory stimulation.


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