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Item Celebrating the Legacy of the Institute of Psychiatric Research (IPR), and Moving Brain Research Forward(2022-06-22) Lahiri, Debomoy K.; Nurnberger, John I.The Institute for Psychiatric Research (IPR) at Indiana University (IU) School of Medicine was a free-standing four-story building on the main IUPUI campus (791 Union Drive) just east of Eskenazi Hospital's present location. It was built in 1955-56 by the State of Indiana to house the laboratories of neuroscience investigators operating under the leadership of the IU Department of Psychiatry. For nearly six decades IPR was the home of innovative research (primarily NIH-funded) in neurochemistry, electrophysiology, genetics, neuroanatomy, animal behavior, and molecular biology. For many years it was also the home of neuroscience education on the IUPUI campus. In 2014 the IPR building was demolished as part of the construction of Eskenazi hospital to replace the venerable Wishard hospital campus. IPR faculty relocated to the IU Neuroscience Building at 320 West 15th Street, where they now continue their work along with researchers at Stark Neurosciences Research Institute and other departments. Former IPR faculty Debomoy Lahiri and John Nurnberger have assembled a history of IPR along with illustrations of the building and the faculty and staff who worked there and contributed significantly to psychiatric research.Item Electrophysiological and Pharmacological Properties of the Neuronal Voltage-gated Sodium Channel Subtype Nav1.7(2007-12) Sheets, Patrick L.; Cummins, Theodore R.; Nicol, Grant D.; Oxford, Gerry S.; Vasko, Michael R.; Schild, John H.Voltage-gated sodium channels (VGSCs) are transmembrane proteins responsible for the initiation of action potentials in excitable tissues by selectively allowing Na+ to flow through the cell membrane. VGSC subtype Nav1.7 is highly expressed in nociceptive (pain-sensing) neurons. It has recently been shown that individuals lacking the Nav1.7 subtype do not experience pain but otherwise function normally. In addition, dysfunction of Nav1.7 caused by point mutations in the channel is involved in two inherited pain disorders, primary erythromelalgia (PE) and paroxysmal extreme pain disorder (PEPD). This indicates Nav1.7 is a very important component in nociception. The aims of this dissertation were to 1) investigate if the antipsychotic drug, trifluoperazine (TFP), could modulate Nav1.7 current; 2) examine changes in Nav1.7 properties produced by the PE mutation N395K including sensitivity to the local anesthetic (LA), lidocaine; and 3) determine how different inactivated conformations of Nav1.7 affect lidocaine inhibition on the channel using PEPD mutations (I1461T and T1464I) that alter transitions between the different inactivated configurations of Nav1.7. Standard whole-cell electrophysiology was used to determine electrophysiological and pharmacological changes in WT and mutant sodium currents. Results from this dissertation demonstrate 1) TFP inhibits Nav1.7 channels through the LA interaction site; 2) the N395K mutation alters electrophysiological properties of Nav1.7 and decreases channel sensitivity to the local anesthetic lidocaine; and 3) lidocaine stabilizes Nav1.7 in a configuration that decreases transition to the slow inactivated state of the channel. Overall, this dissertation answers important questions regarding the pharmacology of Nav1.7 and provides insight into the changes in Nav1.7 channel properties caused by point mutations that may contribute to abnormal pain sensations. The results of this dissertation on the function and pharmacology of the Nav1.7 channel are crucial to the understanding of pain pathophysiology and will provide insight for the advancement of pain management therapies.Item Endocannabinoids Regulate Cerebellar Granule Cell Differentiation(2017-09) Essex, Amanda; Black, Kylie; Baygani, Shawyon; Mier, Tristan; Martinez, Ricardo; Mackie, Ken; Kalinovsky, AnnaThe cerebellum plays a crucial role in learning and execution of complex automated behaviors, including fine motor skills, language, and emotional regulation. Cerebellar development continues throughout an extended postnatal period. The most numerous neurons in the cerebellum, as well as the entire brain, are the cerebellar granule cells (GCs), which are generated in a dedicated secondary proliferative zone, the external granule cell layer (EGL), during the first three postnatal weeks in mice, and over a year in humans. The robust expansion of granule cells during early development is responsible for the majority of cerebellar expansion. Morphological and molecular changes that drive GC proliferation and differentiation have been extensively characterized, starting from the developmental studies by Santiago Ramón y Cajal. GC progenitors (GCPs) proliferate in the outer EGL (oEGL). As they are pushed into the inner EGL (iEGL) by the newly generated GCPs, they exit the cell cycle and begin differentiation, first extending bipolar neurites, followed by tangential migration, and eventually radial migration to the inner granule cell layer (IGL), their target territory. Deregulation of GCPs expansion, proliferation to differentiation switch, or the rate of migration could contribute to abnormal cerebellar size and compartmentalization and disrupt cerebellar circuits’ wiring and function. Endocannabinoids (eCBs) have been identified as key players regulating neuron proliferation and migration in the fore- and mid-brain development, however their role in cerebellar development has not yet been explored in detail. Our preliminary results show robust expression of cannabinoid receptor 1 (CB1) in iEGL GCs, concomitant with expression diacylglycerol lipase α (DGLα) a major enzyme required for the synthesis of eCB 2-arachidonoylglycerol (2-AG), in PCs. Furthermore, our preliminary results show that cerebellar size is reduced in CB1 KOs. In this study we investigate the mechanisms through which eCB signaling may regulate GC proliferation and differentiation, focusing on the GCPs cycle length, rate of differentiation and migration.Item The Ex Vivo Human Translaminar Autonomous System to Study Spaceflight Associated Neuro-ocular Syndrome Pathogenesis(Nature, 2022-10) Peng, Michael; Curry, Stacy M.; Liu, Yang; Lohawala, Husain; Sharma, Gaurav; Sharma, Tasneem P.; Ophthalmology, School of MedicineSpaceflight-Associated Neuro-ocular Syndrome (SANS) is a significant unexplained adverse reaction to long-duration spaceflight. We employ an ex vivo translaminar autonomous system (TAS) to recreate a human ocular ground-based spaceflight analogue model to study SANS pathogenesis. To recapitulate the human SANS conditions, human ocular posterior segments are cultured in the TAS model for 14 days. Translaminar pressure differentials are generated by simulating various flow rates within intracranial pressure (ICP) and intraocular (IOP) chambers to maintain hydrostatic pressures of ICP: IOP (12:16, 15:16, 12:21, 21:16 mmHg). In addition, optic nerves are mechanically kinked by 6- and 10-degree tilt inserts for the ICP: IOP;15:16 mmHg pressure paradigm. The TAS model successfully maintains various pressure differentials for all experimental groups over 14 days. Post culture, we determine inflammatory and extracellular component expression changes within posterior segments. To further characterize the SANS pathogenesis, axonal transport capacity, optic nerve degeneration and retinal functional are measured. Identifiable pathogenic alterations are observed in posterior segments by morphologic, apoptotic, and inflammatory changes including transport and functional deficits under various simulated SANS conditions. Here we report our TAS model provides a unique preclinical application system to mimic SANS pathology and a viable therapeutic testing device for countermeasures.Item High-frequency forced oscillations in neuronlike elements(APS, 2018-06) Zakharov, D. G.; Krupa, M.; Gutkin, B. S.; Kuznetsov, A. S.; Mechanical and Energy Engineering, School of Engineering and TechnologyWe analyzed a generic relaxation oscillator under moderately strong forcing at a frequency much greater that the natural intrinsic frequency of the oscillator. Additionally, the forcing is of the same sign and, thus, has a nonzero average, matching neuroscience applications. We found that, first, the transition to high-frequency synchronous oscillations occurs mostly through periodic solutions with virtually no chaotic regimes present. Second, the amplitude of the high-frequency oscillations is large, suggesting an important role for these oscillations in applications. Third, the 1:1 synchronized solution may lose stability, and, contrary to other cases, this occurs at smaller, but not at higher frequency differences between intrinsic and forcing oscillations. We analytically built a map that gives an explanation of these properties. Thus, we found a way to substantially “overclock” the oscillator with only a moderately strong external force. Interestingly, in application to neuroscience, both excitatory and inhibitory inputs can force the high-frequency oscillations.Item Human Stem Cell Differentiated Retinal Ganglion Cells for Developing Glaucoma Neuroprotection and Cell Replacement Strategies(2024-07) Anbarasu, Kavitha; Das, Arupratan; Corson, Timothy; Meyer, Jason; Graham, Brett; Janga, SarathProgressive loss of retinal ganglion cells (RGCs) leads to glaucoma. Early diagnosis offers an opportunity to protect existing RGCs. In advanced glaucoma, most RGCs are lost causing blindness and cell replacement therapy the only option. We used a human stem cell-based RGC differentiation model to develop neuroprotection by restoring mitochondrial homeostasis and enhancing RGC differentiation efficiency to increase the success of cell replacement therapy. Unmyelinated axons in RGCs require high levels of ATP, making disrupted mitochondria a risk factor in glaucoma. Our goal was to restore mitochondrial homeostasis through mitophagy (mitochondrial autophagy) and mitobiogenesis (mitochondrial biogenesis). Mutations in the mitophagy protein Optineurin (OPTNE50K) are found in patients with normal tension glaucoma and hence, we also used RGCs with the E50K mutation. We discovered that hRGCE50Ks suffer from mitobiogenesis issues, Parkin/Pink mediated mitophagy defects, and have OPTNE50K-Tank binding kinase-1 (TBK1) aggregates. hRGCE50Ks have lower mitochondrial mass and a higher mitochondrial load. We inhibited TBK1 to induce mitochondrial biogenesis and dissolve OPTNE50K-TBK1 aggregates. Our results show TBK1 inhibition triggered mitobiogenesis, dissolved aggregates, decreased mitochondrial ATP production load, and increased spare respiratory capacity, leading to neuroprotection. With complete RGC loss, enhancing differentiation to progenitor cells with lower cell division capacity can improve the success of cell replacement therapy and reduce teratoma formation and poor tissue integration. We observed that stem cells use proteasomes for mitochondrial degradation, while hRGCs use the lysosomal mitophagy pathway. Our results indicate that proteasomal activity declines during differentiation to hRGCs. Inhibition of proteasomal activity during early differentiation resulted in higher and faster RGC differentiation, with similar effects seen in motor neuron differentiation. We did not observe metabolic reprogramming in differentiating cells upon proteasomal activity inhibition but saw changes in cell cycle distribution, specifically an increase in the number of cells in the G1 phase. Proteomics analysis post-inhibitory treatment showed elevated neuronal differentiation proteins. Our results can be translated to minimize injection cell numbers and other risks of cell replacement therapy. In summary, my research identifies novel mechanisms for restoring mitochondrial homeostasis for neuroprotection in glaucomatous RGCs and develops an enhanced differentiation strategy to aid the success of cell replacement therapy.Item Identification and Extraction of Binary, Ternary, Transitive associations and Frequent Patterns from Text Documents in an Interactive Way(Office of the Vice Chancellor for Research, 2013-04-05) Waranashiwar, Shruti DilipAs the amount of electronically accessible textual material has been growing exponentially, Text mining is a new and exciting research area that tries to solve the information overload problem. It is a promising and automated approach for extracting knowledge from unstructured textual documents. The purpose of this research in text mining area is to find compact but high quality associations from Neuroscience related text documents. Here, we try to find the relationships (binary, ternary and transitive) between the terms related to some of the common disorders in neuroscience like Alcoholism and Schizophrenia from a database PubMed, using Vector Space Model (VSM) and the Artificial Neural Network (ANN). We also use Graphviz to visualize these associations. This research reveals many stronger and weaker associations between the different terms in different comorbidities, which are otherwise difficult to understand by reading articles or journals manually. Once the model is developed, it can be generalized to different terms and can be used to study different combinations of terms and comorbidities. As response time of these models is very fast, it will greatly contribute towards speeding up medical research. In such light, extracting associations between keywords could provide very interesting insights into their roles in various diseases and other biological processes. We also try to prove that instead of mining all frequent patterns, all of which may not be interesting to user, interactive method to mine only desired and interesting patterns is far better approach in terms of utilization of resources. We find the compact but high-quality frequent patterns in an interactive way using MCMC sampling method. In interactive patterns mining, a user gives feedback on whether a pattern is interesting or not. The discovery of interesting Associations has application in many fields. Few of them are business decision-making processes, web usage mining, intrusion detection and bioinformatics.Item Impact of Acute Ethanol Injections on Medial Prefrontal Cortex Neural Activity(2019-12) Morningstar, Mitchell D.; Lapish, Christopher; Goodlett, Charles; Linsenbardt, DavidThe medial prefrontal cortex (mPFC) is a cortical brain region involved in the evaluation and selection of motivationally relevant outcomes. mPFC-mediated cognitive functions are impaired following acute alcohol exposure. In rodent models, ethanol (EtOH) doses as low as 0.75 g/kg yield deficits in cognitive functions. These deficits following acute EtOH are thought to be mediated, at least in part, by decreases in mPFC firing rates. However, these data have been generated exclusively in anesthetized rodents. To eliminate the potentially confounding role of anesthesia on EtOH modulated mPFC activity, the present study investigated the effects of acute EtOH injections on mPFC neural activity in awake-behaving rodents. We utilized three groups: the first group received 2 saline injections during the recording. The second group received a saline injection followed 30 minutes later by a 1.0 g/kg EtOH injection. The last group received a saline injection followed 30 minutes later by a 2.0 g/kg EtOH injection. One week following the awake-behaving recording, an anesthetized recording was performed using one dose of saline followed 30 minutes later by one dose of 1.0 g/kg EtOH in order to replicate previous studies. Firing rates were normalized to a baseline period that occurred 5 minutes prior to each injection. A 5-minute time period 30 minutes following the injection was used to compare across groups. There were no significant differences across the awake-behaving saline-saline group, indicating no major effect on mPFC neural activity as a result of repeated injections. There was a significant main effect across treatment & behavioral groups in the saline-EtOH 1.0 g/kg group with reductions in the EtOH & Sleep condition. In the saline-EtOH 2.0 g/kg, mPFC neural activity was only reduced in lowered states of vigilance. This suggests that EtOH only causes gross changes on neural activity when the animal is not active and behaving. Ultimately this means that EtOH’s impact on decision making is not due to gross changes in mPFC neural activity and future work should investigate its mechanism.Item The Institute of Psychiatric Research: A Historical Perspective from the 1950s to the 2000s(2021-09-13) Lahiri, Debomoy K.Presentation on the history of the Indiana University School of Medicine's Institute of Psychiatric Research (1957-2013), a free-standing center developed by the State of Indiana to investigate the causes of mental illness. Includes historical photographs of directors, researchers, equipment, and facilities within the IPR.Item Measurement of mitochondrial respiration in the murine retina using a Seahorse extracellular flux analyzer(Elsevier, 2021-06) Shetty, Trupti; Park, Bomina; Corson, Timothy W.; Ophthalmology, School of MedicineMitochondrial metabolism is a critical mechanism that is deregulated in numerous retinal diseases. Here, we elaborate a protocol to quantify oxygen consumption rate as a measure of mitochondrial respiration directly from mouse retinal tissue pieces. Our procedure combines the use of Seahorse extracellular flux technology and ex vivo retinal tissue isolation and is robustly reproducible under different treatment conditions. This protocol allows direct assessment of mitochondrial function in response to drug treatments or genetic manipulation in mouse models.