Browsing by Author "Colon-Perez, Luis"
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Item Cocaine Administration but Not Morphine Leads to Increases in Impulsivity as Measured in a Delay Discounting Task(2024-03-21) Keitzer, Jeri; Anchondo, Olivia; Brunetti, Kaylee; Shuchi, Samia; Colon-Perez, LuisCocaine Administration but Not Morphine Leads to Increases in Impulsivity as Measured in a Delay Discounting Task Jeri Keitzer, Olivia Anchondo, Kaylee Brunetti, Samia Shuchi, and Luis Colon-Perez Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX, 76107 Purpose: Inhibitory and cognitive control are mental process susceptible to repeated exposure to drugs of abuse. Specifically, impulsivity refers to the tendency to act prematurely without regard of the future. Substance use disorders patients (SUD) show impaired impulsivity; however, it is unclear whether psychostimulant use precedes impulsive behavior or vice versa. The delay discounting task is an assessment of impulsive choice used in behavioral neuroscience research. In this task, subjects are given a choice between an immediate small reward or a delayed large reward in which the time of delay increases across trials. Subjects that discount the delayed reward earlier are determined to act with more impulsivity. In this current study, we looked at impulsivity as it relates to performance in a delay discounting task before and after IP injection drug administration of either morphine or cocaine. We hypothesized that the subjects that were administered drugs would devalue the delayed reward earlier within the delay discounting task than control subjects. Methods: For this study, we used Sprague Dawley rats split into 4 different groups: cocaine, morphine, saline, and naïve. All subjects were food restricted to increase motivation to obtain the reward food pellets. Rats began training on the delay discounting task after a training phase in which the rats were introduced to the behavioral chambers and exposed to the levers within the chambers in which they were trained to press to receive pellets. The delay discounting task consisted of a daily session in which the subject went through 5 phases (a total of 60 total trials) choosing between two levers to receive pellets. Each phase is characterized by two forced trials and ten choice trials. In the forced choice trials, the animal has only one option: either the immediate small reward or delayed choice reward. At each phase the delay increases from no delay to 4s, 8s, 16s, and 32s. During choice trials, rats choose between the immediate and delayed levers. Once a decision has been made, both levers retract until the next trial. First, baseline data of each subject’s impulsive choice was acquired, then the subjects underwent IP injection of either cocaine, morphine, or saline. A naïve group did not receive any injections. Rats were injected with drugs according to their weight (5 mg/kg) once per day for seven days, then they completed the delay discounting task again under experimental conditions. Results: The cocaine drug group showed a significant decrease in delayed lever presses compared to all other groups during the delay discounting task following drug administration. No other significant differences were seen across any of the other groups. Conclusion: The results of the study suggest that passive administration of cocaine in rats may lead to an increase in impulsivity but not morphine.Item Early psychosis structural abnormalities in the midbrain correlate with positive and negative symptoms(2024-03-21) Zhou, Zicong; Jones, Kylie; Ivleva, Elena; Colon-Perez, LuisEarly psychosis (EP) is a critical period in developing psychotic disorders. During the EP period, timely intervention strategies can effectively mitigate symptoms of psychotic disorders. A primary target in current therapeutics for psychotic disorders is the dopaminergic system; however, current therapeutics are often inadequate in treating the advanced stages of psychotic disorders. Currently, there are hypotheses that the advent of psychotic disorders are alterations in the brain’s structure and functional connectivity leading to aberrant network organization. Given the prominence of the midbrain in synthesizing dopamine and being a hub in the circuitry of dopaminergic function in this study, we will quantify the structural properties of the midbrain using a publicly available dataset of EP subjects. The Human Connectome Project (HCP) is a global effort to determine human brain connectivity objectively. Specifically, there is a subset where the focus is on subjects within five years of their first psychotic episode, which is the focus of this study. In this project, we employ various computational tools (including FSL, ANTs, packages of Python and RStudio, etc.) to acquire relevant measures of brain structure in EP. Specifically, we performed gross anatomical analysis of brain volumetrics, regional microstructural analysis, and correlation analysis between brain and behavior indices. First, Deformation-based Morphometry (DBM) is a test performed on T1 MRI scans to determine brain volumes. DBM measures shape movements to align individuals with a registration template using the Jacobian determinant (JD), whereas a standard VBM focuses on voxel intensity differences between individuals and the template. In our results, DBM revealed mild changes around the midbrain between EP and healthy controls. Second, we analyzed Diffusion Tensor Imaging (DTI) data by obtaining indices such as Fractional Anisotropy (FA), Axial Diffusivity (AD), and Mean Diffusivity (MD). A midbrain mask was created based on Freesurfer atlas ROI labels, allowing a seed-based analysis centered around the midbrain. Group differences were estimated using the Welch two-group t-tests on ROI means of JD, FA, AD, MD, and midbrain volumes. Interestingly, group differences in JD and midbrain volumes were insignificant, but differences were more pronounced for FA, AD, and MD. Third, we employed Tract-Based Spatial Statistics (TBSS) to determine microstructural changes in white matter tracts. TBSS successfully captured structural variabilities within the midbrain, aligning with our study’s expectations, in addition to moderate changes in other main white matter tracts, such as corticospinal tract and cingulum, suggesting an initiation of altered brain connectivity emanating from alterations in the midbrain or a putative reorganization of dopaminergic circuitry. Fourth, correlations between these quantities in the EP group and behavioral scores (i.e., PANSS and CAINS tests) were explored. It is found that midbrain volume noticeably correlates with the Cognitive score of PANSS and JD, strongly correlates with AD and MD; FA correlates with the Negative score of PANSS, and MD correlates with the Positive score of PANSS. Overall, these findings contribute to understanding midbrain involvement in early psychosis and underscore the interest for further investigation in this research path.Item Experimental ischemic stroke induces secondary white matter degeneration and long-term cognitive impairment(2024-03-21) Berry, Raymond; Liu, Ran; Winters, Ali; Spann, Clair; Ampofo, Hannah; Colon-Perez, Luis; Sumien, Nathalie; Yang, Shao-HuaClinical investigations have detected extensive white matter degeneration in individuals affected by ischemic stroke. Nonetheless, current stroke research has primarily concentrated on the infarct and periinfarct penumbra regions. The exploration of white matter degeneration's role after ischemic stroke and its contribution to post-stroke cognitive impairment and dementia (PSCID) has been limited in experimental models. Understanding the impact of white matter degeneration on PSCID in these models could offer valuable insights into potential therapeutic targets and interventions for alleviating cognitive decline following ischemic stroke. In this study, we analyzed the progression of locomotor and cognitive function up to 4 months after inducing ischemic stroke by middle cerebral artery occlusion in young adult rats. Despite evident ongoing locomotor recovery, long-term cognitive and affective impairment persisted after ischemic stroke, as indicated by Morris water maze, elevated plus maze, and open field performance. At 4-month after stroke, multimodal MRI was conducted to assess white matter degeneration. T2-weighted MRI (T2WI) unveiled bilateral cerebroventricular enlargement after ischemic stroke. Fluid Attenuated Inversion Recovery MRI (FLAIR) revealed white matter hyperintensities in the corpus callosum and fornix across bilateral hemispheres. A positive association between the volume of white matter hyperintensities and total cerebroventricular volume was noted in stroke rats. Further evidence of bilateral white matter degeneration was indicated by the reduction of fractional anisotropy (FA) and quantitative anisotropy (QA) in diffusion-weighted MRI (DWI) analysis. FA measures water diffusion directionality; reduced FA implies decreased white matter tract coherence. QA, linked to diffusion directionality, indicates microstructural white matter changes with decreased QA. Reduced FA and QA in DWI MRI suggest brain microstructural integrity changes, involving myelin sheath disruption, axonal damage, or overall white matter deterioration. Additionally, microglia and astrocyte activation were identified in the bilateral corpus callosum after stroke. This inflammatory response indicates the involvement of glial cells in the post-stroke environment, suggesting a complex interplay between structural alterations and neuroinflammatory processes that may contribute to the observed changes in white matter integrity. Understanding these multifaceted mechanisms is crucial for developing targeted interventions aimed at promoting recovery and minimizing long-term neurological consequences following ischemic stroke. The importance of these results is underscored by their potential connection to neurological or neurodegenerative conditions, given that white matter degeneration is commonly noted in diverse neurological disorders, including Alzheimer's disease, multiple sclerosis, and other related conditions. Our study suggests that experimental ischemic stroke induced by MCAO in young rats replicates long-term cognitive impairment and pervasive white matter degeneration observed in ischemic stroke patients. This model provides an invaluable tool for unraveling the mechanisms underlying post-stroke secondary white matter degeneration and its contribution to PSCID. Researchers and clinicians use these metrics to understand and monitor the progression of neurological diseases, potentially aiding in early diagnosis and treatment planning. This research may pave the way for a more comprehensive understanding of the mechanisms underlying post-stroke cognitive impairment and dementia, ultimately leading to improved strategies for patient care and rehabilitation.Item Neuroinflammation and gut diversity effects due to opioid self-administration(2024-03-21) Brunetti, Kaylee; Shuchi, Samia; Colon-Perez, LuisPurpose: Opioids are a great resource to treat pain in humans, but prolonged use can lead users to physical dependence and opioid use disorders (OUD). The use of opioids increases the risk of developing OUDs in humans via activation ofμ-opioid receptors. OUD is extensively studied for its effects in the central nervous system including the brain; however, Gut-Brain Axis (GBA) research will potentially expand our understanding of addiction and provide a new paradigm for developing new substance use disorder (SUD) therapeutics. GBA in animal models of OUDs can elucidate the complex interactions between the brain and gut that lead to pathological drug seeking and consumption and their relation to GBA components (i.e., bacterial populations, gut peptides, and gut signaling). In this study, we will share the determining temporal hallmarks of gut alterations in rats self-administering morphine for 15 days and relate it to neuroinflammatory features in the brain. One of our hypotheses is that abuse of drugs, such as morphine, starts by inducing inflammation of the brain and gut taxonomic changes similar to those observed in human opioid users. Methods: In this project, we used Sprague Dawley (SD) rats, and both the experimental and control groups were surgically implanted with intravenous (IV) catheters. The control group was exposed to the self-administration box, but only received sucrose pellets instead of morphine to avoid differences in behavior due to instrument learning or exposure to self-administration chambers. The experimental group was trained to self-administer morphine dosed to their body weight of 0.4 mg/kg for 14 days. The experimental timeline was (1) baseline: 7 days after catheter implantation, (2) acute: 24 hours after the second day of self-administration, and (3) chronic: 24 hours after completion of the 12 days of self-administration. Fecal samples were acquired at the three-time points and analyzed with 16s DNA sequencing to determine the relative abundance of microbial species at the time points. After the last day, we collected the brains from all animals and prepared tissue FFPE for immunohistochemistry and spatial transcriptomics analysis. Concurrently we acquired MRI diffusion-weighted scans in a 7.0 T preclinical scanner. Rats were restrained under sedation (isoflurane 5% induction, 2% maintenance) reducing the stressor of noise and restriction while scanning. This project will help us identify whether neuroinflammation markers occur due to large doses of morphine repetitively in rodents. Results: Preliminary analysis points out that chronic and voluntary administration of morphine leads to a neuroinflammatory response in the habenula possibly detected with diffusion MRI. Our preliminary16s DNA sequencing analysis has shown some key microbiome differences in our experimental drug group versus our control pellet group. Conclusion: As we continue analyzing our data, we hope to provide more insight on early effects of chronic drug use on gut-brain axis.Item Tractography as a method for mapping brain connectivity(2024-03-21) Spann, Claire; Yang, Shaohua; Liu, Ran; Berry, Raymond; Ampofo, Hannah; Colon-Perez, LuisPurpose. Mapping the brain and its complex connectivity has proved a challenging feat for neuroscience, though with the development of diffusion tensor imaging and tractography, we are one step closer to understanding brain anatomical connections. This method utilizes diffusion-weighted magnetic resonance imaging, which takes advantage of the Brownian motion of water molecules, to produce a diffusion tensor. In the white matter of the brain, diffusion varies in direction due to cellular membranes and myelin, and the diffusion tensor measures this anisotropic diffusivity to indicate possible tissue orientation. The generalized q-sampling imaging tractography method, developed by Frank Yeh in 2010, uses the diffusion tensor to approximate the course of white matter tracts and can be used to determine the exact location and termination of white matter bundles to assess connectivity between and within different brain regions. Despite limitations that decrease the accuracy of white matter tracking, tractography remains the only method to visualize white matter trajectories in vivo and non-invasively. Though commonly used for human diffusion-weighted images, here we verify tractography as a method to visualize and measure white matter trajectories in the rat brain. Methods. A male 3-month Sprague Dawley rat was used to acquire DWI images that were analyzed using DSI Studio. The DWI was superimposed with the corresponding T2W image and regions of interest (ROIs) were drawn in the corpus callosum and were applied via the built-in Waxholm Space rat atlas. Fiber tracking was seeded from the ROI, and fractional anisotropy, quantitative anisotropy, isotropy, mean diffusivity, axial diffusivity, and radial diffusivity was calculated at each ROI by DSI software. Results. Tractography of the corpus callosum was easily visualized using both drawn and atlas-applied ROIs. Fiber tractography from both ROIs included fibers from the internal and external capsules to ensure the integrity of all corpus callosum fibers. Diffusion metrics were not drastically different between the two seeding methods. Conclusion. This study presents tractography as a tool for visualizing white matter tracts and quantifying different diffusion metrics. Using both hand-drawn regions and regions from the rat atlas, white matter tracts in diseased brains can be compared to controls to measure several aspects of pathology, such as edema, axonal integrity, and axonal density. One application includes the imaging and quantification of both acute and chronic stroke, which exhibit different pathologies that can be visualized and measured with diffusion metrics, allowing for more precise targets of therapy. The use of tractography in adjunct with other established methods can improve the understanding of disease and assist in the development of better treatment.