Browsing by Subject "behavior"
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Item 1H NMR-Based Metabolic Signatures in the Liver and Brain in a Rat Model of Hepatic Encephalopathy(ACS, 2020) Pathania, Anjana; Rawat, Atul; Dahiya, Sitender Singh; Dhanda, Saurabh; Barnwal, Ravi Pratap; Baishya, Bikash; Sandhir, Rajat; Surgery, School of MedicineHepatic encephalopathy (HE) is a debilitating neuropsychiatric complication associated with acute and chronic liver failure. It is characterized by diverse symptoms with variable severity that includes cognitive and motor deficits. The aim of the study is to assess metabolic alterations in the brain and liver using nuclear magnetic resonance (NMR) spectroscopy and subsequent multivariate analyses to characterize metabolic signatures associated with HE. HE was developed by bile duct ligation (BDL) that resulted in hepatic dysfunctions and cirrhosis as shown by liver function tests. Metabolic profiles from control and BDL rats indicated increased levels of lactate, branched-chain amino acids (BCAAs), glutamate, and choline in the liver, whereas levels of glucose, phenylalanine, and pyridoxine were decreased. In brain, the levels of lactate, acetate, succinate, citrate, and malate were increased, while glucose, creatine, isoleucine, leucine, and proline levels were decreased. Furthermore, neurotransmitters such as glutamate and GABA were increased, whereas choline and myo-inositol were decreased. The alterations in neurotransmitter levels resulted in cognitive and motor defects in BDL rats. A significant correlation was found among alterations in NAA/choline, choline/creatine, and NAA/creatine with behavioral deficits. Thus, the data suggests impairment in metabolic pathways such as the tricarboxylic acid (TCA) cycle, glycolysis, and ketogenesis in the liver and brain of animals with HE. The study highlights that metabolic signatures could be potential markers to monitor HE progression and to assess therapeutic interventions.Item Aromatase inhibitors produce hypersensitivity in experimental models of pain : studies in vivo and in isolated sensory neurons(2014) Robarge, Jason Dennis; Flockhart, David A.; Fehrenbacher, Jill C.; Khanna, Rajesh; Skaar, Todd C.; Vasko, Michael R.Aromatase inhibitors (AIs) are the current standard of care for the treatment of hormone receptor positive breast cancer in postmenopausal women. Nearly one-half of patients receiving AI therapy develop musculoskeletal toxicity that is characterized by joint and/or muscle pain and approximately one-fourth of patients discontinue their therapy as a result of musculoskeletal pain. Since there are no effective strategies for prevention or treatment, insight into the mechanisms of AI-induced pain is critical to improve treatment. However, there are few studies of AI effects in animal models of nociception. To determine whether AIs produce hypersensitivity in animal models of pain, I examined the effects of AI administration on mechanical, thermal, and chemical sensitivity in rats. The results demonstrate that (1) repeated injection of 5 mg/kg letrozole in male rats produces mechanical, but not thermal, hypersensitivity that extinguishes when drug dosing is stopped; (2) administering a single dose of 1 or 5 mg/kg letrozole in ovariectomized (OVX) rats also induces mechanical hypersensitivity, without altering thermal sensitivity and (3) a single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats augments flinching behavior induced by intraplantar ATP injection. To determine whether the effects of AIs on nociceptive behaviors are mediated by activation or sensitization of peptidergic sensory neurons, I determined whether letrozole exposure alters release of calcitonin gene-related peptide (CGRP) from isolated rat sensory neurons and from sensory nerve endings in rat spinal cord slices. No changes in basal, capsaicin-evoked or high extracellular potassium-evoked CGRP release were observed in sensory neuronal cultures acutely or chronically exposed to letrozole. Furthermore, letrozole exposure did not alter the ability of ATP to augment CGRP release from sensory neurons in culture. Finally, chronic letrozole treatment did not augment neuropeptide release from spinal cord slices. Taken together, these results do not support altered release of this neuropeptide into the spinal cord as mediator of letrozole-induced mechanical hypersensitivity and suggest the involvement of other mechanisms. Results from this dissertation provide a new experimental model for AI-induced hypersensitivity that could be beneficial in delineating mechanisms mediating pain during AI therapy.Item Caenorhabditis elegans as a model system to identify therapeutics for alcohol use disorders(Elsevier, 2019-06) Katner, Simon N.; Bredhold, Kristin E.; Steagall, Kevin B., III; Bell, Richard L.; Neal-Beliveau, Bethany S.; Cheong, Mi C.; Engleman, Eric A.; Psychiatry, School of MedicineAlcohol use disorders (AUDs) cause serious problems in society and few effective treatments are available. Caenorhabditis elegans (C. elegans) is an excellent invertebrate model to study the neurobiological basis of human behavior with a conserved, fully tractable genome, and a short generation time for fast generation of data at a fraction of the cost of other organisms. C. elegans demonstrate movement toward, and concentration-dependent self-exposure to various psychoactive drugs. The discovery of opioid receptors in C. elegans provided the impetus to test the hypothesis that C. elegans may be used as a medications screen to identify new AUD treatments. We tested the effects of naltrexone, an opioid antagonist and effective treatment for AUDs, on EtOH preference in C. elegans. Six-well agar test plates were prepared with EtOH placed in a target zone on one side and water in the opposite target zone of each well. Worms were treated with naltrexone before EtOH preference testing and then placed in the center of each well. Wild-type worms exhibited a concentration-dependent preference for 50, 70 and 95% EtOH. Naltrexone blocked acute EtOH preference, but had no effect on attraction to food or benzaldehyde in wild-type worms. Npr-17 opioid receptor knockout mutants did not display a preference for EtOH. In contrast, npr-17 opioid receptor rescue mutants exhibited significant EtOH preference behavior, which was attenuated by naltrexone. Chronic EtOH exposure induced treatment resistance and compulsive-like behavior. These data indicate that C. elegans can serve as a model system to identify compounds to treat AUDs.Item Direction Selectivity in Drosophila Proprioceptors Requires the Mechanosensory Channel Tmc(Elsevier, 2019-03-18) He, Liping; Gulyanon, Sarun; Mihovilovic Skanata, Mirna; Karagyozov, Doycho; Heckscher, Ellie S.; Krieg, Michael; Tsechpenakis, Gavriil; Gershow, Marc; Tracey, W. Daniel; Department of Computer and Information sciences, School of ScienceSummary Drosophila Transmembrane channel-like (Tmc) is a protein that functions in larval proprioception. The closely related TMC1 protein is required for mammalian hearing and is a pore-forming subunit of the hair cell mechanotransduction channel. In hair cells, TMC1 is gated by small deflections of microvilli that produce tension on extracellular tip-links that connect adjacent villi. How Tmc might be gated in larval proprioceptors, which are neurons having a morphology that is completely distinct from hair cells, is unknown. Here, we have used high-speed confocal microscopy both to measure displacements of proprioceptive sensory dendrites during larval movement and to optically measure neural activity of the moving proprioceptors. Unexpectedly, the pattern of dendrite deformation for distinct neurons was unique and differed depending on the direction of locomotion: ddaE neuron dendrites were strongly curved by forward locomotion, while the dendrites of ddaD were more strongly deformed by backward locomotion. Furthermore, GCaMP6f calcium signals recorded in the proprioceptive neurons during locomotion indicated tuning to the direction of movement. ddaE showed strong activation during forward locomotion, while ddaD showed responses that were strongest during backward locomotion. Peripheral proprioceptive neurons in animals mutant for Tmc showed a near-complete loss of movement related calcium signals. As the strength of the responses of wild-type animals was correlated with dendrite curvature, we propose that Tmc channels may be activated by membrane curvature in dendrites that are exposed to strain. Our findings begin to explain how distinct cellular systems rely on a common molecular pathway for mechanosensory responses.Item Effects of Nicotine Exposure in Adolescent Rats on Acquisition of Alcohol Drinking and Response to Nicotine in Adulthood(2009-09-30T19:25:40Z) Bracken, Amy L.; McBride, William J.; Chambers, R. Andrew; Murphy, James M.; Rodd, Zachary A.Nicotine is one of the most widely abused drugs in the world, and most smokers begin smoking during their adolescent years. Adolescence is a unique developmental period during which vulnerability to the effects of drug exposure is especially high. This dissertation uses rodent models to investigate the persistent effects of adolescent nicotine exposure on both neurobiological and behavioral measures of drug sensitivity in adulthood. The aims of this dissertation were to 1) determine whether nicotine would be self-administered into the posterior ventral tegmental area (pVTA), a neuroanatomical component of the mesolimbic dopamine (DA) system, which is known to be involved in reward and reinforcement; 2) investigate whether adolescent nicotine exposure would alter the sensitivity of the mesolimbic DA system as measured by DA release in the nucleus accumbens (NAc) in response to nicotine microinjections into the pVTA; 3) examine the effects of adolescent nicotine exposure on behavioral sensitization to nicotine in adulthood; and 4) investigate whether adulthood alcohol drinking behavior, in both Wistar and alcohol-preferring (P) rats, would be augmented by nicotine exposure during adolescence. Results of this dissertation demonstrated that 1) the pVTA is a neuroanatomical site that supports nicotine self-administration; and that adolescent nicotine exposure results in 2) increased nicotine-stimulated DA release in the NAc during adulthood; 3) augmented behavioral sensitization to nicotine in adult animals; and 4) enhanced acquisition of alcohol drinking behavior in adult Wistar and P rats. Overall, this dissertation provides insight into the diverse and persistent changes, in both neurobiology and behavior, caused by exposure to nicotine during the critical developmental period of adolescence.Item ELUCIDATING GENE SIGNATURES THAT CONTROL THE CIRCADIAN RHYTHM IN CYANOBACTERIA USING BIOINFORMATICS METHODS(Office of the Vice Chancellor for Research, 2012-04-13) Nandu, Tulip; Pradhan, Meeta; Palakal, Mathew J.Background: The daily light-dark cycle govern rhythmic changes in the behavior and physiology of most species. This circadian rhythm, or bi-ological “clock,” allows the organism to anticipate and prepare for the changes in the physical environment that are associated with day and night, thereby ensuring that the organism carry our specific processes at the right time of the day. Studies have found that the internal clock con-sists of an array of genes and the protein products they encode, which regulate various physiological processes throughout the body. Cyanothece sp. ATCC 51142 is an organism that has both photosynthetic (producing oxygen) and nitrogen fixing ability. The N2-fixing enzyme, nitrogenase, is highly sensitive to oxygen for which it has developed a temporal regula-tion in which N2 fixation and photosynthesis occur at different times throughout a diurnal cycle with very high levels of CO2 fixation during the light and high levels of N2 fixation in the dark. The mechanisms underly-ing the circadian rhythm and the signature genes elucidating this mecha-nism are addressed in this research. Objective: The objective is to integrate gene expression data with da-ta and knowledge from prior studies using bibliomics techniques, in the de novo construction of quasi-complete transcriptional regulatory networks to identify gene signatures in functional motifs and elucidate their role in circadian rhythms in cyanothece sp. ATCC 51142. Methodology: The sequence data of Transcription profiling time se-ries of cyanothece sp. ATCC 51142 grown in 12-hour light/12 hour dark then 24 h light from Array Express was used to construct the initial global regulatory network. Different network topological features (degree, betweeness and eccentricity) are used to identify the signature pathways during the day and night. The genes of the global regulatory network were used to construct networks of homologous species. The functions of the already known genes in well-studied homologous species were mapped to the function of the unannotated genes of cynaothece sp. ATCC 51142. Results: We have identified significant (p<0.05) signature pathways like photosynthesis, pantothenate and CoA biosynthesis and Glyoxylate and dicarboxylate metabolism that operate during the day. And during the night, pathways such as ribosome, riboflavin metabolism, and fatty acid biosynthesis sulfur metabolism were found to be significant (p<0.05). We will further investigate the genes that were already known to be significant using cyanobase database in a particular biological path-way and the novel genes that are identified by bibliomics approach.Item Healthcare providers’ beliefs and attitudes regarding risk compensation following HPV vaccination(Elsevier, 2016-05-28) Kasting, Monica L.; Wilson, Shannon; Dixon, Brian E.; Downs, Stephen M.; Kulkarni, Amit; Zimet, Gregory D.; Epidemiology, School of Public HealthBackground Provider recommendation is a significant predictor of HPV vaccine uptake. Prior research suggests that concerns regarding risk compensation could cause some providers to hesitate recommending the HPV vaccine. Methods During 15–30 min semi-structured interviews in early 2015, 22 U.S. pediatric providers were asked about their beliefs regarding sexual risk compensation and cervical cancer screening following HPV vaccination. Providers were asked if these beliefs result in reservations recommending the vaccine. Interviews were audio-recorded, transcribed, and analyzed using inductive content analysis. Results None of the providers believed the HPV vaccine would result in risky sexual behavior. Half indicated it was better to start vaccination early, before sexual activity was a worry. Others noted that patients’ risky behavior decisions happen independently of vaccination. When providers were asked if they were concerned about decreased cervical cancer screening, half said they did not know and some stated they had never thought about it before. The main themes addressed were the significant time lapse between vaccination and screening and that women tend to get over-screened as opposed to under-screened. Conclusion Providers were generally in favor of HPV vaccination and do not perceive risk compensation as a barrier to HPV recommendation.Item Minimal Clinically Important Difference for the Rasch Neuropsychiatric Inventory Irritability and Aggression Scale for Traumatic Brain Injury(Elsevier, 2017) Malec, James F.; Hammond, Flora M.; Physical Medicine and Rehabilitation, School of MedicineObjective To determine the minimal clinically important difference (MCID) for a Rasch measure derived from the Irritability/Lability and Agitation/Aggression subscales of the Neuropsychiatric Inventory (NPI)—the Rasch NPI Irritability and Aggression Scale for Traumatic Brain Injury (NPI-TBI-IA). Design Distribution-based statistical methods were applied to retrospective data to determine candidates for the MCID. These candidates were evaluated by anchoring the NPI-TBI-IA to Global Impression of Change (GIC) ratings by participants, significant others, and a supervising physician. Setting Postacute rehabilitation outpatient clinic. Participants 274 cases with observer ratings; 232 cases with self-ratings by participants with moderate-severe TBI at least 6 months postinjury. Interventions Not applicable. Main Outcome Measure NPI-TBI-IA. Results For observer ratings on the NPI-TBI-IA, anchored comparisons found an improvement of 0.5 SD was associated with at least minimal general improvement on GIC by a significant majority (69%–80%); 0.5 SD improvement on participant NPI-TBI-IA self-ratings was also associated with at least minimal improvement on the GIC by a substantial majority (77%–83%). The percentage indicating significant global improvement did not increase markedly on most ratings at higher levels of improvement on the NPI-TBI-IA. Conclusions A 0.5 SD improvement on the NPI-TBI-IA indicates the MCID for both observer and participant ratings on this measure.Item Molecular targets of alcohol action: translational research for pharmacotherapy development and screening.(Elsevier, 2011) Gorini, Giorgio; Bell, Richard L.; Mayfield, R. Dayne; Department of Psychology, School of ScienceAlcohol abuse and dependence are multifaceted disorders with neurobiological, psychological, and environmental components. Research on other complex neuropsychiatric diseases suggests that genetically influenced intermediate characteristics affect the risk for heavy alcohol consumption and its consequences. Diverse therapeutic interventions can be developed through identification of reliable biomarkers for this disorder and new pharmacological targets for its treatment. Advances in the fields of genomics and proteomics offer a number of possible targets for the development of new therapeutic approaches. This brain-focused review highlights studies identifying neurobiological systems associated with these targets and possible pharmacotherapies, summarizing evidence from clinically relevant animal and human studies, as well as sketching improvements and challenges facing the fields of proteomics and genomics. Concluding thoughts on using results from these profiling technologies for medication development are also presented.Item Selection for High Alcohol Preference Drinking in Mice Results in Heightened Sensitivity and Rapid Development of Acute Functional Tolerance to Alcohol’s Ataxic Effects(Wiley, 2013-02) Fritz, Brandon M.; Grahame, Nicholas J.; Boehm, Stephen L. II; Department of Psychology, School of ScienceSelection for High Alcohol Preference Drinking in Mice Results in Heightened Sensitivity and Rapid Development of Acute Functional Tolerance to Alcohol’s Ataxic Effects Brandon M. Fritz , Nicholas J. Grahame , and Stephen L. Boehm II Indiana Alcohol Research Center and Department of Psychology, Indiana University – Purdue University Indianapolis, Indianapolis, IN 46202 Abstract Propensity to develop acute functional (or within session) tolerance to alcohol (ethanol) may influence the amount of alcohol consumed, with higher drinking associated with greater acute functional tolerance (AFT). The goal of the current study was to assess this potential correlated response between alcohol preference and AFT in second and third replicate lines of mice selectively bred for high (HAP2&3) and low (LAP2&3) alcohol preference drinking. Male and female mice were tested for development of AFT on a static dowel task which requires that animals maintain balance on a wooden dowel in order to prevent falling. On test day, each mouse received one (1.75g/kg; Experiment 1) or two (1.75g/kg and 2.0g/kg; Experiment 2) injections of ethanol; an initial administration before being placed on the dowel and in Experiment 2, an additional administration after the first regain of balance on the dowel. Blood samples were taken immediately after loss of balance (when BECs were rising) and at recovery (during falling BECs) in Experiment 1, and after first and second recovery in Experiment 2. It was found that HAP mice fell from the dowel significantly earlier and at lower BECs than LAP mice following the initial injection of ethanol and were therefore more sensitive to its early effects. Furthermore, Experiment 1 detected significantly greater AFT development (BECfalling - BECrising) in HAP mice as compared to LAP mice which occurred within ~30 min, supporting our hypothesis. However, AFT was not different between lines in Experiment 2, indicating that ~30–60 min following alcohol administration, AFT development was similar in both lines. These data show that high alcohol drinking genetically associates with both high initial sensitivity and very early tolerance to the ataxic effects of ethanol.