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ItemRepeated Daily Drinking-in-the-Dark Results in Inflexible Ethanol Drinking in C57BL/6J Mice(Office of the Vice Chancellor for Research, 2015-04-17) Companion, Michel A.; Boehm II, Stephen L.We recently demonstrated that repeated daily binge ethanol (EtOH) intake (Drinking-in-the-Dark; DID) alters the pattern of subsequent binge drinking, suggesting neuroadaptation as a consequence of repeated binge drinking. The current objective was to determine whether repeated binge drinking behavior using DID procedures produces a compulsive pattern of drinking. We took advantage of a paradigm in which the aversive stimulus quinine is used to adulterate the EtOH solution after a history of EtOH drinking. Using this approach, Lesscher et al. (2010) demonstrated that C57BL/6J (B6) mice develop inflexible drinking after repeated binge-like EtOH drinking; that is, mice with longer drinking histories become insensitive to the quinine addition, “compulsively” consuming the EtOH solution despite the aversive stimulus. Seventy male B6 mice (PND 60) from Jackson Laboratory were randomly assigned to one of seven fluid consumption groups using DID procedures (daily 2hr EtOH access, 3 hrs into the dark cycle). The first group received access to a 20% (v/v) EtOH in tap water for 6 weeks. The second group also received access to the EtOH solution for six weeks, but with the addition of a low concentration of quinine (0.35mM) that produces minimal avoidance in naïve B6 mice in the sixth week. The third group was treated similarly; however, on the sixth week a higher concentration of quinine (0.45mM) that produces clear avoidance in naïve B6 mice was added to the EtOH solution. The fourth and fifth groups received access to the EtOH solution two weeks prior to adulteration with the low or high quinine concentration, respectively, for one week. Groups six and seven were allowed access to the EtOH solution for one week before the lower or higher concentrations of quinine were added, respectively, for one week. Two naïve groups with no previous DID exposure were also presented with low or high concentrations of quinine adulterated EtOH solution for comparison. We predicted that daily binge EtOH drinking for two and five weeks (but not one week) would result in resistance to the aversive quinine (inflexible drinking). However, results showed that even one week of DID produced inflexible drinking. Future studies are planned to examine binge drinking durations within the first week of DID to determine precisely when this shift to more compulsive drinking occurs. This work was supported by NIH grants AA007611 (SLB) and GM109432 (MAC). Item"Wired," yet intoxicated: modeling binge caffeine and alcohol co-consumption in the mouse(Wiley Blackwell (Blackwell Publishing), 2014-08) Fritz, Brandon M.; Companion, Michel; Boehm, Stephen L.; Department of Psychology, IU School of ScienceBACKGROUND: The combination of highly caffeinated "energy drinks" with alcohol (ethanol [EtOH]) has become popular among young adults and intoxication via such beverages has been associated with an elevated risk for harmful behaviors. However, there are discrepancies in the human literature regarding the effect of caffeine on alcohol intoxication, perhaps due to confounding factors such as personality type, expectancy, and history of exposure. Animal models of co-exposure are resistant to such issues; however, the consequences of voluntary co-consumption have been largely ignored in the animal literature. The primary goal of this work was to characterize a mouse model of binge caffeine and EtOH co-consumption employing the limited access "Drinking-in-the-Dark" (DID) paradigm. METHODS: Caffeine was added to a 20% alcohol solution via DID. Alcohol/caffeine intake, locomotor behavior, ataxia, anxiety-like behavior, and cognitive function were evaluated as a consequence of co-consumption in adult male C57BL/6J mice. RESULTS: Caffeine did not substantially alter binge alcohol intake or resultant blood EtOH concentrations (BECs), nor did it alter alcohol's anxiolytic effects on the elevated plus maze or cognitive-interfering effects in a novel object-recognition task. However, no evidence of alcohol-induced sedation was observed in co-consumption groups that instead demonstrated a highly stimulated state similar to that of caffeine alone. The addition of caffeine was also found to mitigate alcohol-induced ataxia. CONCLUSIONS: Taken together, our mouse model indicates that binge co-consumption of caffeine and alcohol produces a stimulated, less ataxic and anxious, as well as cognitively altered state; a state that could be of great public health concern. These results appear to resemble the colloquially identified "wide awake drunk" state that individuals seek via consumption of such beverages. This self-administration model therefore offers the capacity for translationally valid explorations of the neurobiological consequences of binge co-consumption to assess the public health risk of this drug combination. ItemUsing MaxMSP to Integrate Learning of Physics and Music(Office of the Vice Chancellor for Research, 2015-04-17) Tyson II, Alan B.; Deal, ScottThis project integrates musical activity with the learning of concepts in areas such as physics and computer science. While the expression of musical ideas utilizes the laws of physics on many levels, the study of the two fields often is disparate. Traditional music education does little to promote understanding of the scientific concepts behind disciplines such as acoustics. Similarly, the field of acoustics only tangentially addresses issues relatable to a student educated in the traditional U.S. music system. The goal of this research is to develop a computer software application that will more closely integrate learning and understanding of both music and the physics of sound, which is the scientific field of acoustics. This work will take place utilizing the MaxMSP programming environment, which enables the construction of small applications known as Max Patches. These patches can be tailored in an infinite number of ways for teaching, study, and musical expression. The Max patch to be developed will include a virtual keyboard, an oscillator, and a series of computer objects that will visually output mathematical information based on the waveform that is created by the notes on the keyboard. Hence the virtual keyboard will provide understanding into basic acoustics through the exposition of the fundamental musical waveforms and the underlying principles of their nature. Playing the notes on the keyboard serves two purposes. First, it will help participants grasp basic musical concepts such as note memorization and relative pitch. Simultaneously, it will expose subjects to a visual approach to understanding the physics of the notes being played. The goal is to more closely integrate scientific understanding of sound while teaching the user to engage those concepts in a musical fashion. ItemChlorpyrifos Oxon Primes Microglia: Enhanced LPS-Induced TNFα Production(Office of the Vice Chancellor for Research, 2016-04-08) Kouame, Elaine; Brookins, Savannah; Jayaraj, Richard L.; Taetzsch, Thomas; Mumaw, Christy; Block, Michelle L.Microglia, the resident innate immune cells of the brain, respond to various environmental stimuli, including factors from surrounding tissue and from systemic inputs. These stimuli impact microglial function in both health and disease. Increasing evidence implicates microglia and neuroinflammation in Gulf War illness (GWI) pathology. Gulf War illness is an untreatable chronic multi symptomatic disorder that affects about 30% of Gulf War veterans. It has been proposed that “multiple hits” from exposure to various environmental neurotoxicants such as Chlorpyrifos (CPF), an organophosphate pesticide, combined with low inflammation may initiate exaggerated and persistent central nervous system (CNS) pathology to drive GWI. CPF oxon, an active metabolite of CPF, is associated with deleterious CNS effects, but the role of microglia behind this phenomenon is not fully understood.To investigate the effects of CPF oxon on microglia, we assessed microglial ROS, pro-inflammatory cytokine factors, and NF-κB p50 DNA binding activity in the presence of CPF oxon. HAPI microglia cells were treated with CPF oxon (1μM-1nM), which resulted in a dose dependent increase in H2O2 production at 3 hours and elevated superoxide at 30 minutes. CPF oxon failed to initiate TNFα and nitric oxide from microglia cultures. However, CPF oxon significantly decreased NF-κB p50 binding to DNA in microglia, a key redox signaling mechanism linked to microglial priming. Consistent with this premise, pre-treatment with CPF oxon (0.5μM) amplified LPSinduced TNFα production in microglia and neuron-glia cultures. Moreover, when CPF oxon and LPS challenged cells were pre-treated with DPI, a NOX2 inhibitor, we found a significant reduction in TNFα response when compared to non-treated cells, supporting that NOX2 may regulate CPF oxon priming in microglia. These data suggest that CPF oxon may induce ROS production in microglia to reprogram these cells to become more sensitive to pro-inflammatory stimuli (priming). ItemIdentifying Factors that Impact the Educational Success of Veterans at IUPUI(Office of the Vice Chancellor for Research, 2016-04-08) Parrish, Blake K.; Salyers, Michelle P.; Rattray, NicholasIncreased post-secondary enrollment among US military veterans using benefits from the Post-9/11 Veterans Educational Assistance Act of 2008 has led to a newfound emphasis on expanded student services on college campuses. We examined academic performance, social support, and mental health through a cross-sectional survey of 101 Veterans who were enrolled in at least one course at IUPUI in the last 12 months in order to identify barriers and facilitators to academic success. In addition to educational outcomes, we also assessed a variety of measures related to community reintegration, quality of life, and resilience. We conceptualized academic success as higher GPA, student status, and lower levels of reported difficulty in reintegration, concentrating in the classroom, and completing coursework. We hypothesized that use of student services and financial aid, involvement with student affairs, perceived social support, encountered barriers, and completion of transition assistance programs were expected to influence success variables. More than half of participants reported experiencing educational barriers unique to their Veteran status, including moderate difficulties with concentration and completing tasks for school. Although high mean scores of grit, resilience, and perceived social support were recorded, high scores of reintegration difficulty suggest that the sample may be at probable risk for post-traumatic stress disorder and substance abuse. Despite these difficulties, most student Veterans did not report using Veteran specific resources, with only one in ten participants reporting any use of campus-based adaptive education services and psychological services. No significant difference was found between groups utilizing or failing to utilize 6 separate sources of financial aid, 6 services, and 9 types of student affairs. Our findings suggest potential ways to enhance current support programs. Future research that tracks longitudinal change and explores student experience in-depth may help explore mechanisms related to the academic success of military Veterans. ItemArtsmesh- An Incremental Development in Telematic Art(Office of the Vice Chancellor for Research, 2016-04-08) Tyson II, Alan B.; Deal, Scott; Fields, KennethWithin the past two decades, telematic art has pushed technological boundaries and created opportunities for artists to collaborate in ways that were not once possible. For example, Auksalaq, a telematic opera created by Scott Deal, DMA, in 2011, incorporates both JackTrip Audio and ConferenceXP Video. Some social media platforms such as Skype and Google Hangouts have also integrated audio and video within their interfaces in order to explore these possibilities; however, there are limitations that some practices have failed to address such as compressed (lossy) formats of audio and/or video. Similarly, other barriers such as high latency and minimal navigation control have often made network music performance (NMP) a limited experience and not an equal alternative to traditional, real-time performance. The purpose of this project is to help test a beta prototype of Artsmesh, a protocol that integrates high quality audio and video for live peer-to-peer (P2P) NMP. Artsmesh contains fourteen panels that are customizable to fit a wide range of network setups. It also incorporates Internet Protocol version 6 (IPv6), Open Sound Control (OSC), Jacktrip, ffmpeg, Youtube, along with other features, making it the ideal choice for artists that have focused/professional needs. The ability for Artsmesh to precisely route high quality audio also makes it a preferable option for recording and mixing engineers who participate in telematic collaborations. Artsmesh is a step forward for creating an environment that integrates necessary features for an optimal NMP platform. ItemAvenanthramides Prevent Osteoblast and Osteocyte Apoptosis and Induce Osteoclast Apoptosis in Vitro in an Nrf2-Independent Manner(MDPI, 2016-07-11) Pellegrini, Gretel G.; Morales, Cynthya C.; Wallace, Taylor C.; Plotkin, Lilian I.; Bellido, Teresita; Department of Anatomy & Cell Biology, IU School of MedicineOats contain unique bioactive compounds known as avenanthramides (AVAs) with antioxidant properties. AVAs might enhance the endogenous antioxidant cellular response by activation of the transcription factor Nrf2. Accumulation of reactive oxygen species plays a critical role in many chronic and degenerative diseases, including osteoporosis. In this disease, there is an imbalance between bone formation by osteoblasts and bone resorption by osteoclasts, which is accompanied by increased osteoblast/osteocyte apoptosis and decreased osteoclast apoptosis. We investigated the ability of the synthethic AVAs 2c, 2f and 2p, to 1-regulate gene expression in bone cells, 2-affect the viability of osteoblasts, osteocytes and osteoclasts, and the generation of osteoclasts from their precursors, and 3-examine the potential involvement of the transcription factor Nrf2 in these actions. All doses of AVA 2c and 1 and 5 µM dose of 2p up-regulated collagen 1A expression. Lower doses of AVAs up-regulated OPG (osteoprotegerin) in OB-6 osteoblastic cells, whereas 100 μM dose of 2f and all concentrations of 2c down-regulated RANKL gene expression in MLO-Y4 osteocytic cells. AVAs did not affect apoptosis of OB-6 osteoblastic cells or MLO-Y4 osteocytic cells; however, they prevented apoptosis induced by the DNA topoisomerase inhibitor etoposide, the glucocorticoid dexamethasone, and hydrogen peroxide. AVAs prevented apoptosis of both wild type (WT) and Nrf2 Knockout (KO) osteoblasts, demonstrating that AVAs-induced survival does not require Nrf2 expression. Further, KO osteoclast precursors produced more mature osteoclasts than WT; and KO cultures exhibited less apoptotic osteoclasts than WT cultures. Although AVAs did not affect WT osteoclasts, AVA 2p reversed the low apoptosis of KO osteoclasts. These in vitro results demonstrate that AVAs regulate, in part, the function of osteoblasts and osteocytes and prevent osteoblast/osteocyte apoptosis and increase osteoclast apoptosis; further, these regulatory actions are independent of Nrf2. ItemNrf2 regulates mass accrual and the antioxidant endogenous response in bone differently depending on the sex and age(Plos, 2017-02-02) Pellegrini, Gretel Gisela; Cregor, Meloney; McAndrews, Kevin; Morales, Cynthya Carolina; McCabe, Linda Doyle; McCabe, George P.; Peacock, Munro; Burr, David; Weaver, Connie; Bellido, Teresita; Department of Anatomy & Cell Biology, IU School of MedicineAccumulation of reactive oxygen species (ROS) is an important pathogenic mechanism underling the loss of bone mass and strength with aging and other conditions leading to osteoporosis. The transcription factor erythroid 2-related factor2 (Nrf2) plays a central role in activating the cellular response to ROS. Here, we examined the endogenous response of bone regulated by Nrf2, and its relationship with bone mass and architecture in the male and female murine skeleton. Young (3 month-old) and old (15 month-old) Nrf2 knockout (KO) mice of either sex exhibited the expected reduction in Nrf2 mRNA expression compared to wild type (WT) littermates. Nrf2 deletion did not lead to compensatory increase in Nrf1 or Nrf3, other members of this transcription factor family; and instead, Nrf1 expression was lower in KO mice. Compared to the respective WT littermate controls, female KO mice, young and old, exhibited lower expression of both detoxifying and antioxidant enzymes; young male KO mice, displayed lower expression of detoxifying enzymes but not antioxidant enzymes; and old male KO mice showed no differences in either detoxifying or antioxidant enzymes. Moreover, old male WT mice exhibited lower Nrf2 levels, and consequently lower expression of both detoxifying and antioxidant enzymes, compared to old female WT mice. These endogenous antioxidant responses lead to delayed rate of bone acquisition in female KO mice and higher bone acquisition in male KO mice as quantified by DXA and μCT, demonstrating that Nrf2 is required for full bone accrual in the female skeleton but unnecessary and even detrimental in the male skeleton. Therefore, Nrf2 regulates the antioxidant endogenous response and bone accrual differently depending on sex and age. These findings suggest that therapeutic interventions that target Nrf2 could be developed to enhance the endogenous antioxidant response in a sex- and age-selective manner. ItemDecoy peptide targeted to Toll-IL-1R domain inhibits LPS and TLR4-active metabolite morphine-3 glucuronide sensitization of sensory neurons(Springer Nature, 2017-06-16) Allette, Yohance M.; Kim, Youngsook; Randolph, Aaron L.; Smith, Jared A.; Ripsch, Matthew S.; White, Fletcher A.; Anesthesia, School of MedicineAccumulating evidence indicates that Toll-like receptor (TLR) signaling adapter protein interactions with Toll/Interleukin-1 Receptor (TIR) domains present in sensory neurons may modulate neuropathic pain states. Following ligand interaction with TLRs, TIR serves to both initiate intracellular signaling and facilitate recruitment of signaling adapter proteins to the intracytoplasmic domain. Although TLR TIR is central to a number of TLR signaling cascades, its role in sensory neurons is poorly understood. In this study we investigated the degree to which TLR TIR decoy peptide modified to include a TAT sequence (Trans-Activator of Transcription gene in HIV; TAT-4BB) affected LPS-induced intracellular calcium flux and excitation in sensory neurons, and behavioral changes due to TLR4 active metabolite, morphine-3-glucuronide (M3G) exposure in vivo. TAT-4BB inhibited LPS-induced calcium changes in a majority of sensory neurons and decreased LPS-dependent neuronal excitability in small diameter neurons. Acute systemic administration of the TAT-4BB reversed M3G-induced tactile allodynia in a dose-dependent manner but did not affect motor activity, anxiety or responses to noxious thermal stimulus. These data suggest that targeting TLR TIR domains may provide novel pharmacological targets to reduce or reverse TLR4-dependent pain behavior in the rodent. ItemElectroacupuncture Promotes Central Nervous System-Dependent Release of Mesenchymal Stem Cells(Wiley, 2017-05) Salazar, Tatiana E.; Richardson, Matthew R.; Beli, Eleni; Ripsch, Matthew S.; George, John; Kim, Youngsook; Duan, Yaqian; Moldovan, Leni; Yan, Yuanqing; Bhatwadekar, Ashay; Jadhav, Vaishnavi; Smith, Jared A.; McGorray, Susan; Bertone, Alicia L.; Traktuev, Dmitri O.; March, Keith L.; Colon-Perez, Luis M.; Avin, Keith; Sims, Emily; Mund, Julie A.; Case, Jamie; Deng, Shaolin; Kim, Min Su; McDavitt, Bruce; Boulton, Michael E.; Thinschmidt, Jeffrey; Calzi, Sergio Li; Fitz, Stephanie D.; Fuchs, Robyn K.; Warden, Stuart J.; McKinley, Todd; Shekhar, Anantha; Febo, Marcelo; Johnson, Phillip L.; Chang, Lung Ji; Gao, Zhanguo; Kolonin, Mikhail G.; Lai, Song; Ma, Jinfeng; Dong, Xinzhong; White, Fletcher A.; Xie, Huisheng; Yoder, Mervin C.; Grant, Maria B.; Ophthalmology, School of MedicineElectroacupuncture (EA) performed in rats and humans using limb acupuncture sites, LI-4 and LI-11, and GV-14 and GV-20 (humans) and Bai-hui (rats) increased functional connectivity between the anterior hypothalamus and the amygdala and mobilized mesenchymal stem cells (MSCs) into the systemic circulation. In human subjects, the source of the MSC was found to be primarily adipose tissue, whereas in rodents the tissue sources were considered more heterogeneous. Pharmacological disinhibition of rat hypothalamus enhanced sympathetic nervous system (SNS) activation and similarly resulted in a release of MSC into the circulation. EA-mediated SNS activation was further supported by browning of white adipose tissue in rats. EA treatment of rats undergoing partial rupture of the Achilles tendon resulted in reduced mechanical hyperalgesia, increased serum interleukin-10 levels and tendon remodeling, effects blocked in propranolol-treated rodents. To distinguish the afferent role of the peripheral nervous system, phosphoinositide-interacting regulator of transient receptor potential channels (Pirt)-GCaMP3 (genetically encoded calcium sensor) mice were treated with EA acupuncture points, ST-36 and LIV-3, and GV-14 and Bai-hui and resulted in a rapid activation of primary sensory neurons. EA activated sensory ganglia and SNS centers to mediate the release of MSC that can enhance tissue repair, increase anti-inflammatory cytokine production and provide pronounced analgesic relief.