Browsing by Author "Molkov, Yaroslav I."
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Item 25th Annual Computational Neuroscience Meeting: CNS-2016(BioMed Central, 2016-08-18) Sharpee, Tatyana O.; Destexhe, Alain; Kawato, Mitsuo; Sekulić, Vladisla; Skinner, Frances K.; Wójcik, Daniel K.; Chintaluri, Chaitanya; Cserpán, Dorottya; Somogyvári, Zoltán; Kim, Jae Kyoung; Kilpatrick, Zachary P.; Bennett, Matthew R.; Josić, Kresimir; Elices, Irene; Arroyo, David; Levi, Rafael; Rodriguez, Francisco B.; Varona, Pablo; Hwang, Eunjin; Kim, Bowon; Han, Hio-Been; Kim, Tae; McKenna, James T.; Brown, Ritchie E.; McCarley, Robert W.; Choi, Jee Hyun; Rankin, James; Popp, Pamela Osborn; Rinzel, John; Tabas, Alejandro; Rupp, André; Balaguer‑Ballester, Emili; Maturana, Matias I.; Grayden, David B.; Cloherty, Shaun L.; Kameneva, Tatiana; Ibbotson, Michael R.; Meffin, Hamish; Koren, Veronika; Lochmann, Timm; Dragoi, Valentin; Obermayer, Klaus; Psarrou, Maria; Schilstra, Maria; Davey, Neil; Ju, Huiwen; Hines, Michael L.; Chen, Liang; Kim, Jimin; Leahy, Will; Shlizerman, Eli; Birgolias, Justas; Gerkin, Richard C.; Crook, Sharon M.; Viriyopase, Atthaphon; Memmeshei, Raol-Martin; Dabaghian, Yuri; DeVuti, Justin; Perotti, Luca; Kim, Ammo J.; Fenk, Lisa M.; Lyu, Cheng; Malmon, Gabby; Zhao, Chang; Widmer, Yves; Sprecher, Simon; Halnes, Geir; Tuomo, Maki-Martun; Keller, Daniel; Petterson, Klas H.; Andreassen, Ole A.; Elnevoll, Gaute T.; Yamada, Yasnori; Steyn-Ross, Moira L.; Steyn-Ross, D. Alistair; Meijas, Jorge F.; Murray, John D.; Kennedy, Henry; Kruscha, Alexandra; Grewe, Jan; Lidner, Benjamin; Badel, Laurent; Kasumi, Ohta; Tsuchimoto, Yoshiko; Kazama, Hokto; Kahng, B.; Tam, Nicoladie D.; Pollonini, Luca; Zouridakis, George; Soh, Jaehyun; Kim, DaeEun; Yoo, Minsu; Palmer, S.E.; Culmone, Viviana; Bojak, Ingo; Ferrario, Andrea; Merriosn-Hort, Robert; Borisyuk, Roman; Kim, Chang Sub; Tezuka, Taro; Joo, Pangyu; Young-Ah, Rho; Burton, Shawn D.; Bard, G.; Marsalek, Petr; Kim, Hoon-Hee; Moon, Seok-hun; Lee, Do-won; Molkov, Yaroslav I.; Hamade, Khaldoun; Teka, Wondimu; Barnett, William H.; Kim, Taegyo; Markin, Sergey; Rybak, Ilya A.; Forrow, Csaba; Demutz, Harald; Demkó, László; Vörös, János; Dabaghian, Yuri; Babichev, Andrey; Huang, Haiping; Metzner, Christoph; Schwikard, Achim; Zurowski, Bartosz; Roach, James P.; Sander, Leonard M.; Zochowski, Michal R.; Skilling, Quinton M.; Ognjanovski, Nicolette; Aton, Sara J.; Zochowski, Michal; Wang, Sheng-Ju; Ouyang, Guang; Zhang, Mingsha; Wong, Michael; Zhou, Changsong; Robinson, Peter A.; Sanz-Leon, Paula; Drysdale, Peter M.; Fung, Felix; Abeysuriya, Romesh G.; Rennle, Chris J.; Zhao, Xuelong; Choe, Yoonsuck; Yang, Huei-Fang; Mi, Yuanyuan; Lin, Xiahoan; Wu, Si; Liedtke, Joscha; Schottdorf, Manual; Wolf, Fred; Yamamura, Yorkio; Wickens, Jeffery R.; Rumbell, Timothy; Ramsey, Julia; Reyes, Amy; Draguljić, Daniel; Hof, Patrick R.; Luebke, Jennifer; Weaver, Christina M.; He, Hu; Yang, Xu; Ma, Hailin; Xu, Zhiheng; Wang, Yuzhe; Baek, Kwangyeol; Morris, Laurel S.; Kundu, Prantik; Voon, Valerie; Agnes, Everton J.; Vogels, Tim P.; Giese, Martin; Kuravi, Pradeep; Vogels, Rufin; Seeholzer, Alexander; Podlaski, William; Ranjan, Rajnish; Vogels, Tim; Torres, Joaquin J.; Baroni, Fabiano; Latorre, Roberto; Varona, Pablo; Gips, Bart; Lowet, Eric; Roberts, Mark J.; de Weerd, Peter; Jensen, Ole; van der Eerden, Jan; Goodarzinic, Abdorreza; Niry, Mohammad; Valizadeh, Alireza; Pariz, Aref; Parsi, Shervin S.; Valizadeh, Alireza; Warburton, Julia M.; Marucci, Lucia; Tamagnini, Francesco; Brown, John; Tsaneva‑Atanasova, Krasimira; Kleberg, Florence I.; Triesch, Jochen; Moezzi, Bahar; Iannella, Nicolangelo; Schaworonkow, Natalie; Plogmacher, Lukas; Goldsworthy, Mitchell R.; Hordacre, Brenton; McDonnell, Mark D.; Ridding, Michael C.; Trisch, Jochen; Zaptocky, Martin; Smit, Daniel; Fouquet, Coralie; Trembleau, Alain; Dasgupta, Sakyasingha; Nishikawa, Isao; Aihara, Kazuyuki; Toyoizumi, Taro; Robb, Daniel T.; Mellen, Nick; Toporikova, Natalia; Tang, Rongxiang; Tang, Yi-Yuan; Kiser, Seth A.; Howard Jr., James H.; Tang, Yi-Yuan; Goncharenko, Julia; Davey, Neil; Schilstra, Marla; Steuber, Volker; Voronenko, Sergej O.; Linder, Benjamin; Ahamed, Tosif; Stephens, Greg; Yger, Pierre; Lefebvre, Baptiste; Spampinato, Giulia Lia Beatrice; Esposito, Elric; Stimberg, Marcel; Marre, Olivier; Choi, Hansol; Song, Min-Ho; Chung, SueYeon; Lee, Dan D.; Sompolinsky, Haim; Phillips, Ryan S.; Smith, Jeffrey; Chatzikalymniou, Alexandra Pierri; Ferguson, Katie; Skinner, Frances K.; Gajic, N. Alex Cayco; Clopath, Claudia; Silver, R. Angus; Gleeson, Padraig; Marin, Boris; Sadeh, Sadra; Quintana, Adrian; Cantarelli, Matteo; Dura‑Bernal, Salvador; Lytton, William W.; Davison, Andrew; Silver, Angus; Li, Luozheng; Zhang, Wenhao; Mi, Yuanyuan; Wang, Dahui; Wu, Sl; Song, Youngjo; Park, Sol; Choi, Ilhwan; Jeong, Jaeseung; Shin, Hee‑sup; Choi, Hannah; Pasupathy, Anitha; Shea-Brown, Eric; Huh, Dongsung; Sejnowski, Terrence J.; Vogt, Simon M.; Kumar, Arvind; Schmidt, Robert; Werdt, Stephen Van; Schiff, Steven J.; Veale, Richard; Scheutz, Matthias; Lee, Sang Wan; Gallinaro, Júlia; Rotter, Stefan; Sanz‑Leon, Paula; Robinson, Peter A.; Rubchinsky, Leonid L.; Cheung, Chung Ching; Ratnadurai‑Giridharan, Shivakeshavan; Shomali, Safura Rashid; Ahmadabadi, Majid Nili; Shimazaki, Hideaki; Rasuli, Nader; Zhao, Xiaochen; Rasch, Malte J.; Witting, Jens; Priesemann, Viola; Levina, Anna; Priesemann, Viola; Lizler, Joseph T.; Spinney, Richard E.; Rubinov, Mikail; Wibral, Michael; Bak, Ji Hyun; Pillow, Jonathan; Zaho, Yuan; Park, Memming; Kang, Jiyoung; Park, Hae‑Jeong; Jang, Jaeson; Paik, Se-Bum; Choi, Woochul; Lee, Changju; Jang, Jaeson; Paik, Se‑Bum; Song, Min; Lee, Hyeonsu; Yilmaz, Ergin; Baysal, Velt; Ozer, Mahmut; Koren, Veronika; Obermayer, Klaus; Saska, Daniel; Nowotny, Thomas; Chan, Ho Ka; Diamond, Alan; Hermann, Christoph S.; Murray, Micha M.; Ionta, Silvlo; Hutt, Axel; Lefebvre, Jérémie; Weidel, Philipp; Duarte, Renato; Morrison, Abigail; Iyer, Ramakrishnan; Mihalas, Stefan; Petrovici, Mihai A.; Leng, Luziwei; Breitwieser, Oliver; Stöckel, David; Bytschok, Ilja; Martel, Roman; Bill, Johannes; Schemmel, Johannes; Meier, Karlheinz; Esler, Timothy B.; Burkitt, Anthony N.; Grayden, David B.; Kerr, Robert R.; Tahayori, Bahman; Meffin, Hamish; Moezzi, Bahar; Iannella, Nicolangelo; McDonnell, Mark D.; Nolte, Max; Reimann, Michael W.; Muler, Eilif; Markram, Henry; Parziale, Antonio; Senatore, Rosa; Marcelli, Angelo; Maouene, M.; Skiker, K.; Neymotin, Samuel A.; Dura‑Bernal, Salvador; Seidenstein, Alexandra; Lakatos, Peter; Sanger, Terence D.; Lytton, William W.; Dura‑Bernal, Salvador; Menzies, Rosemary J.; McLauchlan, Campbell; van Albada, Sacha J.; Kedziora, David J.; Neymotin, Samuel; Kerr, Cliff C.; Ryu, Juhyoung; Lee, Sang-Hun; Lee, Joonwon; Lee, Hyang Jung; Lim, Daeseob; Lee, Jung H.; Wang, Jisung; Lee, Heonsoo; Jung, Nam; Quang, Le Anh; Maeng, Seung Eu; Lee, Tae Ho; Lee, Jae Woo; Park, Chang-hyun; Ahn, Sora; Moon, Jangsup; Choi, Yun Seo; Kim, Juhee; Jun, Sang Beom; Lee, Seungjun; Lee, Hyang Woon; Jo, Sumin; Jun, Eunji; Yu, Suin; Goetze, Felix; Lai, Pik‑Yin; Kwag, Jeehyun; Liang, Guangsheng; Jang, Hyun Jae; Filipovi, Marko; Reig, Ramon; Aertsen, Ad; Silberberg, Gilad; Kumar, Arvind; Bachmann, Claudia; Buttler, Simone; Jacobs, Heidi; Dillen, Kim; Fink, Gereon R.; Kukolja, Juraj; Kepple, Daniel; Giaffar, Hamza; Rinberg, Dima; Shea, Steven; Koulakov, Alex; Bahuguna, Jyotika; Tetzlaff, Tom; Kotaleski, Jeanette Hellgren; Kunze, Tim; Peterson, Andre; Knösche, Thomas; Kim, Minjung; Kim, Hojeong; Park, Ji Sung; Yeon, Ji Won; Kim, Sung-Phil; Lee, Chungho; Kim, Sung-Phil; Spiegler, Andreas; Petkoski, Spase; Palva, Matias J.; Jirsa, Viktor K.; Saggio, Maria L.; Siep, Silvan F.; Stacey, William C.; Bernard, Christophe; Choung, Oh‑hyeon; Jeong, Yong; Lee, Yong‑il; Jeong, Jaesung; Kim, Su Hyun; Lee, Jeungmin; Kwon, Jaehyung; Kralik, Jerald D.; Hwang, Dong‑Uk; Park, Sang-Min; Kim, Seongkyun; Kim, Hyoungkyu; Lim, Sewoong; Yoon, Sangsup; Park, Choongseok; Miller, Thomas; Clements, Katie; Hye Jr., Eoon; Issa, Fadi A.; Baek, JeongHun; Oba, Shigeyuki; Yoshimoto, Junichiro; Doya, Kenji; Ishii, Shin; Mosqueiro, Thiago S; Strube‑Bloss, Martin F.; Smith, Brian; Huerta, Ramon; Hadrava, Michal; Hlinka, Jaroslav; Bos, Hannah; Helias, Moritz; Welzig, Charles M.; Harper, Zachary J.; Kim, Won Sup; Shin, In-Seob; Baek, Hyeon-Man; Han, Seung Kee; Richter, René; Vitay, Julien; Beuth, Frederick; Hamker, Fred H.; Kameneva, Tatiana; Graham, Bruce P.; Kale, Penelope J.; Gollo, Leonardo L.; Stern, Merav; Abbott, L.F.; Fedorov, Leonid A.; Giese, Martin A.; Ardestani, Mohammad Hovaidi; Giese, Martin; Chakravarthy, V.Srinivasa; Chhabria, Karishma; Philips, Ryan T.; Ardestani, Mohammad Hovaidi; Faraji, Mohammad Java; Preuschoff, Kerstin; Gerstner, Wulfram; Briaire`, Jeroen J.; Kalkman, Randy K.; Frijns, Johan H. M.; Lee, Won Hee; Frangou, Sophia; Fulcher, Ben D.; Tran, Patricia H. P.; Fornito, Alex; Gliske, Stephen V.; Stacey, William C.; Holman, Katherine A.; Fink, Christian G.; Kim, Jinseop; Mu, Shang; Briggman, Kevin L; Seung, H. Sebastian; Wegener, Detlef; Bohnenkamp, Lisa; Ernst, Udo A.; Mäki‑Marttunen, Tuomo; Halnes, Geir; Devor, Anna; Dale, Anders M.; Andreassen, Ole A.; Einevoll, Gaute T.; Hagen, Espen; Lines, Glenn T.; Edwards, Andy; Tveito, Aslak; Senk, Johanna; van Albada, Sacha J; Diesmann, Markus; Schmidt, Maximilian; Bakker, Rembrandt; Shen, Kelly; Bezgin`, Gleb; Hilgetag`, Claus‑Christian; Sun, Haoqi; Sourina, Olga; Huang, Guang-Bin; Klanner, Felix; Denk, Cornelia; Glomb, Katharina; Ponce‑Alvarez, Adrián; Gilson, Matthieu; Ritter, Petra; Deco, Gustavo; Witek, Maria A. G.; Clarke, Eric F.; Hansen, Mads; Wallentin, Mikkel; Kringelbach, Morten L.; Vuust, Peter; Klingbeil, Guido; Schutter, Erik De; Chen, Weiliang; Hong, Sungho; Takashima, Akira; Zamora, Criseida; Gallimore, Andrew R.; Karoly, Philippa J.; Freestone, Dean R.; Soundry, Daniel; Kuhlmann, Levin; Paninski, Liam; Cook, Mark; Lee, Jaejin; Fishman, Yonatan I.; Cohen, Yale E.; Cocchi, Luca; Sweeney, Yann; Lee, Soohyun; Jung, Woo-Sung; Kim, Bowon; Kim, Youngsoo; Jung, Younginha; Rankin, James; Chavane, Frédéric; Soman, Karthik; Muralidharan, Vignesh; Shivkumar, Sabyasach; Mandall, Alekhya; Priyadharsini, B. Praga; Mehta, Hima; Brinkman, Braden A.; Kekona, Tyler; Rieke, Fred; Shea‑Brown, Eric; Buice, Michael; Pittà, Maurizio De; Berry, Hugues; Brunel, Nicolas; Breakspear, Michael; Marsat, Gary; Drew, Jordan; Chapman, Phillip D.; Daly, Kevin C.; Bradley, Samual P.; Seo, Sat Byul; Su, Jianzhong; Kavalali, Enge T.; Blackwell, Justin; Shiau, LieJune; Buhry, Laure; Basnayake, Kanishka; Lee, Sue-Hyun; Levy, Brandon A.; Baker, Chris I.; Leleu, Timothée; Aihara, Kazuyuki; Department of Mathematical Sciences, School of ScienceItem Balanced excitation and inhibition in temperature responses to meth(Taylor & Francis, 2014-10-30) Molkov, Yaroslav I.; Zaretsky, Dmitry V.; Department of Mathematical Sciences, School of ScienceFatal hyperthermia after administration of various amphetamines is well-known clinical phenomenon, however, there is no consistent theory explaining its etiology and/or pathogenesis. Dose-dependence of temperature responses to methamphetamine is intricate. Recently, using mathematical modeling it was suggested that delicate interplay of excitatory and inhibitory mechanisms underlies this complexity.Item Chemoreception and neuroplasticity in respiratory circuits(Elsevier, 2017-01) Barnett, William H.; Abdala, Ana P.; Paton, Julian F. R.; Rybak, Ilya A.; Zoccal, Daniel B.; Molkov, Yaroslav I.; Mathematical Sciences, School of ScienceThe respiratory central pattern generator must respond to chemosensory cues to maintain oxygen (O2) and carbon dioxide (CO2) homeostasis in the blood and tissues. To do this, sensorial cells located in the periphery and central nervous system monitor the arterial partial pressure of O2 and CO2 and initiate respiratory and autonomic reflex adjustments in conditions of hypoxia and hypercapnia. In conditions of chronic intermittent hypoxia (CIH), repeated peripheral chemoreceptor input mediated by the nucleus of the solitary tract induces plastic changes in respiratory circuits that alter baseline respiratory and sympathetic motor outputs and result in chemoreflex sensitization, active expiration, and arterial hypertension. Herein, we explored the hypothesis that the CIH-induced neuroplasticity primarily consists of increased excitability of pre-inspiratory/inspiratory neurons in the pre-Bötzinger complex. To evaluate this hypothesis and elucidate neural mechanisms for the emergence of active expiration and sympathetic overactivity in CIH-treated animals, we extended a previously developed computational model of the brainstem respiratory-sympathetic network to reproduce experimental data on peripheral and central chemoreflexes post-CIH. The model incorporated neuronal connections between the 2nd-order NTS neurons and peripheral chemoreceptors afferents, the respiratory pattern generator, and sympathetic neurons in the rostral ventrolateral medulla in order to capture key features of sympathetic and respiratory responses to peripheral chemoreflex stimulation. Our model identifies the potential neuronal groups recruited during peripheral chemoreflex stimulation that may be required for the development of inspiratory, expiratory and sympathetic reflex responses. Moreover, our model predicts that pre-inspiratory neurons in the pre-Bötzinger complex experience plasticity of channel expression due to excessive excitation during peripheral chemoreflex. Simulations also show that, due to positive interactions between pre-inspiratory neurons in the pre-Bötzinger complex and expiratory neurons in the retrotrapezoid nucleus, increased excitability of the former may lead to the emergence of the active expiratory pattern at normal CO2 levels found after CIH exposure. We conclude that neuronal type specific neuroplasticity in the pre-Bötzinger complex induced by repetitive episodes of peripheral chemoreceptor activation by hypoxia may contribute to the development of sympathetic over-activity and hypertension.Item Circadian variability of body temperature responses to methamphetamine(American Physiological Society, 2018-01) Behrouzvaziri, Abolhassan; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Zaretsky, Dmitry V.; Molkov, Yaroslav I.; Mathematical Sciences, School of ScienceVital parameters of living organisms exhibit circadian rhythmicity. Although rats are nocturnal animals, most of the studies involving rats are performed during the day. The objective of this study was to examine the circadian variability of the body temperature responses to methamphetamine. Body temperature was recorded in male Sprague-Dawley rats that received intraperitoneal injections of methamphetamine (Meth, 1 or 5 mg/kg) or saline at 10 AM or at 10 PM. The baseline body temperature at night was 0.8°C higher than during the day. Both during the day and at night, 1 mg/kg of Meth induced monophasic hyperthermia. However, the maximal temperature increase at night was 50% smaller than during the daytime. Injection of 5 mg/kg of Meth during the daytime caused a delayed hyperthermic response. In contrast, the same dose at night produced responses with a tendency toward a decrease of body temperature. Using mathematical modeling, we previously showed that the complex dose dependence of the daytime temperature responses to Meth results from an interplay between inhibitory and excitatory drives. In this study, using our model, we explain the suppression of the hyperthermia in response to Meth at night. First, we found that the baseline activity of the excitatory drive is greater at night. It appears partially saturated and thus is additionally activated by Meth to a lesser extent. Therefore, the excitatory component causes less hyperthermia or becomes overpowered by the inhibitory drive in response to the higher dose. Second, at night the injection of Meth results in reduction of the equilibrium body temperature, leading to gradual cooling counteracting hyperthermia.Item Exercise activates compensatory thermoregulatory reaction in rats: a modeling study(American Psychological Society, 2015-12-15) Yoo, Yeonjoo; LaPradd, Michelle; Kline, Hannah; Zaretskaia, Maria V.; Behrouzvaziri, Abolhassan; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.; Department of Mathematical Sciences, School of ScienceThe importance of exercise is increasingly emphasized for maintaining health. However, exercise itself can pose threats to health such as the development of exertional heat shock in warm environments. Therefore, it is important to understand how the thermoregulation system adjusts during exercise and how alterations of this can contribute to heat stroke. To explore this we measured the core body temperature of rats (Tc) running for 15 min on a treadmill at various speeds in two ambient temperatures (Ta = 25°C and 32°C). We assimilated the experimental data into a mathematical model that describes temperature changes in two compartments of the body, representing the muscles and the core. In our model the core body generates heat to maintain normal body temperature, and dissipates it into the environment. The muscles produce additional heat during exercise. According to the estimation of model parameters, at Ta = 25°C, the heat generation in the core was progressively reduced with the increase of the treadmill speed to compensate for a progressive increase in heat production by the muscles. This compensation was ineffective at Ta = 32°C, which resulted in an increased rate of heat accumulation with increasing speed, as opposed to the Ta = 25°C case. Interestingly, placing an animal on a treadmill increased heat production in the muscles even when the treadmill speed was zero. Quantitatively, this "ready-to-run" phenomenon accounted for over half of the heat generation in the muscles observed at maximal treadmill speed. We speculate that this anticipatory response utilizes stress-related circuitry.Item Mechanisms of Left-Right Coordination in Mammalian Locomotor Pattern Generation Circuits: A Mathematical Modeling View(PLoS, 2015-05) Molkov, Yaroslav I.; Bacak, Bartholomew J.; Talpalar, Adolfo E.; Rybak, Ilya A.; Department of Mathematical Sciences, School of ScienceThe locomotor gait in limbed animals is defined by the left-right leg coordination and locomotor speed. Coordination between left and right neural activities in the spinal cord controlling left and right legs is provided by commissural interneurons (CINs). Several CIN types have been genetically identified, including the excitatory V3 and excitatory and inhibitory V0 types. Recent studies demonstrated that genetic elimination of all V0 CINs caused switching from a normal left-right alternating activity to a left-right synchronized “hopping” pattern. Furthermore, ablation of only the inhibitory V0 CINs (V0D subtype) resulted in a lack of left-right alternation at low locomotor frequencies and retaining this alternation at high frequencies, whereas selective ablation of the excitatory V0 neurons (V0V subtype) maintained the left–right alternation at low frequencies and switched to a hopping pattern at high frequencies. To analyze these findings, we developed a simplified mathematical model of neural circuits consisting of four pacemaker neurons representing left and right, flexor and extensor rhythm-generating centers interacting via commissural pathways representing V3, V0D, and V0V CINs. The locomotor frequency was controlled by a parameter defining the excitation of neurons and commissural pathways mimicking the effects of N-methyl-D-aspartate on locomotor frequency in isolated rodent spinal cord preparations. The model demonstrated a typical left-right alternating pattern under control conditions, switching to a hopping activity at any frequency after removing both V0 connections, a synchronized pattern at low frequencies with alternation at high frequencies after removing only V0D connections, and an alternating pattern at low frequencies with hopping at high frequencies after removing only V0V connections. We used bifurcation theory and fast-slow decomposition methods to analyze network behavior in the above regimes and transitions between them. The model reproduced, and suggested explanation for, a series of experimental phenomena and generated predictions available for experimental testing.Item Meth math: modeling temperature responses to methamphetamine(American Physiological Society (APS), 2014-04-15) Molkov, Yaroslav I.; Zaretskaia, Maria V.; Zaretsky, Dmitry V.; Department of Emergency Medicine, IU School of MedicineMethamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.Item Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach(PLoS, 2015-05-20) Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.; Department of Emergency Medicine, IU School of MedicineExperimental Data Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t>60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t<60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. Mathematical Modeling We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods.Item Tissue oxidative metabolism can increase the difference between local temperature and arterial blood temperature by up to 1.3oC: Implications for brain, brown adipose tissue, and muscle physiology(Taylor & Francis, 2018-04-04) Zaretsky, Dmitry V.; Romanovsky, Andrej A.; Zaretskaia, Maria V.; Molkov, Yaroslav I.; Emergency Medicine, School of MedicineTissue temperature increases, when oxidative metabolism is boosted. The source of nutrients and oxygen for this metabolism is the blood. The blood also cools down the tissue, and this is the only cooling mechanism, when direct dissipation of heat from the tissue to the environment is insignificant, e.g., in the brain. While this concept is relatively simple, it has not been described quantitatively. The purpose of the present work was to answer two questions: 1) to what extent can oxidative metabolism make the organ tissue warmer than the body core, and, 2) how quickly are changes in the local metabolism reflected in the temperature of the tissue? Our theoretical analysis demonstrates that, at equilibrium, given that heat exchange with the organ is provided by the blood, the temperature difference between the organ tissue and the arterial blood is proportional to the arteriovenous difference in oxygen content, does not depend on the blood flow, and cannot exceed 1.3oC. Unlike the equilibrium temperature difference, the rate of change of the local temperature, with respect to time, does depend on the blood flow. In organs with high perfusion rates, such as the brain and muscles, temperature changes occur on a time scale of a few minutes. In organs with low perfusion rates, such changes may have characteristic time constants of tens or hundreds of minutes. Our analysis explains, why arterial blood temperature is the main determinant of the temperature of tissues with limited heat exchange, such as the brain.