Research Proposal

I.             Title of Project: 

          Analyzing the Impact of Brain Lesions, Medications, and Other Stimuli on Thermoregulation Response and Behavior Modification

II.           Statement of Purpose:            

               My senior research project will analyze the effect of brain lesions on temperature response and determine which areas of the brain’s thermoregulation centers cause response to extreme temperature. The primary question my senior research project will answer is “Which areas of the brain’s thermoregulatory centers cause response to noxious cold or hot stimuli?” While I will experiment on rats, the experimentation and conclusions can be extrapolated to the human body and its response to noxious cold and hot stimuli. Additionally, I am doing human data collection in a retrospective clinical study, which aims to see how prolonged exposure to extreme temperatures affects patient outcome.

III.          Background: 

              Thermoregulation is the process that allows the body to maintain its core internal temperature. All thermoregulation mechanisms return the body to homeostasis, which is the state of having an even internal temperature. Thermoregulation is fascinating to me, which led me to seek out an internship experience that would allow me to investigate thermoregulation mechanisms in further detail and depth. Over the summer, I interned in this laboratory (Systemic Inflammation Laboratory at Barrow Neurological Institute) and learned about selective lesions and rat surgery. I have taken anatomy & physiology, as well as AP Biology, AP Chemistry, and Catalase Chemistry.

IV.         Prior Research:

         Research on thermoregulation has been extensive; however, researchers have not yet definitively identified specific areas of the brain’s thermoregulation centers that affect response to noxious hot and cold stimuli. Two articles that piqued my interest in thermoregulation were “Skin temperature: its role in thermoregulation” and “Cellular and Molecular Bases of the Initiation of Fever,” as they explain thermoregulation and its relation to fever and hypothermia.

         “Bases of Initiation of Fever” defines fever as a defensive response and a common symptom of infection and systemic inflammation. The article discussed the effects of antibody PGE₂ and its role in suppressing fever. The research found that small amounts of PGE₂ antibody are not sufficient to suppress fever. This research is important to the field of thermoregulation as it shows that in small doses, PGE₂ is not effective at inciting homeostasis.

         The article “Skin Temperature” posed the question: Does skin temperature represent ambient temperature/serve as a feed-forward signal for thermoregulation OR Is the skin temperature like other body temperatures and provides feedback? The research conducted posed evidence for both feed-forward and feedback responses; the paper justified the treatment of skin temperature as a feedback signal, despite evidence of thermoreceptors found in organs that primarily assess the external environment, which suggests a role as a feed-forward signal. This research is very significant as answers to the questions posed may provide a new approach to achieving biological effects by blocking temperature signals with drugs.  

V.           Significance: 

                           Analyzing the effect of brain lesions on pain sensitivity and determining which areas of the brain’s thermoregulation centers influence response to noxious cold or hot stimuli is significant in emergency clinical response.  Currently, I am conducting a retrogressive clinical study with a medical student who was a former intern at the laboratory and examining injury conditions in times of extreme hot or cold weather. The medical student will use the data I analyze to examine how exposure to hot and cold weather after a traumatic injury will ultimately affect patient outcomes.

                           Rat models have shown that heating an injured rat leads to higher morbidity. As patients with traumatic injury are unable to thermoregulate on their own, their management and individualized treatment is very important. The research I am conducting now and in the spring has the capability to provide additional information to clinical response teams as to how they should treat the brain in times of extreme heat or cold. Knowing which specific area of a rat’s thermoregulation center affects their cognizant response to extreme temperature is vital, as the information can be then applied to humans in treatment of injuries that occur in times of direct exposure to extreme temperature.

VI.         Research Design & Methods: 

               Using a thermogradient apparatus, I will analyze position/time graphs to determine thermoregulation response in rats, which have been injected with temperature-altering medications. I will then assist my on-site mentor in performing lesions to the rat brain’s thermoregulation centers to compare and contrast position/time graphs between rats with and without lesions. I will be in the laboratory about 30 hours per week for three months.

VII.       Problems: 

               I do not foresee any significant issues that may occur during my senior research project, as my on-site mentor has planned for this project and the rats and all necessary equipment will be in the laboratory for the duration of my senior research project. However, if any problems do occur, I will seek help from my on-site mentor. If my knowledge of the experiment is not sufficient, I will use prior research articles on thermoregulation to aid me.

VIII.      Bibliography:

1.    Romanovsky AA. Skin temperature: its role in thermoregulation. Acta Physiol 210, 498–507, 2014.

2.    Ngampramuan S, Cerri M, Del Vecchio F, Corrigan JJ, Kamphee A, Dragic AS, Rudd JA, Romanovsky AA, Nalivaiko E. Thermoregulatory correlates of nausea in rats and musk shrews. Oncotarget 5: 1565-1575, 2014.

3.    Wanner SP, Yoshida K, Kulchitsky VA, Ivanov AI, Kanosue K, Romanovsky AA. Lipopolysaccharide-induced neuronal activation in the paraventricular and dorsomedial hypothalamus depends on ambient temperature. PLoS One 8: e75733, 2013.

4.    Almeida MC, Hew-Butler T, Soriano RN, Rao S, Wang W, Wang J, Tamayo N, Oliveira DL, Nucci TB, Aryal P, Garami A, Bautista D, Gavva NR, Romanovsky AA. Pharmacological blockade of the cold receptor TRPM8 attenuates autonomic and behavioral cold defenses and decreases deep body temperature. J Neurosci 32: 2086-2099, 2012.

5.    Romanovsky AA. The inflammatory reflex: the current model should be revised (Viewpoint). Exp Physiol 97: 1178-1179, 2012.

6.    Liu E, Lewis K, Al-Saffar H, Krall CM, Singh A, Kulchitsky VA, Corrigan JJ, Simons CT, Petersen SR, Musteata FM, Bakshi CS, Romanovsky AA, Sellati TJ, Steiner AA. Naturally occurring hypothermia is more advantageous than fever in severe forms of lipopolysaccharide- and Escherichia coli-induced systemic inflammation. Am J Physiol 302: R1372-R1383, 2012.

7.    Romanovsky AA. Selective brain cooling in humans: we don’t fly, but we walk just fine (Letter). J Appl Physiol 110: 577, 2011.

8.    Garami A, Shimansky YP, Pakai E, Oliveira DL, Gavva NR, Romanovsky AA. Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia. J Neurosci 30: 1435-1440, 2010.

9.    Romanovsky AA, Garami A. Prostaglandin riddles in energy metabolism: E is for excess, D is for depletion (Editorial). Am J Physiol 298: R1509-R1511, 2010.

10.Ferro TN, Goslar PW, Romanovsky AA, Petersen SR. Smoking in trauma patients: the effects on the incidence of sepsis, respiratory failure, organ failure and mortality. J Trauma 69: 308-312, 2010.

11.Steiner AA, Hunter JC, Phipps SM, Nucci TB, Oliveira DL, Roberts JL, Scheck AC, Simmons DL, Romanovsky AA. Cyclooxygenase-1 or -2 — which one mediates lipopolysaccharide-induced hypothermia? Am J Physiol 297: R485-R494, 2009.

12.Garami A, Almeida MC, Nucci TB, Hew-Butler T, Soriano RN, Pakai E, Nakamura K, Morrison SF, Romanovsky AA. Chapter 14. The TRPV1 channel in normal thermoregulation: What have we learned from experiments using different tools? In: Vanilloid Receptor TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders, ed. by Gomtsyan A, Faltynek CR. Hoboken, NJ: John Wiley & Sons, 2010, p. 351-402.

13.Tjølsen, A., Lund, A., Berge, O-G., Hole, K., An improved method for tail-flick testing with adjustment for tail-skin temperature. J. Neurosci. Meth., 26, 259, 1989.