Thesis (Ph.D.) University of Alaska Fairbanks, 2019Hibernation is a unique adaptation to conserve energy entering a hypometabolic (low metabolic rate) and hypothermic (low body temperature) state called torpor. Torpor is characterized by a drop in metabolism to 1-2% of basal metabolic rate and a decrease in body temperature to one to two degrees above ambient temperature. Metabolic rate is restored to basal metabolic rate and body temperature increases from 2-3⁰C to 36⁰C during the regularly timed arousal. The adenosine A1 receptor agonists promote the onset of hibernation and torpor in different species, through a yet undefined neuronal circuit. In the Arctic ground squirrel, CHA, an adenosine A1 receptor agonist, induces hibernation during the winter- hibernation season but not in summer even when the environmental conditions are kept constant (ambient temperature of 2⁰C and a light cycle of 4L:20D). Thus, the phenomenon of CHA-induced hibernation is entrained to an endogenous circannual rhythm. In this work, I aim to identify the changes in neuronal activation that reflect the circannual rhythm regulating the seasonal difference in response to CHA. Arctic ground squirrels, housed at constant ambient temperature (2°C) and light cycle (4L:20D), were implanted with body temperature transmitters. I collected tissue during Summer, Fall, Winter and Torpor conditions for seasonal analysis. For treatment analysis, I collected tissue form animals treated with CHA or vehicle in Summer and Winter. Primarily, I used immunohistochemistry to identify cell groups affected by season and treatment. I used cFos to identify neuronal activity and other immunohistochemical markers to identify neuronal phenotypes, based on specific cytoplasmic proteins. An overall seasonal decrease in thermogenesis, measured as reduced neuronal activity in the thermoregulatory pathways, and increase in vasoconstriction reflected the higher order processing necessary for CHA-induced hibernation. CHA inhibited the histaminergic neurons in the hypothalamus suppressing wakefulness and dis-inhibited the nucleus tractus solitarius, further suppressing thermogenesis. Preliminary data also suggested a seasonal change in the adenosine metabolic pathway, which may have increased adenosine receptor sensitivity during the hibernation season. Our results suggest that histaminergic neurons in the hypothalamus and the nucleus tractus solitarius are likely targets to manipulate metabolic demand in the clinical setting inducing therapeutic hypothermia or increasing metabolic rate.Institute of Arctic BiologyChapter 1: General introduction -- Chapter 2: The raphe pallidus and the hypothalamic-pituitary-thyroid axis gate seasonal changes in thermoregulation in the hibernating Arctic Ground Squirrel (Urocitellus Parryii) -- Chapter 3: Seasonal decrease in thermogenesis and increase in vasoconstriction explain seasonal response to N⁶-cyclohexyladenosine -induced hibernation in the Arctic Ground Squirrel (Urocitellus parryii) -- Chapter 4: Seasonal changes in adenosine kinase in tanycytes underlie the possible mechanism of adenosine-induced hibernation in the Arctic Ground Squirrel (Urocitellus parryii) -- Chapter 5: General conclusions -- Appendices
