Central nervous system regulation of mammalian hibernation: implications for metabolic suppression and ischemia tolerance

Abstract

Torpor during hibernation defines the nadir of mammalian metabolism where whole animal rates of metabolism are decreased to as low as 2% of basal metabolic rate. This capacity to decrease profoundly the metabolic demand of organs and tissues has the potential to translate into novel therapies for the treatment of ischemia associated with stroke, cardiac arrest or trauma where delivery of oxygen and nutrients fails to meet demand. If metabolic demand could be arrested in a regulated way, cell and tissue injury could be attenuated. Metabolic suppression achieved during hibernation is regulated, in part, by the central nervous system through indirect and possibly direct means. In this study, we review recent evidence for mechanisms of central nervous system control of torpor in hibernating rodents including evidence of a permissive, hibernation protein complex, a role for A1 adenosine receptors, mu opiate receptors, glutamate and thyrotropin-releasing hormone. Central sites for regulation of torpor include the hippocampus, hypothalamus and nuclei of the autonomic nervous system. In addition, we discuss evidence that hibernation phenotypes can be translated to non-hibernating species by H(2)S and 3-iodothyronamine with the caveat that the hypothermia, bradycardia, and metabolic suppression induced by these compounds may or may not be identical to mechanisms employed in true hibernation.

Fig. 1

Seasonal cycle of hibernation, reproduction and fattening in Arctic ground squirrels (AGS). AGS are obligate hibernators with a pronounced circannual cycle. The gray bar in the upper panel highlights a single torpor bout within repeated torpor bouts that occur throughout the hibernation season spanning from September to April. Our model proposes that during the hibernation season a photic-entrained signaling molecule sensitizes the adenosinergic system or alters responsiveness of downstream components of sleep promoting pathways.

Fig. 2

Hypothesized mechanisms regulating onset, maintenance and arousal from an individual torpor bout. This process repeats itself in a regular manner throughout the hibernation season as shown in Fig. 1. Adenosine (1) is hypothesized to initiate the onset of torpor through sleep promoting mechanisms and through a decrease in T_set within the POAH. The decrease in T_set (2) results in an immediate decrease in metabolism via decreased heat production. HR and RR then decrease due to activation of PSNS and decreased energy demand. Direct influence on ANS may also contribute to metabolic suppression. Subsequent cooling (3) decreases neuronal activity. Cooling-induced decrease in activity of medial septohippocampal neurons decreases theta rhythm until EEG becomes isoelectric. Cooling also produces additional metabolic suppression through temperature-dependant (Q₁₀) reductions in metabolic processes. Torpor is maintained via temperature dependent suppression of biochemical processes, -Opioid receptor activation and possibly via melatonin-mediated inhibition of respiration, and glu stimulation of PSNS or glu and HA stimulation of inhibitory pathways influencing arousal. Arousal is hypothesized to result from depletion of a signaling molecule, such as Glu or HA and activation of the SNS via TRH. ADO (adenosine); BF (basal forebrain); LH (lateral hypothalamus); POAH (preoptic anterior hypothalamus); ACh (acetylcholine); HPC (hippocampus); H/Ox (hypocretin/Orexin); Tset (threshold temperature of hypothalamus necessary to induce thermogenesis); PSNS (parasympathetic nervous system), ANS (autonomic nervous system); VO₂ (whole animal oxygen consumption); HR (heart rate); RR (respiratory rate); T_b (core body temperature); Q₁₀ (ratio of reaction rates for a 10°C change in tissue temperature); SCN (suprachiasmatic nucleus); Glu (glutamate); HA (histamine); TRH (thyrotropin-releasing hormone); SNS (sympathetic nervous system); IBE (interbout euthermy).