Brain energy metabolism and neurotransmission at near‐freezing temperatures: in vivo¹H MRS study of a hibernating mammal

Abstract

The brain of a hibernating mammal withstands physiological extremes that would result in cerebral damage and death in a non-hibernating species such as humans. To examine the possibility that this neuroprotection results from alterations in cerebral metabolism, we used in vivo 1 H NMR spectroscopy at high field (9.4 T) to measure the concentration of 18 metabolites (neurochemical profile) in the brain of 13-lined ground squirrels (Spermophilus tridecemlineatus) before, during, and after hibernation. Resolved in vivo 1 H NMR spectra were obtained even at low temperature in torpid hibernators (7°C).The phosphocreatine-to-creatine ratio was increased during torpor (+143%) indicating energy storage, and remained increased to a lesser extent during interbout arousal (IBA) (+83%). The total c-aminobutyric acid concentration was increased during torpor (+135%) and quickly returned to baseline during IBA. Glutamine (Gln) was decreased ()54%) during torpor but quickly returned to normal levels during IBA and after terminal arousal in the spring. Glutamate (Glu) was also decreased during torpor ()17%), but remained decreased during IBA ()20% compared with fall), and returned to normal level in the spring. Our observation that Glu and Gln levels are depressed in the brain of hibernators suggests that the balance between anaplerosis and loss of Glu and Gln (because of glutamatergic neurotransmission or other mechanisms) is altered in hibernation. Keywords: anaplerosis, brain, glutamate-glutamine cycle, ground squirrel, hibernation, magnetic resonance spectroscopy. The adult human brain is responsible for 20% of the body's oxygen consumption despite constituting only 2% of body weight. In contrast to the high energy demand of the human brain, torpid hibernators show a reduction in O 2 consumption by as much as 50-fold and a 10-fold reduction in cerebral blood flow, when compared with a non-hibernating animal (Frerichs et al. 1995). This considerable decrease in energy consumption is accompanied by specialized physiological adaptations including body temperature reduction approaching 0°C and a decrease in heart rate from 300 beats/min to 5-10 beats/min [reviewed in (Boyer and Barnes 1999;Frerichs 1999;Drew et al. 2001;Zhou et al. 2001;Carey et al. 2003)]. Hibernation is a regulated process involving metabolic depression (Hochachka 1986) that is controlled, in part, by the differential expression of genes common to all

Quantitative analysis of liver metabolites in three stages of the circannual hibernation cycle in 13-lined ground squirrels by NMR

“…Because of the low T b of torpor, this degradation of ATP is likely slowed in LT animals. Nevertheless, these results make it unlikely that ATP is severely depleted during LT and are consistent with an earlier report demonstrating elevated hepatic ATP in LT animals (46) as well as a recent report demonstrating increased brain energy stores in torpid hibernators by in vivo magnetic resonance spectroscopy (23). The phospholipid precursors PC and total PME were significantly decreased in LT hibernators compared with SA (down 3.9-and 5.3-fold, respectively), with no significant differences found between Ent hibernators and SA animals.…”

Adaptive mechanisms regulate preferred utilization of ketones in the heart and brain of a hibernating mammal during arousal from torpor

“…1). In vivo high-field proton NMR (9.4 Tesla) of active and hibernating ground squirrel brains also showed an increase in brain glucose concentrations during IBAs with no increase in lactate (10). The increase in serum glucose levels during IBAs is intriguing because our experimental animals did not consume food for periods ranging from 1.5 to 4.5 mo.…”

Hibernation induces pentobarbital insensitivity in medulla but not cortex

“…The GABAergic system is a logical candidate for the induction and maintenance of systemwide CNS inhibition during torpor. However, the role of GABA in hibernation is unclear because GABA levels in torpid animals were reported to either increase by 135% in cortex using proton nuclear magnetic resonance spectroscopy (20), or decrease by 50% in the striatum using microdialysis (49). Because there is no observable neuronal activity in the forebrain at low temperatures during torpor (67,13), it is unlikely that synaptically released GABA is playing a prominent role in neuronal silencing during torpor.…”