Gene Expression in the Brain across the Hibernation Cycle

Abstract

The purpose of this study was to characterize changes in gene expression in the brain of a seasonal hibernator, the goldenmantled ground squirrel, Spermophilus lateralis, during the hibernation season. Very little information is available on molecular changes that correlate with hibernation state, and what has been done focused mainly on seasonal changes in peripheral tissues. We produced over 4000 reverse transcription-PCR products from euthermic and hibernating brain and compared them using differential display. Twenty-nine of the most promising were examined by Northern analysis. Although some small differences were observed across hibernation states, none of the 29 had significant changes. However, a more direct approach, investigating expression of putative hibernationresponsive genes by Northern analysis, revealed an increase in expression of transcription factors c-fos, junB, and c-Jun, but not junD, commencing during late torpor and peaking during the arousal phase of individual hibernation bouts. In contrast, prostaglandin D2 synthase declined during late torpor and arousal but returned to a high level on return to euthermia. Other genes that have putative roles in mammalian sleep or specific brain functions, including somatostatin, enkephalin, growth-associated protein 43, glutamate acid decarboxylases 65/67, histidine decarboxylase, and a sleep-related transcript SD464 did not change significantly during individual hibernation bouts. We also observed no decline in total RNA or total mRNA during torpor; such a decline had been previously hypothesized. Therefore, it appears that the dramatic changes in body temperature and other physiological variables that accompany hibernation involve only modest reprogramming of gene expression or steady-state mRNA levels.

Episode-Specific Differential Gene Expression of Peripheral Blood Mononuclear Cells in Rapid Cycling Supports Novel Treatment Approaches

“…There might well be an interaction between the prostaglandin system found to be episodically regulated here, in the described case, and these inflammatory molecules, also in the CNS (35,39,40). Intriguingly, altered expression of PTGDS marks the hibernation cycle, and accumulation of prostaglandins during hibernation season has been described in hibernating animals (18,22). Based on our molecular data, we speculate that the rapid cycling syndrome in humans may reflect an evolutionary ancient behavioral program resembling the hibernation cycle (with periodic eating, high psychomotor activity and nesting behavior, alternating with episodes of rest and sleep) (41,42) that becomes pathologically re-activated by unknown triggers, thereby creating rapid cycling.…”

“…Prostaglandin synthesis plays a pivotal role in metabolic homeostasis, sleep regulation, adipogenesis, allergic response, and inflammation (18)(19)(20)(21)(22). Altered levels of prostaglandins have been detected in different body fluids in patients with major affective disorders (23)(24)(25)(26)(27)(28).…”

Arousal from hibernation and BAT thermogenesis against cold: central mechanism and molecular basis

“…Since the entry of torpor is synchronized with the entry into sleep, the clock mechanism in SCN has been thought to be intimately associated with the induction of hibernation. A variety of evidence from divers hibernating species confirmed a relationship between SCN and hibernation mechanism (Satinoff, 1967;Kilduff et al, 1982;Kilduff et al, 1989;Dark et al, 1990;Kilduff et al, 1990;Bitting et al, 1994;Grahn et al, 1994;Ruby et al, 1996;Ruby et al, 1998;O'Hara et al, 1999). The contribution of SCN to circadian fluctuation of the body temperature is well documented in cenothermic animals and the existence of the circadian rhythmicity in body temperature was also reported in golden-mantled ground squirrels during the maintenance stage of hibernation (Grahn et al, 1994).…”

A simple molecular mathematical model of mammalian hibernation

“…These differentially expressed genes include α 2 -macroglobulin (Srere et al, 1995), the H3 histamine receptor (Sallmen et al, 2003), TBG (thyroxine binding globulin) (Epperson and Martin, 2002), and the 'early-intermediate' genes such as c-fos and c-jun (O'Hara et al, 1999). The role of these proteins in our model is unclear.…”