Abstract
Mammalian hibernation presents a unique opportunity to study naturally occurring neuroprotection. Hibernating ground squirrels undergo rapid and extreme physiological changes in body temperature, oxygen consumption, and heart rate without suffering neurological damage from ischemia and reperfusion injury. Different brain regions show markedly different activity during the torpor/arousal cycle: the cerebral cortex shows activity only during the periodic returns to normothermia, while the hypothalamus is active over the entire temperature range. Therefore, region-specific neuroprotective strategies must exist to permit this compartmentalized spectrum of activity. In this study, we use the Illumina HiSeq platform to compare the transcriptomes of these two brain regions at four collection points across the hibernation season: April Active, October Active, Torpor, and IBA. In the cerebral cortex, 1,085 genes were found to be differentially expressed across collection points, while 1,063 genes were differentially expressed in the hypothalamus. Comparison of these transcripts indicates that the cerebral cortex and hypothalamus implement very different strategies during hibernation, showing less than 20% of these differentially expressed genes in common. The cerebral cortex transcriptome shows evidence of remodeling and plasticity during hibernation, including transcripts for the presynaptic cytomatrix proteins bassoon and piccolo, and extracellular matrix components, including laminins and collagens. Conversely, the hypothalamic transcriptome displays upregulation of transcripts involved in damage response signaling and protein turnover during hibernation, including the DNA damage repair gene RAD50 and ubiquitin E3 ligases UBR1 and UBR5. Additionally, the hypothalamus transcriptome also provides evidence of potential mechanisms underlying the hibernation phenotype, including feeding and satiety signaling, seasonal timing mechanisms, and fuel utilization. This study provides insight into potential neuroprotective strategies and hibernation control mechanisms, and also specifically shows that the hibernator brain exhibits both seasonal and regional differences in mRNA expression.
Highlights
Hibernation is an adaptive phenotype which allows specific mammals to survive long periods at near-freezing temperatures with little or no food
Overview This study examined the transcriptome of the ground squirrel cerebral cortex and hypothalamus over the course of the hibernation season
Regional Specificity of Gene Expression The hypothalamus exhibited higher mRNA specificity than the cerebral cortex, with six times as many mRNAs that were at least 95% specific to this region (Figure 2). This includes the precursors for the pituitary hormones oxytocin and vasopressin (OXT and AVP), and pro-melanin-concentrating hormone (PMCH), the precursor for melanin-concentrating hormone, which were not found in the cerebral cortex
Summary
Hibernation is an adaptive phenotype which allows specific mammals to survive long periods at near-freezing temperatures with little or no food. Mammals enter a period of heterothermy, characterized by lengthy periods of low body temperature, metabolism, and heart rate called torpor bouts, interspersed with short periodic interbout arousals (IBAs) to normothermia (Figure 1). Thirteen-lined ground squirrels (Ictidomys tridecemlineatus) show a heart rate less than 5% of their normothermic rate, use only 2–3% of their normal oxygen levels, and maintain a body temperature of 2–10uC, physiological characteristics that would result in death for most mammals [1]. The brain is exposed to extreme fluctuations in temperature and blood flow during hibernation. Cerebral blood flow in thirteen-lined ground squirrels is reduced by 90% during torpor, levels that are normally ischemic in nonhibernators [2]. Identifying the molecular mechanisms orchestrating the extreme changes in physiology during hibernation, and the accompanying natural neuroprotection, could be an important contribution to the development of therapeutic strategies for the treatment and prevention of brain injury
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