Hibernation timer mechanisms: What regulates torpor arousal cycling?
Relevance and knowledge gap
Hibernation is a physiological and behavioural adaptation that permits survival during periods of reduced food availability and low environmental temperatures by reducing energy expenditure. During the hibernation season, energy savings are greatest when animals are in a state of ‘torpor’ (metabolic rate can be as low as 1-2% of basal metabolic rate), and body temperature (Tb) falls to only a few degrees above ambient. In most hibernating species, this torpid state is not maintained continuously but is organised into multiday torpor bouts interspersed with briefer periods of ‘spontaneous arousal’ when metabolic rate and Tb rise to euthermic levels. While much has been written on why spontaneous arousals occur, despite the energy expenditure entailed, the issue of how mechanistically arousal is achieved has been neglected – and this outstanding mystery is the focus of this application. Understanding how hibernators can achieve torpor-arousal (T-A) cycling, recover from metabolic shut down, low Tb, and hypoxia has many potential healthcare applications, notably to stroke, surgery and organ cryopreservation.
Approach
To understand T-A cycling we will use the well characterised hibernation model the golden hamster (Mesocricetus auratus). The golden hamster is a commonly used lab animal which is readily available circumventing the need for wild animals to study hibernation. We will use changes in photoperiod and temperature to induce a hibernation phenotype, monitoring food intake, body temperature (by internal temperature loggers) and conduct terminal brain and blood sampling throughout a torpor arousal cycle. Interventions involve surgery and are moderately stressful. Our hypothesis is that T-A cycling is acheived through the control of temperature sensitive regions of the hypothalamus by hormonal and metabolic feedback signals to the hypothalamus. Our secondary hypothesis is that these hormonal/metabolic signals are "gated" by a specialised cell type, the tanycyte. Investigating this requires that we sample hamsters at time-matched points throughout the torpor arousal process. In total we will use 100 hamsters.
3Rs
Replacement: There are no suitable in vitro approaches that can recapitulate the hibernation phenotype.
Reduction: Our sampling strategy will reduce variation between individuals and thereby allow reduction of the number of animals used. We retain frozen tissue samples, reducing the need for further animal experiments.
Refinement: We use a laboratory model animal. Our experimental procedures are refined to minimize pain and suffering and improve welfare.
Hibernation is a physiological and behavioural adaptation that permits survival during periods of reduced food availability and low environmental temperatures by reducing energy expenditure. During the hibernation season, energy savings are greatest when animals are in a state of ‘torpor’ (metabolic rate can be as low as 1-2% of basal metabolic rate), and body temperature (Tb) falls to only a few degrees above ambient. In most hibernating species, this torpid state is not maintained continuously but is organised into multiday torpor bouts interspersed with briefer periods of ‘spontaneous arousal’ when metabolic rate and Tb rise to euthermic levels. While much has been written on why spontaneous arousals occur, despite the energy expenditure entailed, the issue of how mechanistically arousal is achieved has been neglected – and this outstanding mystery is the focus of this application. Understanding how hibernators can achieve torpor-arousal (T-A) cycling, recover from metabolic shut down, low Tb, and hypoxia has many potential healthcare applications, notably to stroke, surgery and organ cryopreservation.
Approach
To understand T-A cycling we will use the well characterised hibernation model the golden hamster (Mesocricetus auratus). The golden hamster is a commonly used lab animal which is readily available circumventing the need for wild animals to study hibernation. We will use changes in photoperiod and temperature to induce a hibernation phenotype, monitoring food intake, body temperature (by internal temperature loggers) and conduct terminal brain and blood sampling throughout a torpor arousal cycle. Interventions involve surgery and are moderately stressful. Our hypothesis is that T-A cycling is acheived through the control of temperature sensitive regions of the hypothalamus by hormonal and metabolic feedback signals to the hypothalamus. Our secondary hypothesis is that these hormonal/metabolic signals are "gated" by a specialised cell type, the tanycyte. Investigating this requires that we sample hamsters at time-matched points throughout the torpor arousal process. In total we will use 100 hamsters.
3Rs
Replacement: There are no suitable in vitro approaches that can recapitulate the hibernation phenotype.
Reduction: Our sampling strategy will reduce variation between individuals and thereby allow reduction of the number of animals used. We retain frozen tissue samples, reducing the need for further animal experiments.
Refinement: We use a laboratory model animal. Our experimental procedures are refined to minimize pain and suffering and improve welfare.