AbstractTorpor is a hypothermic, hypometabolic state engaged when the availability of nutrients is insufficient to maintain homeostasis. It is observed in a wide range of animals, including the laboratory mouse, and if mimicked in humans, a synthetic torpor state could have useful clinical applications. The mechanisms that control torpor are not known. This thesis explores the neuroanatomical basis of torpor induction. The core method used a genetic approach that allowed targeted expression of transgenes in neurons that are active during torpor.
First, two protocols for torpor induction in mice were validated, alongside the use of surface thermography as a proxy for internal body temperature. A method to detect torpor was developed using a moving window of the mean and standard deviation of mouse surface temperature across the 24-hour cycle.
I then used the transgenic mouse model to express a fluorescent protein in neurons that were active during torpor. This identified that the dorsomedial hypothalamus (DMH) and the preoptic area of the hypothalamus (POA) increase activity during torpor.
Next, a chemogenetically modified receptor was expressed in neurons that were active during torpor. Reactivation of those neurons generated a synthetic torpor state in the absence of any natural stimulus for torpor. Targeted reactivation of only the POA neurons that were active during torpor recapitulated this synthetic torpor, demonstrating that the POA contains neurons that are sufficient for torpor induction. A similar approach in the DMH demonstrated that neurons in this nucleus promote, prolong, and deepen torpor bouts in calorie restricted mice, but are neither necessary nor sufficient for torpor induction.
In summary, these findings represent the first demonstration of a synthetic torpor in the mouse. They indicate that the POA is sufficient for torpor induction, and that the DMH promotes torpor but is neither necessary nor sufficient.
|Date of Award||23 Mar 2021|
|Supervisor||Matt W Jones (Supervisor) & Anthony Edward Pickering (Supervisor)|
- therapeutic hypothermia
- critical care