It's hard to ride a seesaw alone. As sad as this mental image is, it's a great way to conceptualize the delicate balance of cortisol regulation. Cortisol is a hormone that travels through the body at high concentrations during stress to induce a number of metabolic and behavioural responses that bring the body back to a resting state. Regulating cortisol levels is critical because it has such a substantial effect on physiology, so cortisol brings friends to the playground to help it balance, including: Negative Feedback, who rides the opposite side of the seesaw and drives cortisol back down when it reaches the top; and Corticosteroid Binding Globulin (CBG), who rides in the middle and buffers cortisol on this wild ride. For most animals, this up-and-down runs smoothly and tissues are protected from excess cortisol. But the southern flying squirrel seems to do things differently. This nocturnal trapeze artist boasts some of the highest non-stress cortisol levels of any vertebrate, yet, unlike other animals with high resting cortisol, its CBG has a poor capacity for buffering this heavy load. How, then, do non-stressed squirrels prevent their tissue from being overloaded with cortisol? This is what researchers from the Burness lab at Trent University, Canada, wanted to find out. They reasoned that the squirrel's negative feedback must have a higher set point, meaning their tissues are less sensitive to cortisol, in order for the animals to maintain continually high cortisol levels in their blood.
The research crew, led by PhD student Lanna Desantis, headed to the deep, dark woods to live-trap flying squirrels and test their cortisol regulating strategy. First, Desantis injected each squirrel with different concentrations of dexamethasone, a synthetic cortisol, and quantified plasma cortisol levels 3 h later to determine how much dexamethasone is needed to engage the negative feedback mechanism. She found that flying squirrels needed 16 times more dexamethasone than that required in related species to drop plasma cortisol below resting levels. This means that the negative feedback set-point is much higher in flying squirrels than in other mammals. The scientists reason that the squirrels likely have low-affinity cortisol receptors, so more cortisol is needed to saturate these receptors and engage negative feedback; or put another way, the squirrels’ tissue sensitivity to cortisol is much lower than in other mammals.
Knowing that cortisol also plays a role in seasonal transitions, such as helping to shift energetic usage between reproduction and growth, Desantis and her colleagues were curious as to whether male and female flying squirrels had different basal cortisol or negative feedback regulation during the breeding and non-breeding seasons. When she compared resting cortisol levels, she found that female squirrels had higher cortisol compared with males, and that non-breeding squirrels had higher cortisol than breeding squirrels. When Desantis gave the squirrels dexamethasone, she found that non-breeding squirrels still had higher plasma cortisol than breeding animals, even if she gave them twice as much dexamethasone as she gave the squirrels in the breeding season. This means that there is both sex-specific and seasonal variation in cortisol negative feedback in flying squirrels, with non-breeding females having the lowest tissue sensitivity to cortisol. This differential sensitivity is likely key to helping these night-time fliers navigate the seasonal trade-offs between survival and reproduction.