Brain freeze: what doesn’t kill you makes you stronger

August 21, 2018

Written by: Barbara Terzic

 

Arctic ground squirrels, Syrian hamsters, and black bears (oh my!). What do all these creatures have in common? Aside from being ridiculously adorable (see 13-lined ground squirrel, Figure 1), these species also all happen to be hibernators. This means that come September, small rodents such as the arctic ground squirrel will burrow deep beneath the earth (over one meter deep, to be exact) and remain dormant for nearly seven months. Hibernation is defined as a seasonal state of metabolic depression that is characterized by several features, most notably a (sometimes staggering) decrease in body temperature, heart rate, and breathing rate¹. In fact, the arctic ground squirrel drops its core temperature to -2.9°C/26.8°F²! Lower than the freezing point of water! How does the ground squirrel survive such extremes for so long without any food or water? Researchers have been captivated by this question for a long time because these hibernating mammals may provide us with a model to learn how to push our own human bodies beyond their ostensible limits.

Sleeping beauty

So why do animals hibernate? The primary goal of hibernation is to conserve energy when sufficient food is unavailable (such as during winter). Hibernating mammals achieve this by decreasing their metabolic rate (causing a sharp drop in body temperature), and can remain dormant for days, weeks, or even months depending on the species and environment. This explains why our furry friends in the arctic tundra, the arctic ground squirrels (Figure 2), hibernate upwards of seven months out of the year. Larger animals such as bears eat excessive amounts of food to store in fat deposits to keep them alive over the hibernating months. However, smaller hibernating rodents like the ground squirrel cannot accumulate the same amounts of fat, which is why their metabolic rate (and body temperature) drops to a record low; the lowest core body temperature recorded in any living mammal.

As a result of this (and perhaps most shocking of all), the brains of these small rodents nearly shut down completely, and the remaining energy reserves overwhelmingly shuttle to keep the nervous system alive³. In fact, while the rest of their body is supercooled below 0°C/32°F, ground squirrels work hard to keep their brains slightly warmer, around 0.5-3°C (32.9-37.4°F). Still, this far down from their ambient 36.4°C/97.5°F, it’s amazing these critters can bounce back with zero brain damage after this temperature Olympics.

So what can we learn from these frozen pop-squirrels

Decreased body temperature and heart rate result in decreased blood flow, which means less oxygen than usual is getting spread to organs across the body (like the brain). Blood flow to the brain is critical because it brings along two main hitchhikers: 1) oxygen (to keep the cells alive) and 2) glucose (the primary energy source for the brain), and even a slight deviation in this balance is bad news bears for our brain health/function. Hibernating ground squirrels achieve a >50% decrease in their blood-oxygen levels in the brain, yet exhibit no brain damage after arousing from hibernation⁴. This is in stark contrast to the extensive brain damage that can occur in human stroke or cardiac arrest patients as a result of even just minutes of oxygen deprivation to the brain’s cells. In fact, of the ~70,000 patients in the United States who are resuscitated from cardiac arrest, over 60% die from extensive brain injury, and only 3-10% are able to resume their former lifestyles⁵. The tolerance of these rodent brains to stroke-like conditions make them an important model for researchers looking to understanding how we can protect the human brain from the ravages of oxygen/nutrient deprivation⁶.

An additional active area of research focuses on the impressive cold-tolerance of the ground squirrel brain⁷. A recent study by scientists at the NIH compared the response to cold temperatures of human- versus ground squirrel-derived brain cells in a dish. Not surprisingly, the brain cells of ground squirrels were much more resilient to cold temperatures. Researchers partially attribute this to the ‘protective’ genes the squirrel cells turned on in response to extreme temperatures⁸. Figuring out a way to identify the pathways involved in this cold-tolerance and applying it to humans will impart unique and powerful clinical potential, such as prolonging the shelf-life of cold-stored organ transplants.

Ground squirrels and…..Alzheimer’s?

Yup, you read that correctly. Decades ago when researchers first began looking into the brains of these animals during hibernation, they were shocked to find that their neurons were withered and shrunken, resembling a neglected house plant. The branches of their brain cells, which are important for receiving information from neighboring cells, were completely stunted, and the number of synapses (small points of communication between cells) was also drastically reduced⁹. The ground squirrels brain was like a barren desert during hibernation, yet somehow, upon awakening their neurons managed to revive, regrow, and re-establish important connections¹⁰. Perhaps it is more efficient for the ground squirrels to let their brain cells shrivel during hibernation, then quickly nurse them back to health when they wake up. Regardless of their reasoning, scientists are very interested in this revival flexibility and whether similar manipulations can be applied to revitalize damaged nerves in patients suffering from neurodegenerative diseases such as Alzheimer’s.

Alzheimer’s disease affects the scaffolding of our brain cells, which is held together by rope-like proteins called microtubules, and another protein named tau which helps to keep them tightly bundled. In Alzheimer’s disease, tau proteins become dysregulated and clump together abnormally, and the ropes supporting our cells start to “slack” and lose shape (read more in a previous weeks article here!). These tau protein clumps are one of the hallmarks of Alzheimer’s pathology, and can lead to perilous dysfunction and even death of our brain cells, which are never reborn again. Scientists see similar dysregulation and ‘clumping’ together of tau protein in ground squirrels during hibernation, yet it is somehow miraculously cleared away when they awaken^11,12! Scientists still aren’t sure what triggers this recovery, but you can bet they’re eagerly working to understand whether similar mechanisms can be applied to reverse the tau clumping in humans with Alzheimer’s.

Don’t you wish you were a hibernator?

As glorious as sleeping for a solid seven month out of the year sounds, most primates such as humans do not hibernate. That is, except for one: the fat-tailed dwarf lemur (Figure 3; yes, he is also ridiculously adorable). Found on the western-most coast of Madagascar, this lemur is special not just because it is the only hibernating primate on the planet, but because it does so in a tropical climate¹³. No frozen tundras here. Due to this and other reasons, scientists think these lemurs may have evolved to hibernate via an independent mechanism from other hibernating mammals, identifying them as an important bridge between hibernation mechanisms in other species and humans.

Elon, where are you?

Stroke revival, extreme cold tolerance, miraculous nerve regrowth; we obviously have plenty to learn from the hibernating ground squirrel. What is happening in their brain cells under such severe conditions that allow them not only to survive, but bounce right back upon waking up months later? Can humans harness any of these advantageous traits for the reversal of neuronal damage? Is a fat lemur on a remote island off the coast of Africa our only hope? Many questions still remain. Aside from immediate clinical and therapeutic applications, many researchers are interested in the idea of hibernation in humans for various other scientific reasons, including different patterns of sleep, permitting otherwise impossible surgeries, or cryopreservation. With sci-fi-esque ventures from entrepreneurs such as Elon Musk (see, SpaceX) becoming less sci-fi and more reality, there is even growing interest in the idea of deep sleep for long-range space travel. Although some researchers have made progress in artificially inducing hibernation in other species, we are far from such an application in humans just yet¹⁴. But hey, we can only dream, right?

 

 

References:

1. Geiser F. Metabolic rate and body temperature reduction during hibernation and daily torpor. Annu. Rev. Physiol. 2008; 66, 239–274.

2. Buck CL & Barnes BM. Annual cycle of body composition and hibernation in free-living arctic ground squirrels. Journal of Mammalogy 1999; 80(2), 430–442.

3. Buck CL, Breton A, Kohl F, Tøien Ø, and Barnes BM. Overwinter body temperature patterns in free-living arctic ground squirrels (Spermophilus parryii). Hypometabolism in Animals: Hibernation, Torpor and Cryobiology. 2008; 317–326.

4. Yasuma Y, McCarron RM, Spatz M, and Hallenbeck JM. Effects of plasma from hibernating ground squirrels on monocyte-endothelial cell adhesive interactions. American Journal of Physiology 1997; 273(6), 1861-1869.

5. Dave KR, Prado R, Raval AP, Drew KL, and Perez-Pinzon MA. The arctic ground squirrel brain is resistant to injury from cardiac arrest during euthermia. Stroke 2006; 37, 1261-1265.

6. Bernstock JD, Ye D, Smith JA, Lee YJ, Gessler FA, Yasgar A, Kouznetsova J, Jadhav A, Wang Z, Pluchino S, Zheng W, Simeonov A, Hallenbeck JM, and Yang W. Quantitative high-throughput screening identifies cryoprotective molecules that enhance SUMO conjugation via the inhibition of SUMO-specific protease (SENP)2. The FASEB Journal 2018; 32(3)

7. Matos-Cruz V, Schneider ER, Mastrotto M, Merriman DK, Bagriantsev SN, and Gracheva EO. Molecular prerequisites for diminsted cold sensitivity in ground squirrels and hamsters. Cell Reports 2017; 21, 3329-3337.

8. Ou J, Ball JM, Luan Y, Zhao T, Miyagishima KJ, Xu Y, Zhou H, Chen J, Merriman DK, Xie Z, Mallon BS, and Li W. iPSCs from a hibernator provide a platform for studying cold adaption and its potential medical applications. Cell 2018; 173, 851-863.

9. Popov VI, Bocharova LS, and Bragin AG. Repeated changes of dendritic morphology in the hippocampus of ground squirrels in the course of hibernation. Neuroscience 1992; 48(1), 45-51.

10. von der Ohe CG, Darian-Smith C, Garner CC, and Heller HC. Ubiquitous and temperature-dependent neural plasticity in hibernators. The Journal of Neuroscience 2006; 26(41), 10590-10598.

11. Stieler JT, Bullmann T, Kohl F, Tøien Ø, Brüchner MK, Härtig W, Barnes BM, and Arendt T. The physiological link between metabolic rate depression and tau phosphorylation in mammalian hibernation. PLoS ONE 2011; 6(1), e14530.

12. Arendt T, Stieler J, Strijkstra AM, Hut RA, Rüdiger J, Van der Zee E, Harkany T, Holzer M, and Härtig W. Reversible paired helical filament-like phosphorylation of tau is an adaptive process associated with neuronal plasticity in hibernating animals. The Journal of Neuroscience 2003; 23(18), 6972-6981.

13. Dausmann KH, Glos J, Ganzhorn JU, and Heldmaier G. Physiology: Hibernation in a tropical primate. Nature 2004; 429, 825-826.

14. Dawe AR & Spurrier WA. The blood-borne “trigger” for natural mammalian hibernation in the 13-lined ground squirrel and the woodchuck. Cryobiology 1972; 9, 163-172.

Images

Cover image and Figure 1 by Matos-Cruz V, Schneider ER, Mastrotto M, Merriman DK, Bagriantsev SN, and Gracheva EO. Molecular prerequisites for diminsted cold sensitivity in ground squirrels and hamsters. Cell Reports 2017; 21, 3329-3337. Journal cover image, CC BY-NC-ND 4.0.

Figure 2 by Jacob W. Frank at the National Park Service (Public Domain Mark 1.0) via Flickr (https://www.flickr.com/photos/alaskanps/20861769923)

Figure 3 by Frank Vassen via Flickr, CC BY 2.0 (https://www.flickr.com/photos/42244964@N03/4337920875)