SPUR 2021: Effects of altitude on brain excitability and migraine

Background

Altitude affects the brain as well as the lungs. It is well known that high altitudes can cause severe headaches and ultimately brain swelling. It is less known that moderate altitudes, like that of Salt Lake City (SLC), can also have effects on the brain. This is important because approximately 1 billion people live at moderate altitudes. Migraine headaches are more common at moderate altitudes, and we have recently shown that migraine aura, a wave of sensory changes that precedes the headache, is significantly more frequent in people who live in SLC compared to lower elevations. This is an important clue because we know that migraine aura is caused by a spreading depolarization (SD), a wave of activity that moves across the brain like a ripple in a pond. While the pain of migraine is difficult to model in the lab, SD is readily measured. We thus have a biomarker that we can use to examine the mechanisms by which altitude affects migraine susceptibility. We have two potentially related hypotheses: 1. Hypoxia, reduced oxygen concentration, is known to trigger SD. Though there are only moderate changes in oxygen levels in SLC and other moderate elevations, they are physiologically significant, and may be sufficient to trigger SD. 2. Red blood cell mass increases significantly, even at moderate elevations. Though this helps deliver oxygen, it also makes the blood thicker and more likely to clot. Even transient clotting can trigger SD. Using optical techniques, we are able to directly visualize blood oxygenation, blood flow, and clotting, in real time in awake animals. We will use these techniques, along with an altitude chamber, to test our hypotheses in wild type mice, and in mutants carrying migraine genes.

Student Role

The student will be able to participate in all aspects of the project, and we can tailor their experience based on their skill set and interests. For example, a student with an interest in biomedical engineering will have the chance to work on an altitude chamber, and with cutting edge optics, including spectroscopy and two photon imaging. A student with interest in sensory neurobiology will be in the position to image neurons in the brain of an awake behaving mouse. Ideally, we will be able to convince our student that both the engineering and neuroscience aspects of our work are fascinating.

Student Learning Outcomes & Benefits

Whether headed toward a scientific career or medical school, the key thing to be able to show from lab experience is publications. This is because a paper is the culmination of many other research-related goals: understanding the scientific literature, knowing laboratory or clinical techniques, generating a dataset, analyzing the data, presenting it at conferences, and writing it up. It is a credible demonstration that the student did ‘real work’ and is being rewarded for it. So this is our primary, focusing, practical goal. But there is more to a lab experience than generating publication quality research. There is the critical skill of learning how to learn; there is no textbook when you are at a knowledge frontier, and this skill is a profound help in any field. Finally there is the confidence that comes from solving problems, and the joy of discovering something truly new.

Remote Contingency Plan

About half of our work - the non-experimental aspect, can be performed from anywhere, with a laptop computer. This half includes data analysis, generation of figures, writeup, and presentation. There are also aspects to the experimental work that can actually be done remotely; for example we can remotely deliver supplies and devices, in order that a student be able to construct an experimental apparatus - in the case of this proposal, an altitude chamber. We want to have a balance of experimental and analytical work, because both are necessary, and neither alone is sufficient, for scientific training. Thus, if the project has to be virtual, we will make sure that at least a third of the work is hands-on, experimental work that can be done remotely. Beyond the altitude chamber work, we have a small 3D printer that can be cleaned and delivered to a student's home, so they can build experimental tools that others (and hopefully they after quarantine) can deploy in lab.

KC Brennan
Professor

Neurology
School of Medicine

The mentorship of junior scientists is one of the most important and satisfying aspects of my career. I try to strike a balance between the freedom to try, fail, think and learn independently; and the support, encouragement, and critical questioning needed to shape that learning. On a practical level, every student has two mentors - a graduate student or postdoc with whom they share daily lab life; and myself, a more senior mentor, who assists in daily mentorship but also focuses on long term career goals. Each of us will interact daily with the student, and I will have regularly scheduled weekly meetings to go over data, troubleshoot, and brainstorm. Beyond their mentors, every student benefits from the lab around them - we are genuinely a team, and have each other's backs.