Gracie Bouker

Mapping Out Learning: How Aerobic Exercise, Sex and Alzheimer’s Disease Impact Learning

April 3, 2021   /  

Name: Gracie Bouker
Major: Neuroscience
Advisor: Dr. Amy Jo Stavnezer

Two of my main research questions for this project were 1) To what extent aerobic exercise might ameliorate the symptoms of Alzheimer’s Disease (AD)? and 2) To what extent is the Morris Water Maze (MWM), a learning and memory task, hippocampally-dependent? My primary research interest excited me because 1) aerobic exercise, namely running and walking, are free and accessible to the vast majority of any population and 2) wellness and health are key in my every life, so much so that I have chosen to pursue as a career centered around rehabilitation. Although the results for my first research question fell short due to some limitations of my study, the results for my second research interest were fascinating: 1) by the end of the fourth day of testing, less than half of the mice used their hippocampus to solve the MWM, and 2) around 20% of mice short-cut cognitive resources by solving the MWM without using their hippocampus, yet with the same efficiency as mice who were using their hippocampus. The MWM is widely accepted as a hippocampally-dependent task, but in context of my second research question, I concluded that the MWM is only hippocampally-dependent if a hippocampal strategy is used—that is to say, less than half of the time. To understand how to best aid AD populations, we must seek to understand the comprehensive process of learning and not mere descriptors. We must think more critically about how we use the test, namely, what measurements we take and what those measurements mean.

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Gracie will be online to field comments on April 16:
noon-2pm EDT (PST 9-11am, Africa/Europe: early evening) and 4-6 pm EDT (PST 1-3pm, Africa/Europe: late evening)

58 thoughts on “Mapping Out Learning: How Aerobic Exercise, Sex and Alzheimer’s Disease Impact Learning”

  1. Congrats again Gracie, it was a pleasure to serve as your second reader and learn about the implications of methodology in drawing conclusions about memory.

    1. Thank you so much Dr. Colvin! It was awesome to meet with you and think more deeply about my project thanks to some of your questions!

  2. Great job Gracie! I am curious, what would your next steps be for this project if you had more time?

    1. Thanks Kate! If I had more time, I’d love to have looked at search strategy in the maze over many more trials. I only had the chance to realistically analyze three trials (day 2, day 4, probe) per mouse (there were about 80 mice). I’d like to see if strategy was consistent across trials within the same day, for example, to draw more definitive conclusions about their learning over time. Thanks for this great question!! 🙂

  3. Gracie! I’m impressed! I won’t pretend to be exceptionally knowledgeable in this field, but you managed to make it accessible enough that I understood, which is a good sign. I also know you’ve been interested in (and a proponent of) the positive effects of aerobic exercise for a while now, so I’m glad you got to translate that into this work! Cheers, and congratulations!

    1. Thank you so much Nick! I so appreciate your continuing support and enthusiasm. I’m also so ecstatic to know that you have been benefiting from some of the wonderful neuro advantages that come along with aerobic exercise! Keep up the great work! 🙂

  4. Why do you think that the mice used thigmotaxis instead of hippocampal-derived pathways? Have previous studies indicated that using MWM activated the mice’s hippocampuses? If so, why do you think your results differed?

    1. Wow, thank you for these wonderful questions! I think that thigmotaxis was readily employed by mice in the MWM rather than a direct strategy because this strategy is efficient yet shortcuts cognitive resources. By using a direct strategy, mice are required to form an allocentric cognitive map. In other words, they need to know exactly where they are in space, taking all of the spatial cues around them (i.e. door, colors around the room, lights, the layout of the room in general) and understand that the escape platform is somewhere in relation to all of those cues. The formation of this map in their mind requires the use of the hippocampus, to process and store memories. When they enter the maze, the mice using the direct strategy know exactly where the platform should be based on this map in their mind. The thigmotaxis mice, however, do not require this map. What these mice have discovered is that if they swim in a circle a certain distance from the wall, they’ll eventually find the platform. They haven’t created a map and don’t know where the platform is, but they find it at an equal rate as the mice using the direct strategy. Therefore, to answer your first question, I think mice use thigmotaxis instead of a direct strategy because it is efficient and shortcuts cognitive resources.

      Previous studies have indicated that using the MWM requires the hippocampus. Many of these early studies were conducted by Richard Morris, the man who invented the maze in the 1980s. In my IS, I cite literature indicating that hippocampal-lesioned rats showed high spatial learning impairment (didn’t solve the maze as efficiently), that they never reached the same level of learning as the control group, and that they suffered profound navigational impairment. The one caveat here is that despite their lower level of performance, these rats still learned how to perform consistently above chance (Morris et. al, 1986). These studies looked at latency and distance to platform, not strategy. But I would bet that the mice that performed consistently above chance were using thigmotaxis to solve the maze, if the researchers ever bothered to assess their strategy.

      Thanks for your questions! Let me know if I can follow up on anything.

  5. Thanks for presenting today Gracie and thanks for having such an amazing personality and spirit throughout this project. I am wondering how we might figure out how to train our software to recognize at least direct and thigmotaxis strategies so that in the future we can differentiate these learning styles without needing to watch all of the videos and hand-scoring them. You have opened up a lot of interesting future possibilities for IS students in my lab for sure!

    1. Truly, thank YOU Dr. Stav, for your creativity, enthusiasm, kindness, and belief in me! Having you as my advisor has been the sweetest privilege. The idea of training software to recognize thigmotaxis and direct strategies sounds epic, and I really hope something like this develops! I’m excited to hear more as more information becomes available! 🙂

  6. Great job Gracie! looks very thorough! Are there any other common tests you put mice through to try and understand how they use memory?

    1. Thank you very much, Big Bird! What a great question, there are actually a plethora of common learning and memory tests for mice and rodents!! I can’t paste images here, but three extremely common tests are the Radial Arm Maze, the Barnes Maze, and the Y Maze. In the Radial Arm Maze, there are 8 arms that branch out from a center point (like a clock). Some type of reward (i.e. food) is placed in some of the arms. Learning and memory is tested by seeing how many arms the mice RE-enter (these are considered errors, and thus mistakes in learning and memory). The Y Maze is shaped like a Y, and mice start in one section of the maze and can choose to go in one of two directions. The Barnes Maze is most similar to the MWM, in my opinion. Mice are placed on a circular board with tons of little holes around the circumference of the board. One of these holes is an escape hole. So those are some of the different mazes! They’re all awesome, but I chose the MWM because looking at strategy as a way to map out the process of learning is most evident in this maze. 😀

  7. Hi Gracie! Great job on your research 🙂 I am so impressed with you! I never considered that some tasks that test for hippocampally-dependent factors may not actually use hippocampal strategies! That is such a creative finding and interpretation of your data! I hope the mice enjoyed the exercising!

    1. Hey Becca! Thanks so much for your comment!! It means so much coming from you, someone I respect and love, who has also done research in this field! I think the mice enjoyed exercising, but not as much as I do! 😀

  8. Gracie! That was such a lovely presentation very succinct and engaging! I am very proud of your hard work and the passion you poured into completing this project. If you were given 1 more year to work with mice what else would you like to investigate?

    Don’t worry I will continue to exercise despite your findings.

    1. Thank you so much Asvin! If I was given 1 more year, I’d probably like to look at more trials! I realistically only had time to look at three trials (day 2, day 4, probe) per mouse (there were about 80 mice). So if I had more trials to work with, I might be able to draw more definitive conclusions about the learning process over time by determining if strategy was consistent across trials. Also, as you know, my mice exercised using running wheels… If I had more time and no COVID, I would have LOVED to plop them on a treadmill so that they were required to exercise for a set time and set number of days per week!! Thanks for your question! 😀

  9. Excellent work, Gracie! I’m very proud of you. I came in thinking I probably wouldn’t understand much, but you have a talent for making the topic accessible. Much love.

    1. Thank you so so much Henry! Your interest in my topic means the world to me 🙂 So much love to you my friend!

  10. Gracie this is really amazing! You put a lot of time, thought, and care into your research and work and I’d expect nothing less! Really great work- thanks for sharing your methods, findings, and passions!

    Congratulations!

    1. Thanks so much, Lauren! It means so much that you stopped by, thanks for engaging with my research and being such an awesome role model for me over the years! <3

  11. Great work Gracie!

    Not a biology expert but impressed by the work that was done. I concur with your conclusion that regardless of concrete data from this experiment on the hyppocampus, exercise can only be beneficial.

    Were there any common traits in the mice that used neither the thigmotaxis nor hippocampally based methods?

    1. Hey Dad!!!! Thank you for your love and support! Actually, the majority of my research questions (which aren’t listed in my poster or presentation for the sake of simplicity) were based around this idea! A plethora of previous literature indicates that Alzheimer’s Disease mice, non-exercise mice, and female mice are more likely to use strategies NOT reliant on the hippocampus. But due to some limitations to my study, I wasn’t able to statistically confirm these findings. There is very little published research on thigmotaxis, so this strategy and its implications for future research feel huge to me! Thanks for this great question!! LY!

  12. Your presentation is very clear and impactful for modern science. It looks great, too! Your diagrams of the different mouse strategies helped a lot with my understanding of your research.

    I have a question that might be a side tangent: how similar is Alzheimer’s Disease in mice compared to AD in humans? It is so fascinating that a mouse, an animal that we see as being so different from ourselves, can experience AD like us.

    Awesome job, Gracie!

    1. Thank you, Sam!! You’re asking an awesome question. AD in mice is actually a bit different than AD in humans. In humans, AD is hallmarked by neurofibrillary tangles and amyloid plaques. The tangles essentially collapse the internal transport network of neurons, inhibiting the ability of neurons to work together and damaging signal propagation, causing marked damage to movement, perception, and cognitive function. The plaques aggregate and disrupt cell communication, as well as activate immune cells which trigger inflammation and destroy neurons. So that’s what goes on in a human brain. In the specific type of transgenic mouse used in this study, their brains would only have plaques, and no tangles. However, the plaques are sufficient for causing outward symptoms of the disease, such as loss of cognitive function. Thanks for this really thoughtful question! 😀

  13. Great job Gracie! I am so proud of you for finishing this project despite all the difficulties during covid times!

    I was wondering if the mice who didn’t use the hippocampally-dependent strategy (those other than direct) were either had deficit in their hippocampus or they shared other traits that might led them not to use the direct strategy. Another question I had was if the stress mice had experienced during the task in maze had any effects on their hippocampus.

    Wishing you the best after graduation!:))

    1. Thank you so much Hitomi! <3 These are such thoughtful questions! In previous studies, certain characteristics would lead some mice to use strategies other than direct, because they wouldn't be engaging the primary use of their hippocampus. Actually, the majority of my research questions (which aren’t listed in my poster or presentation for the sake of simplicity) were based around this idea!! A plethora of previous literature indicates that Alzheimer’s Disease mice, non-exercise mice, and female mice are more likely to use strategies NOT reliant on the hippocampus. I expected that they would use thigmotaxis, random, scanning, and looping strategies more than male, control, and exercise mice. But due to some limitations to my study, I wasn’t able to statistically confirm these findings.

      In response to your stress question, it's true that the MWM is a stressful event for mice! Mice do not like swimming and do not like being out in the open. I know that there's an abundance of research that looks at the impact of stress on learning and memory– namely that acute stress improves learning and memory while chronic stress decreases it. Given the fact that this is a task that acutely stresses the mice, I would guess that it isn't detrimental to their learning and memory, but I'm not totally positive.

      Thank you so much for your comment and questions!! Excited to hear all about what IS will be for you next year! <3

  14. Hi Gracie,

    Love this topic and your passion for the work you have done! For mice who did use hippocampus, after they discovered the location, did they consistently find the platform every time? Were there any lapses in their memory?

    1. Hey Biggest Fans! Thank you for your comment and question! Unfortunately, I was only able to look at 3 trials (day 2, day 4, probe) across the 5 days of testing. This means that I’m not actually sure if, once they developed a direct strategy, that it was consistently successful. If I had more time I would have loved to see more trials to determine the nature of the learning process (linear or not?).

  15. Another question, did you find any common characteristics with mice that did not use the hippocampus or thigmotaxis strategies?

    Also, we want to understand your data better. What is D2? D4? WT? TG? CON? I assume EX is exercised mice, correct?

    1. For sure! This is what I said in response to Dad’s question above:
      Actually, the majority of my research questions (which aren’t listed in my poster or presentation for the sake of simplicity) were based around the idea that certain characteristics might predict strategies based on knowledge of how certain populations use their hippocampus! A plethora of previous literature indicates that Alzheimer’s Disease mice, non-exercise mice, and female mice are more likely to use strategies NOT reliant on the hippocampus. But due to some limitations to my study, I wasn’t able to statistically confirm these findings. There is very little published research on thigmotaxis, so this strategy and its implications for future research feel huge to me! Thanks for this great question!!

      As for clarifying those code words, D2 and D4 refer to the trials I looked at on Day 2 and Day 4 of testing in the MWM. WT = wild-type (non-Alzheimer’s Disease mice); TG=transgenic (mice that carry a set of genes essentially giving them Alzheimer’s Disease); EX = exercise mice; CON = control (non-exercise mice). Thanks for this important clarifying question!

  16. For those that did use their hippocampus, was there a common strategy for their first time discovering the platform? Were there any patterns in gender for which mice used which strategy?

    1. Great questions! Indeed, when most mice were put in the maze for the first few trials and in those initial days, the majority of mice used a random strategy. They were just exploring and didn’t really know what they were looking for or where it would be. It was only after several trials that mice started developing a strategy to find the platform (and be out of the water as soon as possible).

      In previous literature, there is a sex-based pattern! In my IS, I cite some literature that says that hormone levels may influence search strategy, such that males (with more testosterone) are more likely to use strategies requiring the hippocampus. Females are also known to heavily prefer non-spatial strategies, like serial searching (looping), chaining, and scanning (Astur et. al, 2004; Schoenfeld et. al, 2010).

      Thanks for these questions, you’re really getting to the heart of my study here! 😀

  17. Hey Gracie, seems like a lot of works have been done here! 😀
    Great job.
    I can imagine that you take and put the mouse so many times into the water. And they would be so confused lol.

    Did you put a birdview camera to record how the mice swim and analyze it later?
    Probably I missed it. But is this just one mouse or 100? Are they all normal mouse?
    So the mice used different patterns every time, do you expect the same mouse to behave differently if you do the experiment for so many times? Or do you expect different behavior for different mouse because they have different brain?

    1. Hey Dajo! Thank you so much for stopping by!! 😀 Yeah, I’m sure those mice are exhausted by the end of testing haha.

      To answer your first question, yes! There is a camera placed above the pool and it records every trial. I analyzed search strategy by watching hundreds of these videos!

      The study included 74 mice. Here were my experimental groups: 37 with Alzheimer’s Disease, 37 without Alzheimer’s Disease; 37 male, 37 female; and 35 with exercise, 39 without exercise. 😀

      And yes! I found statistical significance indicating that the mice behaved differently over time/more exposure to the maze. Specifically, they learned where the platform was and significantly used more efficient strategies over time! However, some improved more than others over time, most likely due to their brains, like you said!

      Thanks for engaging with my research and supporting me!! And thank you for some awesome questions!

  18. Your presentation was very clear and succinct. Thanks for sharing. Congrats! I have 2 questions.

    Does the thermotaxis method not require some mental image of the terrain? because the mouse must know when to stop touching the wall and approach the food. Are you certain that it is not hippocampally dependent?

    You indicated that past research has shown that exercise helps with Alzheimer’s. Is that because of neurogenesis, neuroplasticity, and all the other cool things exercise does?

    1. Hey Carlos! Thank you for coming to see what my IS was all about! You’re asking some EXTREMELY thought-provoking questions!! Research on thigmotaxis is scarce, so I’ll do my best to answer your question. I think there is certainly a level of cognitive engagement necessary for the use of thigmotaxis as a search strategy. As you said, it needs to know how far to move away from the wall to find the platform. For that reason, I think that they have a basic understanding of where the escape platform might be. However, it’s clear that they haven’t formed a cognitive allocentric map (aka map of their surroundings, including where the platform is in relation to their surroundings) in their mind; if they had, they’d swim directly to the platform. It’s the absence of this map that leads me to conclude that thigmotaxis doesn’t require the hippocampus. Does this makes sense? Let me know if I can elaborate somehow!

      To answer your question, yes!!! I’m so glad you asked. I’m so passionate about the positive impact of exercise on the brain. The real beauty about aerobic exercise is that the power (most of it) lies in the oxygen. When you’re running/engaging in aerobic exercise, you are breathing more and delivering more oxygen to your bloodstream and ultimately your brain. The results in this presentation are only relevant for aerobic exercise– not anaerobic exercise, like lifting weights. Isn’t that cool?! So yes, aerobic exercise promotes cognitive function in all populations, but is especially important for AD populations because that population suffers specifically from cognitive function. And like you said, cognitive function is promoted through increases in neurogenesis, neuroplasticity, BDNF, glial cell proliferation, LTP functionality, and even more. 😀

      Thanks for these incredible questions, Carlos!

  19. Congratulations Gracie!! This is such an interesting topic!! Wishing you all the best!!

  20. Gracie, good to see you again here, and congratulations on your major achievement on this exciting topic. Thank you for sharing your project in such an engaging way here! What would you like to do further regarding your first research interest if the chance is given?

    Wishing you the best in your future endeavors!

    1. Thanks for stopping by, Dr. Park! Another aspect of MWM performance that I’d love to explore more is the concept of flexibility within the probe trial. To give some context, the in the final trial of MWM testing, the platform is removed from the maze and mice just swim around. Normally researchers assess how much time was spent in the target quadrant, but I’d like to actually watch the performance and determine at what point the mouse realizes the platform isn’t where it used to be and explores other options. I think this would be a fascinating avenue of research because it may possibly flip a commonly accepted measurement of learning and memory on its head! Thanks for asking this question Dr. Park! I hope you’re well!

  21. Congratulations Gracie!! Getting to read more about your research was really cool, and the work you did on the relation between aerobic exercise and Alzheimer’s is really impressive!! 🙂 I wish you all the best for your time after Wooster!!

  22. Dang…maybe I should go for a light job tomorrow after reading through this. Great job Gracie! You’ve done a fantastic job here.

    1. Haha Marcel, you flatter me. Thank you so much for taking the time to engage with my project! 😀

  23. This was such an interesting topic and an amazing presentation! It was great being a Stav advisee with you!!

  24. Gracie- this presentation is amazing. You are a huge role model for future neuroscience students! Wishing you the best of luck for future endeavors!

    1. Thank you so much Rajani, that means so much to me! Excited for all that’s ahead for you! 😃😃

  25. Well done Gracie!!! Your success on this is a direct indicator of how you will excel in occupational therapy. So glad you’ve found your niche ☺️

  26. Congratulations Gracie! I really enjoyed reading about your IS, and I think your work is of the utmost importance. Your research helps deepen our understanding of AD and the effects (or lack thereof, depending on the strategy) of the MWM on the hippocampus. I think your research helps bring new knowledge into the world that can really have a positive impact on people’s lives. Good work!

    1. Hey Joe, thank you so much for taking the time to really understand my project! I appreciate you! 🙂

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