Analysis for Science Librarians of the 2014 Nobel Prize in Physiology or Medicine: The Life and Work of John O’Keefe, Edvard Moser, and May-Britt Moser

Navigation and awareness of space is a complicated cognitive process that requires sensory input and calculation, as well as spatial memory. The 2014 Nobel Laureates in Physiology or Medicine, John O’Keefe, Edvard Moser, and May-Britt Moser, have worked to explain how an environmental map forms and is used in the brain (Nobelprize.org 2014b). O’Keefe discovered place cells that allow the brain to learn and remember specific locations. The Mosers added the second part of the “positioning system in the brain” with their discovery of grid cells, which provide the brain with a navigational coordinate system (Nobelprize.org 2014b).


INTRODUCTION
Alfred Nobel dictated in his will that his millions were to be used to create the Nobel Foundation in order to fund Nobel Prizes, the first of which was awarded in 1901 (Nobelprize.org 2014g). The Prize for Physiology or Medicine is given to those who are found to have made a major discovery that changes scientific thinking and benefits mankind. Between 1901 and 1953 there were over 5,000 individuals nominated for the Physiology or THE SCIENCE The medial temporal lobe, including the hippocampus, amygdala, and entorhinal cortex, is the brain's memory center (Squire and Zola-Morgan 1991) (see Figure 1). The term hippocampus comes from the combination of the Greek words for horse (hippos) and caterpillar (kampe) and was first used in Greek literature when referring to seahorses. In 1587 the anatomist Arantus was studying the human brain and used the word to describe a previously unnamed structure that he thought resembled the shape of a seahorse. Although there is some debate about what exact region of the brain Arantus was describing when he applied the term, it has come to be the name used today (Walther 2002).
The hippocampal region was studied extensively in the 1950s and 1960s (Burgess, Maguire, and O'Keefe 2002;Walther 2002). Probably the most defining study on the hippocampus is that by Scoville and Milner in 1957. In this study, experimental operations excising part of the hippocampus were performed on three patients. Two of the patients suffered from mental disorders and one suffered from epilepsy. All three patients recovered from the surgery, improved though with severe memory disturbances. The two patients with mental disorders appeared to have better temperament but later showed memory loss. The epileptic patient, H. M., recovered from surgery with less-incapacitating seizures but showed the most immediate signs of memory problems (Scoville and Milner 1957). The case of H. M. is often regarded as the first study showing the role of the hippocampus in the memory process. Even though the hippocampus and surrounding features had been studied for centuries, an article by Vanderwolf (1969) indicated that its function was still not very well known. O'Keefe and Dostrovsky (1971) furthered Vanderwolf's research on the hippocampus, publishing his research and arguing that the hippocampus serves as a "spatial map" and discussing the cells that make up the map. These cells were named place cells in a later article by O' Keefe er al. (1975) and were more thoroughly described in O' Keefe's (1976) article "Place Units in the Hippocampus of the Freely-Moving Rat." O'Keefe's work built upon previous research done on rats and navigation. Tolman (1948) discussed navigation and a way of thinking that imagined rats in a maze building a "field map" of their environment in order to learn how to quickly navigate to food. O' Keefe and Dostrovsky (1971) were able to go beyond previous research, including that of Tolman and Vanderwolf, by attaching electrodes onto the skulls of rats, which allowed them to visualize and record brain activity. They saw that certain cells fired when the rat was in a certain space and position but then stopped firing as soon as the rat moved (see Figure 2). The firing in individual cells seemed to be in response to specific locations and demonstrated that place cells work together to form a spatial map.
Since the discovery of rodent place cells, scientists have continued to study these cells and explore whether there are similar sets of cells in the human brain. Ekstrom et al. (2003) recorded the firing of neurons FIGURE 2 Electrodes inserted into a rat's hippocampus show individual cells firing when the rat is in a specific place. (Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Neuroscience, "NMDA receptors, place cells and hippocampal spatial memory," copyright 2004.) while humans explored a virtual town. They found hippocampal cells that responded to place, view, goal, and combinations of the three, suggesting that humans have analogous cells to rodent place cells. A couple of years after Ekstrom, the Mosers discovered the second half of the brain's navigational system: grid cells (Hafting et al. 2005).
Edvard and May-Britt Moser learned O'Keefe's techniques for monitoring rat brain cell activity while working in his laboratory in 1996. When they returned to their own lab, they used these techniques and continued studying the hippocampal formation in regards to space and location (Nobelprize.org 2014d). When experimental lesions on the hippocampus did not result in the expected loss of navigation, the Mosers looked at other features, including the entorhinal cortex (Norwegian University of Science and Technology 2014) (refer to Figure 1). The entorhinal cortex has not been studied as extensively as the hippocampus. A search for articles on the topic of the entorhinal region indexed in Web of Science showed that relatively little research was done in this area prior to the 1990s. What was known about the entorhinal cortex was that it has a role in providing sensory input to the hippocampus, has an important function in memory storage, and may play a role in some neurodegenerative diseases such as Alzheimer's (Levisohn and Isacson 1991). After a few years of not getting the response they were looking for from hippocampal lesions, the Mosers decided to look more closely at the entorhinal cortex and were able to record spikes in activity in the dorsocaudal medial entorhinal cortex (dMEC) of moving rats. Mathematical calculations of the recorded spikes in activity showed equilateral triangles between three cells, which in turn form perfect hexagonal patterns. These hexagonal patterns form a location grid, allowing for high precision in determining position and route (Hafting et al. 2005) (see Figure 3). The Mosers' research on the entorhinal cortex identified grid cells and showed that they work with the hippocampal place cells in navigation, awareness of space, and location memory. Grid cells have since been observed in bats and monkeys, and Jacobs et al. (2013) discussed the discovery of grid-like cells in humans. The study of navigation and spatial orientation is often discussed in regards to two frames of reference. Allocentric refers to the relationship between objects, while egocentric refers to the relationship between an object, or objects, and the subject (Zaehle et al. 2007). The discoveries of place cells and grid cells lead scientists to believe that navigation is a combination of stimuli from the environment such as landmarks (allocentric map), as well as stimuli from the individual (egocentric map). Early studies such as Tolman's focused more on the idea of an egocentric map, but the discovery of place and grid cells show evidence of an allocentric map (Manning et al. 2014). Exactly how place cells in the hippocampus work with grid cells in the entorhinal cortex is still not entirely understood, and research continues (Azizi, Schieferstein, and Cheng 2014;Zhang et al. 2014).
The exact role of the hippocampal formation, the area of the brain that includes the hippocampus and the entorhinal cortex, is also still debated. It has been shown to affect memory and learning, perception, place learning, navigation, responsiveness to the environment (orienting reflex), and approach behavior (Eichenbaum, Otto, and Cohen 1992;Lee, Yeung, and Barense 2012;Vanderwolf 1969). It is also known that this part of the brain is affected early on in diseases such as Alzheimer's (Nobelprize.org 2014a). An early indication of Alzheimer's is memory impairment, including the loss of spatial memory. A recent study by Zhao et al. (2014) discussed hippocampal place cells altered by the buildup of amyloid proteins, such as what occurs with Alzheimer's disease, and the resulting functional decline in spatial information. The discoveries of the 2014 Physiology or Medicine Nobel Laureates have laid the framework for even more research into the brain, how humans navigate space, and brain disorders that affect memory. The scientific community owes a great deal to the discovery of place and grid cells. From the beginning of his scientific studies O'Keefe has been interested in the brain and behavior. He has focused his research on the limbic system and medial temporal lobe, specifically the amygdala and hippocampus. While attending McGill University O'Keefe met Professor Brenda Milner, who ran the noted study on the patient H. M. This study took place less than 10 years before O'Keefe began work on his doctorate, and it influenced him greatly. As a doctoral student, he studied how lesions on the hippocampus affect rodent behavior; the 1957 Milner and Scoville study convinced him that there was more to learn and, in part, resulted in his focus on the hippocampus (Sweet 2014 O'Keefe has given praise to those around him. He credits both CCNY for allowing him to get an education and to start his career and McGill University for the good fortune of earning his Masters under Donald Hebb's Psychology Department. During his interview with Adam Smith from nobelprize.org, O'Keefe stated "I think the Prize actually is as much for the field as for myself and the Mosers. I think, you know, we're just representatives of a large number of people who are working away at the hippocampus and memory and spatial navigation" (Nobelprize.org 2014d).    Figure 5). His research on the brain's role in navigation and spatial sense has become fundamental research. Web of Science calculates his h-index as 47, with an average of more than 190 citations per article published. After removing self-citations, O'Keefe has been cited around 15,000 times in nearly 9,000 articles. His 1971 article is now his second-most-highly cited article, averaging more than forty citations a year. All of O'Keefe's most frequently cited articles deal with place cells (see Table 1). O'Keefe tends to publish in high-impact journals. The journal he has published in most frequently is Hippocampus, which has a 5-year impact factor of 5.059 and is ranked as number forty-nine of all the neuroscience journals summarized by Journal Citation Reports (JCR) as of 2014. O'Keefe publishes in both narrowly focused brain and neuroscience journals and broad multidisciplinary science journals such as Nature (see Table 2). He has also published books, including his influential and freely available The Hippocampus as a Cognitive Map, coauthored with Lynn Nadel. According to Google Scholar, this book has been cited almost 7,500 times since its publication in 1978. May-Britt's interest and research passion is cognition, focusing on the sense of space. She continues to work with her husband and other colleagues on grid cells, their circuit, and how they work with the hippocampus on memory (M.-B. Moser 2014). Similar to O'Keefe, May-Britt expressed how the award was not just for the three of them. In her interview with nobelprize.org she said the award is as much for all those who supported them and everyone in their laboratory as it is for herself, her husband, and O'Keefe (Nobelprize.org 2014e). In other interviews she has expressed admiration for her research subjects, the rats, saying "if we wouldn't have the rats, and they would not like to collaborate with us, we would have no data . . . . If they are not happy, if they are not well, they are not going to give us good data" (Körber Foundation 2014).

BIBLIOMETRICS
May-Britt's bibliography is extensive, with eighty-one publications indexed in Web of Science since 1988, averaging more than three articles per year (see Figure 6). She has an h-index of 44 and, correcting for self-citations, she has been cited almost 8,700 times in almost 4,600 articles. The impact of her research can be partially inferred through the steady increase in her citation counts (see Figure 7).
It makes sense that May-Britt's most highly cited article, with almost 750 citations, is the 2005 publication on the discovery of grid cells. Her other most-cited articles have approximately 400-500 citations each (see Table 3). Similar to her mentor O'Keefe, Moser's publications are in both high-impact neuroscience and high-impact multidisciplinary sciences journals (see Table 4). Thirteen of her eighty-one publications are in the journal Neuron, which has a 5-year impact factor of 16.485 and is ranked fifth among neuroscience journals.    negotiate for both of their Associate Professorships at NTNU, but they had to build their lab from scratch in an old bomb shelter (Bazilchuk 2014 Edvard shares the interests of his wife, May-Britt, and mentor John O'Keefe. He is interested in how the brain figures out where we are in space and how we remember that space. His research with May-Britt continues the study of the entorhinal cortex and organization and formation of grid cells (E. I. Moser 2014). Like his wife and O'Keefe, Edvard expressed gratitude and praise for those around him. In Edvard's interview with nobelprize.org, his words were almost verbatim those of his wife and O'Keefe-even though he had not yet had a chance to speak to either of them. He views their discoveries as being a result of teamwork with a lot of people "who are completely invisible" (Nobelprize.org 2014c). BIBLIOMETRICS Edvard Moser's bibliography is another impressive example of research and publication. He has 112 publications indexed in Web of Science, averaging four articles published each year since 1986 (see Figure 8). His articles are highly cited, with almost 9,500 total citations, not including self-citations, in nearly 5,000 articles. This gives him a strong h-index of 51 and an average of almost ninety-one citations per article published. Most of these citations occurred after his influential 2005 article (see Figure 9).
Not surprisingly, Edvard's publications match those of his wife, and longtime collaborator, May-Britt. They have worked, researched, and written together for their entire careers. His most-highly cited articles are the same as those of May-Britt (see Table 5). The same is true for the journals in which Edvard has published. His top five journals are the same high-impact journals as May-Britt, although his publication numbers are slightly higher (see Table 6).

The Mosers
It is hard to miss the overlap of the Mosers' lives and careers. They have known each other since high school and worked side by side since their undergraduate days at Oslo. The couple shares everything. They work on the same research, run the same organizations, supervise the same postdoctoral and PhD students, win the same awards, serve on the same committees, and have jointly raised their two daughters. As for winning the Nobel, they are the fourth married couple to win it in the sciences, and the fifth pair to win any Nobel. Gerty and Carl Cori were the first couple to win the Physiology or Medicine Prize in 1947, and the Mosers are the second. They are also the first scientists in Norway to win the Medicine Nobel (Nobelprize.org 2014g). Looking at their publications, it is evident that since 1988, if not earlier, their interests have both been on exploratory behavior and spatial learning in rats. John O'Keefe knew that his mentees were going to do extraordinary work together and says that they put what they learned in his lab "to very good use" (Nobelprize.org 2014d). They built their first lab together when it was just the two of them. As their lab grew and they started winning grants, both together and individually, they improved the lab. Eventually the influence and importance of their work allowed them to turn their Centre for the Biology of Memory (CBM) into the Kavli Institute for Systems Neuroscience and the Centre for Neural Computation (KI/CNC). In 2005, after the discovery of grid cells, Fred Kavli and the president of the Kavli Institute, David Auston, visited the CBM. In 2007 it became one of only four Kavli Foundationrecognized neuroscience institutes in the world. Due to the success of the CBM, the Norwegian Research Council extended funding beyond the initial 10 years, turning the CBM into the CNC. The Mosers run the organization together, with Edvard serving as Director of the Kalvi Institute and May-Britt serving as Director of the Centre for Neural Computation (Norwegian University of Science and Technology n.d.).

CONCLUSION
The 2014 Nobel Prize in Physiology or Medicine was awarded to three exceptional scientists "for their discoveries of cells that constitute a positioning system in the brain" (Nobelprize.org 2014b). John O'Keefe made the groundbreaking discovery of hippocampal place cells in 1971, and May-Britt and Edvard Moser built upon his work, discovering grid cells in the entorhinal cortex in 2005. The married couple worked with O'Keefe, learned from him, and continue to think of him as a mentor. The work of these three scientists has led to a better understanding of the brain, memory, and sense of space and navigation. This understanding and increased knowledge of the hippocampal formation, including the entorhinal cortex, can lead to research that will provide a better understanding of higher cognitive functions and of diseases such as Alzheimer's.