Healthy Brain, Happy Life: A Personal Program to to Activate Your Brain and Do Everything Better (2016)

SOLVING THE MYSTERIES OF MEMORY:
How Memories Are Formed and Retained

After spending my senior year back at U.C. Berkeley in Diamond’s lab, I completed my senior thesis, which focused on examining the brain sizes of rat babies after placing rat mothers in enriched environments. I then graduated with high honors and I knew I wanted to go to graduate school and learn how to become a neuroscientist myself. My time in the Jaffard lab in Bordeaux had also piqued my interest in the brain basis of memory. After all, memory is one of the most common categories of brain plasticity. We know that every single time we learn something new, something in our brain changes. But for me, at the beginning of graduate school, the question was how does the brain change. I was also interested in another question: Could we find a way to visualize what was happening the moment something was learned?

The many facets of memory intrigued me. In an intuitive way, I understood that when the brain learns something new, it must change. But where was this happening? What are the challenges to learning something new? And what did learning have to do with memory? My hunch was that all these questions had to do with how memories are structured and formed in the brain. When I was accepted into the graduate program for neuroscience at U.C. San Diego, I wanted to discover everything there was to know about memory; it turns out I was about to become involved in one of the most dramatic and far-reaching areas of neuroscience research.

A SEISMIC SHIFT IN OUR UNDERSTANDING OF MEMORY AND THE BRAIN

U.C. San Diego had a top-notch neuroscience faculty, including Larry Squire and Stuart Zola-Morgan, two neuroscientists whom I had first learned about in Jaffard’s course on memory. I didn’t know it the day I accepted the offer, but I was soon going to be in the eye of the firestorm over memory function that Jaffard had described in class.

The late 1980s was an electric time to be studying memory. A gigantic memory mystery had emerged in the field centering on the question of a specific brain region that was really critical for memory. This mystery had actually started thirty years earlier, with the most famous amnesic patient ever studied, a man known as H.M.

At the heart of this groundbreaking discovery in the 1950s was a neuroscientist named Brenda Milner, a Brit who got her degree at Cambridge University and was working at McGill University in Montreal, Canada. Milner, an assistant professor at the time, had been working with the eminent neurosurgeon Wilder Penfield, who specialized in brain surgery for serious cases of epilepsy that did not respond to drug treatment. This surgical intervention involved removing the hippocampus and amygdala from the side of the brain where the specialists thought the seizures started. Milner was testing Penfield’s epilepsy patients before and after their brain surgery to see if removing the hippocampus and amygdala had any adverse effect on their brain function. She found mild memory impairment for spatial information if the right hippocampus was removed and mild verbal memory impairments if the left hippocampus was removed, but these deficits were considered acceptable given that the surgeries greatly reduced or eliminated the devastating epileptic seizures that these patients had been suffering for years before the operation.

And then the team was absolutely flabbergasted when Penfield treated two new patients with the same brain surgery and got completely different results: After surgery, these patients showed profound and devastating memory deficits. Penfield and his colleagues had done more than a hundred similar operations with only mild memory impairments. They immediately wrote an abstract and addressed the unusual and disturbing findings in a presentation that was to be discussed at a meeting of the American Neurological Association in Chicago in 1954.

You might ask, what was known about the brain basis of memory in those days? In fact, the prominent theory of the time was championed by a famous Harvard psychologist named Karl Lashley, who had done a series of experiments in rats through which he tried to understand how memory was organized in the brain. He first taught the rats a maze and then systematically damaged different parts of the outer covering of their brains, or cortex, to see which area, when damaged, would lead to the most severe memory impairment for performance in the maze. What he found was that the location of the damage did not seem to make any difference. Instead he found that only when he damaged enough of the cortex did he see a memory deficit emerge. Based on these findings he concluded that memory was not localized to any particular part of the brain. Instead he believed memory was so complex that a large cortical network was involved and only when you damaged a significant part of that network would the memory system fail. This prominent view at the time made the striking memory deficits that Milner and Penfield saw even more puzzling because the memory issues they observed seemed connected to the removal or damage of specific brain regions.

Several hundred miles away in Hartford, Connecticut, another neurosurgeon by the name of William Scoville read the abstract Penfield and Milner had submitted for the American Neurological Association conference and immediately contacted Penfield. Scoville had been treating a young man with such severe epilepsy that he, with the consent of the patient’s family, had decided to do what he referred to as a “frankly experimental operation.” Scoville removed the hippocampus and amygdala on both sides of the patient’s brain, not just one. Scoville was correct about the reduction of epileptic seizures that took place, but immediately after the patient woke up it became clear that he, like Penfield and Milner’s patients, had a profound memory deficit. He didn’t know it at the time, but Scoville’s patient (H.M.) was to become the most famous neurological patient ever studied.

Remember, this surgery took place at the height of the era when neurosurgeons were using brain operations—such as frontal lobotomies and procedures that damaged parts of the frontal and temporal lobes—to cure various psychiatric diseases like schizophrenia and bipolar disorder. This practice is referred to as psychosurgery. It’s difficult to imagine what the mind-set was like at that time to believe it was okay to experiment with taking out parts of people’s brains, even if it was supposed to be for their own good.

Scoville not only attended the 1954 meeting of the American Neurological Association but also presented a paper describing his patient H.M. Scoville then invited Milner to Connecticut to study patient H.M. She immediately jumped at the opportunity.

Milner has described herself as a “noticer,” and her observations and testing of patient H.M. and nine other of Scoville’s patients helped reveal something completely radical in our understanding of how memory works in the brain. H.M. was the easiest to test and evaluate because most of Scoville’s other patients suffered from various psychiatric disorders, including schizophrenia and bipolar disorder. While she found H.M.’s intelligence to be quite high (and even improved a small amount after his surgery), he had a profound inability to remember anything that happened to him. He could not remember any of the hospital staff or doctors he came in contact with at the hospital (including Milner herself), could not find his way to the bathroom in the hospital or remember the location or address of the home his family moved to after his operation. Despite this profound inability to remember anything new, he knew his parents and the layout and location of his childhood home, and had apparently normal memories of his childhood. This meant that the operation carried out on H.M. impaired his ability to lay down new memories but spared his general intelligence (for example, he still continued to enjoy doing crossword puzzles—though he could do the same one over and over) and generally spared his memories of events that occurred before his operation.

This showed that Lashley’s theory was wrong: There is a particular part of the brain that is specifically involved in allowing us to create new memories. What part of the brain was it? This is where Scoville and Milner were appropriately cautious. H.M.’s operation damaged both the hippocampus and the amygdala on both sides of the brain. This general region of the brain that houses the hippocampus and amygdala is often referred to as the medial temporal lobe. That is, it’s the part of the brain’s temporal lobe located toward the middle of the brain (medial in anatomical terminology). But in examining the nine other psychiatric patients who had varying amounts of medial temporal lobe damage, Scoville and Milner noticed that the more the hippocampus was damaged on both sides, the more severe the memory deficit. This led them to suggest that the large extent of hippocampal damage on both sides was likely underlying the severe memory deficit in H.M.; however, they could not rule out the possibility that concurrent damage of the amygdala plus the hippocampus was at the root of the memory loss.

THE FASCINATING STORY OF PATIENT H.M.

Patient H.M. is one of the most fascinating and most extensively studied neurological patients in the learning and memory literature. After Brenda Milner’s work with him, her then graduate student and now professor emerita at MIT Suzanne Corkin studied H.M. for a total of forty-seven years, until his death in 2008. If you want to know more about patient H.M. and his story, I recommend Corkin’s wonderful book, Permanent Present Tense: The Unforgettable Life of the Amnesic Patient H.M. Listen to me interview Suzanne about H.M. on the podcast Transistor by PRX.

But this was not all Milner noticed. Once she characterized the severity of H.M.’s everyday memory loss, she got to work figuring out if there was anything at all he could learn and remember normally. She and others later showed that H.M. had an inability to form any new memories for facts (termed semantic memory) or events (termed episodic memory), typically referred to together as declarative memory—the kind of memory that can be consciously brought to mind. Next Milner revealed that H.M. did have normal memory for some things. Namely, she showed that he still had the ability to learn new motor or perceptual skills at the same rate as people who had not undergone surgery. Milner had him do tests in which he had to learn how to trace a figure accurately while looking in a mirror. H.M. improved steadily day by day but, strikingly, had no memory of ever having done the task before. Similarly, he was able to learn perceptual tasks in which he was given a vague outline of a picture and, after a variable amount of time looking at the incomplete figure, gradually picked out the image. He learned to identify those objects at the same rate as nonpatients as well. This was another revelation in the memory field. This finding suggested that different brain areas outside of the hippocampal region were necessary for these forms of motor and perceptual memory.

So the partnership of Scoville and Milner revolutionized the way we understand memory. Their studies led to our understanding that the medial temporal lobe, which includes the hippocampus, is essential for our ability to form new memories for facts and events. The researchers also showed that memories are not stored in the hippocampus because H.M. retained normal memories of his childhood and demonstrated that different forms of memory, including perceptual memory and motor memory, depend on different brain areas outside the medial temporal lobe.

But one additional contribution of that original Scoville and Milner paper cannot be overlooked. The report served as a grave warning to the neurosurgical community that the bilateral removal of the hippocampus should never be done again. H.M. lost his ability to form any new memories and spent the rest of his life depending on his family to care for him. The operation took away his ability to retain anything new about what happened to him and what was going on in the world. It was a terrible price to pay for the reduction of his epileptic seizures, and Scoville and Milner made sure that the entire neurosurgical community understood.

DIFFERENT KINDS OF MEMORY

The kind of memory that H.M. lost with his brain damage is called declarative memory, which refers to those forms of memory that can be consciously recalled. In addition, there are two major categories of declarative memory that depend on the structures of the medial temporal lobe:

Episodic memory, or memory for the events of our lives, which are those memories of our favorite Christmas celebrations or summer vacations; such “episodes” make up our unique personal histories.

Semantic memory, which includes all the factual information we learn throughout our lives, such as the name of the states, the multiplication table, and phone numbers.

We now know there are many forms of memory that do not depend on the medial temporal lobe, for example:

Skills/habits: These are the motor-based memories that allow us to learn to play tennis, hit a baseball, drive, or put our keys in our front door automatically. They depend on a set of brain structures called the striatum.

Priming: This describes the phenomenon that exposure to one stimulus can affect the response to another stimulus. For example, if you give someone an incomplete sketch of an object that she can’t identify but then show her a more complete sketch of the image, on the next round, she will be able to recognize the object even if less information is provided. Many different brain areas participate in priming.

Working memory: This form of memory has been called the mental scratchpad and helps us keep relevant information in mind where it can be manipulated. For example, you are using your working memory during a talk with your financial adviser, who is describing the different mortgage rates for you as you try to decide which one is best for your situation. The ability to keep the figures in mind and manipulate them to come to a decision is an example of working memory. That H.M. could keep topics in mind enough to have normal conversations showed that his working memory was intact.

FINDING MY PLACE IN THE MEMORY MYSTERY

The groundbreaking report of Scoville and Milner in 1957 cracked the study of memory wide open and started an avalanche of new questions for neuroscientists to explore. Two questions at the top of the list were, first, figuring out which exact structures in the medial temporal lobe were critical for declarative memory: Was it just the hippocampus or the hippocampus and the amygdala? And, second, how do you visualize the specific change that occurs in the normal brain when a new declarative memory is formed? I didn’t know it when I first began graduate school, but I was going to tackle the first question as my graduate thesis and the second question when I was an assistant professor at NYU.

By the time I entered U.C. San Diego in 1987, we knew a lot more about the important contribution of the hippocampus to memory, but the raging debate at the time focused on whether it was damage to the hippocampus alone that was underlying H.M.’s deficit, as Scoville and Milner hypothesized, or if it was the combined damage to the hippocampus and the amygdala, another possibility that could not be ruled out. A benchmark finding in animals in 1978 by Mort Mishkin appeared to provide evidence that it was the combined damage to both the hippocampus and the amygdala that led to the most severe memory deficits. Yet, in 1987 when I entered graduate school, Squire and Zola-Morgan at U.C. San Diego were finding evidence that the amygdala might not be involved after all. They had shown in animals that damaging the hippocampus on both sides caused a clear memory deficit, but they found no deficit after damaging just the amygdala on both sides of the brain. Then they did what turned out to be a key experiment. They added very precise damage to the amygdala in animals that had both their hippocampi removed. The researchers saw the addition of the selective amygdala damage did not in fact make the memory deficit worse, as predicted. The question was, If the additional memory impairment was not due to damage to the amygdala, then damage to what brain structure was it due to? A clue to this mystery came from a careful examination of the anatomy of the brain lesions. Neuroanatomist David Amaral was looking at the extent of damage in the brains of these animals in thin sections of tissue and noticed something obvious only to a neuroanatomist: There was a lot more damage than to just the hippocampus and amygdala. Namely, a lot of the cortex surrounding the brain areas of these animals was also damaged, in varying degrees. It was likely that the same damage would be present in patient H.M., given the surgical approach used to make his brain lesion. Maybe the nondescript cortical areas surrounding the hippocampus and amygdala that nobody had ever considered very important, and had previously thought to be part of our visual system, were the key to the mystery.

This is where I entered the picture. Amaral ran a neuroanatomy lab at the Salk Institute in San Diego right across the street from U.C. San Diego, and he was a leading expert on the anatomical organization of the medial temporal lobe. It seemed clear to me that we needed a more careful understanding of the basic structure of this part of the brain, so when they asked me if I wanted to take on that challenge, I jumped at the opportunity. I literally felt like a neuroscientist version of David Livingstone, entering one of the deepest, darkest parts of the brain—somewhere few others had gone before.

I had thought for sure that all parts of the brain had been carefully examined and mapped in 1987 when I entered graduate school, but I soon found out that the areas I was focusing on had fallen through the cracks. I was one of the first to study them carefully. I used some of the same basic techniques that had been used by neuroanatomists since the early 1900s. I examined thin slices of the brain from key temporal lobe areas and stained them with a chemical to show the size and organization of the cell bodies of the neurons and glia that made up the tissue (this technique is called a Nissl stain). I looked at some slices to see if I could identify features that would allow me to differentiate one area from the next. In other studies, I tracked where these areas received inputs from and where they projected to.

I spent hundreds of hours over six years sitting alone in a darkened room staring at brain tissue under a powerful microscope trying to discern a clear pattern. Some days, after hours and hours of looking in the microscope at the cells that made up these brain regions, the images started dancing in front of my eyes like beautiful abstract pieces of art. It was hard, detailed work. Often, to fill the silence, I listened to classical music. Saturday mornings were my favorite microscope days. Sitting in the lab all alone in the dark with my slice of brain tissue I listened to a radio program called Adventures in Good Music with Karl Haas—a wonderful show from which I learned about everything from the mysteries of how Stradivarius made his famous violins to subtleties of the violin passages in Mendelssohn’s symphonies. Adventures in Good Music was followed by the Metropolitan Opera’s Saturday matinee, which broadcasts operas in their entirety. I should have gotten an additional PhD in classical music appreciation with all the hours I spent listening to these programs during graduate school. I had no human company during the time I spent in that dark room, but at least I had the music.

What did all this work tell me? It turns out that the cortical areas in the medial temporal lobe I studied, called the perirhinal and parahippocampal cortex, provide massive input into the hippocampus via a structure called the entorhinal cortex. In addition, my studies showed that these cortical areas are a major brain interface, or “gateway,” receiving input from a wide range of brain areas involved in all kinds of sensory functions and other higher-level brain areas important for things like reward, attention, and cognition. Far from being simple visual areas, as researchers had previously thought, these regions are where high-level information converges in the brain. While I used relatively old-fashioned research approaches, my work revealed new information about why these brain areas might be so important for memory. Their connections were the key.

But just characterizing the connections of this region could not tell us exactly what its functions are. I went on to show that damage limited to these mystery cortical areas in animals causes devastating memory impairment that is similar in severity to the magnitude of impairment seen in H.M. This was another shocking finding. All the attention on memory research so far had been focused on the hippocampus and the amygdala. These new studies showed that neuroscience had been missing a key player in the game all along—the cortical areas that surround the hippocampus and amygdala. It was also clear that just because we implicated selective cortical areas important for memory, that did not mean that Lashley was vindicated. He had proposed that memory emerges from a complex interaction from widespread cortical areas across the brain and that no single area can underlie memory function. My findings showed that, in fact, you can identify specific and highly interconnected areas critical to the ability to form new long-term memories: specifically, the hippocampus and the cortical areas that immediately surround these structures. While Lashley was wrong about the localization of brain areas important for the formation of new memory, his ideas about the importance of large networks of brain areas did foreshadow findings that long-term memories can be stored in the same widespread cortical networks that process the incoming information in the first place.

My graduate studies helped identify two new brain areas and showed exactly how important they are for long-term memory function. In addition, the studies also pointed to another brain area, sitting between the perirhinal and parahippocampal cortices and the hippocampus, called the entorhinal cortex. Research shows that this area also plays a big part in the system of brain areas critical for declarative memory. Indeed, the recent Nobel Prize in Science or Medicine was awarded to two colleagues from Norway who characterized a major function of the entorhinal cortex in the processing of spatial information.

The U.C. San Diego research team and I hypothesized that patient H.M.’s severe memory impairment had to have been due to the damage both of the hippocampus and of these surrounding cortical areas. And sure enough, as soon I completed researching and writing my thesis, a brain scan was taken of H.M., which allowed researchers to visualize for the first time the true extent of his brain damage. This historic MRI scan (this is a technique that allows brain structure, including differentiating white matter, or axons, from gray matter, or cell bodies, to be visualized) confirmed that H.M. did sustain damage: not only to the hippocampus and amygdala but also to the surrounding cortical areas. This scan validated all the work that I had done for my dissertation, for which I earned my PhD and was awarded the prestigious Lindsley Prize, given by the Society for Neuroscience to the best doctoral dissertation in the field of behavioral neuroscience.

While I never met patient H.M., I thought so much about his brain and about what he could and could not remember that I felt like I knew him. I’ll never forget the morning of December 4, 2008, when I opened up the New YorkTimes to see his obituary on the front page. My first shock was to learn his full name for the first time in the twenty years I had been studying him. Henry Molaison. This was very likely the best-kept secret in all of neuroscience, revealed only at the time of his death. It was like learning something precious and very personal about a friend the day that he died. I happened to be teaching a big lecture course that day on the topic of memory. I shared the news with the class and even got a little emotional as I told them. They must have all thought I was a bit strange, but I couldn’t help it. Henry Molaison, patient H.M., had given up so much in his life for our understanding of memory. Since the day of his surgery, he could never remember another Christmas or birthday celebration or vacation—he couldn’t have a deep relationship with another person or make any plans for his future. He lost something precious the day of his surgery, but his misfortune enriched our knowledge of the brain and memory in a profound way. I will always honor his sacrifice.

MRI

MRI stands for “magnetic resonance imaging,” and it is a powerful and common imaging tool that uses strong magnetic fields and radio waves to form images of the body, including the brain. This general imaging approach, also called structural imaging, is widely used to see the gross structure of the brain and the boundary between the so-called gray matter (cell bodies) and white matter (axonal pathways) of the brain.

MOVING ON: STUDYING MEMORY AT NIH AND STARTING MY OWN LAB

I had spent six years at U.C. San Diego mastering neuroanatomy and behavioral approaches to examine the connections of key brain areas in the medial temporal lobe as well as the effects of damage to those areas. While these are important areas of study, they still don’t let you look firsthand at what’s happening in the brain during the formation of new memories. That’s what I wanted to do next. I wanted to learn new approaches by which I could examine the patterns of electrical activity in brain cells as animals performed different memory tasks. I wanted to look directly at the cells and the activity in the hippocampus that was occurring as animals learned something new. I secured a position as a postdoctoral fellow in the lab of Robert Desimone at the National Institutes of Health to do just that.

Desimone’s lab was in the larger laboratory of neuropsychology run by Mort Mishkin, the same neuroscientist who had published key findings on the effects of hippocampus and amygdala lesions in animals and whom I had first heard about while in France. I spent the next four and a half years at NIH learning how to record the activity of individual and small groups of living brain cells as animals performed various memory tasks. This general approach is called behavioral neurophysiology, and it’s powerful because we can examine how patterns of electrical activity in the brain relate to actual behavior. It is also powerful because it gives us a direct window on understanding exactly how particular brain cells respond to a given behavioral task. This contrasts with the studies of what happens with brain damage, like in the case of H.M. While transformative for our understanding of memory, lesion studies are, by their nature, indirect. We are studying the lack of function that used to be there before the damage. By contrast with behavioral neurophysiology, we can start to understand how the normal brain typically responds during a memory task.

It’s important to note that there are no pain receptors in the brain, so the microelectrodes we used for the recordings didn’t cause any discomfort, but they did allow us to record the brief electrical bursts of activity (called action potentials or spikes) that occur as an animal is learning or remembering something new. I basically trained animals to play video games focused on learning and memory and then recorded the activity of individual cells to figure out how the brain signals different aspects of the task and what happens to the pattern of brain activity when the brain remembers or forgets. I focused on one of the cortical brain areas in the medial temporal lobe, the entorhinal cortex, and characterized the patterns of neural activity in this area as animals performed a memory task. This was one of the only studies like this done in the entorhinal cortex. But I knew that there was much more left to understand relative to the physiological response properties of other key areas of the medial temporal lobe. That’s what I wanted to focus on in my own lab.

Those four years at NIH were intense and very valuable because they taught me the ins and outs of this powerful approach of behavioral neurophysiology, which I brought with me when I started my own neuroscience research lab in 1998. This is where things really got interesting in my career. I had at this point been studying memory for ten years. I was thrilled beyond belief to now be able to build my own research program focused on my scientific obsession—understanding what happens in the hippocampus when a new memory is first formed. My desire to learn this was inspired directly by the original description of patient H.M. He could appreciate the things around him in the present moment, but unlike us, he could not make that information stick in his brain longer than he could focus his attention on it. We knew that the ability to retain it depends on the hippocampus and surrounding cortical areas, but we had no idea what these cells do when a new memory is formed. That was the question that I wanted to investigate in my lab.

So as head of my own lab, the first decision I needed to make was what kind of information I was going to have the animals learn. It had to be something relatively simple, so they could do it easily, and be a task we knew was impaired by damage to the hippocampus and surrounding structures. I settled on something that required animals to associate particular visual cues (such as a picture of a dog or a house or a building) with a particular rewarded target to the north, south, east, or west on the computer monitor. We knew this form of learning, called associative learning, was a subcategory of declarative memory (in other words, it could be consciously learned and brought to mind), and there was good evidence that damage to the hippocampus and/or its surrounding brain structures caused significant impairment in learning these picture–target associations.

I set about teaching animals to learn multiple new associations each day, and when they could do the task very well, I introduced a thin electrode into their brain to record activity as they were in the process of learning.

Finally! I was going to be able to peer into the brain and see what happens in the hippocampus as we learn something new.

One reason people had not done this kind of experiment before is because it’s difficult to get animals to learn new associations. It turns out that the task that I chose was a good one; animals could learn multiple new associations in a given session. This was exactly what we needed to start looking at how new associations are signaled in the hippocampus.

Recording the activity of individual cells in the brain is a little like fishing. First, you set yourself up in a good part of the lake (or brain) where you think there will be some nice big fish (or brain cells), and then you wait. I was recording with a very thin microelectrode as it passed hundreds, probably thousands of cells through other parts of the brain before it reached the hippocampus. I sampled the electrical activity of the brain cells as the electrode passed by, and the brief burst of electrical activity registered as little “pops,” which you can hear on an audio monitor. My goal was to figure out if the pattern of this firing from a given cell had anything to do with the animal learning a new association between a picture and a reward. But there were no guarantees. There were plenty of days when I listened to the activity of many cells with the electrode, and not a one did anything much at all. It just sounded like a bunch of radio hash with no rhyme or reason to the pattern of firing. Other days, however, I got lucky and caught a nice big fish in the form of a cell that had interesting activity—for example, cells that seemed to fire only when a particular picture was shown or cells that fired a lot during the blank delay interval of the task between the presentation of the picture and when the animal made a response to one of the targets.

I kept fishing in the hippocampus with the hope of finding something interesting, and over the first few months of recording something did start to emerge. I noticed that a particular cell we were monitoring seemed to have little or no firing associated with the task early in the trial when the animal had not learned any of the associations. But then, the cell seemed to increase its firing rate later in the session when more associations were learned. I didn’t fully appreciate the pattern until we analyzed the data later. Then it was as obvious as the nose on your face.

Just as I had noticed when listening to the cells during the experiment, these cells had little or no specific firing related to the task early in the learning session when the association had not been formed. But as the animal learned a new association, certain cells would dramatically increase their firing to double or sometimes triple their earlier rate. The increase in activity didn’t happen when all associations were learned, just during particular associations. This suggested that there were particular groups of cells in the hippocampus that signaled the learning of new associations by changing their firing rate. I realized I had been listening to the birth of a new memory in the firing of these neurons! Nobody had ever characterized learning in the hippocampus in quite this way before. We were seeing exactly how hippocampal cells encoded newly learned associations, and because we know that damage to this brain region impairs the creation of such associations, the study suggested that this pattern of brain activity was the key to the new associative learning process.

This was not only exciting for my research partners and me but for the field of neuroscience in general. Ours was one of only a handful of demonstrations of brain plasticity occurring in real time and directly associated with a change in behavior, in this case, new associative learning! Diamond had shown that rat brains had more synapses in general if the animal was raised in an enriched environment relative to an impoverished environment, but her studies did not measure behavior while learning was occurring or while a memory was forming. It was kind of assumed that if your brain got bigger, this was generally a good thing for behavior or performance. The long-term implication of our work is that if we understand this functionality in the brain, we might be able to replicate it when a brain is handicapped by various neurological problems. In other words, these findings showed us how cells in a normal hippocampus work as new memories are being formed. Because this brain area was missing in H.M., he was not able to form new memories. Importantly, these results are also key first steps to developing possible therapies for the associative or episodic memory deficits that occur in Alzheimer’s disease, traumatic brain injury, and normal aging. We must understand how the normal brain works to form new memories before we can fix what goes wrong with them in these neurological conditions.

TAKE-AWAYS: FORMING NEW MEMORIES

• Parts of the temporal lobe, including the hippocampus, entorhinal, perirhinal, and parahippocampal cortices (one on each side) are critical for a fundamental form of memory called declarative memory.

• Declarative memory is named for its ability to be consciously declared and includes memory for our life experiences (episodic memory) as well as memory for facts (semantic memory).

• For a new declarative memory to be laid down, these key temporal lobe regions must be working. These regions are also required as this new memory is repeatedly recalled and possibly associated with other information on its way to becoming a long-term memory.

• Once these temporal lobe areas do their job of forming a long-term memory, the areas are no longer required. The memories are then thought to reside in complex networks of cells in the cortex.

• If you damage your hippocampus as an adult, there are no other brain areas that can take over. So there is no plasticity left if you lose this area of the brain.

• We now know that cells in the hippocampus can signal the formation of new associative memories by changing their firing rate in response to particular learned associations. Learn someone’s name and there will be a group of cells in the hippocampus that are firing specifically to that newly learned name–face association.