HIPPOCAMPAL HITORY TOUR PART 13: OZZIE STEWARD

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This entry from Oswald (Ozzie) Steward introduces another branch of the hippocampal tree -- those who were drawn to it as a model system, useful for studying pharmacology, physiology, and more. Already in the 1970s there were quite a few of these, and Ozzie was amongst the leaders. Some new names come up, and. a few old ones resurface. UC Irvine, where I spent about 5 years in the early 1980s, was already then, and continues to be now, a world center for brain research on learning and memory. Here's how Ozzie remembers it.

Oswald Steward's hippocampal reminiscences:

Something that makes me a bit different from many “hippocampologists” is that I have loved the hippocampus as a model system for studies of basic neuronal cell biology and synaptic growth and plasticity, not so much as an object of study in and of itself. Consequently, my contributions to understanding the hippocampus itself are perhaps more limited than others.

My fascination with the hippocampus began at the start of my second year in graduate school in the Department of Psychobiology at the University of California Irvine. I came to graduate school with a core interest in mechanisms of learning and memory, which had been seeded by my undergraduate advisor at the University of Colorado, Kurt Schlesinger. Kurt had been at North Carolina at the time the idea was advanced that memory might use the same basic mechanisms as genetic memory (DNA-RNA-protein). The North Carolina group was one of the first to report that blocking RNA synthesis impaired memory in mice and Kurt was working on this idea when I took my first course in “Biological Psychology” from him at the University of Colorado (my introduction to Neuroscience).

With a somewhat unimpressive academic pedigree, I was incredibly fortunate to be accepted into the graduate program at UCI, albeit not in the first round. I got a phone call from my future graduate advisor Carl Cotman several weeks after initial offers had gone out; the gist of his call was: “Well, our top candidates turned us down but you looked interesting a possible backup”. I didn’t really care whether I was first or dead last as long as I got an offer--UCI was my first choice.

My first-year project in Carl’s lab foreshadowed what has been a focus throughout my career—how synaptic activity regulates postsynaptic gene expression. Using the Aplysia abdominal ganglion, I tested whether synaptic activation would trigger increases in protein synthesis (incorporation of radioactive amino acids into protein) in a postsynaptic neuron (R2, the largest neuron in Aplysia). I didn’t get any useful data though; consequently, at least a few Aplysia Californica were spared from the species’ only predator (graduate student neuroscientists in Southern California collecting for experiments).

During my first year in graduate school, Gary Lynch carried out the very first experiment showing “sprouting” (growth of axons and synapses) in the hippocampus. His initial study was motivated by Geoff Raisman’s publication a year earlier showing electron microscopic (EM) evidence of new synapse formation on septal nucleus neurons after deafferenting lesions. Gary was fascinated by the idea of using histochemical markers for pathways, which could be readily deployed. He reasoned that AChE staining for the cholinergic septal projections to the hippocampus might reveal post-lesion growth if it occurred. Gary described the study to Walle J.H. Nauta during a visit to Irvine, and Nauta said “Well, good idea, but most good ideas don’t pan out”. This one did! The experiment was to lesion the entorhinal cortex (EC) and stain for AChE to reveal septo-hippocampal projections. The result was dramatic—huge increases in AChE in the dentate gyrus molecular layer that had been denervated by the EC lesion. You could hold the microscope slide up and see this by eye without a microscope!

That year, Gary visited Per Anderson and presented the data. Per’s comment was in essence—“Well this sprouting is interesting but the question is whether sprouting axons are functional.” And that’s where I came in. At Irvine, graduate students were accepted into one lab (in my case, Carl’s) but were required to do a second-year project in another lab. There was great excitement about the cholinergic sprouting, so I chose Gary’s lab where I would learn hippocampal neurophysiology to try to determine whether sprouted septal projections formed functional synapses. I didn’t get any useful data (is there a repeating theme here?). The synaptic physiology of the cholinergic pathway from the septum to the dentate gyrus was (is) too complex. But in the process of testing pathways to the dentate gyrus after unilateral EC lesions, I discovered that unilateral lesions of the EC triggered sprouting of a crossed pathway from the contralateral EC. This type of sprouting was unique in that it led to the re-establishment of synapses with dentate granule cells that were homologous with the ones that were lost. My dissertation research characterized this new form of sprouting.

Studies of reinnervation of the dentate gyrus and recovery of function were the focus of my research for the first decade of my career. During our EM studies of reinnervation, we discovered the selective location of protein synthetic machinery (polyribosomes) at individual spine synapses. This founded a field of research on protein synthesis at synapses that now involves numerous labs across the world. Later, the highly laminated structure of the hippocampus allowed definitive studies on localization of mRNAs in dendrites. And the highly laminated inputs to the hippocampus provided the model system for my subsequent studies showing that newly synthesized Arc mRNA was selectively targeted to active synapses.

What findings about the hippocampus other than mine most excited me? LTP and LTD—synaptic plasticity mechanisms consistent with Hebb’s postulates that could plausibly account for memory.

A personal story about interactions with colleagues: Many to choose from, but the one that stands out is my collaboration with William B. (Chip) Levy on “Hebbian” plasticity. Chip realized that my data on the convergence of a sparse (weak) crossed projection from the EC to the dentate gyrus with the ipsilateral (strong) projection provided an ideal model system (there it is again) to test synapse cooperativity in LTP and LTD. Chip gave up a tenure track position at UC Riverside to come to UVA to collaborate on this. We showed that high frequency stimulation of the weak crossed pathway did not lead to LTP, but pairing of ipsi- and contralateral stimulation produced robust LTP of the crossed pathway. Moreover, stimulation of the strong ipsilateral pathway alone actually produced LTD of the crossed pathway (heterosynaptic LTD). To the best of my knowledge, our first paper together (XX), was the first to use the term “Hebb synapse” (actually, we said “Hebb-like synapse”) to describe the phenomena. A follow-up paper together (Temporal contiguity requirements…)” remains one of my most highly cite papers. Chip and I also collaborated on the initial EM description of selective localization of polyribosomes at synapses.

What would I tell a young researcher interested in the hippocampus to focus on now? Focus on questions, not a particular structure or system. If the hippocampus is a good model to answer fundamental questions, great! But whatever model system you use, develop deep knowledge of structure, connections, and function. New discoveries that stand the test of time and scrutiny are based on a solid foundation.

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HIPPOCAMPAL HISTORY TOUR PART 12: Charan Ranganath...part 2

What would tell a young researcher interested in the hippocampus to focus on now?
Think bigger–in terms of the brain, in terms of tasks, and in terms of models or theories.

There is a paradigm shift on the horizon. The idea that we can understand (at the computational or functional levels) the hippocampus as a module, independent of its connections, is untenable. Menno Witter’s detailed neuroanatomy, for instance, has made it very clear that the functions of the entorhinal cortex are inextricably linked with the hippocampus, such that you cannot understand one without the other. And the entorhinal cortex is the master hub of the brain, interacting with other major hubs, such as the prefrontal, perirhinal, and parahippocampal cortex, as well as subcortical areas like the amygdala. Then we can talk about neuromodulatory inputs like dopamine, cortisol, estrogen, etc. All this means that the computational environment of the hippocampus, by extension, its functions will be volatile and context dependent.

Moreover, the idea of the hippocampus as storing static “engrams” that are simply passed on to the cortex to reinstate memories is becoming increasingly untenable. We know that hippocampal representations are subject to substantial updating, but also they are dramatically modulated on the fly. A hippocampal “memory” of the same experience can be used for different purposes, and the representational space that you see in the hippocampus can look totally different depending on one’s goals or task context.

This brings us to the computational level. All the functions assigned to the hippocampus–which include everything from statistical learning and transitive inference to forming hyper-specific, pattern-separated memories–are computationally incompatible. They cannot be done by a single brain region. We can’t understand the hippocampus in isolation–we have to understand it in the context of dynamic interactions with other brain areas. That means we need to understand the characteristics of the animal’s environment (in a broad sense, not simply in terms of spatial geometry), its prior knowledge, and its goals. Trying to understand the hippocampus by asking people to memorize words in a word list, stretch out bird necks, or chasing fruit loops in an empty box is going to tell us nothing beyond what it does in those degenerate contexts.

If the goal is to understand episodic memory, we need to study events that have the complexity and timescale of events in the real world, and we need to consider how humans understand events in real time. If the goal is to understand navigation in a meaningful sense, we need to study navigation to a goal, in an animal with knowledge of its environment. If we want to understand the relationship between synaptic plasticity and forgetting, we need to study an animal that has more than two meaningful events in its lifetime, because retaining memories means maintaining robust connections amidst a daily barrage of interference.

So I think we need to study tasks that have a larger spatiotemporal scale, and think about the brain in terms of dynamic large-scale networks, and develop large-scale models that bridge these levels. This is going to be hard work and not for the faint of heart.

If you want me to get specific, one big opportunity that is waiting to be grabbed is to understand gating and regulation of information flow in the hippocampus. Right now, there’s a widespread implicit assumption that whenever hippocampal cells are active, that the neural activity is somehow behaviorally relevant. That assumption is probably wrong. For instance, we don’t think that the visual cortex is doing meaningful stuff when you sit around in the dark. Why should we assume that the hippocampus is constantly being consulted in the service of encoding and retrieval? There’s compelling evidence to suggest that, in fact, we don’t use the hippocampus constantly, and that a lot of what people see in hippocampal activity is just housekeeping. So, we need to understand when and how the hippocampus is brought in and out of action to serve behavior.

HIPPOCAMPAL HISTORY TOUR PART 12: Charan Ranganath

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#hippocampusGurus

Today's comments come from a contemporary of Mike Hasselmo's -- and someone I've enjoyed exchanging ideas with from the very first time we met. And it continues to this day. Charan's comments will have to be broken into two parts.

Charan Ranganath

What got you interested in the hippocampus?
I know it is a cliche, but what got me interested was hearing about Brenda Milner’s work with H.M., reading her work with temporal lobectomy patients… and also the general contrasts between declarative and nondeclarative memory described by Larry Squire, Neal Cohen, and Dan Schacter.

Really, though, all that work was part of my bigger interest in memory, and my first love was the prefrontal cortex. Having gotten my feet wet as an undergraduate in Art Shimamura’s lab, I was doing clinical neuropsychology in grad school. Later, having read Joaquin Fuster’s eloquent book on the prefrontal cortex and Marcia Johnson’s work on Source Monitoring, I was sold. That interest was reinforced by testing so many people in the clinic with frontal dysfunction.

I later fell into the hippocampus when I was doing my postdoc in Mark D’Esposito’s lab to study how the prefrontal cortex contributes to working memory and long-term memory. I started to read the monkey lesion and single-unit recording literature, and I noticed that many of the tests used to test the role of the prefrontal cortex in working memory were hardly different from the tests used to investigate effects of medial temporal lobe lesions on memory in monkeys. At the time, people who were doing standard tests of declarative memory in fMRI studies could not get hippocampal activation, and surprisingly, we found hippocampal activation when people were asked to do a working memory task. Our publication even included a replication–in the exact same voxels that we had investigated in the original study. Chantal Stern had gotten similar results with an n-back working memory paradigm. No one wanted to believe our results and I took a ton of flak from people–our paper was rejected by a number of top journals. But the findings were replicated by others, and other labs that ran our paradigm in amnesic patients found that hippocampal damage could impair working memory. I soon did a deeper dive, and I saw all these flaws in the previous literature on working memory and long-term memory, and I began to question all the standard dogma about the hippocampus. That led me to do all sorts of other studies to challenge the standard model of hippocampal function.

Aside from your own work, what findings about the hippocampus (and related brain parts) in the past 50 years most excited you, and why?
I think the most exciting and eye-opening thing was the discovery of what the hippocampus doesn’t seem to do, and that the “related brain parts” really do most of the heavy lifting in many memory tasks. One study that stands out was Betsy Murray’s study showing that the perirhinal cortex is the essential player for object recognition memory, not the hippocampus (as well as the work from Howard Eichenbaum, John Aggleton, etc.). Then I went back and noticed that Larry Squire’s lab had shown relatively minor memory deficits in humans with hippocampal damage (compared to those with perirhinal damage). Putting that together with the failure to find hippocampal activation in fMRI studies of “declarative memory” made me rethink all of my assumptions about what the hippocampus does.

Then there were the studies that revealed something different about hippocampal function. For instance, I was really influenced by Jen Ryan and Neal Cohen’s study, suggesting that the hippocampus may be critical for spatial relational memory even in the absence of awareness. I was also amazed by the convergence between Andy Yonelinas’ work in human amnesics and Howard Eichenbaum’s parallel studies in rats showing that the hippocampus seems to be critical for recollection. The Nadel and Moscovitch review on retrograde amnesia was another paper that took a while to pass through my defenses, eventually leading me to the realization that the standard systems consolidation theory actually made no sense. All of this stuff led me to really think about “context” and its central role in memory.

On a related note, context is also connected to a completely different area of research on the “P300” event-related potential, which is a neural response to unexpected events or targets in simple detection tasks. Donchin and Coles proposed that the P300 is an index of “context updating,” a process that we now call “event segmentation”. Bob Knight had shown that the P300 was abolished in patients with hippocampal damage, and many intracranial EEG studies showed that the P300 is ubiquitous in the human hippocampus. P300 effects are far more robust than any other neurophysiological signal in the human hippocampus. Thomas Grunwald basically demonstrated that if a hippocampus doesn’t generate a P300 it is non-functional.

Finally, I was drawn to the “time cell” studies from Gyuri Buzsaki and Howard Eichenbaum’s labs, and Howard’s work examining representation of item and context information in the hippocampus. All that stuff led me back to the foundational work on spatial memory done by John O’Keefe, Richard Morris, Edvard and May-Britt Moser, etc.

And since you mentioned “related brain parts,” the confluence of findings showing a critical role for the parahippocampal cortex (and possibly also the retrosplenial cortex) in all aspects of context representation in memory was probably the biggest bombshell for me, although the importance of that discovery has been overlooked by much of the field.

Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
This is the question that held me up. It is hard to pick one because our community has a lot of different personalities. I can tell a couple of stories of social interactions that laid bare the behavior of highly influential scientists who abused their power in ways that really hurt vulnerable people both personally and professionally. But I can equally tell of stories of incredible senior scientists like Howard Eichenbaum, Ray Kesner, and you Lynn, who would talk to students, postdocs, and junior faculty members (male and female, white or POC) like what they had to say was incredibly important. That gives you a kind of boost that is hard to put into words.

I’ll choose one story which captures the most collaborative and constructive aspects of our world. In 1999 or 2000, at the Cognitive Neuroscience Society meeting, I literally bumped into Andy Yonelinas as he was presenting a poster on his work showing that hypoxia patients had impaired recollection and intact familiarity. At the time, I was a true believer in this whole thing that the hippocampus does “declarative memory,” and I told him that I was skeptical about this whole recollection/familiarity thing. It would have been reasonable for him to blow off this silly comment from a postdoc who knew almost nothing about cognitive theories of memory. Instead he totally disarmed me when he said, “You should be skeptical!” What followed was a cool conversation/debate about the topic and how the distinction between recollection and familiarity could be tested with fMRI. We designed a study together and made a bet that if the hippocampus and perirhinal cortex contributed differently to recollection and familiarity, I’d buy him a beer, and if not, he’d buy me one. For a while, it looked like I was right but when we got enough data to do a group analysis, it turned out he was right–and that result pretty much changed my view of the hippocampus, and in turn about what memory is in the first place. By now I owe Andy a lot of beers and probably will not live long enough to pay off my tab.

HIPPOCAMPAL HISTORY TOUR PART 11: Mike Hasselmo

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Today's tour expands to colleagues from the generation that followed most of those who've been featured up to now. Mike Hasselmo gets us started - a friend whose work I've followed and admired for several decades. Here's what Mike has to say:

What got you interested in the hippocampus?
As an undergraduate, I was interested in how the complexity of thought could be described in terms of the principles of physics. I started out as a linguistics major, but I remember going up to Noam Chomsky after a talk and asking him if he could recommend a book that describes how neurons mediate language function. Such a book does not exist even today. However, I came across O'Keefe and Nadel's The Hippocampus as a Cognitive Map in the 6th floor library at William James Hall. Their book made me realize that memory function was a complex cognitive process that could be understood in terms of neurophysiological circuits. I wrote a letter to John O'Keefe to ask to work in his lab (he politely wrote to say there was no room), and then I joined the Rolls lab at Oxford in 1984 because I wanted to do unit recording in hippocampus. Edmund encouraged me to work on inferotemporal cortex instead, but I learned about hippocampal modeling there (and met people like Larry Weiskrantz and Richard Morris). I went as a post-doc to Jim Bower's lab at Caltech partly because he was modeling the piriform cortex as an associative memory in a manner very similar to region CA3 of the hippocampus. It was only once I was an Assistant Professor in 1991 that I could finally start projects focused on the hippocampus (initially studying the cholinergic presynaptic inhibition of glutamatergic transmission that I had studied in the piriform cortex).

Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?
The finding of theta phase precession was particularly exciting. I remember Matt Wilson telling me about his Hippocampus paper with Bill Skaggs and Bruce McNaughton over lunch during the 1996 Computational Neuroscience conference in Cambridge. I knew about the O'Keefe and Recce, 1993 paper, but the full excitement of the finding sank in then. To me, theta phase precession is still one of the most intriguing phenomena in brain function, as it provides such clear evidence for temporal coding by spike times. I have always found rate coding to be very unsatisfying as a framework for coding the complexity of experience. Theta phase precession is exciting as it so clearly links dimensions of behavior to a temporal code in individual neurons. Also, because it involves a precession of membrane potential relative to field potential, it indicates that membrane potential dynamics are essential to the code. I still think we have not fully explored the ramifications of this phenomenon.
Another exciting finding was the dramatic hippocampal fMRI activation during encoding of complex novel stimuli (Stern et al., 1996). Previous studies of encoding and retrieval in verbal memory tasks had seen little hippocampal activity, so this study was striking for the robustness of hippocampal activity.
And of course the discovery of both grid cells and boundary vector cells were exciting as they both showed such elegant quantitative properties of neurons that appear to contribute to place cell firing properties.

Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
To me, the world of hippocampal research is exemplified by the friendliness and enthusiasm of the researchers. I remember first meeting Howard Eichenbaum after a talk that he gave when I was a junior faculty member. He gave me priceless advice to switch from submitting NIA R01 grants to submitting applications to the Computational Neuroscience program run by Dennis Glanzman at NIMH. I am grateful for the support Howard and others gave me, and I have sought to be similarly supportive of my junior colleagues. I don’t have specific stories, but I have many fond episodic memories of meeting researchers for the first time and feeling the excitement of shared interest in understanding the hippocampus. I remember meeting Gyuri Buzsaki for the first time at a conference in Paris and discussing his two stage model of memory. (I also remember asking him at dinner about what something was on the menu and when it turned out to be kidney, Gyuri actually exchanged dinners with me!) I remember the first time I met Lynn Nadel at a meeting at the Arizona Inn in Tucson. I remember Bruce McNaughton coming to my poster at SFN and our discussion of facilitating synapses in different lamina of dentate gyrus. I remember the excitement of meeting younger researchers and connecting over our shared interests. I remember the first time I met David Redish at the Computational Neuroscience meeting, the first time I met Neil Burgess at the NeurIPS meeting, the first time I met Colin Lever at UCL, and the first time I met Randy O’Reilly at the student lunch when I spoke at Carnegie Mellon. I also have fond memories of the first time that I met my future grad students such as Brad Wyble and Lisa Giocomo and Mark Brandon and Jim Heys. There are so many memories that I can’t list them all. My associative network of knowledge about the hippocampus is intertwined with my memories of conversations with the researchers that shared that knowledge with me.

What would tell a young researcher interested in the hippocampus to focus on now?

I would tell young researchers to focus on linking membrane potential dynamics to network function. That has always been my ultimate goal and I'm afraid that the field has drifted away from this goal rather than embracing it. The third wave of neural network research has distracted us from the central question of how the complexity of membrane potential dynamics of neurons mediates complex function. The new label of deep learning doesn’t change the fact that the current models use essentially the same backprop algorithms used in the second wave of neural networks in the late 1980s. With the recent focus on RNNs and DNNs, I see less focus on essential neurophysiological properties such as spike frequency adaptation and presynaptic inhibition and rebound spiking and bursting and dendritic dynamics than twenty years ago, but I still feel these neuronal dynamics are essential to understanding the network dynamics of brain circuits. We aren't going to understand the brain with ReLu units in DNNs or RNNs. We need theory and experiments that link membrane conductances to network function. My hope is that development of voltage imaging in population of neurons will finally provide the data to make this link.

HIPPOCAMPAL HISTORY TOUR PART 10. BRUNO POUCET

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Continuing the international theme, today's comments come from Bruno Poucet, from the south of France, long an outpost of excellence in neuroscience and behavior, with a focus on spatial behavior over the years. Some old favorites will come up again!

BRUNO'S Comments:

What got you interested in the hippocampus?
After a degree in mathematics, I switched to biology, and more specifically to neuroscience. During my Master's degree, I became interested in studying decision making and choice processes in animals. Thus, in 1979 I did an internship in a cat breeding unit in which I was asked to study the influence of breeding conditions on some cognitive behaviors. The aim was essentially to test animals raised in cages of the same volume but with different proportions in height, width and length on the choice of paths in different tests of exploration and spatial navigation. I did not observe any differential effect of rearing conditions, but I did find that different animals could use different spatial strategies. It was then that a senior researcher (mostly interested in human motor behavior) introduced me to the book of O'Keefe and Nadel (The hippocampus as a cognitive map) and drew my attention to the dichotomy they established between the "taxon system" and the "locale system". These two systems overlapped, more or less, my observations on the strategies used by cats. I was even able to model a "taxon" type behavior with a magnetic mobile attracted by a magnet in a space structured by obstacles forcing the mobile to make detours. One thing led to another and I started to study O'K & N's work in depth and was fascinated by their analysis of the role of the hippocampus in spatial navigation. This is how I got interested in the hippocampus …

Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?
There are many discoveries in 50 years! If I go back to my background, after my PhD in 1981 I did several post-doctoral fellowships in Canadian and American laboratories in teams that were working, both theoretically and experimentally, on the hippocampus. It was only a few years later that I set up my first recording system in Marseille to record neural (unit) activity in behaving animals. I was fascinated by the observation of the activity of place cells, those surprising little beasts. However the discovery of the equally amazing head direction cells by Jim Ranck and Jeff Taube in Brooklyn was certainly instrumental in supporting the idea that place cells were not an idiosyncratic phenomenon, but that there was a real system in the brain devoted to the processing of spatial information necessary for spatial navigation. Later, the discovery of grid cells in the entorhinal cortex by the Moser group in 2005 brought another masterful element to convince the most skeptical.

Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
In 1988, I participated in the Society for Neuroscience conference in Toronto. I presented a poster showing that exploratory behavior could be used to determine the spatial information encoded by the animal. Two senior scientists were interested in my poster and discussed it not only with me but also with each other. Both guys had strong personalities and were talking loudly, so a small group of other people joined in the conversation. When the group dispersed, I continued the conversation with the two researchers who wanted to convince me to make recordings of the unit neural activity of the hippocampus in the behavioral situation I had developed. I answered them that I had neither the means nor the skills. They insisted and offered me their help. Three years later, thanks to their help, I carried out my first recording experiments in Marseille. The two researchers were John O'Keefe and Bob Muller. The latter was crucial because he invited me to Brooklyn many times to learn the basics of recording and data analysis, and he regularly came to Marseille to follow the evolution of my research. All this thanks to a simple conversation around a poster a few years earlier... and to a robust friendship that lasted over the years!

What would tell a young researcher interested in the hippocampus to focus on now?
Many would say that the key to the future of this research lies in even more technology to record even more neurons and lead to even more complex analyses of their activity, and that we should combine these recordings of large populations of neurons with optogenetic or pharmacogenetic approaches.
But, even if I have no legitimacy to predict the future and say what should be done, I would rather go back to a certain craft in this field. It seems to me that we don't pay enough attention to the behavior itself and all that it can teach us. One example of this deep understanding of the behavior is exemplified by Redish's work on microdecisions at choice-points, which illustrates the sophistication of decision processes. If we were able to relate the diversity of behaviors to the complexity of neural activities in the finest possible way, we could make a decisive step forward in our understanding of the functional brain.
Another lead, in my opinion, is the one provided by recent advances in structural and functional anatomy techniques. The brain is a network whose different parts are closely connected and establish a permanent dialogue. Understanding this dialogue can only be based on a fine-grained understanding of the role of the partners, which is only possible through anatomy.
With regard to the more specific issue of place cell, head direction cell and grid cell activity, I think it would be a challenge, but really interesting, to see what happens in real naturalistic (large, complex and structured) environments during exploration and navigation. This, in principle, could be possible with sophisticated telemetry systems coupled with harmonic radar localization such as that used for bees by the group of Menzel in Berlin.

HIPPOCAMPAL HISTORY TOUR

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The well has run dry. I am awaiting further promised reminiscences, and I can promise a very short publication lag.

Perhaps now would be a reasonable time to raise questions brought up by the personal histories published so far.

But, to contribute something historical today - I'm sometimes asked: why did you and O'Keefe write a book about your theory, since that's a pretty unusual choice for scientists, at least back it was back then. Our initial plan was to write a Psychological Review article, which is what one did with theoretical contributions in those days. But I ruled that out by unknowingly insulting the Editor of Psych Review at a sherry party in Elizabeth Warrington's office off Queen Sq. one evening in the early 1970s. I knowingly insulted a pompous speaker, but I didn't know he was the Psych Review Editor. A fact John O'Keefe conveyed to me shortly after we left the party. What started as a 50 page article aimed at Psych Review became a 350 page hand-typed draft that we circulated for comments to about 30 leaders in the field, including philosophers, psychologists and brain researchers. It took nearly 6 years to revise and publish the final version.

HIPPOCAMPAL HISTORY TOUR PART 9. ROB SUTHERLAND

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#hippocampusHistory
#HippocampusGurus

Rob Sutherland was a graduate student at Dalhousie when I spent two years there, already referred to by Carol Barnes. Rob's work has helped shaped the field, his focus on the role of the hippocampus in the prcoessing of configural relations (along with Jerrry Rudy) continues to to bear fruit.

Rob's comments:

What got you interested in the hippocampus?

I completed my graduate work at Dalhousie University during the 70s. It was a special time and place for hippocampal work. My supervisor, Shinshu Nakajima, worked on hippocampus, corticosterone, and memory. Graham Goddard had recruited Rob Douglas, Bruce McNaughton, and Carol Barnes as trainees. Lynn Nadel was a term faculty member and we had visits from Tim Bliss and Richard Morris. The animal learning area at Dalhousie was imbued with an interest in cognitive processes. In addition, I was lucky to read an early draft of “The Hippocampus as a Cognitive Map”. Every day the atmosphere was thick with hippocampus, space, memory, and LTP. I am grateful that all of these people were very generous with ideas and time. I worked on trying to figure out the functions of the habenula. It was impossible in that context not to absorb an abiding interest in hippocampal function. As soon as I finished my PhD and, more importantly, set up my own lab, I began working on hippocampal problems that I thought I could solve.

Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?

The discovery of place cells, the demonstration that hippocampal LTP is associative, the demonstration of the function of the NMDA receptor, the melding of neural network concepts with hippocampal physiology, the discovery of head direction cells and grid cells, and Richard Morris’ demonstration of place learning and memory in a swimming pool, all created in the scientific imagination the possibility to develop a rigorous, system-to-molecule understanding of cognitive processes carried out in a portion of cerebral cortex in mammals.

Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?

For my first sabbatical, after obtaining promotion and tenure, I decided to travel to UC Boulder, to work with Carol Barnes and Bruce McNaughton for a year. It was great fun recording from CA1, retrosplenial cortex, and area 24 in rats on an 8-arm radial maze, plus recording from CA1 with most of the hippocampal granule cells eliminated. Parenthetically, we tripped over a couple of border cells, but picked ourselves up and hurried on. Their lab was, understandably, very busy and my schedule had large swathes of non-recording, non-analysis time. I had agreed to prepare a review of the edited Volumes 3 & 4 of The Hippocampus. After pushing my way through nearly all of the chapters, I had started one of the chapters several times and was having trouble forcing myself to read even half of it. At Boulder, Dr. Jerry Rudy, an animal learning mogul, was starting to use the Morris water task to study development of memory in rats and I had given him some practical advice on collecting reliable and valid data. Hoping not to have to read the painful chapter, I asked Jerry if he wanted to take some time to read it, and if his review was on point, I was open to him being co-author on the review. A few days later, during down-time in recording, he shared his views on the painful chapter. My complete (and deliberately dramatic) rejection of his take on the chapter, led to some of the most entertaining and stimulating conversations that I had enjoyed about hippocampus, learning, and memory, up to my sojourn in Boulder. Ultimately, the book review was published without Jerry (The hitchhikers guide to The Hippocampus. Psychobiology, 1987, 15, 102- 104 (https://link.springer.com/content/pdf/10.3758/BF03327270.pdf?pdf=button)). Bruce, Carol and I published excellent work and, on the serendipitous side, Jerry and I generated a number of high impact experimental and theoretical papers leading to new work on rodents, monkeys, and humans.

What would tell a young researcher interested in the hippocampus to focus on now?

If I truly knew what to focus on, I would be working on it and not discussing it here. Take a chance (a fool’s name for fate) and pursue something that makes sense given your current work and findings, especially if it flies in the face of current wisdom contained in the papers you are reading (and perhaps you are reading too much when you should be making discoveries). Make sure that your current work is imbued with the best technology/tools that you can master. Take time to think and discuss ideas with colleagues and collaborators, take more time than your colleagues/mentors believe is appropriate. Tie your work to the biggest ideas that you value; work on the most fundamental problem that you can.

HIPPOCAMPAL HISTORY TOUR PART 8: CAROL BARNES
#hippocampus #hippocampusHistory #hippocampusGurus

Today's installment is devoted to comments by Carol Barnes. A colleague and friend for nearly 50 years. We ran rats together in the 1970s. Her work on normal aging has changed the field, and she is still going strong with a massive new grant to explore 'precision aging'.

Carol's comments:

1. What got you interested in the hippocampus?
Several things that happened in the early 1970s:
a) A call from my mother my first semester as a graduate student at Carleton University (1971) – about my grandfather getting ‘turned around’ on his long walks. This got me curious about what happens to memory in aging – at the time, the available literature (books on aging) suggested that “you get old, you loose neurons, you become senile” – your memory is toast. It was the classic Scheibel picture of entorhinal neurons from your 20s through intervening decades until 90 years suggesting that aging was a forest fire of dendrites and shriveled cell bodies.
b) At Carleton University a draft of the O’Keefe and Nadel monograph (the precursor to your book) was being passed around (I think it was ~1972) – which made me aware of the structure responsible for navigation and spatial memory – linking back to my grandfather. So that was my initial hook into the hippocampus.
c) Your draft monograph helped me understand the potential of studying nonhuman animals to reveal mechanisms of memory in humans (if we only understood ‘what memory was’ – Bruce McNaughton was looking at axonal transport as a potential mechanism).
d) Also at Carleton, Dan MacIntyre suggested really complex articles in his graduate ‘biopsychology’ seminar course – and I chose Marr’s 1971 article on the archicortex (Bruce chose Marr’s neocortex model). It took me a while to digest this so that I could present it to the class. But that was another hook into the hippocampus.
e) In 1973 Bruce’s mother supported him to go to a school in Erice – I believe it was organized by Bernard Katz. It was at this school in Italy that he heard Terje Lomo present his data on LTP. Bruce came back completely energized by the experience – we got the papers, and read them, and were both convinced that the biological basis of memory had been discovered in this ability to modify the strength of synapses – again, this was demonstrated at the entorhinal cortical synapse onto granule cells of the hippocampus. So that was final anchor that firmly ‘attached me’ to the hippocampus.
f) With all these pieces in place, I knew I was in the wrong lab to finish my dissertation at Carleton with Peter Fried (so I finished a Masters degree with him). I knew that I wanted to do my dissertation on aging rats, spatial memory, and hippocampal plasticity – to see whether an association could be built to establish a neural mechanism for the basis of age-related memory decline. Peter was Graham Goddard’s student – Peter ‘phone-introduced me’ to Graham, and I asked if I could finish my dissertation in his lab (his was the only one in the world then conducting LTP experiments in awake rats). He said yes, he said he’d buy me rats and would start aging them (after he said yes to me, I introduced him to Bruce who wanted to do EM studies on LTP at hippocampal synapses). So Bruce and I moved to Halifax, and I started laying the groundwork for my dissertation experiments in August 1974.
g) One last story – you arrived in Halifax to take up a position to replace Goddard (who had gotten a Killam fellowship I believe) in 1977ish. It was exciting for me to meet you and to have deeper conversations about your “Hippocampus as a Cognitive Map” idea – and how I might test further ideas about changes in spatial memory with age. I had developed the circular platform there as one way to test spatial memory in old rats, and had been testing them with that apparatus. This was the time period when you and I essentially did the ‘Tolman experiment’ with aging rats – showing that the older animals, tended to prefer the use of a response (striatal?) strategy to solve the T-maze problem, whereas the younger animals preferred to use a place (hippocampal) strategy. You put your squash shoes on, a lab coat, a stopwatch around your neck – and you helped me run that experiment that was published as Barnes, Nadel and Honig (1980). We interpreted the data as being consistent with the idea that the older animals may have less effective hippocampal function, and so used an alternative strategy to solve the T-maze (they showed just as good performance in learning the task as did the younger animals – they just ‘solved it differently).

2. Aside from your own work, what findings about the hippocampus (and related brain parts) in the past 50 years most excited you , and why?
Nothing right now leaps forward – except for head direction and grid cells – pretty close to home and predictable that I’d be blown away by each of these discoveries.

3. Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
Maybe the ‘hippocampal world’ at least in ‘older times’ could be described as sort of an extended ‘family’. A few things come to mind.
I guess I already ‘did’ relay one such story – in 1973 there were only 3 labs in the world actively doing LTP work (Bliss in London, Lynch in Irvine, Goddard in Halifax) – and only Graham was preparing awake animals (which I needed for my aging study) – so this is where the ‘classic hippocampal network’ (with a Canadian twist) kicked in – I was immediately connected with Graham (at that time the best funded neuroscientist in Canada) and the rest is history. I was the first to show LTP and memory might be related, Bruce was the first to show that LTP was cooperative (the EM thing didn’t work out for him …).

I needed to do intracellular recordings from old cells as the next step in interpreting what the effect of aging at the synapse meant (from my dissertation) and so needed to learn the hippocampal slice technique. So I contacted Per Andersen (the guru of the hippocampal slice preparation), and asked if he would take me into his lab if I was able to get an American postdoctoral fellowship (NRSA). He said he would. Here I was, an American who had been out of the country for 7 years – I applied to NIH’s National Institute on Aging that was ‘just getting up and running’ – and they gave me the very first NRSA in neuroscience from NIA – and shipped me from Canada to Norway (2 years, all of 1979 and 1980). Again, it was Zaven Khatchaturian (Head of the Neuroscience program at NIA then, and a fellow electrophysiologist) who was intrigued by the physiology I proposed – and I got one step deeper into the ‘hippocampal experience’ (Per had many American, Europe and Australasian post docs coming to learn the hippocampal slice technology in Oslo).

In 1980 John O’Keefe dropped by Per’s lab to see what was going on – Bruce and I were thinking about going back to Canada – Bruce had been given an offer at McMaster of a position (and the idea was that I would go and “figure it out”). John said – “why do you want to get a job? Why don’t you come to London for a year – I might be able to find some money”. I was pretty excited because I had wanted to set up unit recordings in old animals – so Bruce declined the Canadian job, and in January 1981 we left for London (John found Bruce some MRC money, I was able to get a NATO Fellowship in Science, starting a couple of months after I arrived). Again, it was just ‘luck’ that John stopped by to check out what was happening in the hippocampus in Per’s lab (as the ‘hippocampal family routinely did’) – and it changed the direction of my life (and Bruce’s). We published 3 important papers from that one year stint.

4. What would tell a young researcher interested in the hippocampus to focus on now?
I don’t know, really, what I would say other than “whatever excites you most”. I keep waiting for a young student to call me on the phone, and to propose a dissertation experiment that was a bit off the wall, but potentially important that I could support – I haven’t yet received one of those phone calls.

HIPPOCAMPAL HISTORY TOUR PART 7. BOLEK SREBRO part 1

#hippocampus #hippocampusHistory #hippocampusGurus

Today we hear from Bolek Srebro, at length. Many of you will not have heard of Bolek, but after you read his comments you'll see how involved he was in some very major developments in the field. Bolek mentions many new names, and many old ones we've heard about already. Jonathan Winson was the very first to show reactivation in the hippocampus, and wrote an absolutely fascinating book called Brain and Psyche (1985) that had a big impact on me and others. Bolek's story reinforces the point made earlier about Norwegian science, and its outsized impact on the world of the hippocampus.

Here, in three separate entries, are Bolek's thoughts.

1. What got you interested in the hippocampus?

My interest in the hippocampus and the very first experimental study began when I was a Ph.D. student in the Laboratory of Neurophysiology of the Nencki Institute in Warsaw led by Professor Jerzy Konorski. My supervisor, Jadwiga Dabrowska, introduced me to a postdoc Phillip Liss, who completed his Ph.D. in the Department of Psychology of McGill University in Montreal. Phillip received two years NIMH scholarship to work at the Nencki Institute on the recommendation of Professor Konorski. In a short time, I become a student of Phillip and a close friend. Phillip, exceptionally bright and knowledgeable person, introduced me to the newest literature on the function of the hippocampus and the latest ideas in neuropsychology unfamiliar for us in Poland at that time. The core literature included the Montreal Bible “The Organization of Behavior” by Donald Hebb. McGill’s Department of Psychology in Montreal, where Phillip got his education, was at that time the epicentrum of emerging neuroscience of the hippocampus. Many of the Ph.D. students from that department became leaders of the research groups in Canada, the USA, England, and New Zealand.
My first experimental study under the supervision of Phillip dealt with the effects of the limbic (septal, hippocampal and transections of the fornix) and frontopolar lesions on the rat on several behavioral tasks. Some of those tasks were used for the very first time in the Nencki Institute. Phillip introduced in our lab a stereotaxic lesions technique for the rat, which was a novelty in the field. Several facts motivated my initial interest in the functions of the hippocampus and septum. Anatomical data indicated that the medial septum provides the major subcortical input to the hippocampal formation as well as the lateral septum is a target of the main subcortical output from the hippocampus. It was known that the medial septum contains a pacemaker for an enigmatic theta-rhythm in the hippocampal formation which had clear behavioral correlates in the rat. My early observations indicated that rats with septal lesions displayed a variety of behavioral changes much more pronounced than those observed in rats with hippocampal lesions. This septohippocampal connection was the reason for my early study of the cholinergic innervation of the hippocampus arising in the medial septum. Regrettably, the results of the complex behavioral experiments with Phillip remained unpublished due to several reasons, one of them my emigrating from Poland in the fall of 1969. However, when I left Poland, I was well prepared to do my experiments on the functions of the septohippocampal network in the rat brain. I also acquired a good overview of the existing literature on this subject.

Thanks to my contacts from the Nencki Institute I was invited to Norway by Dr. Holger Ursin and got a temporary job in a newly open medical school in Bergen. My choice of Norway was not accidental. Oslo, the capital Norway, became in the late sixties one of the leading academic centers in Europe for the studies of hippocampal anatomy, neurophysiology, and neurochemistry. Professors Theodor Blackstad, Per Andersen, and Frode Fonum created their own schools of young scientists who subsequently become the leaders of several independent research groups in Norway, Denmark, and Sweden. From the very begging, I was able to continue my behavioral studies in Bergen and got a lot of support from the head of my research group Holger Ursin and a professor of neuroanatomy Willhem Harkmark. Both of them were medical doctors educated in Oslo and knew the brain research laboratories in Norway. They facilitated my contacts with the experts in Oslo.

After several years of my behavioral research, I realized that the lesion technique has limitations, and it will not provide further insight into the functions of the septohippocampal system. The major event that changed my research strategy was a symposium “The Septal Nuclei” organized by John F. DeFrance in Detroit in 1974. During this meeting, the two most memorable lectures for me were presented by James B. Ranck Jr., who was at that time in Ann Arbor, Michigan, and by Jonathan Winston from the Rockefeller University in New York. James Ranck presented new findings on the single unit’s activity in the septum and hippocampus of freely moving rats. Jonathan Winson presented results showing that the behavioral state of the animal modulates hippocampal theta rhythm and that lesions of the medial septum caused a memory deficit correlating with a loss of theta activity in the hippocampus. It had become clear for me that further progress in the studies of the septohippocampal system will require a combination of electrophysiological and behavioral methods. I returned to Bergen to complete my ongoing experiments, but I already knew what would be my next research strategy. A few years later I visited Jonathan Winson at Rockefeller University and asked him if I could spend a sabbatical year in his laboratory in New York. He invited me but on the condition that I will design my research project.

The other important event that brought the new ideas to Bergen was a nine-month sabbatical term of Lynn Nadel in fall 1974 to the spring of 1975. Lynn was in the last phase of writing the book with John O Keefe “The Hippocampus as a Cognitive Map”. The sabbatical term in Bergen allowed Lynn to complete the book, to solve some complicated family problems and to look for a new job in the US or Canada. I had met Lynn for the first time in Bergen during the Easter break of 1970, only a half year after I came to Norway. We found a lot common interests, besides the hippocampus, and become close friends. Lynn knew my friend and mentor from the Nencki Institute Phillip Liss. They were both graduate students in the Department of Psychology of McGill University and, like Phillip, Lynn decided to spend his postdoc in Europe in the laboratory of Jan and Olga Bures in Prague, Czechoslovakia. The political upheavals and the invasion of Czechoslovakia in 1968 forced Lynn and his young family to leave Prague for a while, and he was back in Prague when we met in 1970.
Lynn’s presence in Bergen had an important influence on my thinking about the hippocampus. The book he was working on synthesized the state of knowledge on the hippocampal anatomy, neurophysiology and behavioral findings to propose a new hypothesis that the main function of the hippocampus is a mental representation of space named: a cognitive map. Reading the manuscript and daily conversations with Lynn expanded my knowledge about the hippocampus, and especially on the role of hippocampus in cognitive processes of the human brain, a subject not familiar for me. Lynn and John’s book was circulating as a manuscript among many colleagues and friends well before it was published in 1978 and had a significant conceptual impact on many research groups working with the hippocampus.
My project during a sabbatical term in Jonathan Winson’s laboratory dealt with the role of the serotonergic innervation of the hippocampus on behavioral modulation of the field potentials in the dentate gyrus of the rat. Jonathan’s previous studies showed that the behavioral state of the animal modulates the size of the evoked field potentials in the three major hippocampal fields. The recording technique in his experiments employed a movable recording and stimulation electrode connected to a head stage containing an amplifier to reduce movement artifacts. The project combined Jonathan’s recording technique and my previous experience with the selective neurotoxic lesions of the 5-HT system in the rat brain. Since the neurochemical analyses were not available at the Rockefeller lab, they were made in the laboratory of Efan Azmitia from the Mount Sinai Medical School in NYC. The results of our study showed that a selective lesion of the serotonergic innervation of the hippocampus abolished the behavioral modulation in the dentate gyrus. My main gain of the sabbatical term in Jonathan’s lab was learning the electrophysiological recordings in the freely moving rat.

HIPPOCAMPAL HISTORY TOUR PART 6

#hippocampus #hippocampusGurus #hippocampusHistory

Today we hear from Phil Best, who passed away a few months ago. His extensive comments show clearly how central to the place cell field he was in the early days. An absolute gem of a person - always open to sharing ideas and helping his colleagues. I will be breaking Phil's contribution up into several separate postings, give the 10K character limit.

Phil Best
1. What got you interested in the hippocampus?
I was never interested in the hippocampus or its functions until after I began studying single cell activity in brain neurons in 1966. My original reasons for studying the activity of hippocampal neurons had nothing to do with their behavioral or cognitive function. It was merely expedient. When I started recording it was easier to record from neurons in the hippocampus than anywhere else in the brain. The signals were very strong, the signal to noise ratio was excellent, and the isolation was very good, and the hippocampus in a rat is hard to miss.

When I began studying biological psychology (or behavioral neuroscience) while in college and graduate school (1958 -1965) I had little interest in the hippocampus and did not pay much attention to research on the behavioral functions of the hippocampus. At that time the only studies on the role of the hippocampus in behavior were based on the behavioral effects of hippocampal lesions, or the relationship of hippocampal EEG with behavior. I did not find the results consistent or interesting. I was much more interested in the role of the neocortex in behavior and cognition. My research was limited to comparing learning style of the two hemispheres in split brain rats, and the studying the differences between Conditioned taste aversion learning and traditional Pavlovian conditioning. I was warned by a professors and colleagues that I would not be taken seriously by the behavioral science community if I even alluded to an interest in cognition.

Most studies published in the Journal of Comparative and Physiological Psychology in the late 60’ and the 70’s investigated the effects of brain lesions on behavior. or the effects of electrical stimulation of the brain on behavior. Following Olds and Milner’s discovery of the rewarding effects of brain stimulation in 1954.the number of brain stimulation studies had burgeoned. There were many fine experiments on recording single cell activity in the brain, but these were typically done in anesthetized or others immobilized animal. While these studies discovered much about brain organization, they added little to our understanding of the relationship of brain activity to behavior (or cognition)

In 1965 I began a postdoctoral fellowship with Jim Olds at the Brain Research Laboratory at the University of Michigan. I was attracted to Olds’ lab because he was initiating a project to study single cell activity from individual neurons in the brain of freely behaving rats. The goal of the project was quite simple; we would figure out how the brain worked by recording cellular activity of neurons from all over the brain, while the animals where provided lots of different experiences and were trained on many different tasks. The goals were also quite grandiose and obviously naïve.

The methods were very primitive. However, to me they seemed much more advanced and sophisticated than the lesion and EEG studies that had been done in the past. At that time not much commercially developed equipment was available, so most amplification and filtering circuits were homemade. Happily, we eventually acquired a small, relatively inexpensive laboratory Digital Equipment Corporation PDP 8 computer that could be dedicated to an individual experiment and engage in real-time online analysis. It is hard to imagine the opposition to the use of these small dedicated computers by central university computer operations. They were completely hostile to anyone proposing to do some computing without using their huge expensive computers They did not seem to understand the use of computers for “on-line” for real-time analysis and simply did not believe that our experiments required us to interrupt the computer about every 30 microseconds. They finally relented when we told them that the devices were not truly “computers” but were programmed data processers. (Digital Equipment Corporation PDP 8 computer).

To record the cellular activity, we used 62-micron diameter nichrome wires, which have a fairly large recording surface. We received some criticism from neurophysiologists because we did not use highly polished and etched tungsten electrodes, which have a very small, high impedance recording tips, and were typically used neurophysiology studies. It turns out that in many situations blunt tipped microwires are superior to etched electrodes. Today I think more studies use blunt tipped microwires than etched tungsten wire. We implanted about six to eight recording wires in each rat. The wires were very flexible, which was good for holding cells, but the flexibility also permitted the wires to curve as they passed through brain tissues, and thus made it difficult to hit smaller brain nuclei. Since the hippocampus is a very large laminar structure oriented perpendicular to the electrode tract, it was easy to hit, in fact, it was very hard to miss. During surgery we cemented the electrodes in place. So, we were likely to lose isolation overnight, or lose cells completely, especially smaller cells. The hippocampal pyramidal cells are enormous, so they were more likely to appear well isolate for many days. So, we started recording from hippocampal pyramidal cells (complex spike cells) simply because it was easier than recording from them than smaller cells in different smaller nuclei.

We had very serious problems with artifacts, which were very large in our system because the cellular signals were not amplified at the rat’s head close to the electrodes. The preamplifiers were located on overhead arm, about 10 inches above the rat. While normally available shielded cables would shield the signal from extraneous electrical noise, normal shielded wires could not eliminate artifact that was due to movement of the central signal carrying wire with respect to the shield. In order to prevent this artifact, we had to use a special type of shielded wire, microdot cable, which was very stiff, and seriously inhibited animal movement.

Even with those efforts, we were still very concerned our signals being contaminated by movement artifact. We decided that our safest bet was to record from those large hippocampal neurons in animals who were not moving. Thus, we studied change in hippocampal activity during a classical conditioning paradigm or during different states of sleep and waking.

The first study we published (Mink, Best, and Olds 1967). examined the difference in cell firing rates in the hippocampus and other areas of the brain during quiet waking, slow wave sleep, and rem sleep. A few studies in that period had shown that cells in most areas of the brain show highest rates of activity during rem sleep, when the neocortical EEG is highly aroused, and slowest activity during Slow Wave Sleep. Our study found that pyramidal cells in the hippocampus fired slowest during rem sleep, which was typically accompanied by theta waves (7-9 hertz). We also studied the effect of classical conditioning on cellular activity in the hippocampus and other structures.
During those years I became interested in studying the hippocampus mainly because it was the easiest area of the brain to study with my very primitive techniques. I did not change the recording methods or the nature of my questions when I moved to Virginia in 1968.

(continued in next message)

@teixi @nadel

Thanks Teixi.
I think #Hippocampus, #HippocampusGurus and #HippocampusHistory are all great for this.

HIPPOCAMPAL HISTORY TOUR PART 4

#hippocampus #hippocampusGurus #hippocampusHistory

Today's tour includes three briefer responses, from Ray Kesner, John Kubie and Jeffrey Taube. Ray Kesner, in my view, never got the recognition he deserved for his attributes view of hippocampus - he was also one of the initial organizers of the Park City Learning & Memory (and ski) meeting (which continues to this day under new leadership), along with Aryeh Routtenberg, Jim McGaugh and Larry Squire. A name that pops up in the last two reflections is Bob Muller, who sadly passed away well before his time. Bob was a unique character, a gruff New Yorker with a sharp mind and tongue. He and I went to high school together (Stuyvesant), with him sitting exactly in front of me in our homeroom class, which was organized alphabetically. Another name that pops up is Jim Ranck, whose contributions to the hippocampal world were immense, and who was and remains one of the nicest people in the field. I expect we'll hear more about Jim along the way. Finally, Dave Olton is noted -- Dave was a central figure in the hippocampal world in the 1970s and early 1980s but died quite young. A major loss to the field. We crossed swords on many occasions, but (almost) always in good humor.

RAY KESNER
1. What got you interested in the hippocampus?
As a postdoctoral fellow I worked in Bob Doty's lab, where I had the opportunity to work with cats to study the effects of electrical brain stimulation of the hippocampus within the context of a passive avoidance paradigm. Given positive results I was hooked on understanding the role of the hippocampus in learning and memory.
2. Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?
The discovery of neurogenesis within the dentate gyrus and with the findings that neurogenesis in the dentate gyrus plays an important role in long term memory.
3. Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
I had many exciting discussions with Dave Olton especially because both of us carried out similar experiments to examine the role of the hippocampus in understanding memory.
4. What would tell a young researcher interested in the hippocampus to focus on now?
Young researchers should concentrate on the different roles of the subregions of the hippocampus both at the behavioral and cellular levels, based on the recognition that each subregion subserves a unique role in processing mnemonic function.
 
JOHN KUBIE

1. What got you interested in the hippocampus?

I was interested in 2 things: the limbic system and single cell recording. My earlier work (PhD and 1st post doc) was in olfaction. I wanted to return to the limbic system, likely amygdala, olfaction and emotion. But first, I wanted to learn the techniques of single-cell recording in behaving rats, at the time (1979) done if very few labs. I asked Jim Ranck if I could do a second post-doc with him. My first “assignment” was to continue work Jim had been doing, recording single hippocampal neurons across 3 behaviors (8-arm maze, operant chamber, maternal behavior). Saw strong place cell responses in all 3 tasks and I was hooked.

2. Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?

a. Following the discovery of place cells were the discoveries of Head-direction cells (Ranck) and grid cells (Norway group). These seemed (and seem) like the building blocks of a remarkable navigational system. These strong signals were completely unanticipated.

b. Replay and pre-play of path sequences during sleep and slow-wave ripple. This seems like a critical link between navigation and episodic memory.

3. Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?

> A drive with Bob Muller and Lynn Nadel from San Francisco area to San Diego. Two strong personalities, not always on the same wavelength.

> Not a specific event, but a decade, the 1980s, in Brooklyn with Jim Ranck, Bob Muller and Steve Fox. Some intense fights, but we got along very well. No real papers were produced until 1987, but the atmosphere was different — slow paced, fun, but we felt we were on the right track.

> I remember Bob Muller pulling me aside duing the SfN meeting in Boston (?1985) where we presented the work that went into the 1987 papers. Bob said we’d accomplished something.

4. What would tell a young researcher interested in the hippocampus to focus on now?

a. Explore the link between spatial representation and episodic memory.
b. Understand the network properties of entorhinal cortex that produce grid cells.
c. Go from knowing where you are (place cells) to neuronal mechanisms of navigation; getting from here to there.
d. The nature of hippocampal plasticity in spatial representation, navigation and episodic memory.
e. Remapping and the representation of specific, bounded environments.
f. Long distance navigation (vectors) connecting familiar locations.
g. In general, move from phenomenology to mechanism.
h. Explore other species, including marsupials, birds and reptiles.

JEFFREY TAUBE

1. What got you interested in the hippocampus?

I got interested in neuroscience because I was interested in how the brain did learning and memory. Two reasons for this: 1) I think our species (humans) has had the utmost success evolutionarily speaking because of our abilities to learn and remember. It’s not that other animals can’t do it, but we’ve taken it to the nth degree. So, I was very curious as to how the brain did learning and memory and was disappointed to find out when I was an undergraduate in college that scientists really didn’t know. 2) One of my younger sisters has had a learning disability all her life, and I was always interested in knowing why – what was different about her brain from others. Being interesting in learning and memory – I naturally gravitated to wanting to learn more about the hippocampus.

2. Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?
The discovery of LTP. Up until that time, the other candidate mechanisms were not all that attractive or seemed reasonable. I also think the discovery of place cells by John O'Keefe was a momentous occasion that changed the course of research in this area. Up until then, very few people had thought of the hippocampus from a spatial perspective – as the findings from HM seemed to dominate our thinking about the hippocampus (for understandable reasons). You certainly played a major part in highlighting the hippocampus’ role in spatial processing.
3. Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
Hmmmm. I might have to think about that one for awhile, but I do remember a day hike that I took with John O'Keefe and a few others down into a canyon at a small conference we had in Provence (organized by Alain Berthoz) in the early 2000s. Lots of good collegial conversation, as well as a lot huffing and puffing on the way back up.

There are of course lots of Jim Ranck and Bob Muller stories (as well of Kubie and Fox) I could share but that is probably best done another day over a beer.
4. What would tell a young researcher interested in the hippocampus to focus on now?
Probably understanding the computational algorhythms the hippocampus undoubtedly performs. This is not an easy task but until we understand the algorhythm(s) it performs we really won’t get a handle on the precise function it performs.

HIPPOCAMPAL HISTORY TOUR, PART 3

#hippocampus #HippocampusGurus
#HippocampusHistory

Today we hear from Gyuri Buzsaki, whose career reminds us that some very important neuroscience happened in what was then behind the so-called iron curtain separating west from east in Europe. Endre Grastyan, who Gyuri mentions, was the head of a very important lab in Pecs, Hungary, and published a number of critical papers in the 1950s and 60s. He visited McGill when John O'Keefe and I were grad students and we were all very impressed. Perhaps we will hear more about Grastyan down the road. For now, here is what Gyuri had to say about my questions. I hope readers will note, once again, the incredible sense of community and sharing that existed in our field in the early days.

1. What got you interested in the hippocampus?
My dear mentor, Endre Grastyan was the first investigator to record from the hippocampus of a freely moving animal. He recognized that theta is much faster (5-6 Hz) when the cat orients towards and approaches a novel signal, compared to the slow rhythm in the anesthetized rabbit (Green and Arduino, 1954). Thus, I ‘inherited’ the hippocampus, theta oscillations and all their problems from Endre.

2. Aside from your own work, what findings about hippocampus (and related brain parts) in the past 50 years most excited you, and why?
Place cells of course. However, for many years place cell research remained a bit of phenomenology. Although I have seen them myself and proudly showed them to the visitors of my lab, my real interest in place cells started with John O’Keefe’s second discovery, the phenomenon of phase precession. Now, time (i.e., phase) entered into the place field literature and my interests in theta and other oscillations and behavioral correlates of pyramidal cell firing inevitably converged. My fascination was really about this problem: how can the spike phase of theta inform the rest of the brain about the animal’s position when theta is internally generated thus it’s phase varies randomly every time the animal enters the place field. Eventually, this was the path for our formulation of internally generated neuron assembly sequences that could be related to episodic memory. Perhaps I should mention another fascinating aspect of the hippocampus that bugs me a lot but never devoted enough time to address it. What make the hippocampus special is the granule cell. There is no such cell type in the neocortex. Granule cells keep dividing postnatally and the only cell type known whose life depends on circulating hormones (steroids). The latter was discovered by Bob Sloviter yet nobody really followed up on this. Why is there such hormone-neuron connection?

3. Can you relate one personal story about interactions with colleagues that most exemplifies the world of hippocampal research?
Although back then I took it for granted, in retrospect I am amazed how kind people were toward me in my younger days. John O’Keefe, Phil Best, John Disterhoft, Chuck Ribak, Fernando Lopes da Silva and others visited us behind the Iron Curtain to see our set up and methods. And when I eventually could leave Hungary, I was invited to give departmental seminars as if I was somebody. Here is a story my wife and I will always remember. I drove up from San Antonio, TX (where I did my first of many postdocs with Eddie Eidelberg) to NYC to pick up my wife who was eventually allowed to visit me. I had enough money to buy her a ticket to NYC but not all the way to Texas. On the way back from New York, I visited several neuroscience lab and we were always hosted by neuroscientist colleagues and their families wherever we stopped. The great Mort Mishkin invited me to give a seminar and arranged to pay me an honorarium of $150. For this large sum of money, we could get our first Peking duck dinner, buy enough gas to drive back to Texas and visit the famous jazz places in New Orleans. On our trip to California, I gave two departmental seminars at UCI and Jim McGaugh put us up in the Laguna Beach Hotel (I cannot afford it today!) and invited us for a pool party in his house. Looking for a new postdoc, my wife and I drove to Canada. Brian Bland hosted me for two weeks in Calgary and our families became good friends. I called up Case Vanderwolf telling him that I need a job and he hired me instantly (after we drove the Trans-Canada highway from Calgary to London, Ont). And the list goes on. I could never repay the generosity of these and many other future colleagues for their support.

4. What would tell a young researcher interested in the hippocampus to focus on now?
Whatever their interests are. Remember, the most important question in science is always YOUR question.

@nadel Another amazing episode! So clearly written and interesting. Thank you so much again for sharing.
Adding some hashtags to help this gem being discovered:

#HippocampusGurus #HippocampusHistory #hippocampus #PlaceCells #EntorhinalCortex #GridCells

@nadel
And please tag them with a hashtag so they are easy to find and follow. Maybe #HippocampusHistory or #HippocampusGurus ?