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Image courtesy of Laura Elizabeth Hand, CC’19

The hippocampus is one of those brain regions that pops up again and again in popular science literature, and for good reason. Most people associate the hippocampus with memory, mainly thanks to Henry Molaison, better known as H.M. Over fifty years ago, a hotshot neurosurgeon named William Scoville removed most of his hippocampus in an attempt to cure his severe epilepsy. The treatment worked but at a severe cost, as H.M. lost the ability to form new memories.

This curious case kicked off modern memory research as we know it. Decades of follow-up research has connected activity in the hippocampus to a variety of functions, most famously  the formation of episodic memories. Inspired by this human case, researchers peered into the brains of awake mice in an attempt to learn more.

One of the reasons why we can investigate this brain region in particular across species is just how similar the hippocampus of a mouse is to a human. It is an ancient structure, millions of years old, but it is arguably the first of the most ‘advanced’ brain regions to develop. While there are obviously differences in size between the species, the underlying organizational principles are nearly identical. What makes the hippocampus so special that we and our rodent cousins have one, but frogs don’t?

During one of these mouse experiments, a scientist named John O’Keefe made a curious finding. When the animal ran around in its environment, a certain kind of cell in the hippocampus would consistently fire only when the mouse navigated through a particular position. This finding later won him the Nobel Prize in Physiology or Medicine and spurred another avenue of research into how these ‘place cells’ (as they have since been dubbed) form a sophisticated ‘cognitive map’ of space.

Meanwhile, the development of fMRI in humans enabled human researchers to study learning, memory, attention, curiosity, and many other cognitive functions of the hippocampus. More than just memory, this enigmatic part of the brain is necessary for imagination, planning, and many other processes we consider so essential to our human existence.

Given the similarities between mice and men, it’s reasonable to expect that the mouse and human hippocampus are doing similar things. So why are their scopes of research so radically different? How exactly do cells that respond to a rodent’s current location in place create memory? While long existing in different spheres, new research aims to bridge the gap.

From the mouse side, non-place features of place cells are increasingly providing evidence for a broader, more integrative role of hippocampal pyramidal neurons than simply recording place. Recent findings, some unpublished, from the Society for Neuroscience 2017 Annual Meeting demonstrated many of these newly discovered, more diverse functions.

In highly social bats, ‘place’ cells can record the location of their fellow bats just as well as their own. In rats, ‘place’ cells can ‘map out’ a representation of sound. In monkeys, ‘place’ cells can fire without movement simply by looking around the environment. Most convincingly, a number of studies have shown that ‘place’ cells can also record a detailed representation of time.

Increasingly, it seems that these special hippocampal cells fire not only to locations, but a number of other things too. Some, if not most, of these cells respond to multiple things at once, like place and time, or sound and place.That feature, crucially, is indispensable in creating a memory. These cells aren’t just recording places, they’re combining different aspects of an experience together. Put another way, a ‘place cell’ isn’t simply mapping space, it’s making a memory.

While neither I nor neuroscience more generally has an answer to the question I posed at the beginning of this column, combining decades of research in mice and humans will help guide the way forward.

 

Citations and further reading:

  1. Scientific reviews are a great way to delve deeper than articles like mine without wading too deep into the terminology of primary articles. For an overview of the importance of H.M. to the field, I recommend: Squire, L. R. (2009). The legacy of patient H.M. for neuroscience. Neuron, 61(1), 6–9.
  2. To read the seminal place-cell study by O’Keefe: O’Keefe, J., & Dostrovsky, J. (1971). The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. Brain Research, 34(1), 171–175.
  3. For a broader review of place cells by nobel laureates in the field: Moser, M.-B., Rowland, D. C., & Moser, E. I. (2015). Place cells, grid cells, and memory. Cold Spring Harbor Perspectives in Biology, 7(2), a021808.
  4. Bats encoding in 3D, same lab with the preliminary unpublished social findings (primary paper): Sarel, A., Finkelstein, A., Las, L., & Ulanovsky, N. (2017). Vectorial representation of spatial goals in the hippocampus of bats. Science, 355(6321), 176–180.
  5. Rats encoding non-spatial ‘sound map’ (primary paper): Aronov, D., Nevers, R., & Tank, D. W. (2017). Mapping of a non-spatial dimension by the hippocampal–entorhinal circuit. Nature, 543, 719.
  6. Monkeys encoding a non-movement based ‘visual map’ (primary paper): Killian, N. J., Jutras, M. J., & Buffalo, E. A. (2012). A map of visual space in the primate entorhinal cortex. Nature, 491(7426), 761–764.
  7. Review of time cells by a giant in the field: Eichenbaum, H. (2014). Time cells in the hippocampus: a new dimension for mapping memories. Nature Reviews. Neuroscience, 15, 732.
  8. To read more about a fascinating brand-new big-picture theory about the hippocampus: Stachenfeld, K. L., Botvinick, M. M., & Gershman, S. J. (2017). The hippocampus as a predictive map. Nature Neuroscience, 20(11), 1643–1653.
Official White House Photo by Lawrence Jackson

 

Some of our loyal readers may have noticed this column has had an irregular publication schedule lately. This is because I wanted to give everyone a fresh update from the Society for Neuroscience 2017’s annual meeting, the largest gathering of over 30,000 neuroscientists every year to discuss the most fascinating and cutting-edge research.

Unfortunately, that update will have to wait another week, because today I feel compelled to use my platform to talk about the current tax bill making its way through congress. This bill, if passed, would effectively make graduate school impossible for all those but the independently wealthy, and would decimate the structure of science as we know it.

I typically keep this column apolitical, as my goal is to spread interesting neuroscience knowledge to everyone, rather than wading into the political thicket. Were this bill to have been proposed by the other side of the aisle, I would take equal issue. This overarching legislation aims to in part simplify taxes to, as its proponents so often state, ‘the back of a postcard.’

One such ‘simplification’ is the repeal of Section 117(d)(5), a tiny piece of the tax code that makes a huge difference to graduate students. In most STEM graduate programs, students have their tuitions waived and are awarded a modest stipend of approximately $20,000-$30,000 per year to focus on their research. Under the current tax code, graduate students are only taxed on their stipends, which makes sense, as this is the only money they actually take home.

In the tax bill just approved by the house, this exemption is removed. That means a catastrophic increase in tax burdens for all STEM graduate students. Let’s take an average graduate student in Columbia’s Neurobiology PhD program. Their take-home income is just under $30,000 from their stipends, but Columbia’s tuition (which, again, a graduate student never sees or pays), is nearly $50,000. If the senate passes the current version of this bill, graduate students will see a tripling of their tax burden, an increase of over $10,000.

Essentially, by trying to simplify the tax code, this bill would prevent all but the most wealthy of graduate students from pursuing higher education. While some universities may be able to increase stipends to compensate, most cannot afford to. Graduate students are the backbone of labs, and their projects make up the bulk of research happening in the US; without them, there is no science as we know it.  

Without this tiny line of tax code, programs will slash acceptances, US science productivity will plummet, and the hundreds of innovations which have made us a superpower will grind to a halt. Like all of STEM, neuroscience is reliant on the productive output of graduate students. While we are on the cusp of incredible breakthroughs in understanding the brain — many of which can lead to cures for heartbreaking diseases — none of that is possible with the passage of this tax bill in its current form.

This is bigger than politics, and this is bigger than just science. This is about ensuring that the United States continues to be the world’s leader in innovative scientific and technological breakthroughs. If you enjoy the tiny computer in your pocket, have yourself been or known someone helped by modern medicine, or believe in the necessity of scientific progress, please take the time to speak out against this bill and ensure that if it progresses, it does so without this provision. You can find your representative’s information here; ask them to oppose the repeal of Section 117(d)(5) within the Tax Cut and Jobs Act.

Next week, I promise we’ll be back to our regularly scheduled programming with some fun, new neuroscience findings.

Illustration made by Laura Elizabeth Hand, CC’19

Why are we all so unsatisfied? It’s both an existential and practical question, facing down administrators at colleges across the country. As diagnoses of mental disorders have skyrocketed and the palpable aura of discontent has began to seep into millennial spaces, especially the college campus, most experts are left wringing their hands without explanation. While hundreds of think pieces have been written about the existential dread of the modern world, very few have wondered if our brains themselves may be incompatible with the society we’ve made.

To understand where the disconnect between brains and our society comes from, it’s worth focusing on biology. Humans have evolved our complex brains over millennia to do one thing better than other species — to reduce uncertainty. We do this by predicting the future based on our past experiences, and then adjusting those models when they’re wrong. We call this process learning.

The neurons in our cortex and hippocampus, two areas essential for learning and prediction, are especially wired for these tasks. These neurons have two kinds of channels at their synapses that bind to glutamate, the primary excitatory neurotransmitter in the brain. The simpler channel opens up whenever glutamate is around, causing quick but fleeting pulses of activity. The more complex one needs a lot of glutamate to open, but when it does, it triggers a host of structural changes in the neuron to make it more responsive in the future.

This process is called long-term potentiation, and it is the molecular basis of learning from sea slugs all the way up the food chain to Homo Sapiens. But one innovation made by mammals is the addition of dopamine to the picture. For us, whenever something unexpectedly good happens that doesn’t meet our predictions, our brains send those neurons a pulse of dopamine. This cements those molecular changes of LTP on a scale of weeks to months, and makes sure that the association is learned.

This process was ideal for the hundreds of thousands of years humans spent as hunter-gatherers. We lived in an much more uncertain world, where many of our predictions were wrong and small unexpected pleasures (such as finding berries where there were none previously) abounded. Our brains would frequently receive small pulses of episodic happiness through dopamine. Learning based on rewarding prediction errors to motivate similar behavior in the future works only when those prediction errors are common.

While the world may seem uncertain existentially, in the most basic of ways it is far more predictable. That lack of constant, small pulses of dopaminergic inputs may be the root cause of many modern issues. When most of our material comforts are taken care of by technology, we turn elsewhere to find those hits of dopamine our brains are wired to crave. Whether that be through an alert notification on our phones, a pint of ice cream, or forcing a dopamine rush through  alcohol, opioids, cannabinoids, or other substances, we increasingly engineer artificial means of dopamine release — sometimes to addictive and destructive ends.

So what can be done to alleviate the issue? Instead of turning to massive and artificial methods of dopamine generation, re-introducing small and, more importantly, surprising pleasures into your life can provide a brain evolved to learn through unpredictability those necessary reward prediction errors. Eat a new food, explore a new place downtown without an agenda, have a conversation with someone unexpected. Our intelligence is how we’ve made it this far — maybe we can think our way out of this one.

 

Full credit for this conceptualization goes to Peter Sterling. For a more detailed elaboration on this idea I wholeheartedly recommend reading his essay “On Human Design” or his book Principles of Neural Design, specifically Chapter 14

Uniquely Human is written by Heather Macomber and runs every other Monday. To submit a comment/question or a piece of your own, email submissions@columbialion.com.

Illustration by Laura Elizabeth Hand, CC’19

 

I’ve spent a lot of time in this column so far talking about studies carried out in humans, usually using techniques like fMRI, EEG, or PET scans. However, a lot of neuroscience research, my own included, happens in what we call ‘model organisms’, one of the most common being the humble mouse. In conversations about my research, I’ve frequently gotten a variant of this question: “Why are you working on mouse brains if you want to understand how humans work?”

Since  I’ll be covering research done in lots of non-human species this semester, I wanted to take a column to talk about why I believe it is necessary to use animals in neuroscience research, and what they can tell us about the brain that human studies cannot.

Basically, it comes down to two things: in mice you can investigate the brain more directly at a much smaller scale, and you have much more causal control over the conditions of your experiments. First, let’s talk about the matter of scale.

In humans, functional magnetic resonance imaging, or fMRI, was a massive breakthrough in neuroscience. To this day, it is considered the highest degree of spatial resolution possible to monitor real-time neural activity in living humans, except for the rare electrodes allowed by a neurosurgery patient. In humans, fMRI is as far as you can ‘zoom in’ on the behaving brain.

However, like with any technique, there are downsides to fMRI. While most popular science articles call fMRI results ‘neural activity,’ fMRI is actually measuring the amount of oxygen that the blood in your brain is using, which serves as a proxy for neural activity. In other words, the assumption is that the more oxygenated blood a brain region is going through, the more neurons are firing in that region.

The other huge issue with fMRI is scale. An fMRI scan is like a 3D video, and just like a movie has pixels, there’s the smallest possible unit of detection in fMRI – the voxel. Its name comes from a combination of the words ‘volume’ and ‘pixel,’and it essentially is a pixel, just in three dimensions. The highest current possible resolution of a single voxel averages the oxygenation of approximately 100,000 neurons over one second, which means that the activity of 100,000 cells is reduced to a uniform greyish box on the display.

While that’s a pretty small percentage compared to the ~80 billion neurons of the brain, an fMRI still can’t tell you what specific kinds of neurons are activating, or anything about the pattern of activity below a voxel scale. So how do we understand neural circuits at a more detailed level?

That’s where mice come in. Mouse brains have most of the major features of human brains – they even have a neocortex that is structured almost identically to our own. In mice, it is much easier to observe these smaller scales, which span from from single neurons to the simultaneous observation of thousands of neurons at a time.

Mice are particularly well-suited to this task because of the immense control an experimenter can have over a given experiment. Every aspect of a lab mouse’s life is regulated from birth to death, which is impossible to control for in human studies.

Beyond behavioral control, genetic techniques enable causal manipulations at a cellular level. Thousands of mouse strains have been specially made to manipulate the expression of particular genes, optogenetic techniques enable researchers to turn on or off specific neuronal populations during behavior, and two-photon imaging paired with calcium labeling lets us observe the activity of individual neurons in real time.

These advantages of experimental control and fine-scale observations are only possible in animal models. While mice have their disadvantages too, namely that without language behavioral motivations becomes difficult to interpret, their use clearly contributes to neuroscience overall. Discoveries in mouse models help guide human researchers to better theories, better treatments, and ultimately, a better understanding of ourselves.

 

Uniquely Human is written by Heather Macomber and runs every other Monday. To submit a comment/question or a piece of your own, email submissions@columbialion.com.

Photo Courtesy of Columbia University.

Welcome back Columbia! From all of us at the Columbia Lion and from here at Uniquely Human, we hope all your summers were fruitful and relaxing. As we get back into the swing of classes, I wanted to write an update on the future of this column and what to expect going forward. First and foremost, Uniquely Human will be continuing its regular release schedule of every other Monday, starting today, so expect a new release two weeks from today.

As a neuroscience student here, I hear about all the impressive, exciting, and paradigm-shifting research coming out of Columbia labs. But no matter how interesting the research, many average Columbia students don’t know what’s coming out of their own institution. Scientists often only share their research in journals aimed solely at other scientists in their subfields. The most interesting conversations about neuroscience are ones that neuroscientists have with each other.

I want to change that.

This is your university, and this research is mostly paid for with your tax dollars. I think you have a right to understand what discoveries in neuroscience are coming out of Columbia, and how they may affect your lives in fascinating and surprising ways.

I believe the best kind of science happens when it’s in communication with the public. In these tumultuous times, now more than ever it’s critical that everyone knows what valuable contributions neuroscientists are making to how we understand ourselves. I think these kinds of conversations are most interesting when they’re had across disciplinary lines – with other scientists, with writers, philosophers, artists – and you, reader, have a worthy perspective to contribute.

So this semester we’ll be thematically shifting our focus away from our series on education and the brain. In its place, I’ll be reviewing the latest and greatest discoveries coming out of Columbia neuroscience using straightforward language, hopefully humorous analogies, and with an eye for the big picture implications. When possible, I’ll be interviewing researchers directly to get the best information directly from the researchers to you.

As always, the contents of this column are mostly dependent on what I want to write, which means not every column will be about Columbia neuroscience discoveries; there will be stories relating neuroscience to both campus and worldwide events.

As always I am happy to take requests. This is only a column in conversation when I can hear your voice. If you have questions that you want answered from a neuroscientific point of view, I’ll do my best to answer them. I can’t wait to share this amazing research with you all, and I hope to see you here next week for our first true installment in our series.

Uniquely Human is written by Heather Macomber and runs every other Monday. To submit a comment/question or a piece of your own, email submissions@columbialion.com.