Tag: Mice

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.
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.