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What Can Mice Say About People?

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.

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