As a kid, I thought biology was stupid.

Biology seemed to be taught mainly in the form of lists and diagrams. Here’s a list of the differences between prokaryotic and eukaryotic cells. There’s a diagram of the circulatory system. Here’s a list of traits specific to mammals. Then there’d be a page on the test where you’d have to label the organelles of a cell on some crappy photocopy where you could barely make out the ribosome from a Xerox smudge.

Then I learned about the brain. Maybe lists and diagrams can describe how the kidney or the heart works, but they can’t explain the brain. At least not at the level I wanted to understand it.

The brain had always seemed pretty cool, what with mediating our thoughts and emotions and all that good stuff. But in most biology classes all we learned about neuroscience were the basics: neurons, dendrites, axons, synapses. I knew that the brain was filled with cells called neurons, that different parts of a neuron send and receive signals, that neurons can communicate with each other. But what the heck did any of that have to do with thinking and feeling? How can the function of individual cells possibly be related to complex behaviors and thoughts?

The moment I decided I wanted to study the brain was the moment I got a glimpse of what bridges that gap. This bridge is called a neural circuit: a pathway of neurons that processes information into forms that are useful for making some kind of decision or response.

This moment came during an introductory biology course in college. Our professor, Robert Sapolsky, described classic experiments on the visual system performed by David Hubel and Torsten Wiesel in the 1950s and 1960s. They sought to understand how the brain takes simple information from the eyes and transforms it into our complex visual perception of the world. In 1981 they received the Nobel Prize (along with neuroscientist Roger Sperry) for their fundamental discoveries.

Light, retina, action

At its core, vision is about detecting light. You’ve probably heard of rods and cones—those are the photoreceptor cells in your eyes that physically detect photons of light. Photoreceptors are distributed across our retina, and each cell can only detect light coming from a particular point in space. To perceive an image, our brains must integrate the information from all those tiny photoreceptors.

Hubel and Wiesel didn’t know about photoreceptors back then, but previous studies had shown that the output neurons of the retina—the cells that send information from your eyes to your brain—display fairly simple responses to light. Each cell fires when you shine light in a specific small circular area of the visual field, with different cells responding to light in different places.¹ These neurons respond this way because they get positive input from photoreceptors that are clustered together in a specific area of the retina.

Additionally, these retinal output neurons are inhibited when you shine light just outside of their preferred circular areas, so they’re called “center-surround” cells. This suppression is due to inhibitory input from the corresponding photoreceptors.

So basically these center-surround cells are really good at detecting little circles of light. Useful, but a long way off from recognizing the real world unless your house is full of polka dots. Hubel and Wiesel realized that a lot more visual processing must occur in the brain to allow us to see more complex things.

The retina sends visual information to the thalamus, a relay station in the brain. But the visual cells of the thalamus also have center-surround properties, suggesting that they don’t really transform the information from the retina; they mostly just pass it on. So Hubel and Wiesel decided to dive deeper into the brain.

The thalamus relays visual information to the visual cortex, a higher-order brain center. Hubel and Wiesel discovered that that’s where things really start to get interesting.² Their basic approach was to record the activity of neurons in cat brains while presenting various visual stimuli (i.e., patterns of light).

Circus tent science

You might think that Nobel Prize-winning research is always conducted with the utmost care and precision. Not so for Hubel and Wiesel, even by the standards of their time. The visual stimuli they showed the cats were crudely cut out of cardboard. Instead of a real projection screen, they hung a bedsheet over the pipes that ran beneath the ceiling, making the experiment room resemble a circus tent. The first time they treated a cat with formaldehyde (a toxic chemical used to preserve tissue), a mishap with the chemical bottles doused them both in a cold formaldehyde shower. “We did not relish being preserved at so young an age!” they lamented.³

They had a frenemy named Vernon Mountcastle, an accomplished neuroscientist who had impressively recorded the activity of hundreds of cells in the brain.⁴ Hubel and Wiesel later confessed, “We knew we could never catch up, so we catapulted ourselves to respectability by calling our first cell No. 3000 and numbering subsequent ones from there,” noting that “Vernon seemed suitably impressed by our series.” See, I told you these guys were geniuses.

With their makeshift experimental setup, Hubel and Wiesel started out by trying to get neurons in the visual cortex to respond to traditional visual stimuli such as dots. They had little success. No matter the size or position of the circles, their neurons just couldn’t care less. They tested more types of visual stimuli. Still no luck. In desperation, they waved their arms and jumped around, and at one point even showed pictures of beautiful women from a magazine. No response.

Then one day while they were recording from yet another stubbornly silent neuron, it suddenly started firing like crazy as they changed the projection slide that they were using to present the stimuli. Turns out, the cell was responding to the edge of the slide. That’s when Hubel and Wiesel discovered that there are cells specialized for detecting lines—a basic feature of the visual world. They recorded from that neuron for nine straight hours and then ran down the halls screaming with joy.

Visual responses in the cortex

While they feared this was some weirdo cell they’d never find again, they discovered that many neurons in cortex (which they called “simple cells”) have this property: they respond to lines presented in a specific location and orientation, such as horizontal, vertical, or something in between. Similar to center-surround cells, simple cells are inhibited by light flanking either side of their preferred linear area.⁵

How might these line-sensitive simple cells arise? Well, remember that each center-surround cell in the thalamus is activated by a dot of light in a particular location. What do you get if you put a bunch of dots side by side? That’s right, a line! Hubel and Wiesel hypothesized that each simple cell might get positive input from a bunch of thalamic center-surround cells whose preferred areas are arranged in a straight line. The simple cell only fires if enough of those inputs are simultaneously active, which occurs when you shine light in a straight line of the correct orientation. A larger shape like a square won’t work: remember how center-surround cells are inhibited by light outside their preferred area, so anything wider than a thin line would trigger too much inhibition.

Hubel and Wiesel also discovered another type of cell in the visual cortex, which they called a complex cell.⁶ Like simple cells, complex cells were activated by lines of a specific orientation, but many of them responded best to a line that was moving steadily through space. So now the brain can detect a totally new feature: movement.

You might guess that detecting movement is a lot more complicated than detecting stationary forms. But actually, we can propose a fairly simple model for how this property arises.

Imagine that a complex cell gets positive input from a very specific group of simple cells: cells that respond to lines with the same orientation but spanning adjacent areas of space. Activating just one of the simple cell inputs, as with a stationary line, isn’t sufficient to make the complex cell respond. But activating multiple simple cells within a small time window, as with a moving line, provides enough excitation to make the complex cell fire.

The basics of a circuit

At this point, if you’re anything like undergrad me, your mind = blown. In just a few steps, we can explain how the visual system goes from detecting individual photons to detecting circles, lines, and movement!

Yes, we’re still far off from recognizing the vast array of visual forms that occur in the real world, but by now you can probably imagine how that occurs: by sequentially integrating information along a neural pathway to detect new features. This is essentially what all neural circuits do: they transform basic signals into useful, often sophisticated information that we can use to understand or interact with the outside world.

For me, this was a epiphany that changed the way I thought about how the brain works. The brain isn’t just a collection of neurons doing their own thing with their precious dendrites and axons; it’s a network of cells that talk to each other and trade information. It’s a community of individuals, each playing a very specific role, who work closely with each other to collectively accomplish important and amazing things. (Basically like the opposite of Congress.)

Hubel and Wiesel were two of the first to show how this might actually work—how the firing of neurons and their organization into circuits can explain our real-life experience of the world. This had a huge impact on the field of neuroscience.⁷ Later studies revealed that the visual system is more complicated than they realized, but the principles they elucidated remain relevant to our modern understanding of information processing in the visual system as well as other brain circuits. Moreover, their insights undoubtedly inspired many budding neuroscientists like me to try to follow in their footsteps and probe the mysteries of the brain.

 

Fellow neuroscientists and neuro-enthusiasts, what inspired your interest in the brain? Leave a comment below!

 

Notes:

1. I should mention that researchers later discovered that there are many different types of retinal output neurons, some of which show much more complicated responses than center-surround cells.

2. Again, apologies to those who study the early visual system such as the retina, which turns out to do a lot of sophisticated information processing. But Hubel and Wiesel didn’t know about that at the time.

3. The Hubel and Wiesel quotes and stories that I relate are based on these sources:

Hubel DH. Evolution of ideas on the primary visual cortex, 1955-1978: a biased historical account. Nobel Lecture, December 1981.

Hubel DH, Wiesel TN. Early exploration of the visual cortex. Neuron 20:401-412 (1998).

Gellene D. “David Hubel, Nobel-Winning Scientist, Dies at 87”. New York Times, Sept. 24, 2013.

4. Mountcastle actually just died this week at the age of 96. Like Hubel and Wiesel, his work on the visual system provided fundamental insights into how the brain works, and some believe that he should have also received the Nobel Prize.

5. Hubel DH, Wiesel TN. Receptive fields of single neurones in the cat’s striate cortex. J Physiol 148:574-591 (1959).

6. Hubel DH, Wiesel TN. Receptive fields, binocular interaction and functional architecture in the cat’s visual cortex. J Physiol 160:106-154 (1962).

7. This article provides a great perspective on how Hubel and Wiesel revolutionized the field of neuroscience:

Wurtz RH. Recounting the impact of Hubel and Wiesel. J Physiol 587: 2817-2823 (2009).