Monday open question: can invertebrates be ‘cognitive’?

Janelia Farm, the research center the Howard Hughes Medical Institute recently announced their upcoming research focuses. One of them was controversial: mechanistic cognitive neuroscience. Here’s what they had to say about it:

How does the brain enable cognition? We are developing an integrated program in which tool-builders, biologists, and theorists collaborate to clear the technical, conceptual, and computational hurdles that have kept the most intriguing aspects of cognition beyond the purview of mechanistic investigation. The program will establish tight links across our existing genetic model systems —flies, fish, and rodents— and exploit their complementary strengths. We aim to make the fly the benchmark for reductionist explanations of neural processes underlying complex behavior, leveraging conceptual research by mammalian neuroscientists. The fly has strong potential as a model for rapid mechanistic insights, due to its small brain size, the likelihood of obtaining a complete wiring diagram of its brain, and increasingly powerful methods for measuring and manipulating genetically defined populations of cells in behaving animals. We expect this research to reveal strategies for better understanding the more sophisticated neural and behavioral features of vertebrates. In turn, we expect our vertebrate research to expose complex computational mechanisms, some of which we can study at a detailed level in the fly.

Why was this so controversial? This sentence: “In turn, we expect our vertebrate research to expose complex computational mechanisms, some of which we can study at a detailed level in the fly“. Yes, the humble fly may or may not have cognitive states.

What are some cognitive behaviors that a fly can perform? They use reinforcement learning, can attend to things, have visual place memory. Other invertebrates can recognize faces and perform complex path integration. On the other hand, they have very poor linguistic abilities.

It’s a truth of biology that theories rarely survive contact with new types of data. There is a kind of clarity from knowing the exact neural circuitry and dynamics that a minimal neural circuit needs. If I were studying, say, attention in primates I would be interested in the precise mechanisms that another species uses to accomplish a task similar to what I’m studying. There’s no guarantee that it will be the same mechanism – but is it so unreasonable? Is there a reason that insects would not display cognitive behavior?

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You should be using the Neuromethods slack

Ben Saunders has started a Slack for those of you in neuroscience who do, uh, neuroscience. The Neuromethods Slack is a place for scientists to discuss questions about experiments. There’s a channel for electrophysiology, a channel for the biophysics of rhodopsins, a channel for Drosophologists, a channel for data visualization, and so on. It is not the robust mix of science and nonsense that Twitter seems to generate but very much on-topic and seems to be giving answers to questions by other experts within a day or so. You should check it out!

Behavioral quantification: running is part of learning

One of the most accessible ways to study a nervous system is to understand how it generates behavior – its outputs. You can watch an animal and instantly get a sense of what it is doing and maybe even why it is doing it. Then you reach into the animal’s brain and try to find some connection that explains the what and the why.

Take the popular ‘eyeblink conditioning’ task that is used to study learning. You can puff a harmless bit of air at an animal and it will blink in response (wouldn’t you?). Like Pavlov’s dog, you can then pair it with another signal – a tone, a light, something like that – and the animal will slowly learn to associate the two. Eventually you just show the animal the other signal, flashing the light at them, and they will blink as if they were expecting an air puff coming. Simple enough but obviously not every animal is the same. There is a lot of variability in the behavior which could be due to any of a number of unexplored factors, from individual differences in experience to personality. If this is what we are using to investigate the underlying neuroscience, then, it places a fundamental limit on what we can know about the nervous system.

How can we neuroscientists overcome this? One very powerful technique has been to improve our behavioral quantification. I saw a fantastic example of this from Megan Carey when she visited Princeton earlier this year to talk about her work on cerebellum and learning. She had tons of interesting stuff but there was one figure she presented that simply blew me away.

First a bit of history is in order (apologies if I get some of this a bit wrong, my notes here are hazy). When experimenters first tried to get eyeblink conditioning to work with mice, they had trouble. Even though it seems like such a simple reflex the mice were performing very poorly on the task. Eventually, someone (?) found that allowing the mice to walk on a treadmill while experiencing the cues resulted in a huge increase in performance. Was this because they were unhappy being fixed in one place? Was it that they were unable to associate an puff of air to their eye with an environment when they were unable to manipulate their environment?

But there is still a lot of variability. Where does it come from? What you can now do is measure as much about the behavior as possible. Not just how much the animal blinks its eye, but how much it moves and how fast it moves, and how much it does all sorts of other stuff. And it turns out that if you measure the speed that the animal is walking there is a clear linear correlation with how long it takes the animal to learn.

Look at this figure – on the left, you can see how often each individual animal is responding to the air puff with an eyeblink (y-axis) as it is trained through time (x-axis). And on the right is how long it takes to reach some performance benchmark (y-axis) given the average speed the animal walks (x-axis).

So how do you test this? Make sure it is a causation not a meaningless correlation? Put them on a motorized treadmill and control the speed that they walk at. And BAM, most of the variability is gone! Look at the mess of lines in the behavior above and the clearly-delineated behavior below.

There’s a lesson here: when we study a ‘behavior’, there are a lot of other things that an animal is doing at the same time. We think they are irrelevant – we hope they are irrelevant – but often they are part of one bigger whole. If you want to study a behavior that an animal is performing, how else can you do it but by understanding as much about what the animal is doing as possible? How else but seeing how the motor output of the animal is linked together to become one complex form? Time and again, quantifying as many aspects of behavior as possible has revealed that it is in fact finely tuned but driven by some underlying variable that can be measured – once you figure out what it is.

What people mean when they say “maybe”

What is the probability that people perceive when they hear a word like ‘probably’ or ‘probably not’? Someone went and collected some data on this to get the actual probabilities!

Here is some old data:

[This is mostly a personal reminder so I can find this graph again]

Making MATLAB pretty

Alright all y’all haters, it’s MATLAB time.

For better or worse, MATLAB is the language that is used for scientific programming in neuroscience. But it, uh, has some issues when it comes to visualization. One major issue is the clusterfuck that is exporting graphics to vector files like eps. We have all exported a nice-looking image in MATLAB into a vectorized format that not only mangles the image but also ends up somehow needing thousands of layers, right?  Thankfully, Vy Vo pointed me to a package on github that is able to clean up these exported files.

Here is my favorite example (before, after):

If you zoom in or click the image, you can see the awful crosshatching in the before image. Even better, it goes from 11,775 layers before to just 76 after.

On top of this, gramm is a toolbox to add ggplot2-like visualization capabilities to MATLAB:

(Although personally, I like the new MATLAB default color-scheme – but these plotting functions are light-years better than the standard package.)

Update: Ben de Bivort shared his lab’s in-house preferred colormaps. I love ’em.

Update x2: Here’s another way to export your figures into eps nicely. Also, nice perceptually uniform color maps.

Why does the eye care about the nose?

The ear, the nose, the eye: all of the neurons closest to the environment are doing on thing: attempting to represent the outside world as perfectly as possible. Total perfection is not possible – you can only only make the eye so large and only need to see so much detail in order live your life. But if you were to try to predict what the neurons in the retina or the ear are doing based on what could provide as much information as possible, you’d do a really good job. Once that information is in the nervous system, the neurons that receive this information can do whatever they want with it, processing it further or turning it directly into a command to blink or jump or just stare into space.

Even though this is the story that all of us neuroscientists get told, it’s not the full thing. Awhile back, I posted that the retina receives input from other places in the brain. That just seems weird from this perspective. If the retina is focused on extracting useful information about the visual world, why would it care about how the world smells?

One simple explanation might be that the neurons only want to code for surprising information. Maybe the nose can help out with that? After all, if something is predictable then it is useless; you already know about it! No need to waste precious bits. This seems to be what the purpose of certain feedback signals to the fly eye are for. A few recent papers have shown that neurons in the eye that respond to horizontal or vertical motion receive signals about how the animal is moving, so that when the animal moves to the left it should expect leftward motion in the horizontal cells – and so only respond to leftward motion that is above and beyond what the animal is causing. But again – what could this have to do with smells?

Let’s think for a second about some times when the olfactory system uses non-olfactory information. The olfactory system should be trying to represent the smell-world as well as it can, just like the visual system is trying to represent the image-world. But the olfactory system is directly modulated depending on the needs of an animal at any given moment. For instance, a hungry fly will release a peptide that modifies how much a set of neurons that respond to particular odors can signal the rest of the brain. In other words, how hungry an animal is determines how well it can smell something!

These two stories – how the eye interacts with the motion of the body, how the nose interacts with hunger – might give us a hint about what is happening. The sensory systems aren’t just trying to represent as much information about the world as possible, they are trying to represent as much information about useful stuff as possible. The classical view of sensory systems is a fundamentally static one, that they have evolved to take advantage of the consistencies in the world to provide relevant information as efficiently as possible*. But the world is a dynamic place, and the needs of an animal at one time are different from the needs of the animal at another.

Take an example from tadpoles. When the tadpole is in a very dim environment, it has a harder time separating dark objects from the background. The world just has less contrast (try turning down the brightness on your screen and reading this – you’ll get the idea). One way that these tadpoles control their ability to increase or decrease contrast is through a neuromodulator that changes the resting potential of a cell (how responsive it is to stimuli), but only over relatively long timescales. This is not fast adaptation but slow adaptation to the changing world. The end result of this is that tadpoles are better able to see moving objects – but presumably at the expense of being worse at seeing something else. That seems like a pretty direct way of going from a need for the animal to code certain visual information more efficiently to the act of doing it. The point is not that this is driven by a direct behavioral need of the animal – I have no idea if this is due to a desire to hunt or avoid objects or what-have-you. Instead, it’s an example of how an animal could control certain information if it wanted to.

This kind of behavioral gating does occur from retinal feedback. Male zebrafish use a combination of smell and sight when they decide how they want to interact with other zebrafish. Certain olfactory neurons that respond to a chemical involved in mating signal to neurons in the retina – making certain cells more or less responsive in the same way that tadpoles control the contrast of their world (above). It appears as if the olfactory information sends a signal to the eye that either gates or enhances the visual information – the stripe detection or what-have-you – that the little fishies use when they want to court another animal.

The sensory system is not perfect. It must make trade-offs about which information is important to keep and which can be thrown away, about how much of its limited bandwidth to spend on one signal or another. A lot of the structure comes naturally from evolution, representing a long-term learning of the structure of the world. But animals have needs that fluctuate over other timescales – and may require more computation than can be provided directly in the sensory area. How else would the eye know that it is time to mate?

What this doesn’t answer is why the modulation is happening here; why not downstream?

 

* This is a major simplification, obviously, and a lot of work has been done on adaptation, etc in the retina.

 

Monday Open Question: what do you need to do to get a neuroscience job? (Updated)

Awhile back I asked for help obtaining information on people who had gotten a faculty job in 2016 – 2017. And it worked! With a lot of help, I managed to piece together a list with more than 70 people who had gotten faculty jobs during this last year! I am sure it is incomplete (I keep getting new tips as of ten minutes ago…) but it is time to discuss some of the interesting features of the data.

First, the gender ratio: there are 44 men on the list to 33 women (57%). Over at the neurorumblr, 62% of the people on the Postdoc List were men which is roughly the same proportion.

To get more data, I focused on faculty hires who had a Google Scholar profile – it made it much easier to scrape data. It was suggested that people in National Academy of Sciences or HHMI labs may have a better chance of getting a faculty job. Out of the 51 people with a Google Scholar profile, 4 were in both NAS/HHMI labs, 8 were in HHMI-only labs, and 4 were in NAS-only labs.  Only one person who as in a HHMI/NAS lab in grad school went to a non-HHMI/NAS lab. People also suggested that a prestigious fellowship (HHWF, Damon Runyon, Life Sciences, etc.) It is hard to tell, but there didn’t seem like a huge number of these people gaining a job last year.

The model organisms they use are:

(15) Humans

(13) Mouse

(6) Rat

(4) Monkey

(3) Drosophila

(3) Pure computational

+ assorted others

Where are they all from? Here is the distribution of institutions the postdocs came from (update: though see the bottom of the post for more information):

 

In case you hadn’t noticed, this is a pretty geographically-concentrated pool of institutions. Just adding up schools that are in the NYC+ area (NYC-itself, plus Yale and Princeton), the Bay Area, Greater DC (Hopkins + Janelia), and ‘those Boston schools’. I’m not sure this accurately represents the geographic distribution of neuroscientists.

What about their publications? They had a mean H-index of 11.98 (standard deviation ~ 4.21).

We always hear that “you need a Cell/Nature/Science paper in order to get a job”. 29.4% (15/51) of this pool have a first- or second-author CNS paper. 68% (35/51) have a first- or second-author Nature Neuroscience/Neuron/Nature Methods paper. 78% (40/51) have some combination of these papers. It’s possible that faculty hires have CNS papers in the pipeline, but unless every single issue of CNS is dedicated to people who just got a faculty job this probably isn’t the big deal it’s always made out to be.

There’s a broader theory that I’ve heard from several people (outlined here) that the underlying requirement is really the cumulative impact factor. I have used the metric described in the link, where the approximate impact factor is taken from first-author publications and second-author publications are discounted 75% (reviews are ignored). Here are the CIFs for all 51 candidates over the past 7 years (red is the mean):

I thought there might be a difference by model organism, but within imaginary error bars it looks roughly the same:

In terms of absolute IF of the publications, there is a clear bump in the two years prior to the candidate getting their job (though note all of the peaks in individual traces prior to that):

So far as I can tell, there is no strong signal in terms of publications that you had as a Grad Student. Basically, graduate work or lab don’t matter, except as a conduit to get a postdoc position.

To sum up: you don’t need a CNS paper, though a Nature Neuroscience/Neuron/Nature Methods paper or two is going to help you quite a bit. Publish it in the year or two before you go on the job market.

Oh, and live in New York+ or the Bay Area.

 

Update: the previous city/institution analysis was done on a subset of individuals that had Google Scholar profiles. When I used all of the data, I got this list of institutions/cities:

Updated x2:

I thought it might be interesting to see which journals people commonly co-publish in. It turns out, eh, it is kind and it isn’t kind of. For all authors, here are the journals that they have jointly published in (where links represent the fact that someone has published in both journals):

And here are the journals they have published in as first authors:


Behavioral quantification: mapping the neural substrates of behavior

A new running theme on the blog: cool uses of behavioral quantification.

One of the most exciting directions in behavioral science are the advances in behavioral quantification. Science often advances by being able to perform ever more precise measurements from ever-increasing amounts of data. Thanks to the increasing power of computers and advances in machine learning, we are now able to automatically extract massive amounts of behavioral data at a level of detail that was previously unobtainable.

A great example of this is a recently published paper out of Janelia Farm. Using an absolutely shocking 400,000 flies, the authors systematically activated small subsets of neurons and then observed what behaviors they performed. First, can you imagine a human scoring every moment of four hundred thousand animals as they behaved over fifteen minutes? That is 12.1 billion frames of data to sort through and classify.

Kristan Branson – the corresponding author on the paper – has been developing two pieces of software that allows for efficient and fast estimation of behavior. The first, Ctrax, tracks individual animals as they move around a small arena and assigns a position, an orientation, and various postural features (for instance, since they are fruit flies we can extract the angle of each wing). The second, JAABA, then uses combinations of these features, such as velocity, interfly distance, and so on, in order to identify behaviors. Users annotate videos with examples of when an animal is performing a particular behavior, and then the program will generate examples in other videos that it believes are the same behavior. An iterative back-and-forth between user and machine gradually narrows down what counts as a particular behavior and what doesn’t, eventually allowing fully-automated classification of behavior in new videos.

Then once you have this pipeline you can just stick a bunch of animals into a plate under a camera, activate said neural populations, let them do whatever they feel like doing, and get gobs and gobs of data. This allows you to understand at neural precision which neurons are responsible for any arbitrary behavior you desire. This lets you build maps – maps that help you understand where information is flowing through the brain. And since you know which of these lines are producing which behaviors, you can then go and find even more specific subsets of neurons that let you identify precise neural pathways.

Here are two examples. Flies sometimes walk backwards (moonwalking!). If you look at the image below, you can see (on the bottom) all the different neurons labeled in a fly brain that had an effect on this backward locomotion, and in the upper-right the more specific areas where the neurons are most likely located. In fruit fly brains, the bulbous protrusions where these colors are found are the eyes of the animal, with a couple flecks in the central brain.

This turns out to be incredibly accurate. Some of this moonwalking circuit was recently dissected and a set of neurons from the eye into the brain was linked to causing this behavior. The neurons (in green below) are in exactly the place you’d expect from the map above! They link to a set of neurons known as the ‘moonwalker descending neurons’ which sends signals to the nerve (spinal) cord that cause the animal to walk backwards.

Of course, sometimes it can be more complicated. When a male fly is courting a female fly, he will extend one wing and vibrate it to produce a song. Here are the neurons related to that behavior (there are a lot):

There are two key points from this quantification. First, the sheer amount and quality of data it is possible to gain access to and score these days is allowing us to have immense statistical precision on when and in which contexts behaviors are occurring. Second, the capacity to find new things is increasing because we can be increasingly agnostic to what we are looking for (so it is easier to find surprises in the data!).

References

Mapping the Neural Substrates of Behavior. Robie et al 2017.

See also: Big behavioral data: psychology, ethology and the foundations of neuroscience. Gomez-Marin et al 2014.

 

Monday Open Question: does neuroscience have anything to offer AI?

A review was published this week in Neuron by DeepMind luminary Demis Hassibis and colleagues about Neuroscience-inspired Artificial Intelligence. As one would expect from a journal called Neuron, the article was pretty positive about the use of neurons!

There have been two key concepts from neuroscience that are ubiquitous in the AI field today: Deep Learning and Reinforcement Learning. Both are very direct descendants of research from the neuroscience community. In fact, saying that Deep Learning is an outgrowth of neuroscience obscures the amount of influence neuroscience has had. It did not just gift the idea of connecting of artificial neurons together to build a fictive brain, but much more technical ideas such as convolutional neural networks that use a single function repeatedly across its input as the retina or visual cortex does; hierarchical processing in the way the brain goes from layer to layer; divisive normalization as a way to keep outputs within a reasonable and useful range. Similarly, Reinforcement Learning and all its variants have continued to expand and be developed by the cognitive community.

Sounds great! So what about more recent inspirations? Here, Hassibis &co offer up the roles of attention, episodic memory, working memory, and ‘continual learning’. But reading this, I became less inspired than morose (see this thread). Why? Well look at the example of attention. Attention comes in many forms: automatic, voluntary, bottom-up, top-down, executive, spatial, feature-based, objected-based, and more. It sometimes means a sharpening of the collection of things a neuron responds to, so instead of being active in response to an edge oriented, thisthat, or another way, it only is active when it sees an edge oriented that way. But it sometimes means a narrowing of the area in space that it responds to. Sometimes responses between neurons become more diverse (decorrelated).

But this is not really how ‘attention’ works in deep networks. All of these examples seem primarily motivated by the underlying psychology, not the biological implementation. Which is fine! But does that mean that the biology has nothing to teach us? Even at best, I am not expecting Deep Networks to converge precisely to mammalian-based neural networks, nor that everything the brain does should be useful to AI.

This leads to some normative questions: why hasn’t neuroscience contributed more, especially to Deep Learning? And should we even expect it to?

It could just be that the flow of information from neuroscience to AI  is too weak. It’s not exactly like there’s a great list of “here are all the equations that describe how we think the brain works”. If you wanted to use a more nitty-gritty implementation of attention, where would you turn? Scholarpedia? What if someone wants to move step-by-step through all the ways that visual attention contributes to visual processing? How would they do it? Answer: they would become a neuroscientist. Which doesn’t really help, time-wise. But maybe, slowly over time, these two fields will be more integrated.

More to the point, why even try? AI and neuroscience are two very different fields; one is an engineering discipline of, “how do we get this to work” and the other a scientific discipline of “why does this work”. Who is to say that anything we learn from neuroscience would even be relevant to AI? Animals are bags of meat that have a nervous system trying to solve all sorts of problems (like wiring length energy costs between neurons, physical transmission delays, the need to blood osmolality, etc) that AI has no real interest or need in including but may be fundamental to how the nervous system has evolved. Is the brain the bird to AI’s airplane, accomplishing the same job but engineered in a totally different way?

Then in the middle of writing this, a tweet came through my feed that made me think I had a lot of this wrong (I also realized I had become too fixated on ‘the present’ section of their paper and less on ‘the past’ which is only a few years old anyway).

The ‘best paper’ award at the CVPR 2017 conference went to this paper which connects blocks of layers together, passing forward information from one to the next.

That looks a lot more like what cortex looks like! Though obviously sensory systems in biology are a bit more complicated:

And the advantages? “DenseNets have several compelling advantages: they alleviate the vanishing-gradient problem, strengthen feature propagation, encourage feature reuse, and substantially reduce the number of parameters”

So are the other features of cortex useful in some way? How? How do we have to implement them to make them useful? What are the drawbacks?

Neuroscience is big and unwieldy, spanning a huge number of different fields. But most of these fields are trying to solve exactly the same problem that Deep Learning is trying to solve in very similar ways. This is an incredibly exciting opportunity – a lot of Deep Learning is essentially applied theoretical neuroscience. Which of our hypotheses about why we have attention are true? Which are useless?

The skeletal system is part of the brain, too

It seems like a fact uniformly forgotten is that the brain is a biological organ just the same as your liver or your spleen or your bones. Its goal – like every other organ – is to keep your stupid collection of cells in on piece. It is one, coherent organism. Just like any other collection of individuals, it needs to communicate in order to work together.

Many different organs are sending signals to the brain. One is your gut, which is innervated by the enteric nervous system. This “other” nervous system contains more neurons (~500 million) than the spinal cord, and about ten times as many neurons as a mouse has in its whole brain. Imagine that: living inside of you is an autonomous nervous system with sensory inputs and motor outputs.

We like to forget this. We like to point to animals like the octopus and ask, what could life be like as an animal whose nervous system is distributed across its body? Well, look in the mirror. What is it like? We have multiple autonomous nervous systems; we have computational processing spread across our body. Have you ever wondered what the ‘mind’ of your gastrointestinal system must think of the mind in the other parts of your body?

The body’s computations about what to do about the world aren’t limited to your nervous system: they are everywhere. This totality is so complete that even your very bones are participating, submitting votes about how you should be interacting with the world. Bones (apparently) secrete neurohormones that directly interact with the brain. These hormones then travel through the blood to make a small set of neurons more excitable, more ready to respond to the world. These neurons then become ready and willing to tell the rest of the brain to eat less food.

This bone-based signaling is a new finding and totally and completely surprising. I don’t recall anyone postulating a bone-brain axis before. Yet it turns out that substantial computations are performed all throughout the body that affect how we think. Animals that are hungry make decisions in a fundamentally different way, willing to become riskier and riskier.

 

A lot of this extra-brain processing is happening on much slower timescales than the fast neuronal processing in the brain: it is integrating information along much longer amounts of time. This mix of fast-and-slow processing is ubiquitous for animals; classification is fast. The body is both fast and slow.

People seem to forget that we are not one silicon instantiation of neural architecture away from replicating humans: we are meat machines.

References

 

MC4R-dependent suppression of appetite by bone-derived lipocalin 2. Nature 2017.