Never make a decision on an empty stomach… or a full stomach…

You are hungry already and dinner is hours away.  You’re getting irritable and making stupid decisions that you normally wouldn’t.  Or maybe you just had a big meal and you’re sated.  Your friend who is seated next to you turns and asks for a favor; you pleasantly agree and sink into your chair sleepily.  What’s going on?

An underappreciated fact about the neuromodulatory system is that release of these molecules can have diffuse and widespread effects all across the brain.  Take dopamine and leptin. Dopamine is a chemical that drives decision-making – among other things, but it really does have an important role in this – while leptin is generally thought to signal satiety.  Leptin is released from the fat cells of the body and we typically think of it acting on the hypothalamus, an area responsible for many metabolic behaviors.  When more leptin is circulating in the blood stream, you will eat less food and increase more energy which makes it a natural candidate for yet another failed diet pill.  Since leptin interacts with motivation to eat food, an alternative set of areas it could interact with are the dopamine regions .  And in those regions, in the striatum in particular, the response to food and food pictures will be reduced when there is increased leptin.

It would be nice to know mechanistically how the two systems interact.  One method of going about this is to activate dopamine release through a stress pathway: by keeping pain at a constant self-reported score, a robust and constant amount of dopamine will be released.  Yes, for some reason people actually volunteer for these experiments.  Now we can exploit the fact that there are known variants in the gene responsible for leptin, LEP.  If you look at how people with these variants respond, you get large differences in dopamine release, which seems to preferentially effect the D2/3 receptors.  Although different researchers seem to disagree on which specific regions of the striatum are modified by leptin, a good guess it that this is highly dependent on the task and leptin will change the amount of dopamine available to the areas.

What affect might this have on behavior?  One behavior that these D2/3 receptors are involved in is risky decision-making.  We all have our own preferences for risky bets.  Some people prefer small bets that they are guaranteed whereas others prefer the risky option (these are the compulsive gamblers).  But it’s a bit more complicated than that.  Sure, you’d take a risky bet when the option was between a sure 5 cents and a “risky” $1.  But maybe you wouldn’t if you were guaranteed $100 with a risky option of $2000 or nothing.  How sensitive you are to these bets turns out to rely on the concentration of D2/3 receptors in the dorsal striatum.  Putting two and two together, we can bet that the leptin that has an effect on dopamine levels also has an effect on how willing you are to take a risk as the stakes get larger.

This means that all of our body is linked, together, with the state of the world.  Periods of hunger or bounty will cause people to behave in very different ways, with behavior linked to the body’s hormone signaling.  Particularly prevalent here is that hormones that are generally thought of as responding purely to food may have a broader role in signaling to the body how to properly respond to all sorts of situations.


Burghardt, P., Love, T., Stohler, C., Hodgkinson, C., Shen, P., Enoch, M., Goldman, D., & Zubieta, J. (2012). Leptin Regulates Dopamine Responses to Sustained Stress in Humans Journal of Neuroscience, 32 (44), 15369-15376 DOI: 10.1523/JNEUROSCI.2521-12.2012

Cocker, P., Dinelle, K., Kornelson, R., Sossi, V., & Winstanley, C. (2012). Irrational Choice under Uncertainty Correlates with Lower Striatal D2/3 Receptor Binding in Rats Journal of Neuroscience, 32 (44), 15450-15457 DOI: 10.1523/JNEUROSCI.0626-12.2012

Dunn, J., Kessler, R., Feurer, I., Volkow, N., Patterson, B., Ansari, M., Li, R., Marks-Shulman, P., & Abumrad, N. (2012). Relationship of Dopamine Type 2 Receptor Binding Potential With Fasting Neuroendocrine Hormones and Insulin Sensitivity in Human Obesity Diabetes Care, 35 (5), 1105-1111 DOI: 10.2337/dc11-2250

Photo from

Unrelated to all that, 1/28 edition

When your job is picking up starfish and throwing them as far as they can go, well, your job is pretty good.  A great writeup of Bob Paine and the influence he has had in ecology; few biographical sketches can make you want to go out and read a bunch of scientific papers, but this one did.

John Hawks is now okay with the Dunbar Number.  Or at least the scale of it.

Crowds are not people, my friend.  But they could be if they wanted.

Seed an ecosystem in a bottle then seal it up and let it grow for 53 years.  On the other hand, this is the Daily Mail so it could all be made up.

Dung beetles watch the milky way.  This just furthers my fascination with all things dung beetle.

NPR reports on camel wrestling.  Let me repeat that: Camel Wrestling!

I shall call thee, scorpomouse!

Even the poisonous scorpion cannot escape the savage monster’s little pink paws. It fights bravely, stinging its attacker on the nose. To no avail. The mouse ignores the painful venom and cruelly breaks the scorpion’s tail by pummelling it into the ground, then bites its head and feasts on its flesh. Throwing its head back, the murderous animal howls at the moon.

The majestic Southern Grasshopper mouse!  There are many interesting popular press articles on these guys but very little scientific research.  There are videos on youtube, although they are pretty uniformly terrible but you can watch them howl to signal their territory, fight scorpions and tarantulas, or just learn a bit about their life (with terrible narration).  I’d say these guys would make an awesome model organism for science, but for what exactly I’m not sure.

A mechanics of depression

There are many reactions that can be taken in response to the world going crazy on you, and depression is one of these.  Even though it is (rightly) seen as perhaps not the greatest illness to have, there is a case to be made that depression is an energetically-efficient response to overwhelming stress; it can be better to shrink back and conserve your energy than fight it.  Think about it like this: you probably know some people who are super laid back, who take things as they come and don’t seem to stress out.  And you also probably know some people who freak out at stress, work really hard, and just seem to be stressed out all the time.  These are two different strategies for dealing with stress and one seems more likely to lead into depression.  At the same time that same strategy seems like the person is fighting harder to get out of the stressful situation.  How does the brain do something like that?

It is thanks to tools from the lab of Karl Deisseroth that we are finally able to begin to really, mechanistically, understand what is going on in the brain.  And fortunately, Deisseroth is both a research scientist and a psychiatrist who is interested in helping people with mental diseases.  There are three (!) papers published in Nature over the last month with his name on them, and they shed a lot of light on the mechanisms that are at work.

No one is really sure what it is about the brain that causes depression, although we have some hints: antidepressant drugs tend to work by modifying the release of the neuromodulators serotonin and dopamine (and norepinephrin).  We also know that an area called the prefrontal cortex (PFC) is highly linked to all sorts of psychiatric disorders; the PFC is an area that receives inputs from all over the place and then sends outputs right back out.  He’s the boss, the one that hears everything people have to say and then directs other areas in order to coordinate the brain to accomplish internal goals.  You can imagine what might happen if you have a bad boss: your brain is out of sync, things don’t get coordinated properly and then BAM, schizophrenia and depression.

As you might imagine, these things are all interconnected in the brain: the PFC talks to the serotonin and dopamine areas, and the serotonin and dopamine areas talk to the PFC.  And these connections are particularly important.  Take the connection between the PFC and an area that releases serotonin, the dorsal raphe nucleus (DRN).  This connection is required to motivate an animal to avoid escapable stress.  A mouse that is in a position to escape from stress will clearly do so.  However, if you inactivate the PFC the mouse will not escape from stress and its release of serotonin will look the same as if it were in a stressful situation it can’t escape from.  If you disable the PFC in a stressful situation that it can’t escape from?  No change: the PFC seems to control motivated behavior from escapable situations only, and without it you can’t.

That’s exactly what one of the recent Deisseroth papers examined.  They were able to directly activate only the PFC neurons that send information to the DRN and by doing so they found a way to escape from a learned kind of helplessness.  Rats that are stuck in a cup of water will struggle for a while, attempting to escape.  After a while they learn that struggling isn’t getting them anywhere and they just kind of give up.  But if you activate the PFC connections to the DRN?  The rats launch back into the struggle again!  But this doesn’t happen if you just activate all the neurons of the PFC or all the neurons of the DRN: there is a specific pathway through both of these brain regions that motivates an escape from helplessness.

Release of dopamine can help motivate escape from a helpless condition as well, although it is released from a different part of the brain.  The ventral tegmental area (VTA) is one of the main release sites of dopamine in the brain and is the signal of ‘pleasure’ in the brain, although it is perhaps more accurate to say that it is the primary signal of motivation.  And if you stimulate the neurons in the VTA you get an increase in motivation to escape a depressing circumstance, just as you’d expect from that area.  And specifically, this is because of a release of dopamine from the VTA to another area of the brain, the nucleus accumbens (NAcc).  What is likely to be happening is that the VTA is sending a motivating signal to an action and learning center of the brain (the NAcc), and that center of the brain helps decide what to do next, and what to do next is to get the heck out of there.  Something exciting happens here: if you now go and record the neurons in the NAcc after additional dopamine is released from the VTA, they now respond to different things.  The whole way that an action is represented in the brain changes, and in a way that emphasizes escape.

But this ability to learn escape can have a negative side.  Take the example of another method of stressing out mice, chronic social defeat.  What you do here is force mice to get defeated in battle again and again.  Yes, this is actually a commonly studied behavior; these poor guys are basically given PTSD.  But it turns out that some mice are resilient to this stress, they can withstand it and not get depressed.  If you look at the neurons in the VTA, the susceptible animals show an increased amount of bursts of activity (technically: phasic firing) during stress while the resilient animals just hummed along with no change of activity in the VTA at all!  This natural increase in firing can be simulated in the resilient animals by artificially increasing VTA firing.  Then, when you test whether they have acquired PTSD?  Well, it turns out that they have.  This makes a certain kind of sense: dopamine reinforces behavior, so susceptible animals are seeing more dopamine and hence more reinforcing of defeat than are the resilient animals.  Again, though, different internal pathways have different effects in the brain: if you activate the neurons that send information to the ‘pleasure center’, the nucleus accumbens then you are more vulnerable to stress.  And if you inhibit the activity of neurons that send information to the PFC, then you also become more vulnerable to stress.

The same sets of neurons that can help you escape stress (the VTA to NAcc connection) are the ones that will cause you to be more depressed in the future.  This suggests that there might be a tradeoff in life: you can be stressed out but really motivated to escape stress, or you can put up with a whole bunch of stress and be laid back about it in the future.  But it seems like it might be hard to be both.  There are of course in-betweens: the PFC, the boss, has specific circuits dedicated to telling the VTA and the DRN what to do, and can tell them to do opposite things.  And of course, the more you try to escape stress and fail, the more you learn it is futile to escape stress, triggering a terrible feedback cycle.  But if you want to be learning, you better be trying.


Chaudhury, D., Walsh, J., Friedman, A., Juarez, B., Ku, S., Koo, J., Ferguson, D., Tsai, H., Pomeranz, L., Christoffel, D., Nectow, A., Ekstrand, M., Domingos, A., Mazei-Robison, M., Mouzon, E., Lobo, M., Neve, R., Friedman, J., Russo, S., Deisseroth, K., Nestler, E., & Han, M. (2012). Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons Nature, 493 (7433), 532-536 DOI: 10.1038/nature11713
Tye, K., Mirzabekov, J., Warden, M., Ferenczi, E., Tsai, H., Finkelstein, J., Kim, S., Adhikari, A., Thompson, K., Andalman, A., Gunaydin, L., Witten, I., & Deisseroth, K. (2012). Dopamine neurons modulate neural encoding and expression of depression-related behaviour Nature, 493 (7433), 537-541 DOI: 10.1038/nature11740
Warden, M., Selimbeyoglu, A., Mirzabekov, J., Lo, M., Thompson, K., Kim, S., Adhikari, A., Tye, K., Frank, L., & Deisseroth, K. (2012). A prefrontal cortex–brainstem neuronal projection that controls response to behavioural challenge Nature DOI: 10.1038/nature11617
Amat, J., Baratta, M., Paul, E., Bland, S., Watkins, L., & Maier, S. (2005). Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus Nature Neuroscience, 8 (3), 365-371 DOI: 10.1038/nn1399

Photo from

Oops! Late as always

I couldn’t get my act together to finish a paper write-up early in the week – holidays and then busy in lab, plus it’s about 4 papers (!) instead of the normal 1 – so enjoy these anecdotes from Information Processing:

WSJ: … When the great California Institute of Technology geneticist Seymour Benzer set out in the mid-1960s to find mutations in fruit flies that affected behavior, rather than mere anatomy, he was ridiculed for challenging the consensus that all behavior must be learned.

Benzer told the geneticist Max Delbrück about the plan to find behavioral mutants; Delbrück said it was impossible. To which Benzer replied: “But, Max, we found the gene, we’ve already done it!” (Benzer’s mother was more succinct: “From this, you can make a living?”) He was soon able to identify mutations related to hyperexcitability, learning, homosexuality and unusual circadian rhythms, like his own: Benzer was almost wholly nocturnal.

Since then, thanks to studies of human twins and a rash of genetic investigations in animals, it has become routinely accepted that most things, including personality, sexual orientation and intelligence, are to some degree affected by genes. The University of Virginia’s Eric Turkheimer has declared what he calls the “first law of behavior genetics”: that all human behavioral traits are heritable.

He’s got a lot of good stuff there, read it all!



Big is beautiful

Nervous systems are simple things to hack.


Unrelated to all that (January 16th edition)

Wait, there’s a paper with ‘neuroecology’ in the title?  I’m sold! Well a review of a paper, really, but they did it better and more thoroughly than I could.

That’s…that’s a lot of dopamine and depression.  Scicurious has a series of articles on the link between dopamine and depression.

See schizophrenia isn’t all that bad, you should be thankful really.  And really, the culture that you live in shapes your schizophrenia.

See, being a psychopath isn’t all that bad, you should be thankful really.  This is more evidence for the importance of ‘neurodiversity’.

Maybe if they were psychopaths they just wouldn’t want more friends.  On the Dunbar number, and why we can only have so many friends.

The in-between of nature and nurture

There’s a debate that never seems to die down, and it’s one of nature versus nurture.  It’s a bit of a silly debate because the answer in every debate is (almost) always “both”, but it does seem to get a lot of play.  And it’s even sillier when you realize that one can ask the question about any behavior in our life, and we already know the answer.  Take, for example, what type of food you like.  There are certain foods that, innately, everyone likes, things that are required for survival: I imagine these are things like bacon and butter and otter pops.  But other foods, foods that are not as full of fat and grease and sugar, these things take some acclimation: brussel sprouts and pigs feet and rocky mountain oysters.  There’s always a genetic underpinning – for instance, there is a specific genetic mutation that determines whether we can taste certain bitter flavors – whose behavioral expression gets modified through the environment.  The question is though: when we learn to like these foods, what exactly are we learning?

To understand how this type of learning works, we can turn to the hawkmoth Manduca sexta.  As caterpillars they feed on tobacco and tomato plants, but when they become adult moths they flap about in the dark, feeding on the nectar from night-blooming flowers.  These plants exist in a symbiotic relationship with the hawkmoths – without the moths, the flowers would have trouble getting pollinated.  Perhaps that is why the flowers that the hawkmoths prefer to visit all release a very similar chemical bouquet; other flowers, even genetically related flowers, have different scents, and these flowers do not get pollinated by the hawkmoths.

Now if  you go in and stick an electrode into the antennal lobe, the area where odors are first received by the hawkmoth, what do you see?  Recording from the projection neurons, the neurons most responsible for sending this odor information back to other parts of the hawkmoth brain, you will see what appear to be two different types of responses.  The hawkmoth odor neurons will respond to the attractive odors – the odors that were taken from flowers that the hawkmoths prefer to pollinate – and these responses all look pretty similar.  They are sudden, strong neuronal responses.  But if you now spray the hawkmoth with odors that aren’t particularly attractive, you get much weaker responses that look very little like the responses to attractive odors.

There’s the nature part of your story: there are some odors that even a naive, laboratory-raised hawkmoth will love, and others that it won’t care about.  But that’s clearly not the end of the story.  Just like humans can take that first sip of beer and spit it out because it’s disgusting only to find themselves savoring a good porter years later, hawkmoths can learn that a new, unknown odor might signal something delicious.  And it’s quick: with just three tastes of an odor paired with some nectar, the hawkmoths learn to like the odor.  It’s not just anywhere that the moths learn to like the odor, either.  It could be that the odor becomes more attractive somewhere deep in the brain, where reward neurons respond when they see the responses corresponding to this specific odor.  What actually happens is that it is the olfactory projection neurons themselves that change how they respond, to look like the responses to other attractive odors.  Even though there are odors that are genetically programmed to be attractive to the hawkmoth, interaction with the environment can directly modify how an odor is sensed to make it more or less attractive: nature, and nurture.

Screen shot 2013-01-14 at 10.29.16 AM


Riffell, J., Lei, H., Abrell, L., & Hildebrand, J. (2012). Neural Basis of a Pollinator’s Buffet: Olfactory Specialization and Learning in Manduca sexta Science, 339 (6116), 200-204 DOI: 10.1126/science.1225483
Photo from…I realize this is a different species of Hawkmoth, but work with me here!  There’s only so many decent pictures of Hawkmoths under the Creative Commons license at flickr.