Happy New Year!

Wordless Wednesday – Japanese Set Meal

Tokyo Sea Life Park: Colourful Sea Creatures

The main attraction at Tokyo Sea Life Park is the gigantic tuna tank that I have posted some time ago. However, the other colourful sea creatures are not less attractive.

Serotonin! What Is It Good For?

Absolutely nothing...? Not quite, but it may be good for a lot less than anyone thought. At least according to a recent paper in PLoS One describing what happens to mice given genetic knockout which left them almost completely unable to produce the neurotransmitter serotonin (5HT).

The mice lacked either one, or both, of two genes called TPH1 and TPH2, which code for two related enzymes called tryptophan hydroxylase-1 and tryptophan hydroxylase-2. These are necessary for the production of serotonin from the amino acid tryptophan (which you get from eating turkey... and also most other foods). No tryptophan hydroxylase, no serotonin.

Tryptophan hydroxylase-1 is mostly responsible for making serotonin outside the brain, while tryptophan hydroxylase-2 predominates in neurones. So the mice lacking both enzymes ("double knockouts") should have had no serotonin at all, anywhere. In fact, chemical analysis revealed a small amount present in the brains, but it was >99% less than normal, and even this may have been some kind of contaminant rather than serotonin:

Reduction of 5-HT in TPH2KO mice ranged from 67.5% (cerebellum) to 96.9% (striatum), while 5-HT reduction in DKO mice ["double knockouts" who lacked both TPH1 and TPH2] ranged from 94.4% (cerebellum) to 99.2% (cortex). 5-HT levels were lower in DKO mice than in TPH2KO mice in all brain regions examined. The percentage of 5-HIAA reduction paralleled changes in 5-HT. No generalized changes were noted in other neurotransmitter levels.

So, what happened to these serotonin-less animals? The big story is - remarkably little. They were alive, for one thing. They weren't writhing in pain thinking "Every moment I live is agony!" like that mutant on The Simpsons. The double knockout mice were slightly smaller and leaner than usual (less body fat), but only by a few % points. Otherwise, they were normal on almost every measure. This is very surprising, given that serotonin is one of the oldest neurotransmitters in evolutionary terms. Even insects use serotonin as a transmitter. Even some single-celled organisms have serotonin. There are at least 14 different types of serotonin receptor in the mouse body (same for humans). What are they all doing? Nothing especially important, clearly.

The results dramatically indicate that 5-HT is not essential for overall development and that its role in behavior is modulatory rather than essential. Initial phenotypic analysis of these mutants revealed no differences in a range of measures of physical health including assays for cardiac, immune system, endocrine, and ophthalmic function (unpublished observations).

However, that's not the end of the story. The mice were also tested in a battery of standard behavioural tests used to measure anxiety levels and such like; these are commonly used to measure the effects of antidepressants and other such drugs in rodents. Given that antidepressants such as Prozac are supposed to work by increasing serotonin levels in the brain, you'd expect that mice with no serotonin would be "depressed".

The TPH1 knockout animals showed no differences at all - no surprise since, as you'll recall, they only lacked serotonin outside the brain e.g. in the intestines, where it seems to play a role in digestion - although presumably not a vital one. So, no surprise there. The TPH2 knockouts, and the TPH1/TPH2 double knockouts were remarkably normal too, showing no differences on most of the behavioural tests

For the TPH2KO and DKO, there were no differences between the KO or DKO and WT littermate control mice in motor coordination, acoustic startle response and sensorimotor gating, tonic inflammatory pain sensitivity, and learning and memory as assessed in inverted screen, pre-pulse inhibition, formalin paw, and trace fear conditioning assays, respectively

But they did show differences in the marble burying test, the forced swim test, and the tail suspension test. The double-knockouts generally showed the most profound effects. But here's the twist - far from being "depressed", the knockout mice were less "depressed" on the forced swim test (i.e. the genetic knockout had the same effect to that seen with antidepressants.) That is, they showed more struggling and less immobility. This is the exact opposite of what you might have expected.

On the other hand, the knockouts showed increased immobility on the tail suspension test, which is generally taken to be a depressive behaviour, and they buried more marbles in the marble burying test, which is opposite to the effects of Prozac. It's not clear what if anything burying more marbles means; some have suggested that the frantically burying mice are showing OCD-like symptoms. Hmm.

So, what these results show is that a) mice can live almost normal lives without serotonin, or at best with trace amounts, and b) the main effects of having no serotonin are upon "depression-like" behaviours, but whether the knockouts are more or less depressed is unclear (the authors push the idea that they're more depressed, but really it's impossible to say.) Still, this is a bit more evidence that the serotonin hypothesis of depression isn't quite dead.

To my mind, though, the most interesting result by far is that serotonin is so dispensible. Mice can live essentially normal lives without it, which is not true for most other neurotransmitters. Bear in mind, though, that just because serotonin is not necessary for normal functioning doesn't mean that if you do have serotonin, it isn't doing anything. It might be that in the knockout mice, other systems had taken over the roles normally played by serotonin.

Finally, this study was run by Lexicon Pharmaceuticals, who use genetic knockout technology to discover new drugs. They end by saying...

Our results strongly support targeting the 5-HT system to treat affective disorders and the use of knockout mice as a tool to tease apart mechanisms involved in the etiology of these disorders.

Take that as you will.

Katerina V. Savelieva, Shulei Zhao, Vladimir M. Pogorelov, Indrani Rajan, Qi Yang, Emily Cullinan, Thomas H. Lanthorn (2008). Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants PLoS ONE, 3 (10) DOI: 10.1371/journal.pone.0003301

Seven Things You Didn't Know About Milgram

There's been a lot written about psychology professor Jerry Burger's recent replication of the famous "obedience" experiments first carried out by Stanley Milgram in the early 1960s. Here's Burger's paper in which he reports that obedience rates are almost the same today as they were nearly 50 years ago.

Wikipedia's page on this experiment has an excellent summary of the methodology and results of the original study if you're not familiar with it.

It's a testament to the importance of the original obedience experiment that many who know nothing else about psychology have at least heard of it, and it's common knowledge that Milgram found that a startlingly high proportion of ordinary volunteers were willing to administer very strong "shocks" to an innocent victim, on the orders of the experimenter. But there's much more to the "Milgram Experiment" than many people realize. So - read on. That's an order.

1. There wasn't just one experiment In 1974, Milgram discussed the results and implications of his research in a book, Obedience to Authority: An Experimental View. (The cover is rather amusing). In it he describes no fewer than 19 different experiments, not including pilot studies. Most of the studies included 40 participants, although some of the later ones used 20. The basic nature of the experimental situation was the same in each case, but important factors were varied between expriments, offering some insight into the conditions which drive obedience (see below). All of this work was performed at or near Yale between 1960 and 1963. Milgram also refers to later replication studies carried out in"Princeton, Munich, Rome, South Africa and Australia" where "the level of obedience was invariably somewhat higher than that found [in the Yale studies]". So, whatever was going on in the Milgram experiments, it wasn't unique to the USA, and the fact that Jerry Burger has just obtained very similar results shows that it wasn't unique to the 1960s either (although, to look at it the other way, the USA today is not especially conformist.)
2. Subjects were paid $4 each Milgram's book is full of details such as this, including plenty of photos and drawings illustrating what happened. The picture here shows the designated "victim" in most of the experiments - James McDonough, "a 47-year old accountant, trained for the role; he was of Irish-American descent and most observers found him mild-mannered and affable". This is the face that launched a thousand shocks - seeing it, for me, brought home the results of the obedience studies very starkly. How could anyone shock that guy? Another important detail is that rather than recruiting undergraduate students, as most psychology experiments do, Milgram placed adverts in local newspapers and, when that only got a few hundred volunteers, resorted to cold-calling names in the New Haven telephone directory. This meant that the participants were (as far as possible) representative of the normal population - a crucial point.
   
3. Milgram was an Evolutionary Psychologist Well, sort of. He was into Evolutionary Psychology before it became a buzzphrase - indeed, before the term had been coined. In his book, Milgram notes that "the formation of hierarchically organised groupings lends enormous advantage to those so organized in coping with dangers of the physical environment, threats posed by competing species, and potential disruption from within." In other words, an animal which has the ability to submit to authority when necessary might be more likely to survive than one which was stubbornly individualistic. He goes on to theorize that humans have evolved a psychological mechanism for obedience, which he calls the "Agentic State", a special state of mind in which our normal moral inhibitions are bypassed and we become an agent of an authority. I'm not sure many people would buy this as a good explanation, and it isn't clear if Milgram's evolutionary logic relies on Group Selection theory, but it's certainly interesting.
   
4. It was stressful Most of the subjects were acutely distressed during the procedure - hardly surprising given the screams and protests of their "victim". Some subjects shook with tension; one started laughing whenever they had to give a shock. Yet most of them continued to give the shocks despite being tangibly upset about it. They didn't want to hurt the "victim" - but they did. This inner conflict suffered by the subjects comes across vividly in Milgram's writing, and it led to some fascinating behaviour. In Experiment 7, in which the "experimenter" giving orders left the room and spoke to the subjects by telephone, many subjects continued to give shocks but gave much milder shocks than they were supposed to. In other words, they were unwilling to hurt the victim but also unwilling to openly disobey (although in this case, 80% of subjects eventually did). Most people also seemed to try to keep the shocks as short as possible, and tried to minimize the number of punishments by helping the victim to give the right answers. Milgram argued that this ruled out the view that his experiment showed people to be "aggressive" or "sadistic" - rather, people were naturally averse to causing harm, but the situation they found themselves in led them to do so anyway. As he put it "The social psychology of this century reveals a major lesson: often it is not so much the kind of person a man as the kind of situation in which he finds himself that determines how he will act."
   
5. There was follow-up Milgram's sometimes accused of being a cavalier or even callous researcher who exposed his volunteers to emotional harm. In fact although, as the cliche goes, Milgram's studies would never pass an ethics committee today, he seems (at least on his own account) to have gone to great effort to ensure that his participants were not traumatized and to record how they felt about the experiment. Immediately after the experiment was finished the subjects were "debriefed" and told what had really happened; if they had been obedient, they were reassured that this was normal behaviour (true, of course). Then, a few weeks later, they were sent a write-up of the results of the research and an explanation of the rationale. A questionairre asked how they felt about the study overall; 43% said they were very glad to have done it, 40% said they were glad, and just 1.3% were sorry or very sorry to have done it; there was little difference between those who obeyed and those who didn't. Commenting on the fact that people seemed remarkably relaxed about what they had done, in retrospect, Milgram wryly noted "The same mechanisms that allow the subject to perform the act...continue to justify his behaviour for him".
   
6. Not everyone obeyed You probably already know this, but you think of it as less exciting than the fact that most people did. In the best known version of the experiment (Experiment 5), 35% of people refused to administer the highest shock level, and some of those came close to it. In other experimental set-ups, obedience rates were different - when the study was carried out in a run-down city apartment, rather than in the presitgous surroundings of Yale, obedience rates dropped (but were still 47.5%). When the subjects did not have to administer the shocks themselves but simply sit by and take notes while someone else did, almost everyone complied (92.5%). Yet there were no clear explanations for why some individuals obeyed and some did not. Some people were chillingly obedient, others were boldly defiant, but it's not clear why. Age, religion (Catholic vs. Protestant), and political affiliation did not seem to matter. Most of the studies used male volunteers only, for some reason, but Experiment 8 used women; compared to Experiment 5 the results were pretty much identical. In the early experiments there were some indications that better educated and higher-status men were more defiant, but this did not seem to hold for all of the studies.
   
7. This actually happened Again, you already knew this, but it's worth taking a moment to remember it. This really happened and it's been replicated ad nauseum; so far as I can see, no-one has succesfully criticized the basic assumptions of the paradigm (although if anyone has please let me know.) Milgram's faith in humanity seems to have been shaken by his research - his book contains case studies of individual participants which are are cynical to the point of misanthropy, even down to the level of the physical appearance and personality of the participants ("Mr Batta is a 37-year old welder...he has a rough-hewn face that conveys a conspicuous lack of alertness. His overall appearance is somewhat brutish...[during the experiment] what is remarkable is his total indifference to the learner; he hardly takes cognizance of him as a human being...the scene is brutal and depressing...at the end of the session he tells the experimenter how honored he has been to help him.") The subjects who disobeyed authority get a slightly better treatment, but not much better. Yet who can blame Milgram for this? It's worth bearing in mind also that Milgram was Jewish. His text is full of references to Nazi Germany, Hannah Arendt, the Vietnam War and the Mai Lai massacre. The hero of the book, if there is one, seems to be the young man who took part in the experiment and, as a result, decided to apply for Conscientous Objector status to avoid being sent to Vietnam. He got it.
   

Links: Dr Thomas Blass's StanleyMilgram.com - excellent.
Dr Blass's review paper on the Milgram paradigm.

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Encephalon #61 is up

The 61st edition of neuroscience/psychology-based blog carnival, Encephalon, is up at Sharpbrains. I'm in it, twice, but don't let that stop you - the rest of it is pretty good...

Merry Christmas

I went down to downtown Kuala Lumpur when I was experiencing the flight cancellation and delay into Brisbane. I headed to the latest shopping establishment at Jalan Bukit Bintang, the Pavilion, and the Christmas decoration was already up and glowing.

Merry Christmas!

Wordless Wednesday – Vibrant Samba Girls

Location: Asakusa, Tokyo, Japan
Event: 28^th Asakusa Samba Carnival
Date taken: August 30^th, 2008
Camera equipment: Nikon D70s + Micro-Nikkor 105mm f/2.8D