What is up with the "Dopamine Project"?

Someone is trying to make me eat my words.

yum. (source)

That someone is the Dopamine Project. I am on record as saying "It is better for the public to learn simplified bite-size science morsels than to learn nothing at all." And my specific example was that it's better for people to know that 'dopamine is a reward molecule' than to not even know the term dopamine.

But sometimes things just go too far. The "Dopamine Project" is a website run by Charles Lyell with a stated 'self-help' purpose:

"The Dopamine Project was founded to foster positive change by encouraging open-minded individuals to share readily available research into the connections between dopamine and a growing list of addictive behaviors." -About Tab

Doesn't sound too terrible, right? Share research about dopamine? sign me up! .... However, I don't see ANY research, or even references to research, on this website. In fact it's quite wootastic. Going through the posts, you get some gems like

"A Message from you Dopamine Angel"

and

"Keeping a Dopamine Diary: Wrestling with Dopamine-Induced Ignorance"

It's all about how 'good dopamine' makes you want things you should want (food) and 'bad dopamine' makes you want things that will hurt you later (addictive drugs for example). Basically the website's message is a self-help, self-control one with the word dopamine sprinkled all over it.

The worst part is that not only does the website not include a single citation to a research paper, it actively rails against science.

"The future depends on how long it takes scientists to discover what they haven’t been interested in discovering so far. Rather than wait for the mainstream scientists and media to get started, we’re reaching out to anyone interested in fostering positive change by raising dopamine awareness." -Welcome to the Dopamine Project

Trust me, scientists want to understand dopamine. At the IBAGS conference half the talks related to dopamine, and there is a conference completely devoted to dopamine coming up in May. The specific action of dopamine is really really complex, and scientists are working really really hard to unravel its intricacies. This Charles Lyell guy is pulling out a typical woo card, implying that he knows what scientists don't want you to know.

"If the thought of fostering positive change through dopamine awareness triggers a shot of dopamine that brings a smile to your face, this might be your chance to be among the top .001% who go on record as the first to understand and apply what we know about dopamine to make a difference."  -Welcome to the Dopamine Project

 He also seems to feel personally attacked by Steven Poole's New Statesman article on Neurobollocks.

Is the 'Dopamine Project' ridiculous and unscientific? Absolutely.

Is it harmful and dangerous to people? ... Honestly, I'm not sure. Reading it certainly makes me want to throw up, but there are worse things for pseudoscience to encourage than self-control. I'm not sure if I should devour my earlier words quite yet.

© TheCellularScale

To read more on the confusing line between science and pseudoscience, see Michael Shermer's Scientific American article:



Shermer M (2011). What is pseudoscience? Scientific American, 305 (3) PMID: 21870452

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Is it 'Important' or is it 'valuable'?

We've recently discussed dopamine as a reward prediction signal. But that is really just the start of the complicated dopamine story.

Dopamine's role in reward and punishment (by the hiking artist)

Some research groups have also found that dopamine neurons respond to aversive stimuli, like an air puff to the face or an electric shock. This finding seems to be be completely incompatible with the idea that dopamine is a signal for reward.

Luckily some scientists took the time to try to resolve this discrepancy. Bromberg-Martin, Matsumoto, and Hikosaka (2010) have written an excellent review paper explaining that some dopamine neurons do code for value (reward), but other dopamine neurons code for salience (importance).

Differential Dopamine Coding (Bromberg-Martin et al., 2010 Fig 4)

When researchers are recording from a value coding dopamine neuron, it looks like the neuron responds to reward and actually reduces its response to the air puff. This makes sense as a 'dopamine = good' signal.

However, when a researcher is recording from a salience coding dopamine neuron, it looks like the neuron is responding equally to the good thing (reward) and the bad thing (air puff). This is confusing if you think 'dopamine = good', but makes sense if you think 'dopamine = important'. When the cue comes on (a light or a tone that signifies a reward is coming next or an air puff is coming next), these dopamine neurons fire if that cue means something.


Instead of just being confused about why sometimes dopamine would code for value and sometimes it would code for salience, Hikosaka's group showed that these two types of neurons are actually separate populations, and even seem separated in space.

(Bromberg-Martin et al., 2010 Fig 7B)

The value dopamine neurons are more ventral in the (monkey) brain, while the salience dopamine neurons are more dorsal-lateral. Importantly these two populations of neurons go to slightly different parts of the striatum and receive signals from different parts of the brain. The review paper suggests that the salience coding neurons receive their input from the central nucleus of the amygdala, while the value coding neurons receive their input from the lateral habenula-RMTg pathway.

The important thing here is that dopamine does not do just one thing to the brain. It doesn't just tell the rest of the brain 'yay, you won!' or 'you want that' etc... It says different things depending on different specific conditions. 

Dopamine doesn't 'mean' anything, the cell it comes from and the cell it goes to are what determine what it does. It certainly can't be classified as the 'love molecule'

 © TheCellularScale



Bromberg-Martin ES, Matsumoto M, & Hikosaka O (2010). Dopamine in motivational control: rewarding, aversive, and alerting. Neuron, 68 (5), 815-34 PMID: 21144997

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Dopamine and Reward Prediction Error

I am back from the IBAGS conference and full of new information! I plan to blog about tons of amazing things over the next month or so, but today we'll start with some foundation building.

Dopamine nails (source)

The IBAGS (international basal ganglia society) meeting is all about the basal ganglia (which includes the striatum), and as you may know, dopamine is a super important molecule for the proper function of the striatum (it is the dopamine cells that die in Parkinson's Disease).

There were many fantastic talks during the IBAGS meeting and almost a third of them showed the exact same figure on one of their slides. So much so that everyone would start to laugh when someone showed it. And as you may have guessed, it is about dopamine. Here it is:

Schultz 1998 Figure 2

This figure is the basis for the belief that dopamine represents a 'reward prediction error'.  Let me explain. The scattered dots on the lower half of each panel represent action potentials from individual dopaminergic neurons. The x axis it time in seconds. The black columns above them are a histogram showing how much firing is going on at each point in time. When the black columns are tall, there was more dopamine neuron firing. You can see that the height of the black columns matches up with the density of the scattered dots below them.

During 'reward learning', an animal is trained to associate a stimulus (like a tone or a flash of light) with getting a reward (like a drop of water or juice). These three panels show how dopamine responds to this whole process. The first panel shows that when there is no stimulus (CS) and the reward is a surprise, the dopamine neurons respond very strongly to it. The second panel shows that when there is a stimulus that tells the animal that a reward is soon to come, the dopamine neurons respond to the stimulus, but not to the reward. Finally the third panel shows that when there is a stimulus the dopamine neurons respond to it, but if the reward (R) never comes, the dopamine neurons actually stop firing when the reward should have happened.

What is so fascinating about this is that it shows dopamine neurons do not just fire in response to reward, they encode the actual reward with respect to the expected reward. In the author's words:

"Dopamine neurons report rewards relative to their prediction rather than signaling primary rewards unconditionally (Fig. 2). The dopamine response is positive (activation) when primary rewards occur without being predicted. The response is nil when rewards occur as predicted. The response is negative (depression) when predicted rewards are omitted. Thus dopamine neurons report primary rewards according to the difference between the occurrence and the prediction of reward, which can be termed an error in the prediction of reward..." Schultz 1998

This finding is so important to researchers now because it shows that dopamine neurons can encode learning rules. Dopamine neurons constantly and dynamically tell the rest of the brain which stimuli lead to reward, and which stimuli don't. The implications here for pathological learning are huge as well. Mis-signalling in dopamine neurons could lead to an inability to tell what is rewarding and what is not.

© TheCellularScale



Schultz W (1998). Predictive reward signal of dopamine neurons. Journal of neurophysiology, 80 (1), 1-27 PMID: 9658025

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Honoring a Legend

The Cellular Scale is at the International Basal Ganglia Society meeting this week (#IBAGS2013), and finally has internet!

Sunrise over the Gulf of Aqaba (I took this picture)

It's already been two days of conferencing, and I plan to mainly write some follow up posts when I get back. But I will just briefly mention the "Lifetime Member" lecture that was given on the first evening of the conference.

Mahlon Delong (source)

This year's lifetime member is Mahlon DeLong.
I've written before about deep brain stimulation (DBS) as a treatment for Parkinson's Disease, and DeLong has done some fascinating work that has lead up to DBS in the  subthalamic nucleus (STN).

One particular treat was to see a video during the talk of the very first attempt at alleviating Parkinson's symptoms through a subthalamotomy, the lesion of the subthalamic nucleus.

A Parkinson's Disease monkey was given the subthalamotomy on only one side of the brain and the video shows Mahlon DeLong interacting with the monkey and noting that it's treated side is less stiff than the untreated side. A second video shows the monkey later able to move its arm with no problems.

It was exciting to see this sort of 'moment of discovery' from 1989. There were no cries of "Eureka!" or anything it was more of a 'hm, interesting' tone. You actually hear his post-doc on the video saying
(paraphrasing from memory) "the right side has better tone, at least Mahlon thinks so" and then start laughing.

(source)

One other cool thing about Dr. DeLong is that he is Muhammad Ali's physician.

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Why scientists should play games

I have just finished reading Jane McGonigal's book Reality is Broken: Why games make us better and how they can change the world. It is a fascinating book which presents a strong case for games (including video games) doing good in the world.

Reality is Broken by Jane McGonigal

I have to admit, part of me wanted to read this book to make me feel better about my own video game habit. It certainly helped solidify the vague ideas I had about what good they might be doing me.

Specifically, the book made me think that scientists of all people might benefit greatly from playing games. There is one major reason why:

Games make you more resistant to failure

If there is one thing that scientists need to persist in their research its resilience in the face of failure. If you didn't know this already, just start following some 'life in academia' bloggers on twitter. Failure is a staple of scientific life.

Just yesterday I awoke to a small grant rejection. I started thinking about just how many things I had applied for during my (still new) scientific career, and just what proportion of those applications had resulted in rejections. I tallied it up on a chart (similar to a failure C.V.), and discovered that for about every 3.5 things I have applied for, only one was successful. This includes grant applications, travel fellowships, paper submissions and re-submissions, and miscellaneous things like applying to be an SfN Neuroblogger. (I did not include abstract submissions or applications to graduate school.) I actually think this is a relatively good ratio, and I expect this ratio to get worse in the future, because the competition for the things I am applying for will be even tougher.

Part of the reason I wanted to calculate my success/attempt ratio was to see how many things I had actually applied for. I was glad that the list was long, and that I applied for lots of things, even if it means that my 'ratio' is the worse for it. I would posit that having a good success/attempt ratio is not really that great if you only ever apply for a few things that are easy to get.

In science, you will fail; there is absolutely no scientist EVER who hasn't been rejected from something.

So back to games. Reality is Broken explains that games teach you to persist in the face of failure, and that games increase your optimism.

"Learning to stay urgently optimistic in the face of failure is an important emotional strength that we can learn in games and apply to our real lives. When we're energized by failure, we develop emotional stamina. And emotional stamina makes it possible for us to hang on longer, to do much harder work, and to tackle more complex challenges. We need this kind of optimism in order to thrive as human beings." -Reality is Broken, chapter 4

When I think of my own resistance to failure (which is decent, but could be better), I think of my time spent learning from games that failure is not the end of the world. Ever since I repeatedly failed to jump Mario over the first Goomba, video games were teaching me to try again, and again, and again.

Mario and Goomba level 1. (source)

Jane McGonigal brings up Tetris, one of the most popular video games of all time. Tetris is a game with no possible outcome except failure. You keep playing until you lose, and yet the game is immensely fun and ultimately rewarding. Each time you fail you want to try again, and you feel that you will probably do better next time.

In summary, games reward persistence and desensitize you to failure. When you play video games you learn implicitly that trying again is worth it and that failing isn't the end of the world. These skills are great to have in life and are essential to have in an academic career.

Reality is Broken lists 13 other ways that games 'fix' reality. Some of these fixes are about personal betterment (like persistence in the face of failure), but some of these fixes are about how games can ultimately change the larger reality. Games that combat global warming, for example, or games like Fold-It that actually further scientific progress and human knowledge. Whether you already play games or not, you can get something out of this book.

A nice addition to this book is the appendix "Practical advice for gamers" in which Jane McGonigal lays out some guidelines for getting the most out of games. For example, one rule is to never play more that 21 hours in a week. While video games have benefits, there are problems that can result from compulsive video game play, and you shouldn't think think that you are doing something healthy if you play video games for 50 hours a week and completely ignore reality. The idea is that playing games can help you function in reality. If you never venture into reality, you won't make any use of the benefits that the game might have given you.


© TheCellularScale

Here are further reviews of Reality is Broken:


Ferguson, C. (2011). Reality is broken, and the video game research field along with it. PsycCRITIQUES, 56 (48) DOI: 10.1037/a0026131
 
Farhangi, S. (2012). Reality is broken to be rebuilt: how a gamer’s mindset can show science educators new ways of contribution to science and world? Cultural Studies of Science Education, 7 (4), 1037-1044 DOI: 10.1007/s11422-012-9426-y

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How to Build a Neuron: Step 5

And now, the final step in how to build your computational model of a neuron: Add Synaptic Channels. All the steps in this series can be found here.

Synapses connect neurons (source)

So you already have a neuron, and you've added intrinsic channels to it. The next thing you want to do is add synaptic channels so you can hook this neuron up to other cells.

The main synaptic channels you want to add are the excitatory channels: NMDA and AMPA and the inhibitory channel GABA. These channels don't have the same kind of activation and inactivation curves and the intrinsic channels do because they aren't activated by voltage, they are activated by a neurotransmitter.

AMPA and NMDA receptors are activated primarily by glutamate, and cause an influx of sodium and calcium ions. Since both sodium and calcium ions are positively charged, this depolarizes the cell membrane and brings it closer to firing an action potential.

AMPA receptors (source)

GABA receptors, on the other hand are primarily activated by GABA, and cause and influx of chloride ions into the cell. Because chloride ions are negatively charged, this hyperpolarizes the cell membrane and brings it further away from firing an action potential.

So if you want to have a realistic model of a neuron, you need to add an approximation of these channels. This is easier than adding intrinsic channels, because it is an on/off style (binary) rather than an analogue activation. So basically you just put in the parameters you want like how fast does the channel open and close, how much current does it allow through when activated, and where are they on the neuron.

Of course deciding these parameters is not always easy. A paper out this year in PLoS Computational Biology describes 4 different ways the NMDA receptor can be configured and analyzes the consequences during different stimulation patterns. 

Evans et al., (2012) Figure 3

The 4 NMDA configurations (based on the 4 different GluN2 subunits) vary in their sensitivity to a magnesium block, how fast they decay, and their maximal current. Above are their responses to the same stimulation patterns (an STDP protocol). Even though they were all receiving the same input pattern, they each show a very different response.

So when considering adding synaptic channels to your model neuron, take the time to find out what the configuration of the receptors should actually be in the type of neuron you are building.


© TheCellularScale

If you are good at following clues, you will realize that I am very, very familiar with this paper.


Evans RC, Morera-Herreras T, Cui Y, Du K, Sheehan T, Kotaleski JH, Venance L, & Blackwell KT (2012). The effects of NMDA subunit composition on calcium influx and spike timing-dependent plasticity in striatal medium spiny neurons. PLoS computational biology, 8 (4) PMID: 22536151

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Does a high fat diet lead to a less 'rewarding' life?

Some interesting research out of the University of Pennsylvania suggests that a high fat diet can disrupt dopamine signalling.

This high-fat fed rat sure looks happy to me (source)

As I briefly discussed during my SfN Neuroblogging binge, a high fat diet can alter dopamine levels in the brain. To expand on this, we'll look at new research on how exactly this might happen and which specific areas of the brain are affected.  

Vucetic et. al. (2012) tested the levels of dopamine-related gene expression (via mRNA) in the hypothalamus and the ventral tegmental area (VTA). The hypothalamus is important because it controls your levels of hunger as well as many other things. The VTA is important because it is the main source of dopamine to the ventral striatum (AKA the Nucleus Accumbens). The VTA-nucleus accumbens pathway is generally thought to signify 'reward' when it is activated. Sex, Drugs, Music, and lots of other 'pleasurable' activities all activate this pathway. So alterations in the dopamine levels here might change how 'rewarded' a person (or mouse in this case) feels in response to pleasurable stimuli.

So Vucetic et al., (2012) found that in the VTA, the levels of tyrosine hydroxylase ("TH", an enzyme indicative of how much dopamine can be made) and dopamine active transporter ("DAT", which gets rid of excess dopamine at the synapse) are both reduced in the mice eating the high fat diet.

Vucetic et al. (2012) Figure 1

By contrast, in the hypothalamus, TH and DAT are both increased due to the high fat diet.

So what does this mean? The authors point out that increased dopamine in the hypothalamus actually promotes eating. Consistent with this idea, the authors show that mice eating the high fat diet actually ate more frequently and ate more total food. Secondly, when there is less dopamine in the VTA, it is likely that a rewarding stimuli will seem less rewarding. 

In the author's words:

"Collectively, these behaviors have the potential to promote obesity in two distinct ways: (i) through an increase in food intake and (ii) by increasing the drive for palatable food, as the animal with a blunted response to palatable foods may seek and/or consume these food relatively more than a normal animal in order to reach the same rewarding response. "

So basically the mice aren't obese because the food they are eating is high fat, they are obese because they are eating MORE food. But of course, they are eating more food because the high fat diet makes them 'want' to eat more food, so the high fat diet is indirectly causing the weight gain.

It is truly a vicious cycle.

 *Note: They also look at epigenetic effects on the TH and DAT promoter DNA. If you are interested in that aspect of the study, comment and I can do a follow-up post explaining it, or you can just read the study for yourself, following the link below. 

© TheCellularScale


Vucetic Z, Carlin JL, Totoki K, & Reyes TM (2012). Epigenetic dysregulation of the dopamine system in diet-induced obesity. Journal of neurochemistry, 120 (6), 891-8 PMID: 22220805

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Dopamine and GABA working together

Until recently, the neurotransmitters of the brain have thought to be generally separate. That is, if a neuron is inhibitory, it releases GABA, and if it is neuromodulatory, it releases something else, dopamine perhaps.  But two new papers show that specific neurons release both GABA and Dopamine. I briefly mention these new findings here.

Dopamine and GABA together forever (source)

First a subset of cells that were mainly thought to be GABAergic turn out to release dopamine as well. In 2010, Ibanez-Sandoval et al. found that there are interneurons in the striatum that stain positive for Tyrosine Hydroxylase. Tyrosine Hydroxylase is a precursor molecule needed for the creation of dopamine, and is a telltale sign of a neuron that can make and release dopamine. The authors found that these neurons release GABA and inhibit nearby cells. In this paper they did not confirm that the cells actually release dopamine, just that they have the machinery for it.

This is weird for a few reasons. 1. Why would the striatum need dopamine in its interneurons? The main source of dopamine to this brain region is the substantia nigra pars compacta, and it pretty well covers the entire striatum with dopamine when it wants to. 2. Why would a cell release dopamine and GABA at the same time?  

Second the canonical dopaminergic neurons of the substantia nigra turn out to release GABA as well. In 2012, Tritsch et al., found that when stimulated with light, the dopaminergic neurons of the substantia nigra cause inhibitory responses in the cells in the striatum.

The authors did extensive control experiments to make sure that they were indeed seeing GABA release from dopaminergic axons. They used carbon fiber amperometry to measure dopamine, and confirmed that dopamine was being released, and they blocked GABA receptors to make sure that it was GABA that was causing the inhibitory response. Finally they tested whether these cells were directly releasing GABA or perhaps stimulating other cells that released GABA. They did this by adding TTX, a sodium channel blocker, to prevent action potentials. In this condition, they could still evoke neurotransmitter release by light-based activation of these axons, confirming that these neurons directly release both dopamine and GABA.

So what's with this mash up?

Within two years it's been shown that GABA cells might release dopamine and dopamine cells do release GABA. Why? Neither paper speculates much on why GABA and dopamine might be co-released, or what the consequences of such a partnership might be.

© TheCellularScale


Ibáñez-Sandoval O, Tecuapetla F, Unal B, Shah F, Koós T, & Tepper JM (2010). Electrophysiological and morphological characteristics and synaptic connectivity of tyrosine hydroxylase-expressing neurons in adult mouse striatum. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30 (20), 6999-7016 PMID: 20484642

Tritsch NX, Ding JB, & Sabatini BL (2012). Dopaminergic neurons inhibit striatal output through non-canonical release of GABA. Nature, 490 (7419), 262-6 PMID: 23034651

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Can you turn a rat gay?

What does it take to 'turn a rat gay'? This question may have crossed your mind, but a group in Mexico actually did the experiments to test it.

A weak first attempt (source)

Triana-Del Rio et al., 2011 used a co-habitation conditioning paradigm to see if they could condition a male rat to prefer a male partner.
The basic paradigm was to house the 'experimental rat' to the 'stimulus rat' (who was scented with almond) for a full day every 4 days. Under these conditions, the experimental rat did not show any preference for the almond-scented stimulus rat later on.  However, if the experimental rat was injected with quinpirole, which stimulates dopamine D2 receptors, he did develop a preference for the almond-scented rat. This preference was not sexual in nature. Preference was measured by time spent together, and these guys just wanted to hang out.

Triana-Del Rio et al., 2011 (figure 1)

The authors then did a separate experiment where instead of using 'sexually naive' rats as the stimulus rats, they used 'sexually expert' rats.  They created these Cassanovas by riling them up with very 'receptive' female rats at least 10 separate times. They refer to this as 'sexual training.' When the sexually expert rats were used as stimulus rats, the experimental rats developed a sexual preference when injected with quinpirole. These experimental rats strongly preferred their almond-scented partners as measured by time spent together, mounting, and 'genital investigation.'

So what does this mean? First of all, even the most drastic change was not permanent, partner preference dissipated after 45 days. And as I mentioned in my SfN summary, this protocol did not have the same effect in female rats. I do not think that the researchers here 'turned a rat gay.' While they did succeed in biasing the preference of the experimental rat for the guy he was housed with, they certainly didn't change the rats sexual preference in a deep or universal way. There is no evidence that the experimental rat preferred males in general over females, just that he really likes the one guy he was hanging out with.

So this study does not really tell us anything about the biological basis of homosexuality, and it certainly does not tell us how to make a gay bomb. The most interesting implication for this study is in the activity of the D2 dopamine receptor, which may be involved in pair-bonding. I would be interested to see what some ex vivo cellular studies revealed about this treatment. Does quinpirole application cause a change in the number or location of the D2 dopamine receptors or the activity of the neuron?


© TheCellularScale


Triana-Del Rio R, Montero-Domínguez F, Cibrian-Llanderal T, Tecamachaltzi-Silvaran MB, Garcia LI, Manzo J, Hernandez ME, & Coria-Avila GA (2011). Same-sex cohabitation under the effects of quinpirole induces a conditioned socio-sexual partner preference in males, but not in female rats. Pharmacology, biochemistry, and behavior, 99 (4), 604-13 PMID: 21704064
 

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SfN Neuroblogging 2012: ketamine in neurogenesis and dopamine in obesity

SfN day 3, exhaustion setting in, but the science doesn't quit! Here are some highlights:

ketamine for depression? (source) 

1. Ketamine and the neurogenesis theory of depression. At a nice poster (324.28) R.M. Carter explained that ketamine has fast anti-depressant effects. Some people think that depression is caused by neurodegeneration and cured by neurogenesis (the growth of new neurons). So this group wanted to test whether ketamine could affect the growth of new neurons on the same timescale that ketamine affects depression (a few hours). And it does! Ketamine increased the rate that newly generated neurons in the dentate gyrus became synaptically mature. It will be interesting to see where this theory of depression goes. I would love to see a possible mechanism of action by which an NMDA antagonist could speed up neuron maturity. (Intuitively I would guess it would do the opposite.)

UPDATE 11/5/12: More on mechanisms of ketamine in synaptogenesis.

2. Fat and dopamine. In a nanosymposium (420.06) J. Carlin explained that rats fed a high fat diet from birth had lower dopamine than controls. This goes along with the idea that obesity can be related to a lower sensitivity to reward. The good news is that when the rats were put on a normal diet, the dopamine went back to normal. HOWEVER, this was only true for the males! The female rats did not go back to normal dopamine levels. Yikes, right? Carlin explained that maybe the females do go back to normal dopamine, but just not within the time frame that they tested. As always, more research is necessary.

© TheCellularScale

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LMAYQ: Relationship Advice

We have reached the part of our program where I answer your important google questions. As always, these are real true questions that I found on my 'keyword search terms'. You can see all of these posts and the questions they answer here. 

Today's theme: Relationships

1. "Is there a difference in dopamine level between men and women?"

Great question.  In my post "Neurosexism and Delusions of Gender", I present a graph from Di Liberto et al., 2012 showing that female and male (mice) brains show no difference in the amount of dopamine transporter (DAT) in the striatum.

No Difference in Male and Female Dopamine Transporter

This question is particularly interesting in light of the recent reactions to Naomi Wolf's new book: "Vagina: a New Biography"  (See also Here and Here) In "Vagina", Naomi Wolf explains that "Dopamine is the ultimate feminist chemical in the female brain." ... Which is a a pretty ridiculous simplification of what dopamine is... in that it is completely untrue. First of all, men have dopamine too. And while their may be some differences in dopamine positive cells in the hypothalamus (Lansing and Lonstein 2006), the hypothalamus is  not the brain's main source of dopamine. Basically, the death of the Substantia Nigra (which feeds tons of dopamine into the striatum), results in Parkinson's Disease for men just like it does for women.

Second of all, dopamine doesn't have anything to do with your worldview (except maybe to help color it rosy). Misogynists have dopamine just like feminists do, and there is no reason to think that the amounts differ between them.

Dopamine: the Love molecule... a grossly simplified necklace (source)

However, having not read the book, I am guessing that Naomi Wolf claims dopamine is a feminist chemical because it is released during sex. But guess what, it's released during sex for both males and females, and it's not ONLY released during sex, it is also released when you eat food, do cocaine, or talk about yourself. It is a very complex molecule, with many receptors (at least 5 different kinds).  And dopamine literally does OPPOSITE things depending on whether it binds to the D1 type receptors or the D2 type receptors.


2. "Why are all women bitches?"

Look, you sound like a "Nice Guy", so I'll give you a tip: Some women do bitchy things sometimes, just like some guys do bitchy things sometimes, but your attitude that all women are bitches is probably one of the main reasons that most women are bitches to you. For a couple of reasons:

1. Self-fulfilling prophecy: If you expect to be screwed over by every woman you meet, you will see 'bitchiness' in their actions no matter what, and will probably act preemptively defensive. This will result in women acting on average more bitchy to you.

2. You are an asshole.


 3. "Do guys like cerebral women?"

Yes, guys like cerebral women.  Do all guys like cerebral women? probably not, some might be threatened by a woman who is smart.  But that's their loss.  Those guys probably end up asking the Internet questions like "why are all women bitches?"  But really, most guys I've met do not want vapid self-absorbed or shallow ladies in their lives.

One of my favorite fantasy authors, Robert Jordan has a moderately related quote:

"When I was a boy, just old enough to be starting to date in a fumbling way, I complained something about girls. And my father said to me, “Would you rather hunt leopards or would you rather hunt rabbits? Which is going to be more fun?” And I decided I’d rather hunt leopards." -Robert Jordan

Guys don't want wide eyed rabbit easy to get simple women, they want a challenge. If you are a cerebral woman, I am sure that you are smart enough to know that acting stupid to get a guy is basically the worst possible thing you could do to yourself. You don't want a guy who would fall for that crap.

But the real advice I want to give you is to stop caring what guys like. Do what you like, find yourself an awesome cause and fight for it, or an awesome project and do it. Check out cool things like Girls Who Code and play some Mass Effect. If you are really worried about 'having a partner' doing the things that you love to do will put you near other people who like doing those same things. In my opinion that is the best way to start a deep relationship anyway.

For more on gender et cetera, see the XX tab. 

© TheCellularScale


Lansing SW, & Lonstein JS (2006). Tyrosine hydroxylase-synthesizing cells in the hypothalamus of prairie voles (Microtus ochrogaster): sex differences in the anteroventral periventricular preoptic area and effects of adult gonadectomy or neonatal gonadal hormones. Journal of neurobiology, 66 (3), 197-204 PMID: 16329116

Di Liberto V, Mäkelä J, Korhonen L, Olivieri M, Tselykh T, Mälkiä A, Do Thi H, Belluardo N, Lindholm D, & Mudò G (2012). Involvement of estrogen receptors in the resveratrol-mediated increase in dopamine transporter in human dopaminergic neurons and in striatum of female mice. Neuropharmacology, 62 (2), 1011-8 PMID: 22041555

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The Optimism Bias in Science

"I have always believed that scientific research is another domain where a form of optimism is essential to success: I have yet to meet a successful scientist who lacks the ability to exaggerate the importance of what he or she is doing, and I believe that someone who lacks a delusional sense of significance will wilt in the face of repeated experiences of multiple small failures and rare successes, the fate of most researchers"     -Daniel Kahneman

The Brain: Irrational, Positive, Deceptive

I just finished reading The Optimism Bias by Tali Sharot.  The book explains that most people have an "Optimism Bias," a tendency to over-estimate how smart, good-looking, and capable they are as well as the likelihood that good things will happen to them. 

Sharot points out that in a 1981 study (Swenson O) 93% of participants rated themselves as in the top 50th percentile (i.e. 'above average') for driving ability.  Other studies have shown that this "Better than Average Effect" applies to many aspects of our self-image.  Think about yourself right now... do you think you are smarter than average? better looking than average? nicer than average? etc.  You probably do.  And even though it is logically impossible for 93% of people to be better than the 50% mark, you probably still think that you are actually  better/smarter/nicer. 

So even though you think you are smarter than most people, the reality is that most people think they are smarter than most people.

Similarly people under-estimate the likelihood that bad things will happen in their life and over estimate the likelihood that good things will happen. Ask any newly engaged couple what they think their chances of divorce are, and if not too offended by such a rude question, they will probably rate the chance of divorce as very low or even zero.  However reality says that they actually have a 41-50% chance of divorce. 

divorce cake (source)

But as Sharot claims, this optimistic skew to reality is actually beneficial. Which newly engaged couple would actually get married if they fully realized and believed that their chances of staying married were no better than the chance of flipping heads or tails on a coin? The irrational belief that we are somehow exceptional is motivating. Sharot even suggests that the optimism bias is so prevalent in our species and culture that people who realistically evaluate their situation are not the norm, and may even be clinically depressed. 

While The Optimism Bias has a great premise and recounts some exciting research, I thought the book in general was way too long.  Some very simple concepts (like that people have an optimism bias) were repeated over and over and over, and some (interesting) concepts were introduced that had pretty much nothing to do with optimism (like that memories are unreliable). 

The book didn't really teach me much about how the brain works, but it did set me thinking about how a strong optimism bias is an essential trait in academia.  As the Kahneman quote above states, most scientists face critique after critique and failure after failure.  Successes are few and far between and the same sense of realism that would prevent many a marriage, would also prevent a potential scientist from entering a Ph.D. program. Who would even apply to graduate school if they fully understood and believed the dismal statistics about finishing Ph.D. programs and the subsequent tenure-track job search. 

We have to believe that we are special, that our work is crucial, and that our contributions are significant.  No scientist will succeed if they get their peer-reviewed paper back from a journal and immediately think: 'yep, the third reviewer is correct, this work is flawed and has little impact, I should quit and become a cab driver.' A near-delusional sense of significance and an "it's not me, it's them" attitude is required to stand by your ideas and abilities in the face of these kinds of criticisms. 


© TheCellularScale



Sharot T (2011). The optimism bias. Current biology : CB, 21 (23) PMID: 22153158

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How does Deep Brain Stimulation cure Parkinson's Disease? A Cellular Look

Deep Brain Stimulation (DBS) is one of the miracle cures of our lifetime.  Used to treat Parkinson's Disease, and now being applied to depression, it is a drastic but amazingly effective measure.

EDIT 9/23/12: Just because DBS has been shown to be amazingly effective in treating Parkinson's Disease symptoms, that does not mean that it is right for everyone. There are other effective treatments for PD and DBS involves an invasive surgery. In addition, the long term effects of having a stimulating electrode constantly pulsing electricity in your brain are not yet fully known.  In other words, this blog is not giving medical advice, so please don't take it as such.

Deep Brain Stimulation (DBS)

To apply DBS, an electrode is implanted deep in the brain (the SubThalamic Nucleus for Parkinson's Disease).  An implanted wire under the skin connects the stimulation electrode in the brain to a stimulator implanted on the chest. The stimulation can be turned on and off here. 

Here is a short video showing the effect of DBS on and DBS off.  (The actual demonstration starts at 1 minute in, the rest is some arguing in French)


Once the stimulation is turned off, the man has twitches an tremors that prevent him from functioning normally.  As soon as the stimulation is turned back on, he can walk and talk smoothly. 

This is pretty astounding, right? I mean honestly, if I just saw this video and didn't know anything about it, I might not even believe that it was real.  How can electrical stimulation in the brain completely alter this person's ability to move?

Well, scientists around the world are wondering the exact same thing. One recent study made use of optogenetics to dissect the pathways involved in deep brain stimulation.

They first elicited Parkinson's Disease in mice by destroying the dopaminergic cells (in the substantia nigra which feeds into the striatum) on only one side of the brain. Then they give the mice a stimulant drug which makes them hyper. While normal mice would run all over the place on this stimulant, these hemi-parkinson's mice run in a circle because of the imbalance between the two sides of the brain.



or hemi-parkinson's disease (source)

To test whether the treatment you are giving the mouse 'cures' their Parkinson's Disease, you literally count how many times the mouse runs in a circle.  If it runs in a lot of circles, your 'cure' didn't work.

Implanting an electrode into the STN of the mice and applying the stimulation did reduce their circle running, just like the DBS reduces Parkinson's symptoms in humans.  But here's the thing, the STN has a lot of neurons in it, and a lot of axons passing through it.  Stimulating this brain region could be inhibiting firing, or exciting neurons, or something else entirely. 

So Gradinaru et al. (2009) decided to stimulate specific (genetically identified) classes of neurons to determine which aspect of the electrical stimulation was actually 'curing' the Parkinson's symptoms. 

First they tested the most common hypothesis, that the stimulation inhibited the STN.  However, when they directly inhibited the neurons of the STN, their mice still ran in circles, indicating that the brain was still unbalanced. 

Second they stimulated the glial cells around the STN, but still no luck.

Third they excited the neurons of the STN.... but... still the mouse ran in circles. 

I imagine this was very puzzling to the scientists conducting this research.  If stimulating the STN with a big metal electrode is not exciting, and not inhibiting the STN, what on earth could it be doing?

Finally they tried targeting the axons of the motor cortex which run through the STN.  And! low and behold, the mouse did not run in circles any more. Below, rotations per minute is basically a measure of circle running, and the HFS is the stimulation. You can see that as soon as the stimulation is activated the mice generally stopped running in circles, but when the stimulation was turned off, they ran in circles again. 

Gradinaru et al., 2009

So a new theory has emerged, that the stimulation of the STN might actually be acting on other neurons which are not even located in that brain structure.  It clearly works in mice, but whether this is the way that Deep Brain Stimulation works in humans is still not clear. 



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Gradinaru V, Mogri M, Thompson KR, Henderson JM, & Deisseroth K (2009). Optical deconstruction of parkinsonian neural circuitry. Science (New York, N.Y.), 324 (5925), 354-9 PMID: 19299587

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