Pic of the day: Dopamine from a non-dopamine place

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Reference: Beas BS, Wright BJ, Skirzewski M, Leng Y, Hyun JH, Koita O, Ringelberg N, Kwon HB, Buonanno A, & Penzo MA (Jul 2018, Epub 18 Jun 2018). The locus coeruleus drives disinhibition in the midline thalamus via a dopaminergic mechanism. Nature Neuroscience,21(7):963-973. PMID: 29915192, PMCID: PMC6035776 [Available on 2018-12-18], DOI:10.1038/s41593-018-0167-4. ARTICLE

Apathy

Le Heron et al. (2018) defines apathy as a marked reduction in goal-directed behavior. But in order to move, one must be motivated to do so. Therefore, a generalized form of impaired motivation also hallmarks apathy.

The authors compiled for us a nice mini-review combing through the literature of motivation in order to identify, if possible, the neurobiological mechanism(s) of apathy. First, they go very succinctly though the neuroscience of motivated behavior. Very succinctly, because there are literally hundreds of thousands of worthwhile pages out there on this subject. Although there are several other models proposed out-there, the authors’ new model on motivation includes the usual suspects (dopamine, striatum, prefrontal cortex, anterior cingulate cortex) and you can see it in the Fig. 1.

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Fig. 1 from Le Heron et al. (2018). The red underlining is mine because I really liked how well and succinctly the authors put a universal truth about the brain: “A single brain region likely contributes to more than one process, but with specialisation”. © Author(s) (or their employer(s)) 2018.

After this intro, the authors go on to showcasing findings from the effort-based decision-making field, which suggest that the dopamine-producing neurons from ventral tegmental area (VTA) are fundamental in choosing an action that requires high-effort for high-reward versus a low-effort for low-reward. Contrary to what Wikipedia tells you, a reduction, not an increase, in mesolimbic dopamine is associated with apathy, i.e. preferring a low-effort for low-reward activity.

Next, the authors focus on why are the apathetic… apathetic? Basically, they asked the question: “For the apathetic, is the reward too little or is the effort too high?” By looking at some cleverly designed experiments destined to parse out sensitivity to reward versus sensitivity to effort costs, the authors conclude that the apathetics are indeed sensitive to the reward, meaning they don’t find the rewards good enough for them to move.  Therefore, the answer is the reward is too little.

In a nutshell, apathetic people think “It’s not worth it, so I’m not willing to put in the effort to get it”. But if somehow they are made to judge the reward as good enough, to think “it’s worth it”, they are willing to work their darndest to get it, like everybody else.

The application of this is that in order to get people off the couch and do stuff you have to present them a reward that they consider worth moving for, in other words to motivate them. To which any practicing psychologist or counselor would say: “Duh! We’ve been saying that for ages. Glad that neuroscience finally caught up”.  Because it’s easy to say people need to get motivated, but much much harder to figure out how.

This was a difficult write for me and even I recognize the quality of this blogpost as crappy. That’s because, more or less, this paper is within my narrow specialization field. There are points where I disagree with the authors (some definitions of terms), there are points where things are way more nuanced than presented (dopamine findings in reward), and finally there are personal preferences (the interpretation of data from Parkinson’s disease studies). Plus, Salamone (the second-to-last author) is a big name in dopamine research, meaning I’m familiar with his past 20 years or so worth of publications, so I can infer certain salient implications (one dopamine hypothesis is about saliency, get it?).

It’s an interesting paper, but it’s definitely written for the specialist. Hurray (or boo, whatever would be your preference) for another model of dopamine function(s).

REFERENCE: Le Heron C, Holroyd CB, Salamone J, & Husain M (26 Oct 2018, Epub ahead of print). Brain mechanisms underlying apathy. Journal of Neurology, Neurosurgery & Psychiatry. pii: jnnp-2018-318265. doi: 10.1136/jnnp-2018-318265. PMID: 30366958 ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 24 November 2018

Locus Coeruleus in mania

From all the mental disorders, bipolar disorder, a.k.a. manic-depressive disorder, has the highest risk for suicide attempt and completion. If the thought of suicide crosses your mind, stop reading this, it’s not that important; what’s important is for you to call the toll-free National Suicide Prevention Lifeline at 1-800-273-TALK (8255).

The bipolar disorder is defined by alternating manic episodes of elevated mood, activity, excitation, and energy with episodes of depression characterized by feelings of deep sadness, hopelessness, worthlessness, low energy, and decreased activity. It is also a more common disease than people usually expect, affecting about 1% or more of the world population. That means almost 80 million people! Therefore, it’s imperative to find out what’s causing it so we can treat it.

Unfortunately, the disease is very complex, with many brain parts, brain chemicals, and genes involved in its pathology. We don’t even fully comprehend how the best medication we have to lower the risk of suicide, lithium, works. The good news is the neuroscientists haven’t given up, they are grinding at it, and with every study we get closer to subduing this monster.

One such study freshly published last month, Cao et al. (2018), looked at a semi-obscure membrane protein, ErbB4. The protein is a tyrosine kinase receptor, which is a bit unfortunate because this means is involved in ubiquitous cellular signaling, making it harder to find its exact role in a specific disorder. Indeed, ErbB4 has been found to play a role in neural development, schizophrenia, epilepsy, even ALS (Lou Gehrig’s disease).

Given that ErbB4 is found in some neurons that are involved in bipolar and mutations in its gene are also found in some people with bipolar, Cao et al. (2018) sought to find out more about it.

First, they produced mice that lacked the gene coding for ErbB4 in neurons from locus coeruleus, the part of the brain that produces norepinephrine out of dopamine, better known for the European audience as nor-adrenaline. The mutant mice had a lot more norepinephrine and dopamine in their brains, which correlated with mania-like behaviors. You might have noticed that the term used was ‘manic-like’ and not ‘manic’ because we don’t know for sure how the mice feel; instead, we can see how they behave and from that infer how they feel. So the researchers put the mice thorough a battery of behavioral tests and observed that the mutant mice were hyperactive, showed less anxious and depressed behaviors, and they liked their sugary drink more than their normal counterparts, which, taken together, are indices of mania.

Next, through a series of electrophysiological experiments, the scientists found that the mechanism through which the absence of ErbB4 leads to mania is making another receptor, called NMDA, in that brain region more active. When this receptor is hyperactive, it causes neurons to fire, releasing their norepinephrine. But if given lithium, the mutant mice behaved like normal mice. Correspondingly, they also had a normal-behaving NMDA receptor, which led to normal firing of the noradrenergic neurons.

So the mechanism looks like this (Jargon alert!):

No ErbB4 –> ↑ NR2B NMDAR subunit –> hyperactive NMDAR –> ↑ neuron firing –> ↑ catecholamines –> mania.

In conclusion, another piece of the bipolar puzzle has been uncovered. The next obvious step will be for the researchers to figure out a medicine that targets ErbB4 and see if it could treat bipolar disorder. Good paper!

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P.S. If you’re not familiar with the journal eLife, go and check it out. The journal offers for every study a half-page summary of the findings destined for the lay audience, called eLife digest. I’ve seen this practice in other journals, but this one is generally very well written and truly for the lay audience and the non-specialist. Something of what I try to do here, minus the personal remarks and in parenthesis metacognitions that you’ll find in most of my posts. In short, the eLife digest is masterly done. As my continuous struggles on this blog show, it is tremendously difficult for a scientist to write concisely, precisely, and jargonless at the same time. But eLife is doing it. Check it out. Plus, if you care to take a look on how science is done and published, eLife publishes all the editor’s rejection notes, all the reviewers’ comments, and all the author responses for a particular paper. Reading those is truly a teaching moment.

REFERENCE: Cao SX, Zhang Y, Hu XY, Hong B, Sun P, He HY, Geng HY, Bao AM, Duan SM, Yang JM, Gao TM, Lian H, Li XM (4 Sept 2018). ErbB4 deletion in noradrenergic neurons in the locus coeruleus induces mania-like behavior via elevated catecholamines. Elife, 7. pii: e39907. doi: 10.7554/eLife.39907. PMID: 30179154 ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 14 October 2018

The Mom Brain

Recently, I read an opinion titled When I Became A Mother, Feminism Let Me Down. The gist of it was that some feminists, while empowering women and girls to be anything they want to be and to do anything a man or a boy does, they fail in uplifting the motherhood aspect of a woman’s life, should she choose to become a mother. In other words, even (or especially, in some cases) feminists look down on the women who chose to switch from a paid job and professional career to an unpaid stay-at-home mom career, as if being a mother is somehow beneath what a woman can be and can achieve. As if raising the next generation of humans to be rational, informed, well-behaved social actors instead of ignorant brutal egomaniacs is a trifling matter, not to be compared with the responsibilities and struggles of a CEO position.

Patriarchy notwithstanding, a woman can do anything a man can. And more. The ‘more’ refers to, naturally, motherhood. Evidently, fatherhood is also a thing. But the changes that happen in a mother’s brain and body during pregnancy, breastfeeding, and postpartum periods are significantly more profound than whatever happens to the most loving and caring and involved father.

Kim (2016) bundled some of these changes in a nice review, showing how these drastic and dramatic alterations actually have an adaptive function, preparing the mother for parenting. Equally important, some of the brain plasticity is permanent. The body might spring back into shape if the mother is young or puts into it a devilishly large amount of effort, but some brain changes are there to stay. Not all, though.

One of the most pervasive findings in motherhood studies is that hormones whose production is increased during pregnancy and postpartum, like oxytocin and dopamine, sensitize the fear circuit in the brain. During the second trimester of pregnancy and particularly during the third, expectant mothers start to be hypervigilent and hypersensitive to threats and to angry faces. A higher anxiety state is characterized, among other things, by preferentially scanning for threats and other bad stuff. Threats mean anything from the improbable tiger to the 1 in a million chance for the baby to be dropped by grandma to the slightly warmer forehead or the weirdly colored poopy diaper. The sensitization of the fear circuit, out of which the amygdala is an essential part, is adaptive because it makes the mother more likely to not miss or ignore her baby’s cry, thus attending to his or her needs. Also, attention to potential threats is conducive to a better protection of the helpless infant from real dangers. This hypersensitivity usually lasts 6 to 12 months after childbirth, but it can last lifetime in females already predisposed to anxiety or exposed to more stressful events than average.

Many new mothers worry if they will be able to love their child as they don’t feel this all-consuming love other women rave about pre- or during pregnancy. Rest assured ladies, nature has your back. And your baby’s. Because as soon as you give birth, dopamine and oxytocin flood the body and the brain and in so doing they modify the reward motivational circuit, making new mothers literally obsessed with their newborn. The method of giving birth is inconsequential, as no differences in attachment have been noted (this is from a different study). Do not mess with mother’s love! It’s hardwired.

Another change happens to the brain structures underlying social information processing, like the insula or fusiform gyrus, making mothers more adept at self-motoring, reflection, and empathy. Which is a rapid transformation, without which a mother may be less accurate in understanding the needs, mental state, and social cues of the very undeveloped ball of snot and barf that is the human infant (I said that affectionately, I promise).

In order to deal with all these internal changes and the external pressures of being a new mom the brain has to put up some coping mechanisms. (Did you know, non-parents, that for the first months of their newborn lives, the mothers who breastfeed must do so at least every 4 hours? Can you imagine how berserk with sleep deprivation you would be after 4 months without a single night of full sleep but only catnaps?). Some would be surprised to find out – not mothers, though, I’m sure – that “new mothers exhibit enhanced neural activation in the emotion regulation circuit including the anterior cingulate cortex, and the medial and lateral prefrontal cortex” (p. 50). Which means that new moms are actually better at controlling their emotions, particularly at regulating negative emotional reactions. Shocking, eh?

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Finally, it appears that very few parts of the brain are spared from this overhaul as the entire brain of the mother is first reduced in size and then it grows back, reorganized. Yeah, isn’t that weird? During pregnancy the brain shrinks, being at its lowest during childbirth and then starts to grow again, reaching its pre-pregnancy size 6 months after childbirth! And when it’s back, it’s different. The brain parts heavily involved in parenting, like the amygdala involved in the anxiety, the insula and superior temporal gyrus involved in social information processing and the anterior cingulate gyrus involved in emotional regulation, all these show increased gray matter volume. And many other brain structures that I didn’t list. One brain structure is rarely involved only in one thing so the question is (well, one of them) what else is changed about the mothers, in addition to their increased ability to parent?

I need to add a note here: the changes that Kim (2016) talks about are averaged. That means some women get changed more, some less. There is variability in plasticity, which should be a pleonasm. There is also variability in the human population, as any mother attending a school parents’ night-out can attest. Some mothers are paranoid with fear and overprotective, others are more laissez faire when it comes to eating from the floor.

But SOME changes do occur in all mothers’ brains and bodies. For example, all new mothers exhibit a heightened attention to threats and subsequent raised levels of anxiety. But when does heightened attention to threats become debilitating anxiety? Thanks to more understanding and tolerance about these changes, more and more women feel more comfortable reporting negative feelings after childbirth so that now we know that postpartum depression, which happens to 60 – 80% of mothers, is a serious matter. A serious matter that needs serious attention from both professionals and the immediate social circle of the mother, both for her sake as well as her infant’s. Don’t get me wrong, we – both males and females – still have a long way ahead of us to scientifically understand and to socially accept the mother brain, but these studies are a great start. They acknowledge what all mothers know: that they are different after childbirth than the way they were before. Now we have to figure out how are they different and what can we do to make everyone’s lives better.

Kim (2016) is an OK review, a real easy read, I recommend it to the non-specialists wholeheartedly; you just have to skip the name of the brain parts and the rest is pretty clear. It is also a very short review, which will help with reader fatigue. The caveat of that is that it doesn’t include a whole lotta studies, nor does it go in detail on the implications of what the handful cited have found, but you’ll get the gist of it. There is a vastly more thorough literature if one would include animal studies that the author, curiously, did not include. I know that a mouse is not a chimp is not a human, but all three of us are mammals, and social mammals at that. Surely, there is enough biological overlap so extrapolations are warranted, even if partially. Nevertheless, it’s a good start for those who want to know a bit about the changes motherhood does to the brain, behavior, thoughts, and feelings.

Corroborated with what I already know about the neuroscience of maternity, my favourite takeaway is this: new moms are not crazy. They can’t help most of these changes. It’s biology, you see. So go easy on new moms. Moms, also go easy on yourselves and know that, whether they want to share or not, the other moms probably go through the same stuff. You’re not alone. And if that overactive threat circuit gives you problems, i.e. you feel overwhelmed, it’s OK to ask for help. And if you don’t get it, ask for it again and again until you do. That takes courage, that’s empowerment.

P. S. The paper doesn’t look like it’s peer-reviewed. Yes, I know the peer-reviewing publication system is flawed, I’ve been on the receiving end of it myself, but it’s been drilled into my skull that it’s important, flawed as it is, so I thought to mention it.

REFERENCE: Kim, P. (Sept. 2016). Human Maternal Brain Plasticity: Adaptation to Parenting, New Directions for Child and Adolescent Development, (153): 47–58. PMCID: PMC5667351, doi: 10.1002/cad.20168. ARTICLE | FREE FULLTEXT PDF

By Neuronicus, 28 September 2018

The superiority illusion

Following up on my promise to cover a few papers about self-deception, the second in the series is about the superiority illusion, another cognitive bias (the first was about depressive realism).

Yamada et al. (2013) sought to uncover the origins of the ubiquitous belief that oneself is “superior to average people along various dimensions, such as intelligence, cognitive ability, and possession of desirable traits” (p. 4363). The sad statistical truth is that MOST people are average; that’s the whole definitions of ‘average’, really… But most people think they are superior to others, a.k.a. the ‘above-average effect’.

Twenty-four young males underwent resting-state fMRI and PET scanning. The first scanner is of the magnetic resonance type and tracks where you have most of the blood going in the brain at any particular moment. More blood flow to a region is interpreted as that region being active at that moment.

The word ‘functional’ means that the subject is performing a task while in the scanner and the resultant brain image is correspondent to what the brain is doing at that particular moment in time. On the other hand, ‘resting-state’ means that the individual did not do any task in the scanner, s/he just sat nice and still on the warm pads listening to the various clicks, clacks, bangs & beeps of the scanner. The subjects were instructed to rest with their eyes open. Good instruction, given than many subjects fall asleep in resting state MRI studies, even in the terrible racket that the coils make that sometimes can reach 125 Db. Let me explain: an MRI is a machine that generates a huge magnetic field (60,000 times stronger than Earth’s!) by shooting rapid pulses of electricity through a coiled wire, called gradient coil. These pulses of electricity or, in other words, the rapid on-off switchings of the electrical current make the gradient coil vibrate very loudly.

A PET scanner functions on a different principle. The subject receives a shot of a radioactive substance (called tracer) and the machine tracks its movement through the subject’s body. In this experiment’s case, the tracer was raclopride, a D2 dopamine receptor antagonist.

The behavioral data (meaning the answers to the questionnaires) showed that, curiously, the superiority illusion belief was not correlated with anxiety or self-esteem scores, but, not curiously, it was negatively correlated with helplessness, a measure of depression. Makes sense, especially from the view of depressive realism.

The imaging data suggests that dopamine binding to its striatal D2 receptors attenuate the functional connectivity between the left sensoriomotor striatum (SMST, a.k.a postcommissural putamen) and the dorsal anterior cingulate cortex (daCC). And this state of affairs gives rise to the superiority illusion (see Fig. 1).

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Fig. 1. The superiority illusion arises from the suppression of the dorsal anterior cingulate cortex (daCC) – putamen functional connection by the dopamine coming from the substantia nigra/ ventral tegmental area complex (SN/VTA) and binding to its D2 striatal receptors. Credits: brain diagram: Wikipedia, other brain structures and connections: Neuronicus, data: Yamada et al. (2013, doi: 10.1073/pnas.1221681110). Overall: Public Domain

This was a frustrating paper. I cannot tell if it has methodological issues or is just poorly written. For instance, I have to assume that the dACC they’re talking about is bilateral and not ipsilateral to their SMST, meaning left. As a non-native English speaker myself I guess I should cut the authors a break for consistently misspelling ‘commissure’ or for other grammatical errors for fear of being accused of hypocrisy, but here you have it: it bugged me. Besides, mine is a blog and theirs is a published peer-reviewed paper. (Full Disclosure: I do get editorial help from native English speakers when I publish for real and, except for a few personal style quirks, I fully incorporate their suggestions). So a little editorial help would have gotten a long way to make the reading more pleasant. What else? Ah, the results are not clearly explained anywhere, it looks like the authors rely on obviousness, a bad move if you want to be understood by people slightly outside your field. From the first figure it looks like only 22 subjects out of 24 showed superiority illusion but the authors included 24 in the imaging analyses, or so it seems. The subjects were 23.5 +/- 4.4 years, meaning that not all subjects had the frontal regions of the brain fully developed: there are clear anatomical and functional differences between a 19 year old and a 27 year old.

I’m not saying it is a bad paper because I have covered bad papers; I’m saying it was frustrating to read it and it took me a while to figure out some things. Honestly, I shouldn’t even have covered it, but I spent some precious time going through it and its supplementals, what with me not being an imaging dude, so I said the hell with it, I’ll finish it; so here you have it :).

By Neuronicus, 13 December 2017

REFERENCE: Yamada M, Uddin LQ, Takahashi H, Kimura Y, Takahata K, Kousa R, Ikoma Y, Eguchi Y, Takano H, Ito H, Higuchi M, Suhara T (12 Mar 2013). Superiority illusion arises from resting-state brain networks modulated by dopamine. Proceedings of the National Academy of Sciences of the United States of America, 110(11):4363-4367. doi: 10.1073/pnas.1221681110. ARTICLE | FREE FULLTEXT PDF 

Not all children diagnosed with ADHD have attention deficits

Given the alarming increase in the diagnosis of attention deficit/hyperactivity disorder (ADHD) over the last 20 years, I thought pertinent to feature today an older paper, from the year 2000.

Dopamine, one of the chemicals that the neurons use to communicate, has been heavily implicated in ADHD. So heavily in fact that Ritalin, the main drug used for the treatment of ADHD, has its main effects by boosting the amount of dopamine in the brain.

Swanson et al. (2000) reasoned that people with a particular genetic abnormality that makes their dopamine receptors work less optimally may have more chances to have ADHD. The specialist reader may want to know that the genetic abnormality in question refers to a 7-repeat allele of a 48-bp variable number of tandem repeats in exon 3 of the dopamine receptor number 4 located on chromosome 11, whose expression results in a weaker dopamine receptor. We’ll call it DRD4,7-present as opposed to DRD4,7-absent (i.e. people without this genetic abnormality).

They had access to 96 children diagnosed with ADHD after the diagnostic criteria of DSM-IV and 48 matched controls (children of the same gender, age, school affiliation, socio-economic status etc. but without ADHD). About half of the children diagnosed with ADHD had the DRD4,7-present.

The authors tested the children on 3 tasks:

(i) a color-word task to probe the executive function network linked to anterior cingulate brain regions and to conflict resolution;
(ii) a cued-detection task to probe the orienting and alerting networks linked to posterior parietal and frontal brain regions and to shifting and maintenance of attention; and
(iii) a go-change task to probe the alerting network (and the ability to initiate a series of rapid response in a choice reaction time task), as well as the executive network (and the ability to inhibit a response and re-engage to make another response) (p. 4756).

Invalidating the authors’ hypothesis, the results showed that the controls and the DRD4,7-present had similar performance at these tasks, in contrast to the DRD4,7-absent who showed “clear abnormalities in performance on these neuropsychological tests of attention” (p. 4757).

This means two things:
1) Half of the children diagnosed with ADHD did not have an attention deficit.
2) These same children had the DRD4,7-present genetic abnormality, which has been previously linked with novelty seeking and risky behaviors. So it may be just possible that these children do not suffer from ADHD, but “may be easily bored in the absence of highly stimulating conditions, may show delay aversion and choose to avoid waiting, may have a style difference that is adaptive in some situations, and may benefit from high activity levels during childhood” (p. 4758).

Great paper and highly influential. The last author of the article (meaning the chief of the laboratory) is none other that Michael I. Posner, whose attentional networks, models, and tests feature every psychology and neuroscience textbook. If he doesn’t know about attention, then I don’t know who is.

One of the reasons I chose this paper is because it seems to me that a lot of teachers, nurses, social workers, or even pediatricians feel qualified to scare the living life out of parents by suggesting that their unruly child may have ADHD. In deference to most form the above-mentioned professions, the majority of people recognize their limits and tell the concerned parents to have the child tested by a qualified psychologist. And, unfortunately, even that may result in dosing your child with Ritalin needlessly when the child’s propensity toward a sensation-seeking temperament and extravert personality, may instead require a different approach to learning with a higher level of stimulation (after all, the children form the above study had been diagnosed by qualified people using their latest diagnosis manual).

Bottom line: beware of any psychologist or psychiatrist who does not employ a battery of attention tests when diagnosing your child with ADHD.

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Reference: Swanson J, Oosterlaan J, Murias M, Schuck S, Flodman P, Spence MA, Wasdell M, Ding Y, Chi HC, Smith M, Mann M, Carlson C, Kennedy JL, Sergeant JA, Leung P, Zhang YP, Sadeh A, Chen C, Whalen CK, Babb KA, Moyzis R, & Posner MI. (25 April 2000). Attention deficit/hyperactivity disorder children with a 7-repeat allele of the dopamine receptor D4 gene have extreme behavior but normal performance on critical neuropsychological tests of attention. Proceedings of the National Academy of Sciences of the United States of America, 97(9):4754-4759. doi: 10.1073/pnas.080070897. Article | FREE FULLTEXT PDF

P.S. If you think that “weeell, this research happened 16 years ago, surely something came out of it” then think again. The newer DSM-V’s criteria for diagnosis are likely to cause an increase in the prevalence of diagnosis of ADHD.

By Neuronicus, 26 February 2016

Grooming only half side of the body

Grooming only half side of the body. Credit: http://www.bajiroo.com/2013/04/23-guys-with-half-shaved-beard/
Grooming only half side of the body. Credit: http://www.bajiroo.com/2013/04/23-guys-with-half-shaved-beard/

Contrary to popular belief, rats and mice are very fastidious animals; they keep themselves scrupulously clean by engaging in a very meticulous routine of self-grooming. The routine is so rigorous that allows the researchers to divide the grooming sequence into four different phases, starting with the nose and whiskers and ending with the genitalia and tail. It is also a symmetrical behavior (no whisker left ungroomed, no paw unlicked).

Grooming is sensitive to dopaminergic manipulations, so Pelosi, Girault, & Hervé (2015) sought to see what happens if they destroy the dopamine fibers in the mouse brain. So they lesioned the medial forebrain bundle, which is a bunch axon fibers that contains over 80% of the midbrain dopaminergic axons. But they were tricky, they lesioned only one side.

And the results were that the lesioned mice not only exhibited less self-grooming on the opposite side to the lesion, but the behavior was rescued by L-DOPA, which is medication for Parkinson’s. That is, they gave the mice some L-DOPA and they began to merrily self-groom again on both sides of the body. The authors discuss in depths other findings, like the changes (or absence thereof) in grooming bouts, grooming time, grooming bouts, completeness of grooming etc.

The findings have significance in the Parkinson’s research, where the mild to moderate phases of the disease often present with asymmetrical motor behavior.

Reference: Pelosi A, Girault J-A, & Hervé D (23 Sept 2015). Unilateral Lesion of Dopamine Neurons Induces Grooming Asymmetry in the Mouse. PLoS One. 2015; 10(9): e0137185. doi: 10.1371/journal.pone.0137185. PMCID: PMC4580614. Article | FREE FULLTEXT PDF

By Neuronicus, 29 October 2015

The FIRSTS: Dopamine is a neurotransmitter (1957)

Swedish pharmacologist and Nobel laureate Arvid Carlsson giving a lecture at the 2011 Göteborg Science Festival. By Vogler, released under CC BY-SA 3.0
Swedish pharmacologist and Nobel laureate Arvid Carlsson giving a lecture at the 2011 Göteborg Science Festival. By Vogler, released under CC BY-SA 3.0 on Wikipedia.

Dopamine is probably the most investigated brain substance. Tens of thousands of researchers are owing their career to this small molecule. And quite a few non-scientists, too. The chemical rose to partial notoriety after several studies linked it to the Parkinson’s disease in the 60’s and but its true fame came a decade later when dopamine’s role in pleasure and addiction became apparent.

And yet not so many years before that, not only nobody thought of dopamine as a central player in the neuronal chemical waltz, but even after it was shown that it is a neurotransmitter, few believed it and the authors of those studies were a mark for ridicule. The main author, Arvid Carlsson, was finally vindicated 50 years later when he was awarded the Nobel Prize in Medicine (2000) for showing that dopamine is not a just a precursor of adrenaline and noradrenaline, but also a neurotransmitter in its own right. The work barely covered more than a column in Nature, in 1957. Basically, he and colleagues did a series of pharmacological experiments where they injected rabbits or mice with known antipsychotics and antidepressants and various monoamine precursors. And then observed the critters’ behavior.

Dopamine
Dopamine

The crux of the rationale was (still is in the pharmacological experiments): if drug X modifies behavior and this modification is reversed by drug Y, then drug X and Y interact somehow either directly or have a common target. If not, then they don’t and some other substance, let’s call it Z, is responsible for the behavior. If you go and read the actual paper, for the modern neuroscientist that has been uprooted from his/her chemistry classes, remember that 3-hydroxytyramine is dopamine,  3,4-dihydroxyphenylalanine is L-DOPA, and y’all professionals should know serotonin is 5-hydroxytryptamine with its precursor 5-hydroxytryptophan.

Reference: Carlsson, A., Lindquist, M., & Magnusson, T. (November 1957). 3,4-Dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature, 180(4596): 1200. doi:10.1038/1801200a0. Article | FULLTEXT PDF | Nature cover

By Neuronicus, 19 October 2015

Dopamine role still not settled

vta pfc
No idea why the prefrontal cortex neuron is Australian, but here you go. Cartoon made by me with free (to the best of my knowledge) clipart elements. Feel free to use to your heart’s content.

There have been literally thousands of pages published about the dopamine function(s). Dopamine, which made its stage debut as the “pleasure molecule”, is a chemical produced by some neurons in your brain that is vital to its functioning. It has been involved in virtually all types of behavior and most diseases, from pain to pleasure, from mating to addiction, from working-memory to decision-making, from autism to Parkinson’s, from depression to schizophrenia.

Here is another account about what dopamine really does in the brain. Schwartenbeck et al. (2015) trained 26 young adults to play a game in which they had to decide whether to accept an initial offer of small change or to wait for a more substantial offer. If they waited too long, they would lose everything. After that, the subjects played the game in the fMRI. The authors argue that their clever game allows segregation between previously known roles of dopamine, like salience or reward prediction.

As expected with most fMRI studies, a brain salad lit up (that is, your task activated many other structures in addition to your region of interest), which the authors address only very briefly. Instead, they focus on the timing of activation of their near and dear midbrain dopamine neurons, which they cannot detect directly in the scanner because their cluster is too small, so they infer their location by proxy. Anyway, after some glorious mental (and mathematical) gymnastics Schwartenbeck et al. (2015) conclude that

1) “humans perform hierarchical probabilistic Bayesian inference” (p. 3434) (i.e. “I don’t have a clue what’s going on here, so I’ll go with my gut instinct on this one”) and

2) dopamine discharges reflect the confidence in those inferences (i.e. “how sure am I that doing this is going to bring me goodies?”)

With the obvious caveat that the MRI doesn’t have the resolution to isolate the midbrain dopamine clusters and that these clusters refer to two very distinct population of dopamine neurons (ventral tegmental area and substantia nigra) with different physiological, topographical, and anatomical properties, and distinct connections, the study adds to the body of knowledge of “for the love of Berridge and Schultz, what the hell are you DOIN’, dopamine neuron?”.

Reference: Schwartenbeck, P., FitzGerald, T. H., Mathys, C., Dolan, R., & Friston K. (October 2015, Epub 23 July 2014). The Dopaminergic Midbrain Encodes the Expected Certainty about Desired Outcomes. Cerebral Cortex, 25:3434–3445, doi:10.1093/cercor/bhu159. Article + FREE PDF

By Neuronicus, 8 October 2015