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Posts Tagged ‘Neuron’

A young woman and man embracing while outdoors.
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Please forgive the absurd title here … its just a play on words from a flabby, middle-aged science geek who is as alluring to “the ladies” as an old leather boot.

Like a lot of males (with active fantasy lives I suppose), my interest was piqued by the recent headline, “What Do Women Really Want? Oxytocin” – based on a recent lecture at this years Society for Neuroscience annual conference.

Oxytocin is a small hormone that also modulates brain activity.  Many have referred it as the “Love Hormone” because it is released into the female brain during breastfeeding (where moms report feeling inextricably drawn to their infants), orgasm and other trust-building and social bonding experiences.  So, the premise of the title (from the male point of view), is a fairly simplistic – but futile – effort to circumvent the whole “social interaction thing” and reduce dating down to handy ways of raising oxytocin levels in females (voila! happier females more prone to social (ahem) bonding).

Of course, Mother Nature is not stupid.  Unless you are an infant, there is no “increase in oxytocin” without a prior “social bonding or shared social experience”.  Mother Nature has the upper hand here … no physical bonding without social binding first!

So, what the heck does this have to do with yoga?  Yes, its true that yoga studios are packed with friendly, health conscious females, but, the practice is mainly a solitary endeavor.  Aside from the chatter before and after class, and the small amount of oxytocin that is released during exercise, there is no social bonding going on that would release the so-called “love hormone”.  Thus, even though “women want yoga”, yoga class may not be the ideal location to “score with chicks”.

However, there may be one aspect of yoga practice that can facilitate social bonding (and hence oxytocin release).  One benefit of a yoga practice (as covered here, here) is an increased ability to “be present” – an improved ability to pay closer attention to your own thoughts and feelings, and also, the thoughts and feelings of another person.

The scientific literature is fairly rich in research showing a close relationship between attention, shared- or joint-attention, trust and oxytocin, and the idea is pretty obvious.  If you are really paying attention to the other person, and paying attention to your shared experience in the moment, the social bond will be stronger, more enjoyable and longer-lasting.  Right?

Soooo – if you want the oxytocin to flow – look your partner in the eye, listen to their thoughts, listen to your own reactions, listen to, and feel their breath as it intermingles with your own, feel their feelings and your own, slow-down and enjoy the minute details of the whole experience and be “right there, right now” with them.  Even if you’ve been with the same person for 40 years, each moment will be new and interesting.

Yoga will teach you how to do this.

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Modified drawing of the neural circuitry of th...
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You already know this, but when you are stressed out (chronic stress), your brain doesn’t work very wellThat’s right – just when you need it most – your brain has a way of letting you down!

Here are a few things that happen to the very cells (in the hippocampus) that you rely on:

reorganization within mossy fiber terminals
loss of excitatory glutamatergic synapses
reduction in the surface area of postsynaptic densities
marked retraction of thorny excrescences
alterations in the lengths of the terminal dendritic segments of pyramidal cells
reduction of the dorsal anterior CA1 area volume

Thanks brain!  Thanks neurons for abandoning me when I need you most!  According to this article, these cellular changes lead to, “impaired hippocampal involvement in episodic, declarative, contextual and spatial memory – likely to debilitate an individual’s ability to process information in new situations and to make decisions about how to deal with new challenges.” UGH!

Are our cells making these changes for a reason?  Might it be better for cells to remodel temporarily rather than suffer permanent, life-long damage?  Perhaps.  Perhaps there are molecular pathways that can lead the reversal of these allostatic stress adaptations?

Check out this recent paper: “A negative regulator of MAP kinase causes depressive behavior” [doi 10.1038/nm.2219]  the authors have identified a gene – MKP-1 – a phosphatase that normally dephosphorylates various MAP kinases involved in cellular growth, that, when inactivated in mice, produces animals that are resistant to chronic unpredictable stress.  Although its known that MKP-1 is needed to limit immune responses associated with multi-organ failure during bacterial infections, the authors suggest:

“pharmacological blockade of MKP-1 would produce a resilient of anti-depressant response to stress”

Hmmm … so Mother Nature is using the same gene to regulate the immune response (turn it off so that it doesn’t damage the rest of the body) and to regulate synaptic growth (turn it off – which is something we DON’T want to do when we’re trying to recover from chronic stress)?  Mother Nature gives us MKP-1 so I can survive an infection, but the same gene prevents us from recovering (finding happiness) from stress?

Of course, we do not need to rely only on pharmacological solutions.  Exercise & social integration are cited by these authors as the top 2 non-medication strategies.

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What if you had magic fingers and could touch a place on a person’s body and make all their pain and anguish disappear?  This would be the stuff of legends, myths and miracles! Here’s a research review by Kerry J Ressler  and Helen S Mayberg on the modern ability to electrically “touch” the Vagus Nerve.

The article,  Targeting abnormal neural circuits in mood and anxiety disorders: from the laboratory to the clinic discusses a number of “nerve stimulation therapies” wherein specific nerve fibers are electrically stimulated to relieve mental anguish associated with (drug) treatment-resistant depression.

Vagus nerve stimulation therapy (VNS) is approved by the FDA for treatment of medication-resistant depression and was approved earlier for the treatment of epilepsy20.  …  The initial reasoning behind the use of VNS followed from its apparent effects of elevating mood in patients with epilepsy20, combined with evidence that VNS affects limbic activity in neuroimaging studies21. Furthermore, VNS alters concentrations of serotonin, norepinephrine, GABA and glutamate within the brain2224, suggesting that VNS may help correct dysfunctional neurotransmitter modulatory circuits in patients with depression.

This stuff is miraculous in every sense of the word – to be able to reach in and “touch” the body and bring relief – if not bliss – to individuals who suffer with immense emotional pain.  So who is this Vagus nerve anyway?  Why does stimulating it impart so many emotional benefits?  How can I touch my own Vagus nerve?

The wikipedia page is a great place to explore – suggesting that this nerve fiber is central to the “rest and digest” functions of the parasympathetic nervous system.  As evidenced by the relief its stimulation brings from emotional pain, the Vagus nerve is central to mind-body connections and mental peace.

YOGA is a practice that also brings mental peace.  YOGA,  in so many ways (I hope to elaborate on in future posts),  aims to engage the parasympathetic nervous system (slowing down and resting responses) and disengage the sympathetic nervous system (fight or flight responses).  Since we all can’t have our very own (ahem) lululemon (ahem) vagal nerve stimulation device, we must rely on other ways to stimulate the Vagus nerve fiber.  Luckily, many such ways are actually known – so-called “Vagal maneuvers” – such as  holding your breath and bearing down (Valsalva maneuver), immersing your face in ice-cold water (diving reflex), putting pressure on your eyelids, & massage of the carotid sinus area – that have been shown to facilitate parasympathetic (relaxation & slowing down) responses.

But these “Vagal maneuvers” are not incorporated into yoga.  How might yoga engage and stimulate the Vagal nerve bundle? Check out these great resources on breathing and Vagal tone (here, here, here).  I’m not an expert by any means but I think the take home message is that when we breathe deep and exhale, Vagal tone increases.  So, any technique that allows us to increase the duration of our exhalation will increase Vagal tone. Now THAT sounds like yoga!

Even more yogic is the way the Vagus nerve is the only nerve in the parasympathetic system that reaches all the way from the colon to the brain.  The fiber is composed mainly of upward (to the brain) pulsing neurons – which sounds a lot like the mystical Kundalini Serpent that arises upwards from within (starting at the root – colon) and ending in the brain.  The picture above – of the Vagus nerve (bright green fiber) – might be what the ancient yogis had in mind?

some updates:

here’s a great post on the importance of, and teaching of exhalation

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Peter Mark Roget (Roget's Thesaurus)
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On Fridays, after a regular practice session, our shala is open for quiet meditation.  This is a new experience for me, even as I’ve read much about the mental and physical health benefits accrued by experienced practitioners.  As someone who is totally exhausted after practice – indeed, I couldn’t move another muscle even if I wanted – I always think it will be easy to settle in, and pass 30 minutes  in quiet stillness.

Sure enough though, even as my body is spent and motionless, my mind starts to wander, and wander, and wander some more.  “Damn”, I think, “here we go again”. Just a few minutes in, and I’m losing a battle – with myself.  “This is going to be the longest 30 minutes of my life!” What to do?

Some experts say to simply LABEL your thoughts and feelings.  Just find a word to place on the thought or feeling – and then – let it go.  Does this really work?  How does this trick work?

Recent brain imaging studies seem to show that when a word is applied to a negative emotion,  the brain changes how it processes that emotion and shifts processing to neural systems that avoid centers of the brain (the amygdala, in particular) that send neural projections to our face, gut and heart (areas where we tend to physically “feel” our bad feelings).   It seems that our ability to use words is an important tool in how we cope with emotional experience.  Either we succumb to the storms of negative emotions that can well up inside us from time to time (and feel lousy inside), or we can manage these feelings – using our words – and feel less lousy inside.   Apparently, the use of words, alters neural processing – leading us to experience less tightening in the chest, clenching in the gut, etc.,  etc. than we would otherwise feel when negative emotions come over us.  One of the researchers, David Cresswell, remarks: “This is an exciting study because it brings together the Buddha‘s teachings – more than 2,500 years ago, he talked about the benefits of labeling your experience – with modern neuroscience.”

But this is easier said than done.

How do I label a thought?  How do I label an emotion?  I mean, “I feel, um, um, frustrated, lousy, anxious … crap … I’m not exactly sure how I feel?  What’s the word I’m looking for?

Indeed – the words – the words – as in, “In the beginning was the Word, and the Word was with God, and the Word was God.” WORDS.  Do I know enough words?  How many words are there anyway to describe all the possible feelings that a person can feel?  How many do you know?

Check this list out.    There are more than 3,000 words in the English language to describe various feelings.  Thank you Peter Mark Roget (who, ironically, worked on the first thesaurus as a means to cope with negative feelings associated with depression).  I will bring my thesaurus – full of these tools to help me label my feelings – to meditation practice from now on!

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The 14th Dalai Lama, a renowned Tibetan Buddhi...
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In this essay, His Holiness the 14th Dalai Lama addresses the question, “What possible benefit could there be for a scientific discipline such as neuroscience in engaging in dialogue with Buddhist contemplative tradition?”

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Shakti
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Some of the most epic and beautiful of the yoga sutras are found in the final book IV.  One of them popped into mind when I came across a recent neuroscience report entitled, “Predicting Persuasion-Induced Behavior Change from the Brain” by Emily Falk and colleagues at the Department of Psychology at the  University of California, Los Angeles.  [DOI:10.1523/JNEUROSCI.0063-10.2010].  Here, a research team asks if there are places in the brain that encode future – yes, future actions.  More specifically, they asked 20 volunteers to lay in an MRI scanner and listen/view a series of messages on the benefits and importance of sunscreen.  Then, 1-week later, they inquired about the frequency of sunscreen use.  It turns out that sunscreen use did increase (suggesting the subjects read the messages), but more interestingly, that there were correlations in brain activity (in several regions of the brain) with the degree of increased sunscreen use.  That is, some individuals recorded a bit of brain activity that predicted their future use of sunscreen.

Very neat indeed!  although, there are likely many reasons to remain skeptical.  This is because the brain is a very complex system and, with so much going on inside, its likely anyone could find correlations in activity with any-old “something” and “some area of the brain” if they looked hard enough.  In this article however, the authors had preselected their brain regions of interest – the medial frontal cortex and the precuneus – since another group had shown that activity in these regions were able to predict future actions (on the order of a few seconds).  Thus, the research team was not looking for any willy-nilly correlation, but for a specific type of interaction between the brain and future action (this time on the order of weeks).

The particular ancient sutra that may have some poetic tie-ins here is IV.12 atita anagatam svarupatah asti adhvabhedat dharmanam “the existence of the past and future is as real as that of the present.  As moments roll into movements which have yet to appear as the future, the quality of knowledge in one’s intellect and consciousness is affected.”

Might there be neural traces predicting one future actions?  This research makes it seem possible.  Are these traces accessible to ordinary folks or advanced meditators?  Who knows.  As always, the joy lies in trying to find out and trying to reach ever deeper states of harmony and unity.  One thing I found intriguing was that the research team picked the medial prefrontal cortex and the precuneus because these brain regions,

“are reliably co-activated across a host of “self” processes and the extent to which people perceive persuasive messages to be self-relevant has long been thought to play a part in attitude and behavioral change”.

Certainly, when something feels relevant to “me” and reinforces my own “self” image, I’m more prone to remember and act upon it.  Yoga, for example! I hope I’m encoding signals now that will predict my attendance in class this week!

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Mood Broadcasting
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Like many folks, I generally feel better ever since I started practicing yoga.  Outwardly, my body is (slowly) growing stronger and more flexible and perhaps (hopefully) soon, I’ll even lose a few pounds.  However, even if I was to convince myself that looked slimmer (skinny mirrors?), the only way to really know if I’ve lost weight, is to stand on a scale and record my weight each day (darn! no fatness lost so far).

That takes care of the body right – but what about the inner, emotional improvements I might be experiencing?  How to measure these?

Here are some mobile- and web-based tools to help one track one’s emotions.  Most of these websites, like Moodstats, Track Your Happiness, MoodJam, MoodMill, Finding Optimism and MoodLog seem to function as online diaries which keep a running tab on aspects of ones moods and emotions.  Perhaps such tools – if used over long durations – would enable one to verify a shift toward a less anxious and more contented inner feeling?  I don’t know.

Perhaps the real proof of “inner” progress would be that I had closed my computer and put away my mobile device and, rather, was outside enjoying the sights and sounds of nature.  Perhaps best to avoid mixing yoga and digital distractions.

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Samadhi Statue
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In some ways, the 8 limbs of yoga described in the yoga sutras, seem a bit like a ladder, rather than a concentric set of outreached arms or spokes on a wheel.  It seems like I’m working toward something.  But what?  I certainly feel healthier, and also enjoy the satisfaction of getting slightly more able (ever so slightly) to shift into new postures – so am quite motivated to continue the pursuit.  Perhaps this is how yoga got started eons ago?   Just a pursuit that – by trial and error – left its practitioners feeling more healthy, relaxed and more in touch with their outer and inner worlds?  But where does this path lead, if anywhere?

I was intrigued by a report published in 1973 by an 8-day study carried out on the grounds of the Ravindra Nath Tagore Medical College and Hospital, Udaipur, India and subsequent letter, “The Yogic claim of voluntary control over the heart beat: an unusual demonstration” published in the American Heart Journal, Volume 86 Number 2.  Apparently, a local yogi named Yogi Satyamurti:

Yogi Satyamurti, a sparsely built man of about 60 years of age, remained confined in a small underground pit for 8 days in what according to him was a state of “Samadhi,” or deep meditation, with all bodily activity cut down to the barest minimum.

The medical researchers had the yogi’s heart and other physiological functions under constant watch via electrical recording leads, and watched as the yogi’s heart slowed down (their equipment registered a flatline) a remained so for several days.  Upon opening up the pit, the researchers found:

The Yogi was found sitting in the same posture. One of us immediately went in to examine him. He was in a stuporous condition and was very cold (oral temperature was 34.8O C) [the same temperature as the earth around him].

After a few hours, the yogi had recovered from the experience and displayed normal physiological and behavioral function – despite 8 days underground (air supposedly seeped in from the sides of the pit) with no food or human contact!

An amazing feat indeed – one that has some scientists wondering about the psychology and physiology that occurs when advanced meditators sink into (very deep) states.  John Ding-E Young and Eugene Taylor explored this in an article entitled, “Meditation as a Voluntary Hypometabolic State of Biological Estivation” published in News Physiol. Sci., Volume 13, June 1998.   They  suggest that humans have a kind of latent capacity to enter a kind of dormant or  hibernation-like state that is similar to other mammals and even certain primates.

Meditation, a wakeful hypometabolic state of parasympathetic dominance, is compared with other hypometabolic conditions, such as sleep, hypnosis, and the torpor of hibernation. We conclude that there are many analogies between the physiology of long-term meditators and hibernators across the phylogenetic scale. These analogies further reinforce the idea that plasticity of consciousness remains a key factor in successful biological adaptation.

Practice, practice, practice – towards an ability to engage a latent evolutionary adaptation? Sounds hokey, but certainly an interesting idea worth exploring more in the future.

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The Karma Machine + Easy Photoshop Tattoo Tuto...
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One of the themes that emerges in I.I atha yoganusasanam, and runs throughout the yoga sutras, is the notion that a yoga practice will bring one into a deeper awareness of the self.  To begin to explore the modern science notion of self-awareness, here’s a 2009 paper entitled, “The ‘prediction imperative’ as the basis for self-awareness” by Rodolfo R. Llinas and Sisir Roy [doi:10.1098/rstb.2008.0309].  The paper is part of a special theme issue from the Philosophical Transactions of the Royal Society B with the wonderfully karmic title: Predictions in the brain: using our past to prepare for the future.

Without unpacking the whole (open access) article, here are a few ideas that seem to connect loosely to themes in yoga.

The main issue addressed by the authors is how the brain manages to solve the computational problem of movement.  Here’s the problem: to just, for example,  reach into a refrigerator and grab a carton of milk (a far cry from, say, scorpion pose) they point out that,

“there are 50 or so key muscles in the hand, arm and shoulder that one uses to reach for the milk carton (leading to) over 1,000,000,000,000,000 combinations of muscle contractions (that) are possible.”

Yikes!  that is an overwhelming computational problem for the brain to solve – especially when there are 1,000-times FEWER neurons in the entire brain (only a mere 1,000,000,000,000 neurons).  To accomplish this computational feat, the authors suggest that brain has evolved 2 main strategies.

Firstly, the authors point out that the brain can lower the computational workload of controlling movement (motor output) by sending motor control signals in a non-continuous and pulsatile fashion.

“We see that the underlying nature of movement is not smooth and continuous as our voluntary movements overtly appear; rather, the execution of movement is a discontinuous series of muscle twitches, the periodicity of which is highly regular.”

This computational strategy has the added benefit of making it easier to bind and synchronize motor-movement signals with a constant flow of sensory input:

“a periodic control system may allow for input and output to be bound in time; in other words, this type of control system might enhance the ability of sensory inputs and descending motor command/controls to be integrated within the functioning motor apparatus as a whole.”

The idea of synchronizing sensory information with pulsing motor control signals brings to mind more poetic notions of rhythmicity and the way that yogis use their breath to enhance and unify  their outer and inner world experience.  Neat!  Also, I very much like the idea that our brains have enormously complex computational tasks to perform, so I’m keen to do what I can to help out my central nervous system.  Much gratitude to you brain!

Secondly, the authors then move ahead to describe the way in which neural circuits in the body and brain are inherently good at learning and storing information which makes them very good at predicting what to do with incoming sensory inputs.  This may just be another strategy the brain has evolved to simplify the enormous computational load associated with moving and coordinating the body.  Interestingly, the authors note,

“while prediction is localized in the CNS, it is a distributed function and does not have a single location within the brain. What is the repository of predictive function? The answer lies in what we call the self, i.e. the self is the centralization of the predictive imperative.  The self is not born out of the realm of consciousness—only the noticing of it is (i.e. self-awareness).”  Here’s a link to Llinas’ book on this topic.

The “self” is not just in the brain? but distributed throughout the entire CNS? Whoa!  Much to explore here.  Many thematic tie-ins with ancient Vedic notions of self and consciousness … will explore this in the future!

One last passage I found of interest was written by Moshe Bar, the editor of the special issue, who suggested that neural solutions to these inherent computational challenges make the brain/mind a naturally restless place.  His words,

“As is evident from the collection of articles presented in this issue, the brain might be similarly flexible and ‘restless’ by default. This restlessness does not reflect random activity that is there merely for the sake of remaining active, but, instead, it reflects the ongoing generation of predictions, which relies on memory and enhances our interaction with and adjustment to the demanding environment.”

My yoga teachers often remind me that “monkey mind” is normal and with more practice, it will subside.  Very cool to see a tie-in with modern research.

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OM, computer generated image - Png file, Atten...
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Oxygen is the key to life.  This is because it loves electrons.  In the mitochondria of every cell in your body, oxygen (in is atmospheric O2 state) serves as the ultimate electron acceptor and provides the chemical energy that drives the formation of ATP (a form of chemical energy storage that our body uses for all its cellular functions).

Oxygen is the key to death.  This is because it loves electrons.  When so-called reactive oxygen species (small molecules that contain oxygen in an ionized form) are permitted to roam free in cell and the body, they can indiscriminately pull electrons from other molecules (oxidation) and cause undesirable protein damage and premature cell death.

There is no escaping this chemical reality.  The very substance that giveth life, doth take it away and our longevity teeters on the quantum mechanical balance of electrons whizzing around the nucleus of the oxygen atom.  (I’ll think about this and the chemical symbol for oxygen (O), next time I chant “Om” in yoga class).

So it is with this humbling knowledge that many search for ways to optimize this balance (several populations have already figured out how to routinely live to 100+ years!) or at least improve the quality of our naturally limited life-span.  Light exercise, vegetables, friends and not too much alcohol.

Consider the recent paper, by Srivastava et al., “Association of SOD2, a Mitochondrial Antioxidant Enzyme, with Gray Matter Volume Shrinkage in Alcoholics” [doi: 10.1038/npp.2009.217].  The authors report that shrinkage of the neocortex (gray matter) of the brain is associated  chronic high levels of alcohol consumption.  That’s right, too much alcohol shrinks your brain.  Yikes!  How does alcohol exert its effect on brain shrinkage?  Well,  the authors measured many aspects of liver function (various enzyme levels), but these did not correlate with gray matter shrinkage.  Rather, the authors traced the effect to an enzyme that normally keeps harmful reactive oxygen species at bay – the so-called superoxide dismutase (SOD) enzyme.  We all have this enzyme, but in some of us, those who carry the rs4880 “G” allele of our SOD2 gene produce an enzyme that has an alanine at position 16 (Ala16) and is less active than the rs4880 “A” allele which encodes a more active enzyme with a Valine at position 16 (Val16).  The authors report that the rs10370 “TT”, rs4880 “GG” diplo-genotype (diplotype) was associated with more gray matter shrinkage in 76 individuals who report chronic high levels of alcohol consumption.  Here, the less active form of SOD2 is seemingly less able to metabolize all the harmful superoxide radicals that are generated during chronic exposure to alcohol.  Apparently their neurons are in retreat.

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Kim Kardashian
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Sometimes, when flipping channels late at night, its hard NOT to stop and gawk at the various spectacles on reality-trash-TV.  No self-respecting scientist would admit to being smitten by all the vanity and preening – right?  Well, back in 2002, there was a mouse whose homeobox-B8 gene was disrupted – who caused a minor media sensation in the community – for its tendency toward, “excessive grooming … not unlike that of humans suffering from the OC-spectrum disorder”.  Hunh?  A mouse not-unlike trash-TV celebs who can’t stop fixing their hair?  An interesting genetic effect to be sure.

A recent paper, “Loss of Hoxb8 alters spinal dorsal laminae and sensory responses in mice” reports a closer look at this mouse mutation and provides evidence that the excessive grooming is, instead, a consequence merely of “itch perception” which arises from disrupted development of itch specific GrpR-positive neurons in lamina I of the dorsal spinal cord“.  Indeed, when the investigators applied sub cutaneous lidocaine to the peripheral nerve endings in the groomed regions – the excessive grooming stopped.  If you are interested in the development of the peripheral nervous system, the paper is well worth a read!  If you are into the psychology of excessive grooming, the Kardashian sisters always provide a steady stream of data.

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Diagram to illustrate Minute Structure of the ...
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For a great many reasons, research on mental illness is focused on the frontal cortex.  Its just a small part of the brain, and certainly, many things can go wrong in other places during brain/cognitive development, but, it remains a robust finding, that when the frontal cortex is not working well, individuals have difficulties in regulating thoughts and emotions.  Life is difficult enough to manage, let alone without a well functioning frontal cortex.  So its no surprise that many laboratories look very closely at how this region develops prenatally and during childhood.

One of the more powerful genetic methods is the analysis of gene expression via microarrays (here is a link to a tutorial on this technology).  When this technology is coupled with extremely careful histological analysis and dissection of cortical circuits in the frontal cortex, it begins to become possible to begin to link changes in gene expression with the physiological properties of specific cells and local circuits in the frontal cortex. The reason this is an exciting pursuit is because the mammalian neocortex is organized in a type of layered fashion wherein 6 major layers have different types of connectivity and functionality.  The developmental origins of this functional specificity are thought to lie in a process known as radial migration (here is a video of a neuron as it migrates radially and finds its place in the cortical hierarchy).  As cells are queued out of the ventricular zone, and begin their migration to the cortical surface, they are exposed to all sorts of growth factors and morphogens that help them differentiate and form the proper connectivities.  Thus, the genes that regulate this process are of keen interest to understanding normal and abnormal cognitive development.

Here’s an amazing example of this – 2 papers entitled, “Infragranular gene expression disturbances in the prefrontal cortex in schizophrenia: Signature of altered neural development?” [doi:10.1016/j.nbd.2009.12.013] and “Molecular markers distinguishing supragranular and infragranular layers in the human prefrontal cortex [doi:10.1111/j.1460-9568.2007.05396.x] both by Dominique Arion and colleagues.  In both papers, the authors ask, “what genes are differentially expressed in different layers of the cortex?”.  This is a powerful line of inquiry since the different layers of cortex are functionally different in terms of their connectivity.  For example, layers II-III (the so-called supragranular layers) are known to connect mainly to other cortical neurons – which is different functionally than layers V-VI (the so-called infragranular layers) that connect mainly to the striatum (layer V) and thalamus (layer VI).  Thus, if there are genes whose expression is unique to a layer, then one has a clue as to how that gene might contribute to normal/abnormal information processing.

The authors hail from a laboratory that is well-known for work over many years on fine-scaled histological analysis of the frontal cortex at the University of Pittsburgh and used a method called, laser capture microdissection, where post-mortem sections of human frontal cortex (area 46) were cut to separate the infragraular layer from the supragranular layer.  The mRNA from these tissue sections was then used for DNA microarray hybridization.  Various controls, replicate startegies and in-situ tissue hybridizations were then employed to validate the initial microarray results.

In first paper, the where the authors compare infra vs. supragranular layers, they report that 40 genes were more highly expressed in the supragranular layers (HOP, CUTL2 and MPPE1 were among the most enriched) and 29 genes were highly expressed in the infragranular layers (ZNF312, CHN2, HS3ST2 were among the most enriched).  Other differentially expressed genes included several that have previously been implicated in cortical layer formation such as RLN, TLX-NR2E1, SEMA3E, PCP4, SERPINE2, NR2F2/ARP1, PCDH8, WIF1, JAG1, MBP.  Amazing!! A handful of genes that seem to label subpopulations of projection neurons in the frontal cortex.  Polymorphic markers for these genes would surely be powerful tools for imaging-genetic studies on cognitive development.

In the second paper, the authors compare infra vs. supragranular gene expression in post-mortem brains from patients with schizophrenia and healthy matched controls. Using the same methods, the team reports both supra- and infragranular gene expression changes in schizophrenia (400 & 1200 differences respectively) – more than 70% of the differences appearing to be reductions in gene expression in schizophrenia. Interestingly, the team reports that the genes that were differentially expressed in the infragranular layers provided sufficient information to discriminate between cases and controls, whilst the gene expression differences in the supragranular layers did not.  More to the point, the team finds that 51 genes that were differentially expressed in infra- vs. supragranular expression were also differentially expressed in cases vs. controls  (many of these are also found to be associated in population genetic association studies of schiz vs. control as well!).  Thus, the team has identified layer (function) -specific genes that are associated with schizophrenia.  These genes, the ones enriched in the infragranular layers especially, seem to be at the crux of a poorly functioning frontal cortex.

The authors point to 3 such genes (SEMA3E, SEMA6D, SEMA3C) who happen to members of the same gene family – the semaphorin gene family.  This gene family is very important for the neuronal guidance (during radial migration), morphology, pruning and other processes where cell shape and position are regulated.  The authors propose that the semaphorins might act as “integrators” of various forms of wiring during development and in adulthood.  More broadly, the authors provide a framework to understand how the development of connectivity on the frontal cortex is regulated by genetic factors – indeed, many suspected genetic risk factors play a role in the developmental pathways the authors have focused on.

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One of the complexities in beginning to understand how genetic variation relates to cognitive function and behavior is that – unfortunately – there is no gene for “personality”, “anxiety”, “memory” or any other type of “this” or “that” trait.  Most genes are expressed rather broadly across the entire brain’s cortical layers and subcortical systems.  So, just as there is no single brain region for “personality”, “anxiety”, “memory” or any other type of “this” or “that” trait, there can be no such gene.  In order for us to begin to understand how to interpret our genetic make-up, we must learn how to interpret genetic variation via its effects on cells and synapses – that go on to function in circuits and networks.  Easier said than done?  Yes, but perhaps not so intractable.

Here’s an example.  One of the most well studied circuits/networks/systems in the field of cognitive science are so-called basal-ganglia-thalamcortical loops.  These loops have been implicated in a great many forms of cognitive function involving the regulation of everything from movement, emotion and memory to reasoning ability.  Not surprisingly, neuroimaging studies on cognitive function almost always find activations in this circuitry.  In many cases, the data from neuroimaging and other methodologies suggests that one portion of this circuitry – the frontal cortex – plays a role in the representation of such aspects as task rules, relationships between task variables and associations between possible choices and outcomes.  This would be sort of like the “thinking” part of our mental life where we ruminate on all the possible choices we have and the ins and outs of what each choice has to offer.  Have you ever gone into a Burger King and – even though you’ve known for 20 years what’s on the menu – you freeze up and become lost in thought just as its your turn to place your order?  Your frontal cortex is at work!

The other aspect of this circuitry is the subcortical basla ganglia, which seems to play the downstream role of processing all that ruminating activity going on in the frontal cortex and filtering it down into a single action.  This is a simple fact of life – that we can be thinking about dozens of things at a time, but we can only DO 1 thing at a time.  Alas, we must choose something at Burger King and place our order.  Indeed, one of the hallmarks of mental illness seems to be that this circuitry functions poorly – which may be why individuals have difficulty in keeping their thoughts and actions straight – the thinking clearly and acting clearly aspect of healthy mental life.  Certainly, in neurological disorders such as Parkinson’s Disease and Huntington’s Disease, where this circuitry is damaged, the ability to think and move one’s body in a coordinated fashion is disrupted.

Thus, there are at least 2 main components to a complex system/circuits/networks that are involved in many aspects of learning and decision making in everyday life.  Therefore, if we wanted to understand how a gene – that is expressed in both portions of this circuitry – inflenced our mental life, we would have to interpret its function in relation to each specific portion of the circuitry.  In otherwords, the gene might effect the prefrontal (thinking) circuitry in one way and the basla-ganglia (action-selection) circuitry in a different way.  Since we’re all familiar with the experience of walking in to a Burger King and seeing folks perplexed and frozen as they stare at the menu, perhaps its not too difficult to imagine that a gene might differentially influence the ruminating process (hmm, what shall I have today?) and the action selection (I’ll take the #3 combo) aspect of this eveyday occurrance (for me, usually 2 times per week).

Nice idea you say, but does the idea flow from solid science?  Well, check out the recent paper from Cindy M. de Frias and colleagues “Influence of COMT Gene Polymorphism on fMRI-assessed Sustained and Transient Activity during a Working Memory Task.” [PMID: 19642882].  In this paper, the authors probed the function of a single genetic variant (rs4680 is the Methionine/Valine variant of the dopamine metabolizing COMT gene) on cognitive functions that preferentially rely on the prefronal cortex as well as mental operations that rely heavily on the basal-ganglia.  As an added bonus, the team also probed the function of the hippocampus – yet a different set of circuits/networks that are important for healthy mental function.  OK, so here is 1 gene who is functioning  within 3 separable (yet connected) neural networks!

The team focused on a well-studied Methionine/Valine variant of the dopamine metabolizing COMT gene which is broadly expessed across the pre-frontal (thinking) part of the circuitry and the basal-ganglia part of the circuitry (action-selection) as well as the hippocampus.  The team performed a neuroimaging study wherein participants (11 Met/Met and 11 Val/Val) subjects had to view a series of words presented one-at-a-time and respond if they recalled that a word was a match to the word presented 2-trials beforehand  (a so-called “n-back task“).  In this task, each of the 3 networks/circuits (frontal cortex, basal-ganglia and hippocampus) are doing somewhat different computations – and have different needs for dopamine (hence COMT may be doing different things in each network).  In the prefrontal cortex, according to a theory proposed by Robert Bilder and colleagues [doi:10.1038/sj.npp.1300542] the need is for long temporal windows of sustained neuronal firing – known as tonic firing (neuronal correlate with trying to “keep in mind” all the different words that you are seeing).  The authors predicted that under conditions of tonic activity in the frontal cortex, dopamine release promotes extended tonic firing and that Met/Met individuals should produce enhanced tonic activity.  Indeed, when the authors looked at their data and asked, “where in the brain do we see COMT gene associations with extended firing? they found such associations in the frontal cortex (frontal gyrus and cingulate cortex)!

Down below, in the subcortical networks, a differerent type of cognitive operation is taking place.  Here the cells/circuits are involved in the action selection (press a button) of whether the word is a match and in the working memory updating of each new word.  Instead of prolonged, sustained “tonic” neuronal firing, the cells rely on fast, transient “phasic” bursts of activity.  Here, the modulatory role of dopamine is expected to be different and the Bilder et al. theory predicts that COMT Val/Val individuals would be more efficient at modulating the fast, transient form of cell firing required here.   Similarly, when the research team explored their genotype and brain activity data and asked, “where in the brain do we see COMT gene associations with transient firing? they found such associations in the right hippocampus.

Thus, what can someone who carries the Met/Met genotype at rs4680 say to their fellow Val/Val lunch-mate next time they visit a Burger King?  “I have the gene for obesity? or impulsivity? or “this” or “that”?  Perhaps not.  The gene influences different parts of each person’s neural networks in different ways.  The Met/Met having the advantage in pondering (perhaps more prone to annoyingly gaze at the menu forever) whist the Val/Val has the advantage in the action selecting (perhaps ordering promptly but not getting the best burger and fries combo).

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ruler - STUPID INCOMPETENT MANUFACTURERS
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One of the difficult aspects of understanding mental illness, is separating the real causes of the illness from what might be secondary or tertiary consequences of having the illness.  If you think about a car whose engine is not running normally, there may be many observable things going wrong (pinging sound, stalling, smoke, vibration, overheating, loss of power, etc.) – but, what is the real cause of the problem?  What should be done to fix the car? – a faulty sparkplug or timing belt perhaps?  Such is often the problem in medicine, where a fundamental problem can lead to a complex, hard-to-disentangle, etiology of symptoms.  Ideally, you would fix the core problem and then expect the secondary and tertiary consequences to normalize.

This inherent difficulty, particularly in mental illness, is one of the reasons that genetic research is of such interest.  Presumably, the genetic risk factors are deeper and more fundamentally involved in the root causes of the illness – and hence – are preferable targets for treatment.  The recent paper, “Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability” [Arch Gen Psychiatry. 2009;66(5):467-477] seeks to ascertain whether one aspect of schizophrenia – a widespread and well-documented thinning of the neocortex – is due to genetic risk (hence something that is closer to a primary cause) or – rather – if cortical thinning is not due to genetics, and so more of a secondary consequence of things that go wrong earlier in the development of the illness.

To explore this idea, the team of Goldman et al., did something novel.  Rather than examine the differences in cortical thickness between patients and control subjects, the team evaluated the cortical thickness of 59 patients and 72 unaffected siblings as well as 196 unrelated, matched control participants.  If the cortical thickness of the siblings (who share 50% of their genetic variation) was more similar to the patients, then it would suggest that the cortical thinning of the patients was under genetic control and hence – perhaps – a biological trait that is more of a primary cause.  On the other hand, if the cortical thickness of the siblings (who share 0% of their genetic variation) was more similar to that of the healthy control participants, then it would suggest that cortical thinning was – perhaps more of a secondary consequence of some earlier deficit.

The high-resolution structural neuroimaging allowed the team to carefully assess cortical thickness – which is normally between a mere 2 and 4 millimeters – across different areas of the cortex.  The team reports that, for the most part, the cortical thickness measures of the siblings were more similar to the unrelated controls – thus suggesting that cortical thickness may not be a direct component of the genetic risk architecture for schizophrenia.  Still, the paper discusses several candidate mechanisms which could lead to cortical thinning in the illness – some of which might be assessed in the future using other imaging modalities in the context of their patient/sibling/control experimental design.

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astrocyteIf you compare the left panel to the right panel, you’ll see a dendrite (grey) with dendritic spines (green) on the left-side and then, on the right-side, these spines enveloped by the membrane of an astrocyte (white).  These images were obtained from synapse-web.org who use a method known as 3D reconstruction of serial section electron microscopy – or something like that – to better understand what types of structural factors underlie normal and abnormal synaptic function.  What is so amazing to me are the delicate ruffles of the astrocyte membrane that seem to want to ensheath each spine.  Was any organelle so gently and well cared for?  Perhaps not.  These are dendritic spines afterall – the very structures that form synaptic contacts and process the neural signals – that allow us to think and function.

It turns out that astrocytes not only seem to care for dendritic spines, but also provide the essential signal that initiates the sprouting of neuronal spines in the first place.  As covered in their recent paper, “Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis” [doi:10.1016/j.cell.2009.09.025] Eroglu and colleagues report the discovery – in mice – of CACNA2D1 the alpha-2/delta-1 subunit of the voltage-dependent calcium channel complex encodes a protein that binds to thrombospondins (humans have THBS1 and THBS2) which are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions – and are required for the formation of new dendritic spines.  When neurons are cultured in the absence of thrombospondins, they fail to produce new spines and mice that do not make thrombospondins do not make very many excitatory synaptic spines.

The interesting twist to me is that thrombospondins are secreted solely by astrocytes! The newly identified CACNA2D1 receptor – as revealed by Eroglu et al., – binds to the EGF-repeats of thrombospondin and initiates a signalling cascade that results in the sprouting of new – silent – dendritic spines.  Gabapentin, a drug that is prescribed for seizures, pain, methamphetamine addiction and many other mental health conditions appears to bind to CACNA2D1 and interfere with the binding of thrombospondin and also inhibits the formation of new spines in vitro as well during the development of somatotopic maps in the mouse whisker barrel cortex.

This seems to be an important discovery in the understanding of how cognitive development unfolds since much of the expression of thrombospondin and its effects on synaptogenesis occur in the early postnatal stages of development.  I will follow this thread in the months to come.

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SfNneuroblogbadge Phrenological thinking, a popular pseudoscientific practice in the 1800’s suggested that the structure of the head and underlying brain held the clues to understanding human behavior.  Today, amidst the ongoing convergence of developmental science, molecular & biochemical science and systems-dynamical science (to name just a few), there is – of course – no single or agreed-upon level of analysis that can provide all the answers.  Circuit dynamics are wonderfully correlated with behavior, but they can be regulated by synaptic weights.  Also,  while developmental studies reveal the far reaching beauty of neuronal circuitry, such elegant wiring is of little benefit without healthy and properly regulated synaptic connections.  Genes too, can be associated with circuit dynamics and behavior, but what do these genes do?  Perchance encode proteins that help to form and regulate synapses? Synapses, synapses, synapses.  Perhaps there is a level of analysis – or a nexus – where all levels of analysis intersect?  What do we know about synapses and how these essential aspects of brain function are formed and regulated?

With this in mind I’ve been exploring the nanosymposium, “Molecular Dynamics and Regulation at Synapses” to learn more about the latest findings in this important crossroads of neurobiology.  If you’re like me, you sort of take synapses for granted and think of them as being very tiny and sort of generic.  Delve a while into the material presented at this symposium and you may come to view the lowly synapse – a single synapse – as a much larger, more complex, ever changing biochemical world unto itself.  The number of molecular players under scrutiny by the groups presenting in this one session is staggering.  GTPase activating proteins, kinases, molecular motors, receptors, proteases, cell adhesive proteins, ion channels and many others must interact according to standard biochemical and thermodynamic laws.  At this molecular-soup level, it seems rather miraculous that the core process of vessicle-to-cell membrane fusion can happen at all – let alone in the precise way needed to maintain the proper oscillatory timing needed for Hebbian plasticity and higher-level circuit properties associated with attention and memory.

For sure, this is one reason why the brain and behavior are hard to understand.  Synapses are very complex!

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creb1According to Joseph LeDoux, “One of the most important contributions of modern neuroscience has been to show that the nature/nurture debate operates around a false dichotomy: the assumption that biology, on one hand, and lived experience, on the other, affect us in fundamentally different ways” (ref).  Indeed.  While I know not where the current debate stands, I’d like to point to a fantastic example of just how inextricably linked the genome is to the environment.  In their recent paper, “A Biological Function for the Neuronal Activity-Dependent Component of Bdnf Transcription in the Development of Cortical Inhibition” [doi:10.1016/j.neuron.2008.09.024]  Hong et al., ask what happens when you take away the ability of a given gene to respond to the environment.  This is not a traditional “knockout” experiment – where the gene is inactivated from the moment of conception onwards – but rather a much more subtle type of experimental manipulation.  What happens when you prevent nurture from exerting an effect on gene expression?

The team focused on the BDNF gene whose transcription can be initiated from any one of eight promoter sites (I-XIII).  These sites vary in activity depending on the phase of development and/or the tissue or type of cell – all of which make for a complex set of instructions able to turn the BDNF gene on and off in precise developmental and/or tissue-specific ways.  In the case of promoter IV, it appears to be triggered in the cortex in response to Ca++ release that occurs when neurons are firing – a phenomena called, “neuronal activity dependent transcription” – a top example of how the environment can influence gene expression.  Seeing as how BDNF promoter IV is important for this type of environment-induced gene expression, the team asked what happens when you remove this particular promoter?

To do this, the team constructed – keep in mind that these are – mice that contain mutations in several of the Calcium (Ca++) response elements in the promoter IV region.  They introduced point mutations so that the Ca++ sensitive protein CREB could not bind to the promoter and activate gene expression.  OK, so what happens?

Firstly, the team reports that the mutant mice are more or less indistinguishable from controls in appearance, gait, growth rate, brain size and can also reproduce and transmit the mutations.  WOW! Is that one strike AGAINST nurture? The team then shows that BDNF levels are more than 50% reduced in cultured neurons, but that levels of other immediate early genes are NOT affected (as expected).  In living animals, the effects were similar when they asked how much gene expression occurs in the sensory cortex when animals are exposed to light (after an extended period of darkness).  OK, so there are few effects, so far, other than lower levels of nurture-induced BDNF expression – hmmm. Looking more closely however, the team found that the mutant mice generated lower levels of inhibitory neuron activity – as measured by the firing of miniature inhibitory postsynaptic currents.  Follow-on results showed that the total number of inhibitory neurons (parvalbumin and NPY + GABAergic cells) was no different than controls and so it would seem that the activity dependence of BDNF is important for the maintenance of inhibitory synapses.

Hence, the team has found that what “nurture” does (via the BDNF promoter IV in this case) is to exert an effect on the connectivity of inhibitory neurons.  Wow, thanks mother nurture!  Although it may seem like an obscure role for something as important as THE environment, the team points out that the relative balance of excitation-to-inhibition (yin-yang as covered here for Rett syndrome) is crucial for proper cognitive development.

To explore the notion of inhibory/excitation balance further, check out this (TED link) video lecture, where Michael Merzenich describes this imbalance as a “signal-to-noise” problem wherein some children’s brains are rather noisy (due to any number of genetic/environmental reasons – such as, perhaps, poorly maintained inhibitory connections).  This can make it harder to develop and function in life.  Perhaps someday, the genetic/environment research like that of Hong and colleagues will inform the rehabilitative strategies developed by Merzenich.

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In previous posts, we have explored some of the basic molecular (de-repression of chromatin structure) and cellular (excess synaptogenesis) consequences of mutations in the MeCP2 gene – a.k.a the gene whose loss of function gives rise to Rett syndrome.  One of the more difficult aspects of understanding how a mutation in a lowly gene can give rise to changes in cognitive function is bridging a conceptual gap between biochemical functions of a gene product — to its effects on neural network structure and dynamics.  Sure, we can readily acknowledge that neural computations underlie our mental life and that these neurons are simply cells that link-up in special ways – but just what is it about the “connecting up part” that goes wrong during developmental disorders?

In a recent paper entitled, “Intact Long-Term Potentiation but Reduced Connectivity between Neocortical Layer 5 Pyramidal Neurons in a Mouse Model of Rett Syndrome” [doi: 10.1523/jneurosci.1019-09.2009] Vardhan Dani and Sacha Nelson explore this question in great detail.  They address the question by directly measuring the strength of neural connections between pyramidal cells in the somatosensory cortex of healthy and MeCP2 mutant mice.  In earlier reports, MeCP2 neurons showed weaker neurotransmission and weaker plasticity (an ability to change the strength of interconnection – often estimated by a property known as “long term potentiation” (LTP – see video)).   In this paper, the authors examined the connectivity of cortical cells using an electrophysiological method known as patch clamp recording and found that early in development, the LTP induction was comparable in healthy and MeCP2 mutant animals, and even so once the animals were old enough to show cognitive symptoms.  During these early stages of development, there were also no differences between baseline neurotransmission between cortical cells in normal and MeCP2 mice.  Hmmm – no differences? Yes, during the early stages of development, there were no differences between genetic groups – however – once the team examined later stages of development (4 weeks of age) it was apparent that the MeCP2 animals had weaker amplitudes of cortical-cortical excitatory neurotransmission.  Closer comparisons of when the baseline and LTP deficits occurred, suggested that the LTP deficits are secondary to baseline strength of neurotransmission and connectivity in the developing cortex in MeCP2 animals.

So it seems that MeCP2 can alter the excitatory connection strength of cortical cells.  In the discussion of the paper, the authors point out the importance of a proper balance of inhibition and excitation (yin and yang, if you will) in the construction or “connecting up part” of neural networks.  Just as Rett syndrome may arise due to such a problem in the proper linking-up of cells – who use their excitatory and inhibitory connections to establish balanced feedback loops – so too may other developmental disorders such as autism, Down’s syndrome, fragile X-linked mental retardation arise from an improper balance of inhibition and excitation.

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arinlloydCelebrities and politicians are known for their love of the spotlight.  “Me, me, me!”  are the words to get ahead by in our modern media circus.   As well, it can even be – in the unglamorous world of science – where, in characteristically geeky form, the conventional wisdom is to shout, “my hypothesis, my hypothesis, my hypothesis!”.  Once, for example, I had a grad school professor say she was not allowed by her department to teach about glial cells in her brain development class.  Another distinguished professor once told me, “don’t even bother sending a grant in,  if it is focused on white matter“.   No sir, it appears that modern neuroscience shall only focus on one main hypothesis – the neuron doctrine and not on the lowly support cells (astrocytes, oligodendrocytes & microglia) that, actually, make up more than 90% of the human brain.  Hmmm, who would have thought to find such a cult of neuronal celebrity in the halls of academia?

With this in mind, I really enjoyed the recent paper “Rett Syndrome Astrocytes Are Abnormal and Spread MeCP2 Deficiency through Gap Junctions” [doi:10.1523/jneurosci.0324-09.2009] by Maezawa and colleagues.  The authors point out several critical gaps in the literature – namely that the expression of MeCP2 (the gene that, when mutated, gives rise to Rett syndrome) in neurons does NOT account for all of the many facets of the syndrome.  For example, when MeCP2 is deleted only in neurons (in a mouse model), it results in a milder form of abnormal neural development than when deleted in all CNS cell types ( the full mouse syndrome: stereotypic forelimb motions, tremor, motor and social behavioral abnormalities, seizures, hypoactivity, anxiety-like behavior and learning/memory deficits).  Also, it is not possible to reverse or rescue these deficits when a functional version of MeCP2 is expressed under a neuron-specific promoter.  However, when re-expressed under its endogenous promoter – it is possible to rescue the syndrome (free access article).

The authors thus looked much more closely at the expression of MeCP2 and found that they could indeed visualize the expression of the MeCP2 protein in cultured ASTROCYTES – who are a very, very important type of support cell (just think of the personal secretary Lloyd to Ari Gold on the TV show “Entourage”).  The team then examined how astrocytes that lack 80% of the expression of MeCP2 might interact with neurons – the very cells they normally support with secretions of growth factors and cytokines.   It turns out that both normal and MeCP2-deficient neurons do not thrive when co-cultured with astrocytes that have weak MeCP2 expression.   The team reports that dendritic length is reduced after a day and also a fews days of co-culture,  suggesting that the MeCP2-deficient astrocytes are failing to provide the proper trophic support for their neuronal celebrity counterparts.  Short dendrites are generally considered a bad-thing since this would predict poorer connectivity, and poorer cognition across the brain.

Hence, it seems that the lowly astrocyte is far more important in understanding what goes wrong in Rett syndrome.  Ironically, in this case however, the celebrity status of the neuron remains untarnished as astrocytes can now be blamed for the consequences of MeCP2 mutations.  The authors suggest that treatment of Rett syndrome via astrocytes is a worthwhile avenue of investigation.  This new direction in the search for a cure will be an exciting story to follow!

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