Archive for the ‘Hippocampus’ Category

Probably not.  The T allele at rs7294919  (“each copy of the T allele was associated with lower hippocampal volume (β=−107.8 mm3, p=2.9×10-11)” )  is very common … like 75%-ish … so, yeah, thanks for my TT genotype Mother Nature … and for yet another part of my body that is, um, small.

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Zen meditators are famous for their equanimity in the face of physical discomfort.  How do they do it?  Well, according to a recent neuroimaging investigation, it may be because they do not “think” about pain.  Rather, they just “experience” pain:

An ancient Eastern text describes two temporally distinct aspects of pain perception; the direct experience of the sensation and habitual, negative, mentation which follows. It was suggested that the so-called ‘second dart’ of pain could be removed via meditative training, obliterating the suffering associated with noxious stimulation.

It’s a subtle distinction … to just experience something in the moment  vs. to ruminate on it and its causes, consequences, duration, etc.  How many times have you heard the sage advice, just let it go?  Is this what the brain imaging shows … that the meditators are not ruminating (they have decreased activity in parts of the brain involved in ruminating) … they have experienced the pain and then let it go?  Experience and forget?

Reminded me of an interesting little protein named DREAM.  Interesting because it modulates pain (when DREAM is inactivated in experimental mice the animals feel no pain) and interesting also because the gene plays a role in the formation of memories (mice show poor contextual fear memory when the gene is inactivated).

Experience and forget.  A Zen teaching encoded in our DNA?

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Wobble base pair guanine uracil (GU)

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Hands shake and wobble as the decades pass … moreso in some.

A recently evolved “T” allele (rs12720208) in the  3′ untranslated region (3′ UTR) of the FGF20 gene has been implicated in the risk of Parkinson’s Disease … namely by creating a wobbly G:U base-pair between microRNA-433 (miR-433) and the FGF20 transcript.  Since the normal function of microRNA-433 is to repress translation of proteins (such as FGF20), it is suspected that the PD risk “T” allele carriers make relatively more FGF20 … which, in turn … leads to the production of higher levels of alpha-synuclein (the main component of Lewy body fibrils, a pathological marker of diseases such as PD).  This newly evolved T-allele has also been associated with brain structural differences in healthy individuals.

My hands will shake and wobble as the decades pass … but not because I carry the G:U wobble pairing between miR-433:FGF20.  My 23andMe profile shows that I carry 2 C alleles and will produce the thermodynamically favorable G:C pairing.  Something to keep in mind as I lose my mind in the decades to come.

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Have you ever suddenly realized, “OMG, I’m just like my dad (or mom)!”  Oh, the horror .. the horror.  Here’s John Updike from A Month of Sundays:

Also my father, who in space-time occupied a stark room of a rest home an hour distant, which he furnished with a vigorous and Protean suite of senility’s phantoms, was in a genetic dimension unfolding within me, as time advanced, and occupying my body like, as Colette had written to illustrate another phenomenon, a hand being forced into a tight glove.

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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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remember a day before today
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Most cells in your adult body are “terminally differentiated” – meaning that they have developed from stem cells into the final liver, or heart, or muscle or endothelial cell that they were meant to be.  From that point onward, cells are able to “remember” to stay in this final state – in part – via stable patterns of DNA methylation that reinforce the regulation of “the end state” of gene expression for that cell.  As evidence for this role of DNA methylation, it has been observed that levels of DNA methyl transferase (DNMT) decline when cells are fully differentiated and thus, cannot modify or disrupt their patterns of methylation.

NOT the case in the brain! Even though neurons in the adult brain are fully differentiated, levels of methyl transferases – DO NOT decline.  Why not? Afterall, we wouldn’t want our neurons to turn into liver cells, or big toe cells, would we?

One hypothesis, suggested by David Sweatt and colleagues is that neurons have more important things to “remember”.   They suggest in their fee and open research article, “Evidence That DNA (Cytosine-5) Methyltransferase Regulates Synaptic Plasticity in the Hippocampus” [doi: 10.1074/jbc.M511767200] that:

DNA methylation could have lasting effects on neuronal gene expression and overall functional state. We hypothesize that direct modification of DNA, in the form of DNA (cytosine-5) methylation, is another epigenetic mechanism for long term information storage in the nervous system.

By measuring methylated vs. unmethylated DNA in the promoter of the reelin and BDNF genes and relating this to electrophysiological measures of synaptic plasticity, the research team finds correlations between methylation status and synaptic plasticity.  More specifically, they find that zebularine (an inhibitor of DNMT) CAN block long-term potentiation (LTP), but NOT block baseline synaptic transmission nor the ability of synapses to fire in a theta-burst pattern (needed to induce LTP).

This suggests that the epigenetic machinery used for DNA methylation may have a role in the formation of cellular memory – but not in the same sense as in other cells in the body – where cells remember to remain in a terminally differentiated state.

In the brain, this epigenetic machinery may help cells remember stuff that’s more germane to brain function … you know … our memories and stuff.

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The human brain has some 100 billion neurons.  That sounds like a lot, but I’m still keen on keeping ALL of mine healthy and in good working order.  One way that cells protect themselves from damage and untimely death is by protecting their DNA – by wrapping it up and coiling it tightly – using chromatin proteins – which keeps it away from chemical and viral damage.  This is especially important in the brain, since – unlike the skin or gut – we can’t really re-grow brain tissue once its damaged.  We have to protect the neurons we have!

Here’s the problem. In order to USE the BRAIN (to learn and remember stuff) we have to also USE the GENOME (to encode the proteins that synapses use in the process of memory formation).  When we’re thinking, we have to take our precious DNA out of its protective supercoiled, proteinaceous shell and allow the double helix to melt into single strands and expose their naked A’s, G’s, T’s and C’s to the chemical milieu (to the start the transcription process).  This is risky business damage to DNA can lead to cell death!

One might imaging that its best to carry out this precarious act quickly and in proximity to DNA repair enzymes (I’d think).  A very important job that includes: uncoiling chromatin superstructures, transcribing DNA (that encodes proteinaceous building blocks that synapses use to strengthen and weaken themselves) – and then – making sure there was no damage incurred along the way.  A BIG job that MUST get done each and every time my cells engage in learning.  Wow!  I didn’t realize that learning new stuff means I’m exposing my DNA to damage?  Hmm … I wonder if that PhD was worth it?

To perform this important job, it seems there is an amazing handyman of a molecule named poly(ADP-ribose) polymerase-1 (PARP-1).  Amazing, because it – itself – can function in many of the steps involved in uncoiling chromatin structures, transcription initiation and DNA repair.  The protein that can “do it all” … get the job done quickly and even fix any errors made along the way! It is known to function in the so-called base excision repair (BER) pathway and is also known have a role in transcription through remodeling of chromatin by ADP-ribosylating histones and relaxing chromatin structure, thus allowing transcription to occur (click here for a great open review of PARP-1).  Nice!

According to OMIM, earlier studies by Cohen-Armon et al. (2004) found that poly(ADP-ribose) polymerase-1 is activated in neurons that mediate several forms of long-term memory in Aplysia. Because poly(ADP-ribosyl)ation of nuclear proteins is a response to DNA damage in virtually all eukaryotic cells (indeed, PARP-1 knock-out mice are more sensitive to DNA damage), it was surprising that activation of the polymerase occurred during learning and was required for long-term memory. Cohen-Armon et al. (2004) suggested that the fast and transient decondensation of chromatin structure by poly(ADP-ribosyl)ation enables the transcription needed to form long-term memory without strand breaks in DNA.

A recent article in Journal of Neuroscience seems to confirm this function –  now in the mouse brain.  Histone H1 Poly[ADP]-Ribosylation Regulates the Chromatin Alterations Required for Learning Consolidation [doi:10.1523/JNEUROSCI.3010-10.2010] by Fontán-Lozano et al., examined cells in the hippocampus at different times during the learning of an object recognition paradigm.  They confirm (using a PARP-1 antagonist) that PARP-1 is needed to establish object memory and also that PARP-1 seems to contribute during the paradigm and up to 2 hours after the training session.  They suggest that the poly(ADP-ribosyl)ation of histone H1 influences whether H1 is bound or unbound and thus helps regulate the opening and closing of the chromatin so that transcription can take place. 

Nice to know that PARP-1 is on the job!  Still am wondering if the PhD was worth all the learning.  Are there trade-offs at play here?  MORE learning vs. LESS something?   Perhaps. Check out the paper by Grube and Bürkle (1992) – Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span. This gene may influence life span!

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In his undergraduate writings while a student at Harvard in the early 1900’s E. E. Cummings quipped that, “Japanese poetry is different from Western poetry in the same way as silence is different from a voice”.  Isabelle Alfandary explores this theme in Cummings’ poetry in her essay, “Voice and Silence in E. E. Cummings’ Poetry“,  giving some context to how the poet explored the meanings and consequences of voice and silence.  Take for example, his poem “silence”




ing;edge, of

(inquiry before snow

e.e. cummings

Lately, it seems that the brain imaging community is similarly beginning to explore the meanings and consequences of the brain when it speaks (activations whilst performing certain tasks) and when it rests quietly.  As Cummings beautifully intuits the profoundness of silence and rest,  I suppose he might have been intrigued by just how very much the human brain is doing when we are not speaking, reading, or engaged in a task. Indeed, a community of brain imagers seem to be finding that the brain at rest has quite a lot to say – moreso in people who carry certain forms of genetic variation (related posts here & here).

A paper by Perrson and colleagues “Altered deactivation in individuals with genetic risk for Alzheimer’s disease” [doi:10.1016/j.neuropsychologia.2008.01.026] asked individuals to do something rather ordinary – to pay attention to words – and later to then respond to the meaning of these words (a semantic categorization task). This simple endeavor, which, in many ways uses the very same thought processes as used when reading poetry, turns out to activate regions of the temporal lobe such as the hippocampus and other connected structures such as the posterior cingulate cortex.  These brain regions are known to lose function over the course of life in some individuals and underlie their age-related difficulties in remembering names and recalling words, etc.  Indeed, some have described Alzheimer’s disease as a tragic descent into a world of silence.

In their recordings of brain activity of subjects (60 healthy participants aged 49-79), the team noticed something extraordinary.  They found that there were differences not in how much the brain activates during the task – but rather in how much the brain de-activates – when participants simply stare into a blank screen at a small point of visual fixation.  The team reports that individuals who carry at least one copy of epsilon-4 alleles of the APOE gene showed less de-activation of their their brain (in at least 6 regions of the so-called default mode network) compared to individuals who do not carry genetic risk for Alzheimer’s disease.  Thus the ability of the brain to rest – or transition in and out of the so-called default mode network – seems impaired in individuals who carry higher genetic risk.

So, I shall embrace the poetic wisdom of E. E. Cummings and focus on the gaps, empty spaces, the vastness around me, the silences, and learn to bring my brain to rest.  And in so doing, perhaps avoid an elderly descent into silence.


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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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We are all familiar with the notion that genes are NOT destiny and that the development of an individual’s mind and body occur in a manner that is sensitive to the environment (e.g. children who eat lots of healthy food grow bigger and stronger than those who have little or no access to food).  In the case of the brain, one of the ways in which the environment gets factored into development – is via so-called “sensitive periods” where certain parts of the brain transiently rely on sensory experience in order to develop.  Children born with cataracts, for example, will have much better vision if the cataracts are removed in the first few weeks of life rather than later on.  This is because the human visual system has a “sensitive period” early in development where it is extra-sensitive to visual input and, after which, the function and connectivity of various parts of the system is – somewhat permanently – established for the rest of the person’s life.  Hence, if there is little visual input (cataracts) during the sensitive period, then the visual system is somewhat permanently unable to process visual information – even if the cataracts are subsequently removed.  (To learn more about this topic, visit Pawan Sinha’s lab at M.I.T and his Project Prakash intervention study on childhood blindness.)

What the heck is an “in”sensitive period then?   Well, whereas visual input is clearly a “good thing” for the sensitive period of visual development, perhaps some inputs are “bad” and it may be useful to shield or protect the brain from exposure.  Maybe some environmental inputs are “bad” and one would not want the developing brain to be exposed to them and say, “OK, this (bad stuff) is normal“.  As a parent, I am constantly telling my children that the traffic-filled street is a “bad place” and, like all parents, I would not want my children to think that it was OK to wander into the street.  Clearly, I want my child to recognize the car-filled street as a “bad thing”.

In the developing brain, it turns out that there are some “bad things” that one would NOT like (the brain) to get accustomed to.  Long-term exposure to glucocorticoids is one example – well-known to cause a type of neuronal remodelling in the hippocampus, that is associated with poor cognitive performance (visit Bruce McEwen’s lab at Rockefeller University to learn more about this).  Perhaps an “in”sensitive period – where the brain is insensitive to glucocorticoids – is one way to teach the brain that glucocorticoids are “bad” and DO NOT get too familiar with them (such a period does actually occur during early post-natal mammalian development).  Of course, we do need our brains to mount an acute stress response, if and when, we are being threatened, but it is also very important that the brain learn to TURN-OFF the acute stress response when the threat has passed – an extensive literature on the deleterious effects of chronic exposure to stress bears this out.  Hence, the brain needs to learn to recognize the flow of glucocorticoids as something that needs to be shut down.

OK, so our developing brain needs to learn what/who is “good vs. bad”.  Perhaps sensitive and insensitive periods help to reinforce this learning – and also – to cement learning into the system in a sort of permanent way (I’m really not sure if this is the consensus view, but I’ll try and podcast interview some of the experts here asap).  In any case, in the case of the visual system, it is clear that the lack of visual input during the sensitive period has long lasting consequences.  In the case of the stress response, it is also clear that if there is untoward stress early in development, one can be (somewhat) destined to endure a lifetime of emotional difficulty.  Previous posts here, here, here cover research on behavioral/genomic correlates of early life stress.

Genes meet environment in the epigenome during sensitive and insensitive periods?

As stated at the outset – genes are not destiny.  The DNA cannot encode a system that knows who/what is good vs. bad, but rather can only encode a system of molecular parts that can assemble to learn these contingencies on the fly.  During sensitive periods in the visual system, cells in the visual system are more active and fire more profusely during the sensitive period. This extra firing leads to changes in gene expression in ways that (somewhat) permanently set the connectivity, strength and sensitivity of visual synapses.  The expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections are well-known tagets of activity-induced gene expression.  Hence the environment “interacts” with the genome via neuronal firing which induces gene expression which – in turn – feeds back and modulates neuronal firing.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Similarly, in the stress response system, the environment induces changes in the firing of cells in the hypothalamus which leads (through a series of intermediates) to the release of glucocorticoids.  Genes induced during the firing of hypothalamic cells and by the release of glucocorticoid can modify the organism’s subsequent response to stressful events.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Digging deeper into the mechanism by which neuronal firing induces gene expression, we find an interesting twist.   Certainly there is a well-studied mechanism wherein neuronal firing causes Ca++ release which activates gene expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections – for many decades.  There is another mechanism that can permanently mark certain genes and alter their levels of expression – in a long-lasting manner.  These are so-called epigenetic mechanisms such as DNA methylation and acetylation.  As covered here and here, for instance, Michael Meaney’s lab has shown that DNA CpG methylation of various genes can vary in response to early-life stress and/or maternal care. In some cases, females who were poorly cared for, may, in turn, be rather lousy mothers themselves as a consequence of these epigenetic markings.

A new research article, “Dynamic DNA methylation programs persistent adverse effects of early-life stress” by Chris Murgatroyd and colleagues [doi:10.1038/nn.2436] explores these mechanisms in great detail.  The team explored the expression of the arginine vasopressin (AVP) peptide – a gene which is important for healthy social interaction and social-stress responsivity.  Among many other interesting results, the team reports that early life stress (using a mouse model) leads to lower levels of methylation in the 3rd CpG island which is located downstream in a distal gene-expression-enhancer region.  In short, more early-life stress was correlated with less methylation, more AVP expression which is known to potentiate the release of glucocorticoids (a bad thing).   The team reports that the methyl binding MeCP2 protein, encoded by the gene that underlies Rett syndrome, acts as a repressor of AVP expression – which would normally be a good thing since it would keep AVP levels (and hence glucocorticoid levels) down.  But unfortunately, early-life stress removes the very methyl groups to which MeCP2 binds and also the team reports that parvocelluar neuronal depolarization leads to phosphorylation (on serine residue #438) of MeCP2 – a form of MeCP2 that is less accessible to its targets.  So, in  a manner similar to other examples, early life stress can have long-lasting effects on gene expression via an epigenetic mechanism – and disables an otherwise protective mechanism that would shield the organism from the effects of stress.  Much like in the case of Rett syndrome (as covered here) it seems that when MeCP2 is bound – then it silences gene expression – which would seem to be a good thing when it comes to the case of AVP.

So who puts these epigenetic marks on chromosomes and why?

I’ll try and explore this further in the weeks ahead.  One intriguing idea about why methylation has been co-opted among mammals, has to do with the idea of parent-offspring conflict.  According to David Haig, one of the experts on this topic, males have various incentives to cause their offspring to be large and fast growing, while females have incentive to combat the genomic tricks that males use, and to keep their offspring smaller and more manageable in size.  The literature clearly show that genes that are marked or methylated by fathers (paternally imprinted genes) tend to be growth promoting genes and that maternally imprinted genes tend to be growth inhibitors.  One might imagine that maternally methylated genes might have an impact on maternal care as well.

Lastly, the growth promoting/inhibiting effects of paternal/maternal genes and gene markings is now starting to be discussed somewhat in the context of autism/schizophrenia which have have been associated with synaptic under-/over-growth, respectively.

Building a brain is already tough enough – but to have to do it amidst an eons-old battle between maternal and paternal genomes.  Sheesh!  More on this to come.

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DCDC2 (gene)
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A recent analysis of brain structure in healthy individuals who carry a common 2,445-bp deletion in intron 2 of the doublecortin domain containing 2 (DCDC2) gene found that heterozygotes for the deletion showed higher grey matter volumes for several brain areas known to be involved in the processing of written and spoken language (superior, medial and inferior temporal cortex, fusiform, hippocampal / parahippocampal, inferior occipito-parietal, inferior and middle frontal gyri, especially in the left hemisphere) [doi:10.1007/s11682-007-9012-1].  The DCDC2 gene sits within a well known locus frequently found to be associated with developmental dyslexia, and associations of reading disability with DCDC2 have been confirmed in population-based studies.  dcdc2rnai Further work on DCDC2 (open access) shows that the DNA that is deleted in the 2,445-bp deletion in intron 2 carries a number of repeating sequences to which developmental transcription factors bind and that inhibition of DCDC2 results in altered neuronal migration (the right-hand panel shows altered radial migration when DCDC2 is inhibited).  Perhaps the greater grey matter volumes are related to this type of neuronal migration finding?  Will be interesting to follow this story further!

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Joseph LeDoux‘s book, “Synaptic Self: How Our Brains Become Who We Are” opens with his recounting of an incidental glance at a t-shirt, “I don’t know, so maybe I’m not” (a play on Descartes’ cogito ergo sum) that prompted him to explore how our brain encodes memory and how that leads to our sense of self.  More vividly, Elizabeth Wurtzel, in “Prozac Nation” recounts, “Nothing in my life ever seemed to fade away or take its rightful place among the pantheon of experiences that constituted my eighteen years. It was all still with me, the storage space in my brain crammed with vivid memories, packed and piled like photographs and old dresses in my grandmother’s bureau. I wasn’t just the madwoman in the attic — I was the attic itself. The past was all over me, all under me, all inside me.” Both authors, like many others, have shared their personal reflections on the fact that – to put it far less eloquently than LeDoux and Wurtzl – “we” or “you” are encoded in your memories, which are “saved” in the form of synaptic connections that strengthen and weaken and morph through age and experience.  Furthermore, such synaptic connections and the myriad biochemical machinery that constitute them, are forever modulated by mood, motivation and your pharmacological concoction du jour.

Well, given that my “self” or “who I think of as myself” or ” who I’m aware of at the moment writing this blog post” … you get the neuro-philosophical dilemma here … hangs ever so tenuously on the biochemical function of a bunch of tiny little proteins that make up my synaptic connections – perhaps I should get to know these little buggers a bit better.

OK, how about a gene known as kalirin – which is named after the multiple-handed Hindu goddess Kali whose name, coincidentally, means “force of time (kala)” and is today considered the goddess of time and change (whoa, very fitting for a memory gene huh?).  The imaginative biochemists who dubbed kalirin recognized that the protein was multi-handed and able to interact with lots of other proteins.  In biochemical terms, kalirin is known as a “guanine nucleotide exchange factor” – basically, just a helper protein who helps to activate someone known as a Rho GTPase (by helping to exchange the spent GDP for a new, energy-laden GTP) who can then use the GTP to induce changes in neuronal shape through effects on the actin cytoskeleton.  Thus, kalirin, by performing its GDP-GTP exchange function, helps the actin cytoskeleton to grow.  The video below, shows how the actin cytoskeleton grows and contracts – very dynamically – in dendrites that carry synaptic spines – whose connectivity is the very essence of “self”.  Indeed, there is a lot of continuing action at the level of the synapse and its connection to other synapses, and kalirin is just one of many proteins that work in this dynamic, ever-changing biochemical reaction that makes up our synaptic connections.

In their paper”Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes” [doi: 10.1073/pnas.0904636106] Michael Cahill and colleagues put this biochemical model of kalirin to the test, by examining a mouse whose version of kalirin has been inactivated.  Although the mice born with this inactivated form are able to live, eat and breed, they do have significantly less dense patterns of dendritic spines in layer V of the frontal cortex (not in the hippocampus however, even though kalirin is expressed there).  Amazingly, the deficits in spine density could be rescued by subsequent over-expression of kalirinHmm, perhaps a kalirin medication in the future? Further behavior analyses revealed deficits in memory that are dependent on the frontal cortex (working memory) but not hippocampus (reference memory) which seems consistent with the synaptic spine density findings.

Lastly, the authors point out that human kalirin gene expression and variation has been associated with several neuro-psychiatric conditions such as schizophrenia, ADHD and Alzheimer’s Disease.   All of these disorders are particularly cruel in the way they can deprive a person of their own self-perception, self-identity and dignity.  It seems that kalirin is a goddess I plan on getting to know better.  I hope she treats “me” well in the years to come.

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Among the various (and few) significant results of recent landmark whole-genome analyses (involving more than 54,000 participants) on schizophrenia (covered here and here), there was really just one consistent result – linkage to the 6p21-22 region containing the immunological MHC loci.  While there has been some despair among professional gene hunters, one man’s exasperation can sometimes be a source of great interest and opportunity for others – who – for many years – have suspected that early immunological infection was a key risk factor in the development of the disorder.

Such is the case in the recent paper, “Prenatal immune challenge induces developmental changes in the morphology of pyramidal neurons of the prefrontal cortex and hippocampus in rats” by Baharnoori et al., [doi: 10.1016/j.schres.2008.10.003].  In this paper, the authors point out that Emil Kraepelin, who first described the disorder we now call schizophrenia, had suggested that childhood inflammation of the head might be an important risk factor.  Thus, the immunopathological hypothesis has been around since day 0 – a long time coming I suppose.

In their research article, Baharnoori and colleagues have taken this hypothesis and asked, in a straightforward way, what the consequences of an immunological challenge on the developing brain might look like.  To evaluate this question, the team used a Sprague-Dawley rat model and injected pregnant females (intraperitoneally on embryonic day 16) with a substance known as lipopolysaccharide (LPS) which is known to mimic an infection and initiate an immune response (in a manner that would normally depend on the MHC loci found on 6p21-22). Once the injections were made, the team was then able to assess the consequences to various aspects of brain and behavior.

In this paper, the team focused their analysis on the development of the frontal cortex and the hippocampus – 2 regions that are known to function poorly in schizophrenia.  They used a very, very focused probe of development – namely the overall shape, branching structure and spine formations on pyramidal cells in these regions – via a method known as Golgi-Cox staining.  The team presents a series of fantastically detailed images of single pyramidal cells (taken from postnatal day 10, 35 and 60) from animals who’s mothers were immunologically challenged and those who were unexposed to LPS.

Briefly, the team finds that the prenatal exposure to LPS had the effect of reducing the number of dendritic spines (these are the aspects of a neuron that are used to make synaptic connections with other neurons) in the developing offspring.  Other aspects of neuronal shape were also affected in the treated animals – basically amounting to a less branchy, less spiny – less connectable – neuron.  If that’s not a basis for a cognitive disorder than what else is?  Indeed, the authors point out that such spines are targets – in early development – for interneurons that are essential for long-range gamma oscillations that help distant brain regions function together in a coherent manner (something that notably does not happen in schizophrenia).

Thus, there is many a reason (54,000 strong) to want to better understand the neuro-immuno-genetic-developmental mechanisms that can alter neuronal structure.  Exciting progress in the face of recent genetic setbacks!

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Few genes have been studies as intensely as apolipoprotein E (APOE).  In particular, one of its variants, the epsilon-4 allele has been especially scrutinized because it is correlated with an earlier onset (about 10 years earlier than average) of Alzheimer’s Disease.  Among the many roles of APOE – its just a tiny cholesterol binding protein – are those as participant in synaptic plasticity, early neural development, damage-response and other processes – all of which share the need for the synthesis and movement of neuronal membranes (see the fluid mosaic model) and their component parts – such as cholesterol.   Hence, whenever neural membranes are being synthesized (plasticity & development) or damaged (overstimulation and other sources of oxidative damage) the tiny APOE is there to help with its membrane stabilizing cholesterol molecule in hand. Over the course of a lifetime, routine damage to neuronal membranes adds up (particularly in the hippocampus where constant storage-recall memory functions place enormous demands on synaptic plasticity systems), and individuals (such as epsilon-4 carriers) may simply show more wear-and-tear because their version of APOE is not as optimal as the other forms (epsilon-2 and -3).

apoeWith this etiological model in mind, perhaps you would like to take better care of you cell membranes (much like your car mechanic implores to change your car’s spark plugs and oil to keep the engine clean on the inside).  Moreover, perhaps you would like to do-so especially if you knew that your APOE system was less optimal than average.  Indeed, results from the recent REVEAL study suggest that folks who are in their 50’s are not unduly distressed to make this genetic inquiry and find out their genotypic status at this APOE polymorphism – even though those who discovered that they were epsion-4 carriers reported more negative feelings, understandably.  Still, with a number of education and intervention strategies available, an optimistic outlook can prevail.

Furthermore, there are ever newer diagnostic strategies that can improve the rather weak predictive power of the genetic test.  For example, cognitive assessments that measure hippocampal-dependent aspects of memory or visual orienting have been shown to be valid predictors of subsequent dementia – even moreso in populations that carry the APOE epsilon-4 allele.  Other forms of neuroimaging that directly measure the structure and function of the hippocampus also have tremendous sensitivity (here for a broad review of imaging-genetics of AD) and can, in principle, provide a more predictive view into one’s distant future.

On the very cutting edge of this imaging-genetic crystal ball technology, lies a recent paper entitled, “Distinct patterns of brain activity in young carriers of the APOE-e4 allele” by Fillippini and colleagues [doi: 10.1073/pnas.0811879106].  Here, the research team asks whether individuals in their late 20’s show structural/functional brain differences that are related to APOE genotype.  They employ various forms of imaging analysis such as a comparison of brain activity when subjects were performing a novel vs. familiar memory task and also an analysis of so-called resting state networks – which reflect a form of temporal coherence (brain areas that oscillate in-sync with each other when subjects are lying still and doing nothing in the scanner).  For the analysis of the memory task, the team found that APOEe4 carriers showed more activation in the hippocampus as well as other brain regions like the anterior midbrain and cerebellum.  When the team analysed a particular resting state network – the default mode network – they found differences in the medial temporal lobe (containing head of the hippocampus and amygdala) as well as the medial prefronal cortex.  According to the paper, none of these differences could be explained by differences in the structure or resting perfusion of the young-adult brains in the study.

Wow, these results seem to suggest that decades before any mild cognitive impairments are observable, there are already subtle differences in the physiology of the APOEe4 brain – all of which could be detected using the data obtained in 6 minutes of rest. 6 minutes of rest and spit in a cup – what does the future hold?

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Having blogged here several times on various and sundry roles of BDNF in cognitive function, it was pretty cool to see the recent paper, “Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease” [doi: 10.1073/pnas.0901402106].  It seems that in a transgenic mouse model for Alzheimer’s Disease that injection of neural stem cells into the plaqued/tangled hippocampus can rescue hippocampal-dependent behaviors.  This rescue however, seems to have been dependent on the secretion of BDNF since knock-down of BDNF ablated the rescue, while increasing BDNF improved the rescue.  The stem-cell treatment did not however reduce levels of plaques or tangles but did increase synaptic density – which I’d be happy to have more of – plaques/tangles notwithstanding.  Promising findings!

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Just a salute to Carol L. Thompson and her colleagues at the Allen Institute for Brain Science (Seattle, WA) on their paper entitled,  “Genomic Anatomy of the Hippocampus” [doi: 10.1016/j.neuron.2008.12.008] or (email the corresponding author for a copy).

This paper (and much of the work from the Allen Institute) could be filed under the lonstanding cry heard among grad students, “if every neuron is connected to every neuron, how will we ever make sense of the brain?”  The present paper is an excellent example of how cells within a particular structure – in this case the hippocampus – can be specialized in terms of their structure and connectivity.  Not surprisingly, the differences in structure and connectivity are driven, in part, by differential gene expression, which this group has ably made sense of.  There are a number of great figures that tell the story, but for me, the $$ shot is Figure 3 showing that their “statistical reduction” analysis of 20,000 unique transcripts in the mouse brain led to the identification and 3D-reconstruction of 9 discrete zones of gene expression within the hippocampus.  Further analysis of cell adhesion genes (cadherins, collagens, IgG superfamily) and axon guidance genes (ephrins, slits, robos, semaphorins) showed that these 9 regions differ in their combinatorial expression of these molecules.  Thus, the 9 regions of the hippocampus may reflect different zones in incoming (afferent) and outgoing (efferent) neural transmission (they confirm this for CA3 projections to the lateral septum using retrograde labeling).

At some point in the future, as genetic associations with memory and other hippocampal functions are identified, it may be possible to use this type of atlas (there is a human Allen Brain Atlas atlas in the works) to better understand what functional subdivisions and therefore, what type of circuitry is involved in individual differences in hippocampal function.  A possibility I hope I’ll not soon forget.

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Turn and Cry
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It is commonly known that some of us handle stress better than others.  Some can calmly accept the dire economic news of an impending layoff while others may fret incessantly day-in-and-out and endure many a sleepless night.  Why ?  What are some of the brain systems that mediate the effects of accute and chronic stress ? What genetic and environmental differences might influence the development of these systems ?

In an ongoing set of experiments, Professor Michael Meaney’s laboratory has focused on the role of the glucocorticoid receptor (GR) and its role as a feedback modulator in the so-called hypothalamic-pituitary-adrenal (HPA) axis.  A number of experiments have shown that upregulation of the GR is somewhat beneficial insofar as it dampens the deleterious rise of circulating corticosteroids during stress.  Therefore, any mechanism that downregulates or blocks the expression of GR may make it harder for a person to cope with the typical physiologic responses (increases in corticosteroids) to stressful experiences (news of a layoff).

What Professor Meaney’s lab has shown so convincingly over the past several years is that individual differences in the reactivity of the HPA system are heavily influenced by maternal and early life experience.  That is, offspring (often rat or mouse pups) who have attentive mothers who keep them warm and well groomed, have more responsive HPA systems that more readily dampen the deleterious rise of corticosteroids in response to steroids.  In some cases, the level of maternal care is enough to modify the level of CpG methylation in the promoter region of the glucocorticoid receptor.  This type of “epigenetic” form of gene regulation is a way in which the promoter region can be altered in a long-term manner given a particular early-life experience.  Unfortunately, this type of epigenetic mark, can lead to life-long difficulty in managing stress.

Their recent paper, “Epigenetic regulation of the glucocorticoid receptor in human brain associates with child abuse” [doi 10.1038/nn.2270]  explores the extent of CpG methylation in post-mortem tissue (hippocampus) from 24 individuals who tragically passed away in completion of suicide.  The research team compared the levels of methylation (via bisulfite mapping) in the GR promoter region and found that there was significantly more methylation in (n=12) individuals who had a recorded history of childhood abuse (sexual contact, severe physical abuse and/or severe neglect) as compared to (n=12) individuals with no history of abuse (their CpG levels were not distinguishable from control tissue).  Thus (as confirmed by qRT-PCR) it seems as if epigenetic marks were visible in the genomes of hippocampal cell nuclei – which may have very well been written during early childhood trauma – and may have exacerbated the difficulties these individuals may have had in coping with psychosocial stress.

Further studies conducted by the team evaluate the possibility that the sites of abuse-induced-CpG methylation have the effect of blocking the binding of the EGR1 transcription factor which provides an additional mechanistic part in a larger complex of proteins that transduce the effects of experience into long-lasting behavioral predispositions.

For more on the exciting rise of epigenetics and its role in nature-meets-nuture and cognitive development click here.

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Few may pause on February 12 to note the 200 year anniversary of the birth of Charles Darwin and 150 years since the publication of  “On the Origin of Species” (click here to download).  To some extent, this may be expected since much of the controversy  (creator vs. autonomous biochemical processes) seems to have abated – NOT.  Politically, the issues are still red hot – in Kansas – and elsewhere across the globe.

But what about the science ?  Do we accept the basic tenets of evolution by way of genetic variation and natural selection ?  For goodness sake, I mean, we’ve just about (or soon will have) sequenced every living organsim-on-the-planet’s genome.  Surely there is no doubt about the validity of the so-called neo-Darwinian synthesis of basic/population genetics and the theory of evolution by natural selection.   Is there ?  Perhaps you can’t blame folks for trying to poke holes (as covered extensively by Sandwalk), especially on the big 200th anniversary.

One place where I am hearing some buzz on the teetering of neo-Darwinism and the Modern Synthesis lately is in the area of epigenetics.   Consider the paper by Arai et al., entitled, “Transgenerational rescue of a genetic defect in long-term potentiation and memory formation by juvenile enrichment” [doi: 10.1523/jneurosci.5057-08.2009].  In this paper, the researchers measured a trait known as long-term potentiation (LTP), wherein a synapse fires in a longer and stronger fashion.  This type of potentiation is thought to be a basic mechanism that neural networks use in learning and memory formation.  In their paper, the team found that certain synapses in the hippocampus were potentiated when animals were exposed to an “enriched” environment (normally mice are caged in empty bins lined with woodchips, but an enriched environment is one filled with tunnels, hidden passages, toys, ropes to climb & other stuff to discover and learn about).  The team shows that, in response to an enriched environment, the mice acquire the LTP trait.

The next thing the team found was that the offspring of female (but not male) mice that had acquired the LTP trait – did also show the LTP trait – even when they, themselves, did not experience the enriched environment.  Thus, the so-called acquired trait (LTP) was inherited by the offspring.  Hmmmm – sounds a bit Lamarckian to me, or, as the authors of this research article suggest, “Lamarckian-like”.  Is this a case that violates core tenets of the modern synthesis ?  Does it besmirch Darwin on his 200th birthday ?

No.  Here’s why in a nutshell.  The LTP trait is not passaged via the female germ line.  That is, the physiological and genetic (gene expression) changes that lead to LTP in the mothers are not encoded in the genome of her eggs.  Indeed, her haploid egg cells were set aside long, long before she ever experienced the enriched environment and acquired the LTP trait.  Rather the effect is one that seems to be dependent on her uterine environment and ability to transfer information from unterine milieu to developing offspring – whose developing brains seem to be endowed with the molecular components needed to facilitate LTP.  Figure 4c of the paper shows that the LTP trait was lost in the F2 generation – therefore the effect is not stably transmitted via the germline (as plain vanilla DNA mutations are).

For an overview of the complexities of incorporating the Central Dogma of Molecular Biology into the Theory of Evolution by Natural Selection, read chapter 4 (p76) Weismann, Lamarck and The Central Dogma of John Maynard Smith‘s book “The Theory of Evolution“.  Maynard Smith credits August Weismann’s germ plasm theory as a key factor in the modern synthesis since – by sequestering the germ line very early in development – acquired characteristics cannot be inherited via egg & sperm.  Hence, Lamarckian evolution is (in principle) not possible.  This seems to be the case here with the LTP trait.  In this spirit, the authors do a great job of reviewing other similar examples of how a mother’s uterine environment can lead to epigenetic modifications (click here for review article and here for a PLoS paper on the topic) – such as the viable yellow locus in the mouse [PMID: 18673496] and the effects of endocrine disruptors on methylation of germ cells [PMID: 16973726].

Well, it is amazing indeed how Darwin’s work continues to inspire us.  Happy 200th Birthday !

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Vascular endothelial growth factor AImage via Wikipedia The mitogenic activities of the vascular endothelial growth factor protein family are well researched. A number of findings have linked this gene to learning and memory and hippocampal-dependent response to antidepressant medication. Indeed, its reasonable to expect that a mitogen such as VEGF would regulate hippocampal cell division and the accompanying benefits of new brain cells. Using high resolution structural MRI, Blumberg and team report evidence for such in their paper, “Influence of Vascular Endothelial Growth Factor Variation on Human Hippocampus Morphology“. Individuals with the CC genotype at rs833070 and rs2146323 – located in the intron of the VEGF-A gene displayed smaller hippocampal volumes than T-allele and A-allele carriers, respectively. These 2 snps lie in a haplotype block with rs833068 which was assayed in my 23andMe profile – indicating that I happen to carry the TT genotype at rs833070 giving me slightly larger, more neurogenic & resilient hippocampus – I suppose. Now, if I could just figure out a way to put it to good use !

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