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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