Yesterday was World Diabetes Day.
I almost forgot … which may have something to do with rs6741949.
From the original article:
“… rs6741949 in a DPP4 intron on chromosome 2q24, where the G allele was associated with smaller hippocampal volume (β=−52.8 mm3, p=2.9×10-7).”
The association with DPP4 sheds light on a fascinating connection between diabetes and hippocampal (memory) function.
“Further, DPP4 is an intrinsic membrane glycoprotein and a widely expressed serine exopeptidase. It is also an adipokine over-expressed in visceral adipose tissue of obese persons and those with diabetes, conditions associated with smaller hippocampal volume. A novel class of antidiabetic medications (sitagliptin, and related incretin compounds) inhibits DPP4 to improve insulin sensitivity and glucose tolerance through increased levels of glucagon like proteins-1 and 2 (GLP-1, -2). Interestingly, endogenous incretin GLP-1 is also heavily expressed in some hippocampal neurons and has neuroprotective properties.”
note: 23andMe does not cover rs6741949, but they do cover 2 flanking SNPs that are in pretty good linkage disequilibrium with rs6741949 … so, um, I’m trying to figure out how I might impute/infer my genotype here … hmmm.
rs3788979 (bp162900889) CC D’=0.81 strand + forward
rs6741949 (bp162910223) A?G? strand + forward
rs4664446 (bp162910403) AG D’=0.86 strand + forward
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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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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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The yoga sutras are a lot of fun to read – especially the super-natural ones. I try not to take them too literally, as you never know what might have been warped in translation, or perhaps included merely to inspire yogis to go the extra mile in their practices.
Occasionally, I come across articles in the science literature that reveal how truly weird and wild the human brain can be – and it strikes me – that maybe the ancient yogis were more in tune with the human mind than we “modern science” folks give them credit for. Here’s a weird and wild sutra:
III.55 – tarakam sarvavisayam sarvathavisayam akramam ca iti vivekajam jnanam – The essential characteristic of the yogi’s exalted knowledge is that he grasps instantly, clearly and wholly, the aims of all objects without going into the sequence of time of change.
How can we know things instantly? and without respect to time (ie. never having had prior experience)?
Admittedly, Patanjali may be referring to things that take place in emotional, subconscious or cosmic realms that I’m not familiar with, so I won’t quibble with the text. Besides, it sounds like an AWESOME state of mind to attain, and well worth the effort – even if we concede it is knowingly unobtainable. But is it unobtainable?
Might there be states of mind that make it seem obtainable? Here’s a fascinating science article that appeared in Science Magazine this past week. Paradoxical False Memory for Objects After Brain Damage [doi: 10.1126/science.1194780] describing the effects of damage in the perirhinal cortex (in rats) that led the animals to demonstrate a peculiar form of false memory – wherein the animals treated never-before seen objects as being familiar. Hmmm. An altered form of brain activity where unfamiliar and novel things seem very familiar. Sounds sort of like “instantaneous knowing without respect to time” to me.
Given the tremendous similarity in brain circuits and memory systems across all mammals, I wonder if humans (perhaps in deep meditative states or with various forms of hallucinogenic or damaged states) could experience this? Sutra III.55 seems strange, but not, perhaps unobtainable.
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Posted in Hippocampus, MAPK, MKP-1, tagged Brain, Chemical synapse, Chronic stress, Depression, Gene expression, Hippocampus, Memory, Neuron, Pyramidal cell, Stress on November 10, 2010|
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You already know this, but when you are stressed out (chronic stress), your brain doesn’t work very well. That’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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Posted in BDNF, DNMT, Hippocampus, RLN, tagged Brain, DNA, DNA methylation, DNA methyltransferase, Epigenetics, Gene expression, Memory, Methylation, Rett Syndrome on October 17, 2010|
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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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Posted in Hippocampus, PARP-1, tagged aging, Base excision repair, Chromatin, DNA repair, Epigenetics, learning, Memory, PARP1 on October 11, 2010|
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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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