“This urine wheel was published in 1506 by Ullrich Pinder, in his book Epiphanie Medicorum. It describes the possible colours, smells and tastes of urine, and uses them to diagnose disease.”
Jeremy K. Nicholson & John C. Lindon Nature 2008 (1)

Metabolomics has come a long way since the days of tasting urine. Now techniques like high-throughput mass spectrometry can provide us detailed information about the small molecules we find in the body–which can be influenced by diet, environmental exposure (to toxins, medicine, etc), or even the gut microbiome. Metabolomics will also capture the genetic or epigenetic differences in  how individuals process these exposures.

Dean P. Jones, et al. Annual Reviews (2012)

Metabolome-Wide Association Studies

New high-throughput technologies have great potentials is unbiased case-control studies looking at as many metabolites as possible–Metabolome Wide Association Studies (similar to the GWAS studies done in genetics). These studies would look for the association of any metabolite with a given disease–after which research into that metabolite could indicate a variety of causes–nutritional differences, environmental exposure, or even mutations in metabolic pathways.

Any given study would not be the end all, as metabolomic exposure occurs over a life-time. Other important factors may include exposures while in the womb to teratogens–substances that interfere with the development of an embryo or fetus that cause birth defects.

The most famous example of a teratogen is probably the drug Thalidomide that interfered with limb bud development.

Metabolomics and Neursocience

Metabolomics research is in it’s infancy and it hasn’t yet been applied to psychiatric or neurological disease. The GWAS for psychiatric disease were not as fruitful as was originally hoped–probably due to both the complex natures of the diseases and also the murkiness of symptom-based disease classification of psychiatric disease. The same classification problems would make MWAS of psychiatric disease, but it would be one step to help explain environmental factors (e.g. why one genetically identical twin gets schizophrenia while another doesn’t).

MWAS techniques could also be used identify biomarkers which can be used in either the identification of psychiatric disease, or subcategorization of a disease. A good biomarker would make studies more reproducible, or alternatively multiple markers could and help seperate similarly-manifesting diseases.

We really have a wealth of riches in terms of high-data yielding approaches to tackle these diseases: genomics, epigenomics, metabolomics, and brain-imaging. Unfortunately these methods remain expensive, time consuming. Currently one of the biggest hold-ups in metabolomics is man-power on the bioinformatics side of interpretting the mass/spec results. Further, we haven’t figured out all the best ways to analyze and make sense of all this “Big Data” biology. Personally, I think it will be extremely powerful in situations where the results can be quickly verified using traditional reductionist experimental approaches. If machine learning keeps it up, maybe the data will even analyze itself.

All in all, I am very interested to see where this goes. There are hundreds of thousands of metabolites in what we eat alone and so far we are only scratching the surface.

References

1. Nicholson, J. K. and J. C. Lindon (2008). “Systems biology: Metabonomics.” Nature 455(7216): 1054-1056. http://dx.doi.org/10.1038/4551054a

2. Jones, D. P., Y. Park, et al. “Nutritional Metabolomics: Progress in Addressing Complexity in Diet and Health.” Annual Review of Nutrition 32(1): 183-202. http://www.annualreviews.org/doi/full/10.1146/annurev-nutr-072610-145159

July was an interesting month, including: unconscious passwords stored in procedural memory, neuroethics of the “gay gene,” Virtually THC-free (but CBD-rich) marijuana, oh and lets not forget the Higgs Boson (puts things in historical context).

The Feed:

25 JulNeuroamer Blog ‏@Neuroamer

Brain: The precuneus: review – involved in self-consciousness, engaged in self-related mental representations - http://bit.ly/LO2lnZ 

25 JulNeuroamer Blog ‏@Neuroamer

http://scienceblog.com/55711/children-in-foster-care-develop-resilience-through-compassion/ … children in foster care develop resilience through compassion meditation

25 JulNeuroamer Blog ‏@Neuroamer

List of movies with psychological or cognitive science themes – Indiana http://bit.ly/PIANW8 

25 JulNeuroamer Blog ‏@Neuroamer

A Single Brain Structure May Give Winners That Extra Physical Edge: Scientific American – t http://bit.ly/LNKb5Q 

24 JulNeuroamer Blog ‏@Neuroamer

The American Scholar: Living With Voices – T. M. Luhrmannhttp://bit.ly/PBJ1iN  - Thought-provoking alternative view on auditory hallucinations

23 JulNeuroamer Blog ‏@Neuroamer

The Unknown Why in the Aurora Killings – insightful article about depression, homicide, and how we jump to conclusionshttp://bit.ly/PyANYL 

23 JulNeuroamer Blog ‏@Neuroamer

Eero Antero Mäntyranta won 7 olympic medals for xc skiing. Mutation to the EPOR increases the O2 capacity of blood 50%http://bit.ly/LG5Rkc 

23 JulNeuroamer Blog ‏@Neuroamer

“Man Who Chewed Another Man’s Face Had Only Marijuana” –Why did speculation about bath salts get reported as fact? http://bit.ly/LFAOFp 

23 JulNeuroamer Blog ‏@Neuroamer

“Doctors need to be aware of the risk of injury when they counsel seriously mentally ill patients and their carers” http://bit.ly/LFAFBS 

22 JulNeuroamer Blog ‏@Neuroamer

@madrunkate Hi, thanks for sharing. Its important people take these issues into their own hands, and help educate the greater community!

 View conversation

22 JulNeuroamer Blog ‏@Neuroamer

RT @bgpvideo: Children of mother’s who ate peanuts and tree nuts while pregnant are less likely to develop asthma or allergies http://bit.l…

22 JulNeuroamer Blog ‏@Neuroamer

Bohemian Rhapsody – Vocals only – individual components of music can sound so different from the sum of their parts: http://bit.ly/Py7ENq 

20 JulNeuroamer Blog ‏@Neuroamer

Economist – British government: taxpayer-financed research will be available, free online, for anyone to read! http://bit.ly/NF0jZ4 

20 JulNeuroamer Blog ‏@Neuroamer

Wiki – Macy Conferences1946 to 1953. Conferences to foundations for a general science of the workings of the human mindhttp://bit.ly/Lxxpbt 

20 JulNeuroamer Blog ‏@Neuroamer

Genomic Biostats – Lectures: http://bit.ly/LvzViq  PDFs and Notes:http://bit.ly/Pn8pc9  - by Rafael Irizarry at Johns Hopkins.

19 JulNeuroamer Blog ‏@Neuroamer

http://bit.ly/PmVDKL  Neuroethics Coursera class on to be offered January 2013 – taught by Penn professor John Moreno http://bit.ly/Lvs1pl 

19 JulNeuroamer Blog ‏@Neuroamer

Close to one million gene-expression data sets are now in publicly accessible repositories http://bit.ly/PmVsPC 

19 JulNeuroamer Blog ‏@Neuroamer

Unconscious Passwords? Using implicit memory and skill performance to keep passwords from their own users. http://bit.ly/PmbAki 

19 JulNeuroamer Blog ‏@Neuroamer

Humanists, Neurobabble, and Neuroethics: the neuroethics blog -http://bit.ly/LvmTBI 

19 JulNeuroamer Blog ‏@Neuroamer

DSM-5 and behavioral addictions – Steven Hyman and the Neuroethics Blog - http://bit.ly/LvmyPp 

18 JulNeuroamer Blog ‏@Neuroamer

Obama Proposes $1B for Science, Math Teachers-those selected for the Master Teacher Corps will be paid an extra $20,000http://bit.ly/PhS4FC 

16 JulNeuroamer Blog ‏@Neuroamer

Growers Fret Over New Genetically Engineered Apple That Won’t Turn Brown < NYTimes - http://bit.ly/OJyMFf  - Is it still as delicious?

14 JulNeuroamer Blog ‏@Neuroamer

I want to read:”Life at Home in the 21st Century” US fams are overwhelmed by clutter, rarely eat together, and stressedhttp://bit.ly/MpRVkr 

14 JulNeuroamer Blog ‏@Neuroamer

Amazing story of a professor using tech to help educationally disenfranchised kids http://bit.ly/NsK1Uu  @ASBMB @rajmukhop@angelahopp

14 JulNeuroamer Blog ‏@Neuroamer

Thanks Michelle! @artcoholic @lumosity @TheSocialBrain @sciam@DrMelanieG @OliverSacks @WRY999

13 JulNeuroamer Blog ‏@Neuroamer

Mysterious epigenetic modification 5-OH-Me-C (found in stem cells and brain) can now be sequenced with single bp res. -http://bit.ly/ODhOZb 

13 JulNeuroamer Blog ‏@Neuroamer

SPENDING ON GENETIC TESTS GROWS – UnitedHealth Group, Inc. Report calls for more genetics education and counselors -http://bit.ly/LlTRJt 

13 JulNeuroamer Blog ‏@Neuroamer

New post: Mysterious epigenetic modification 5-OH-Me-Cytosine can now be sequenced with single base resolution - http://bit.ly/ODhOZb 

13 JulNeuroamer Blog ‏@Neuroamer

“The discovery of the protective gene mutation, a product of the revolution that has taken place in genetics, arose wh… http://bit.ly/LTIogZ 

12 JulNeuroamer Blog ‏@Neuroamer

Join Wikipedia Founder Jimmy Wales: Protect Internet Freedom And Seek Justice for Richard O’Dwyer | Demand Progress http://bit.ly/NPXXXI 

12 JulNeuroamer Blog ‏@Neuroamer

Let’s talk about “Precrime” < Emory Neuroethics Blog – Cyd Cipolla -http://bit.ly/LivRXC 

12 JulNeuroamer Blog ‏@Neuroamer

@katie_shen What do you think of this?: Why Women Still Can’t Have It All – By Anne-Marie Slaughter - http://bit.ly/LgipnR 

12 JulNeuroamer Blog ‏@Neuroamer

Mental Illness and Why The Skeptic Community Should Give a Shit, JT Eberhard Skepticon 4 – YouTube http://bit.ly/MjuKrS 

12 JulNeuroamer Blog ‏@Neuroamer

‘This Is Our Planet’ ISS Time-Lapse Video from Satellites Will Blow Your Mind – Set to the Xx’s Intro http://bit.ly/MjtmWg 

12 JulNeuroamer Blog ‏@Neuroamer

@katie_shen I don’t know much. Fascinating though, I’d love to read the book. Elyn Saks could become the @TempleG2697 of schizophrenia.

11 JulNeuroamer Blog ‏@Neuroamer

An interesting look at child prodigies, working memory, and family risk of autism http://bit.ly/Nf08FI 

11 JulNeuroamer Blog ‏@Neuroamer

Gay Brains,Gay Genes,Gay Rights:The Double-Edged Sword of Essentialism-If research were to uncover genes of sexuality.http://bit.ly/LfGmuD 

11 JulNeuroamer Blog ‏@Neuroamer

Tips to make the most out of your national conference or medical meeting http://www.kevinmd.com/blog/2011/06/tips-national-medical-meeting.html … via @kevinmd

11 JulNeuroamer Blog ‏@Neuroamer

Climate change drives salmon evolution – New Scientist -http://bit.ly/MZWIsy 

11 JulNeuroamer Blog ‏@Neuroamer

Comic: Schizophrenia – An eleven page chapter from darryl cunnigham’s Psychiatric Tales http://bit.ly/LNSQGN 

11 JulNeuroamer Blog ‏@Neuroamer

Interview with @brandobalazs - his new doc. is about diagnosed schizophrenic rapper “Conspiracy” (who has a neurotypical identical twin)

11 JulNeuroamer Blog ‏@Neuroamer

Guessing emotions by the eyes alone: Reading the Mind in the Eyes Test http://bit.ly/PPNErQ 

11 JulNeuroamer Blog ‏@Neuroamer

Why Conspiracy thinks he’s possessed by two intergalactic space demons – an Interview with @BrandoBalazs http://bit.ly/PPKCE4 

11 JulNeuroamer Blog ‏@Neuroamer

Quora – Graduate School: What should I do during my PhD studies? – some good advice to young grad students http://bit.ly/S0Lhjr 

10 JulNeuroamer Blog ‏@Neuroamer

A Surgical Implant for Seeing Colors Through Sound – achromatopsic artist to implant the device NYtimes http://bit.ly/N4dCUx @jenny8lee

10 JulNeuroamer Blog ‏@Neuroamer

Oxitec’s mutant mosquitoes-Newyorker http://bit.ly/OjZu7b  Mother Joneshttp://bit.ly/OqJBvV  GMOs need to be evaluated on their mutation

10 JulNeuroamer Blog ‏@Neuroamer

http://bit.ly/OquW3Q  Today’s elites are not “highbrow snobs.” They are “cultural omnivores.” <NY TIMES

10 JulNeuroamer Blog ‏@Neuroamer

Diagnosing Parkinson’s in a phone call with a computer and a speech-processing algorithm from MIT’s Media Lab http://bit.ly/RSYGtG 

10 JulNeuroamer Blog ‏@Neuroamer

Single-microparticle imaging flow analyzer w/ throughput of 100,000particles/s. PNAS: http://bit.ly/Oqqt18  Press rel.: http://bit.ly/OqqCSg 

9 JulNeuroamer Blog ‏@Neuroamer

Future of Online Higher Ed? @bryan_caplan proposes 3models:http://bit.ly/Mbfeyi  @tylercowen proposes a 4th I agree w/ http://bit.ly/OpectE 

9 JulNeuroamer Blog ‏@Neuroamer

http://bit.ly/OqjGV0  - Doctors only trust doctors–How to deliver new clinical knowledge to the clinic? #med #medicine #psychiatry

9 JulNeuroamer Blog ‏@Neuroamer

Nasa’s discovery of an arsenic-friendly microbe refutedhttp://bit.ly/RKUmg3 

9 JulNeuroamer Blog ‏@Neuroamer

Whitman tried to seek help for violent urges before rampage.Turned out he had a glioblastoma. Here’s the note he left: http://bit.ly/PDDRFf 

9 JulNeuroamer Blog ‏@Neuroamer

Apocryphal “last Calvin and Hobbes comic ever.” http://bit.ly/RJSyEf 

9 JulNeuroamer Blog ‏@Neuroamer

I suddenly understand why people say kidney stones are so painful:http://bit.ly/RJHtTu  - that’s not what I was imagining before…

9 JulNeuroamer Blog ‏@Neuroamer

An older but good read, especially after researching my recent post:http://bit.ly/ODDoAm  The Drug Pushers-The Atlantic http://bit.ly/RJGxhW 

8 JulNeuroamer Blog ‏@Neuroamer

Mars Project-Upcoming doc about a diagnosed schizophrenic rapper (with a neurotypical identical twin) http://bit.ly/RJBMFh @BrandoBalazs

8 JulNeuroamer Blog ‏@Neuroamer

Cool .gif movie of a white blood cell in action: http://bit.ly/PCvqdo 

7 JulNeuroamer Blog ‏@Neuroamer

The math that caught the anesthesiologist’s fraud - http://bit.ly/RBjaqG  - faked human data fell outside normal distributions.

7 JulNeuroamer Blog ‏@Neuroamer

172/212 of Fuji’s papers fabricated – 13% of the 2,000 papers retracted over the last 40yrs involved anesthesiologistshttp://bit.ly/PwsEX4 

7 JulNeuroamer Blog ‏@Neuroamer

Do you know the Most Prescribed Psychiatric Drug? Most prescribed overall? What about the drug we spend the most $ on?http://tinyurl.com/cy8n7du 

6 JulNeuroamer Blog ‏@Neuroamer

BBC News – Man and robot linked by brain scanner http://bit.ly/Ou0pFR 

6 JulNeuroamer Blog ‏@Neuroamer

U.S. is 4.6% of the world’s pop., but takes 80% of opioids—and 99% of hydrocodone.Babies are being born dependent!#med http://bit.ly/NbItel 

6 JulNeuroamer Blog ‏@Neuroamer

Top 10 most prescribed psychiatric drugs, top 10 overall, and the 10 we spend the most money on http://wp.me/peVF4-8Y  #medicine#psychiatry

6 JulNeuroamer Blog ‏@Neuroamer

RT@Neuro_Skeptic:Eric Kandel’s new book on psychoanalysis: “The Age of Insight:The Quest to Understand the Unconscious”http://bit.ly/RjcPjv 

6 JulNeuroamer Blog ‏@Neuroamer

@RosieRedfield I agree!–Mendel’s dominance is confusing as hell! We know the mechanisms, so we should teach them!http://tinyurl.com/6qu7yxo 

3 JulEric Topol ‏@EricTopol

Sensors that pick up biorhythms previously not detected, for health/disease http://on.wsj.com/LMawk6  via @ShirleyWang #CDoM#mHealth

Retweeted by Neuroamer Blog

6 JulNeuroamer Blog ‏@Neuroamer

If the Higgs Boson is the “Physics’ Holy Grail,” then, Neuroscientists, what’s your Higgs Boson? Inspired by @Cancer_Cell

6 JulNeuroamer Blog ‏@Neuroamer

RT @brainpicker: Whoa, whoa, whoa. @carlzimmer has an app. And it’s about evolution. And it’s free. http://bit.ly/PiZWsH 

5 JulNeuroamer Blog ‏@Neuroamer

“Students at MIT…the very brightest ones, who would’ve gone into physics 20 ago, are now going into bio” Noam Chomskyhttp://bit.ly/Rg03lQ 

5 JulMariette DiChristina ‏@mdichristina

How to Succeed in Science: tips from the laureates from the last talks at #lnlm12. http://goo.gl/xaUZM  @lindaunobel

Retweeted by Neuroamer Blog

5 JulSteve Silberman ‏@stevesilberman

Israeli scientists develop medical marijuana guaranteed to kill your buzz. http://goo.gl/1XUz1 

Retweeted by Neuroamer Blog

5 JulScience Magazine ‏@sciencemagazine

The still unpublished fraud-finding algorithm that caught Smeesters could shake up psychology http://scim.ag/LWKISm 

Retweeted by Neuroamer Blog

5 JulNeuroamer Blog ‏@Neuroamer

@radiolab: Why Newton Stuck a knife in his eye, 16-cone mantis shrimp, tetrachromatic humans? & the language of colorhttp://bit.ly/MOxxFG 

5 JulNeuroamer Blog ‏@Neuroamer

6mil US teens have Intermittent Explosive Disorder & 2/3 US teens have:threatened,destroyed property,or acted violently http://bit.ly/OuVnJg 

5 JulNeuroamer Blog ‏@Neuroamer

Are we responsible for our actions or the actions we’re capable of in strange sit.s – Grumpy Old Terrorists - @Radiolab http://bit.ly/Re3tWr 

5 JulNeuroamer Blog ‏@Neuroamer

RT @NEJM: Interactive graphic: growth & branching of 200 yrs of clinical trials that redefined #neurology, #psychiatry. http://bit.ly/N8wUo6 

5 JulNeuroamer Blog ‏@Neuroamer

SSRIs for teenagers? http://bit.ly/PeJ1aB  @Katherinesharpe raises issues with identity. @JBoltonFasman says untreated depression is worse.

5 JulNeuroamer Blog ‏@Neuroamer

@hsu_steve - Perhaps by digitizing basic lectures ala Kahn Academy, Profs will have more time for Oxford style tutoringhttp://bit.ly/PgBgAT 

5 JulNeuroamer Blog ‏@Neuroamer

Neurodevelopment: Unlocking the brain’s critical periodshttp://bit.ly/PdCNrD  < Nature News @jon_bardin @NatureNews

4 JulNeuroamer Blog ‏@Neuroamer

Unraveling Bolero – Radiolab – on Frontotemporal Dementia- 1st sx: compulsive and prolific art and creativity - http://bit.ly/MD7Ogz 

4 JulNeuroamer Blog ‏@Neuroamer

New Parkinson’s disease gene identified with help of Mennonite family: DNAJC13 - http://bit.ly/PfEcOo 

4 JulNeuroamer Blog ‏@Neuroamer

“Predator-Prey Equations Govern Gang Territories” http://bit.ly/P8Sz6U  < via @sciam

4 JulNeuroamer Blog ‏@Neuroamer

Graphic – Cocaine, a potent vasoconstrictor, can lead to ischemia, necrosis, and ulceration, and palatal perforation. http://bit.ly/N6a0xP 

4 JulNeuroamer Blog ‏@Neuroamer

New particle at 5-sigma Standard Deviations at 125 GeV fits description of elusive Higgs boson, scientists say http://bit.ly/RbjVGR 

4 JulNeuroamer Blog ‏@Neuroamer

Will the supreme court ruling  access to addiction and drug abuse treatment? – via @neuroghetto - http://bit.ly/R5H25K 

4 JulNeuroamer Blog ‏@Neuroamer

Dr. Drew Pinsky of Loveline & Celebrity Rehab was paid $275,000 by GSK to promote Wellbutrin as lowering sexual side fx http://bit.ly/MSIHKv 

3 JulNeuroamer Blog ‏@Neuroamer

Pope Benedict ‘believes in evolution’ | Mail Online (2007) <- how did I miss this? http://bit.ly/LtTgBX 

3 JulNeuroamer Blog ‏@Neuroamer

Automated Whole-cell patch-clamp of neurons – won’t put electrophysiologist out of work anytime soon, but cool stuffhttp://bit.ly/MPMBor 

3 JulNeuroamer Blog ‏@Neuroamer

DAT1, DRD2 and DRD4 May Play Role in Educational Achievement – APA: http://bit.ly/Lk63eV  - Dev Psych fulltext: http://bit.ly/LPjw80 

3 JulNeuroamer Blog ‏@Neuroamer

3d-gen sequencers produce reads as long as 23,000 bases, but make more errors – new correction alg. removes errors http://bit.ly/LtRKzV 

3 JulNeuroamer Blog ‏@Neuroamer

Has anyone studied twitter inflation? What’s the total number of new followers for all twitter users per day?

3 JulNeuroamer Blog ‏@Neuroamer

New drug, Belviq, approved for obesity. Lowers cravings by activating 5ht-2C in the brain, but not 2B in heart. http://bit.ly/NXDFdq 

2 JulNeuroamer Blog ‏@Neuroamer

This mo.’s cellpress podcast http://bit.ly/NXDbnL  - includes tropical disease’s mental health burden and cell therapy for neuropathic pain.

2 JulNeuroamer Blog ‏@Neuroamer

Reverse epidemiology and the obesity paradox – interesting – Wikipedia, the free encyclopedia http://bit.ly/NczCuS

Cytosine, 5-mC, 5-hmC

5-hydroxy-methyl CpGs (5-hmCs) were first discovered in 2009 and shown to be enriched in the brain, but remain a mysterious epigenetic mark, despite intriguing functional findings such as: environmental enrichment’s reduction of it, MeCP2′s preference for 5mc over 5hmc, and it’s possible role as an intermediate in demethylation. This new technique will aid their characterization by allowing absolute quantification and base-resolution localization of the marks. The technique also serves as a reminder of why you should pay attention in orgo, or at least why you should collaborate with people who did!

Now, Emory’s Peng Jin, has collaborated with University of Chicago chemist He Chuan to develop a new derivative of bisulfite sequencing, Tet-Assisted Bisulfite Sequencing (TAB-Seq) that distinguishes 5-hmcs from 5-mcs, as they describe in cell.

Yu (2012) Cell

Traditional bisulfite sequencing (MethylC-Seq):

1. Sequence the sample
2. Treat the sample with bisulfite, which converts all non-methylated cytosines to uracils, but leaves 5-mCs and 5-hmCs as cytosines. (The even rarer base 5-carboxy-C (5-caC), is converted by bisulfite into 5-caU.)
3. Resequence.
4. Compare your first sequence to your second. You know the unmethylated cytosines from the first sequence will show up as Ts in the second sequence (because when they are amplified, they will be amplified as Thymidine not Uracil). The methylated and hydroxy-methylated cytosines which show up as Cytosines in both sequences.

TAB-seq

So, how can we differentiate 5-hmCs from 5-mCs? In a process that may remind you of all those organic chemistry synthesis problems, TAB-seq involves an extra step to protect the hydroxy-methylated cytosines from TET oxidation.

1. Glucosylate 5hmC using β-glucosyltransferase (βGT).
2. 5mC is oxidized to 5caC by with an excess of recombinant Tet1. (The blocked 5hmCs (β-glucosyl-5-hydroxymethylcytosine (5gmC) ) are not oxidized.)
3. Treat the sample with bisulfite. This converts the Cs and 5-caCs to Us, but doesn’t effect the 5gmC.
4. Resequence
5. Compare back with traditional bisulfite sequencing. The 5-hmCs are the bases that show up as Cs in these two sequences. (5-mCs will show up as Ts in TAB-seq, but Cs in traditional. Unmodified Cs and CaCs will show up as Ts in both sequences.)

Validation and Findings

Validation of new techniques (proof that they work), is always important, and the paper shows that it works using mass spectrometry.

They validated it’s practicality, by using the technique to map 5-hmCs in human embryonic stem cells (hESCs) and mouse embryonic stem cells (mESCs). In hESCs they found 691,414 5hmCs with a false discovery rate of 5%. Interestingly, though mice have similarly sized genomes, they found much higher levels of 5hmCs–2,057,636–which they hypothesize is also due to the higher levels of Tet1 and Tet2 proteins.

So where are 5hmCs enriched, now that we can identify them precisely? H1 distal-regulatory elements including p300-binding sites (observed/expected [o/e] = 7.6), predicted enhancers (o/e = 7.8), CTCF-binding sites (o/e = 5.1)–CTCF is a transcriptional repressor that blocks interactions between promoters and enhancers and also plays a role in stopping the spread of heterochromatin, and DNase I hypersensitive sites (o/e = 3.4) which are associated with active gene expression. Because, 5-hmCs are enriched at enhancers, the authors speculate that 5-hmC may be  specifically recognized by transcription factors as a core base in binding motifs.

Genomic Distribution of 5hmC Sites. Yu (2012) Cell.

Many genes had significant enrichment of 5hmC, but lowly expressed genes had more than highly expressed. 5hmCs  showed asymmetry, with more hydroxylation on strands where the CpG was surrounded by Gs. (A similar pattern wasn’t observed for 5mCs.)

5hmCs also tended to be enriched near low CpG areas

Previous findings that identified 5hmCs in high CpG areas, such as CpG island-containing promoters, but these findings are likely do to the bias of mapping techniques which can amplify frequent weak signals and overshadow sparse but strong ones.  The present study, found that 5hmCs tended to be enriched in lower CpG areas, especially those with H3K4me3 or bivalent (H3K4Me3 and H3K27ac) chromatin modifications, but how 5hmC interacts with the histone code is still up in the air.

Conclusion

It will be interesting to see if the findings from, generalize to different cell-types, but since hESCs and mESCs showed similar patterns, it suggests that the regulation at least in stem cells is evolutionarily conserved.

It seems this tree will have bountiful fruit, weighing down the branches for some time. I’ll leave a final summary in the authors’ own words:

“We have developed a genome-wide approach to determine 5hmC distribution at base resolution and have generated base-resolution maps of 5hmC in both hESCs and mESCs. These maps provide a template for further understanding the biological roles of 5hmC in stem cells as well as gene regulation in general. In conjunction with methylC-Seq, the TAB-Seq method described here represents a general approach to measure the absolute abundance of 5mC and 5hmC at specific sites or genome-wide, which could be widely applied to various cell types and tissues.”

References
Kriaucionis, S., & Heintz, N. (2009). The nuclear DNA base , 5-hydroxymethylcytosine is present in brain and enriched in Purkinje neurons. Science,  324(5929), 929-930. (Free full text.)

Szulwach, K. E., Li, X., Li, Y., Song, C.-X., Wu, H., Dai, Q., Irier, H., et al. (2011). 5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging. Nature neuroscience, 14(12), 1607-16. Nature Publishing Group. doi:10.1038/nn.2959

Yu M, Hon GC, Szulwach KE, Song CX, Zhang L, Kim A, Li X, Dai Q, Shen Y, Park B, Min JH, Jin P, Ren B, & He C (2012). Base-resolution analysis of 5-hydroxymethylcytosine in the Mammalian genome. Cell, 149 (6), 1368-80 PMID: 22608086

Guo, J. U., Su, Y., Zhong, C., Ming, G.-li, & Song, H. (2011). Emerging roles of TET proteins and 5-hydroxymethylcytosines in active DNA demethylation and beyond. Cell Cycle, 10(16), 2662-2668. doi:10.4161/cc.10.16.17093

———-

You may also be interested in the brief article I wrote previously about 5-hmCs and a paper that showed that they are highly enriched in the cerebellum and hippocampus (10x higher than in stem cells), and they increase with age. Further, the authors showed that MeCP2–which strongly binds the unhydroxylated and more ubiquitously expressed version, 5-methyl CpGs–does not bind 5-hmCs. Overexpression of MeCP2 even seems to block TETs from converting 5-mCs into 5-hmCs.

Update:

Just learned about oxBS-Seq another method for sequencing, need to look into this. Does anyone know off-hand advantages/disadvantages of either?

http://epigenie.com/oxbs-seq-breaks-through-5hmc-sequencing-barrier/

http://www.sciencemag.org/content/336/6083/934.abstract

http://www.sciencemag.org/content/336/6083/934.abstract

You may have seen my tweet about the upcoming documentary Mars Project, which tackles complex issues such as mental illness, drug use, psychiatry, race, and stigma. When director Jonathan Balazs contacted me about his film, I got really excited about it.

Khari “Conspiracy” Stewart, rapper in the Canadian indie hip hop group Supreme Being Unit

If you liked the teaser but want to learn more about the project, check out Balazs’s Indie-Go-Go page (the film is still in production and could really use your help). You might also be interested in the original short film, and my interview with Balazs below.

It’s great topic for Balazs to have chosen, and extremely courageous of “Conspiracy” to discuss and publicize his diagnosis of schizophrenia–a heterogenous disorder that is often swept under the rug, despite the fact that ~1% of the human population suffers from it’s symptoms. There is are a lot of misconceptions surrounding schizophrenia, and I think Mars Project will reach a lot of people that might otherwise be misinformed about the disorder. Further, with a neurotypical identical twin, I think “Conspiracy” is an especially great example of the complexity of psychiatric disease–although schizophrenia has a genetic component, it is far less heritable than autism, and GWAS studies have failed to turn up likely candidate genes.

Despite the difficulty of the problem, I think that genetics will give us the insights to explain schizophrenia biologically within my lifetime. But it will be important for psychiatrists and neuroscientists to remember the other side of biological reductionism–our experiences and thoughts are constantly affected the biochemistry of our brain. We need to explore the whole bio-psycho-social environment for therapies in addition to looking for cleaner drugs.

Jonathan Balazs

What inspired you to make a film where schizophrenia and mental illness plays such a central role?I felt like this whole process was an exercise in self-discovery. The whole process was cumulative, one that developed quite opposite of an Archimedean moment. I had some academic influences sure, but my education came from an innate sense of curiosity toward this mysterious and sometimes terrifying mental disorder called Schizophrenia. As I tried to pin down what it meant to me or how to make sense of it, the more elusive a definition came. I’m probably more confused by that label now than I was when I first began my inquiry.

In doing research for the film, did you find any good resources explaining schizophrenia, mental illness, etc.?

Yes and no. Symptoms of Schizophrenia (and pretty much any mental disorder) are not so cut-and-dried like a knee-scrape or heart condition, as these are easily observable medical phenomenon. Schizophrenia on the other hand seems more like a philosophical concept, rather than a medical one – a split between a shared universally accepted human reality (if there is such a thing) and someone who’s simply too involved in their own mind. The dimensions of human expression are too complex, unpredictable and culturally influenced that there can be no concrete definition as they currently stand. I was quite surprised to discover a growing number of psychiatrist doctors who agreed with this and who defined people by their identity vs. their brain organ.
My research into these issues is ongoing, but I have found a great deal of value in the work of Dr. R.D. Laing (someone I wish I could have shared a drink with) and Dr. Thomas Szasz. I think it’s unfortunate that they have been labeled as patriarchs of the “Anti-Psychiatry” movement because there is value in what they have written. One of our interview subjects Dr. Gordon Warme has been a defining influence in my study of mental illness and on Mars Project. I’ve been trudging through Michel Foucault’s writings and wonder where the popular philosophers are in 2012 – it seems like they’ve been replaced by the theoretical physicists and astronomers.

What was it like to meet “Conspiracy” for the first time?

Loud, I think we were at a rap show.

How did you find the psychiatrists you interviewed for the film? Was it difficult finding academics willing to go on camera?

I have to give credit where it’s due; executive producer David Reville was instrumental in those interviews as I’m still very “green” with respect to disabilities studies and psychiatry. He was the one who put together the interviews with Dr. Gordon Warme, Dr. Kwame McKenzie and disabilities scholar Erick Fabris. We were very fortunate to receive insight from these people all doing important work in their area(s). I think the most difficult aspect of interviewing them was scheduling them all on the same day. I don’t think it could have been more successful honestly.

Do you think mental illness can be explained entirely through biology? Are you, yourself, a spiritual person?

Those are two different questions, I think. No, I don’t think the biological argument is entirely sufficient to explain these mental illness phenomena. I don’t think I’m qualified to say that there could never be a biological explanation, though I will note that ‘biology’ seems to be a primer for something that can’t be explained fully. I have too much respect for human culture to chalk up society as a vast network of neurons farting out serotonin and dopamine. For some people the medical model might ring true; those who do follow the path of the shaman in the white lab-coat are free to do so because the path of “recovery” (or more aptly management) lies within the individual.

I am not a spiritual person by most definitions and definitely not religious, I sometimes refer to myself as a rational agnostic.

What role do artists play in spreading scientific information?

I think it’s important that more artists recognize and value the influence of scientific discourse, though I admit that there is a concern with this information being presented accurately (and to an extent objectively) while still keeping with the identity of the artist. I would add that art and science are far too often pitted against each other when they’re essentially cut from the same cloth. It encouraged me to hear Dr. Kwame McKenzie discuss the art of psychiatric medicine in our interview.

After getting to know “Conspiracy” so well, are there parts of the psychiatric system or the way we address these illness,that you personally think need to be changed?

I can only say what I might do for myself, because fixing the mind lies with the patient alone – psychiatry is just one of the tools available. If I ever suffer from prolonged psychosis, who knows what I’d do? My feeling though, is that many of these potent, mind-altering psychiatric drugs are prescribed too freely – as if the answer to your crisis can be sought through a little pill. Some of these drugs essentially dull every aspect of your spirit and not just those undesirable or offensive aspects of behavior. The systematic, state-imposed ‘zombification’ of vulnerable individuals doesn’t seem like the best path; some might read this and ask what business a filmmaker has on mental health policies.

When will the movie be released, and do you have other upcoming projects?

The film will be completed by the fall and hopefully it will hit festival screens in the autumn. I hope that we’ll be able to negotiate wide distribution in theatres and certain online and V.O.D. platforms. With the amount of cussing in the film, I doubt that many networks will want to program it on their channels.

I’m working on a short documentary featuring the work of illustrator Pearl Rachinsky and I’m hoping to shop around an expanded treatment based on a short film I wrote a few years ago called Thane Spa on the monetization of suicide.

For more information on Mars Project see www.marsprojectmovie.com, ‘like’ us on Facebook, check our Youtube channel and please help us support our indiegogo campaign. I’m a little too serious on Twitter, but you can follow me just the same @BrandoBalazs.

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Know of any good movies or documentaries out there about mental illness or schizophrenia? I need to watch something while I wait for Mars Project, so suggestions would be great!

Rank	Brand Name	Generic Name	# of U.S. Prescriptions	Use
10	Valium	Diazepam	14,009,000	Anxiety, Panic disorder
Benzodiazapene – Positive allosteric modulation of GabaA Receptors – (Facilitates GabaA inhibition in use dependent manner)
9	Effexor XR	Venlafaxine	14,992,000	Depression,Anxiety, Panic disorder – “Off-label” for diabetic neuropathy and migrane
Serotonin-norepinephrine reuptake inhibitor (SNRI) – increases serotonine and norepinephrine
8	Seroquel	Quetiapine	15,814,000	Schizophrenia, Bipolar disorder, “add-on” for Depression
“Atypical antipsychotic” – Blocks dopamine, serotonin, adrenergic and histamine receptors
7	Cymbalta	Duloxetine	16,626,000	Depression,Anxiety, fibromyalgia, diabetic neuropathy
Serotonin-norepinephrine reuptake inhibitor (SNRI) – increases serotonine and norepinephrine in a use dependent manner
6	Desyrel	Trazodone	18,873,000	Depression, Bipolar Depression (sometimes), Anxiety
Predominantly a 5-HT2A receptor antagonist, also 5-HT1A partial agonist and Selective Serotonin Reuptake inhibitor (SSRI)
5	Prozac	Fluoxetine	19,499,000	Depression, Anxiety, OCD, Bulemia, PMDD
Selective Serotonin Reuptake inhibitor (SSRI), 5-HT2C receptor antagonist, σ1 Receptor agonist
4	Zoloft	Sertraline	19,500,000	Depression,Anxiety, OCD,PTSD, PMDD
Selective Serotonin Reuptake inhibitor (SSRI) – Weak σ1 receptor agonist and α1-adrenoreceptor antagonist
3	Ativan	Lorazepam	25,868,000	Anxiety, panic disorder
Benzodiazapene – Positive allosteric modulation of GabaA Receptors – (Facilitates GabaA inhibition in use dependent manner)
2	Lexapro	Escitalopram	27,698,000	Depression,Anxiety
Selective Serotonin Reuptake inhibitor (SSRI)
1	Xanax	Alprazolam	44,029,000	Anxiety
Benzodiazapene – Positive allosteric modulation of GabaA Receptors – (Facilitates GabaA inhibition in use dependent manner)

It’s a little crazy, pun totally intended, how much we’re prescribing SSRIs, when some meta analyses say they aren’t much better than placebo. Placebo effects are probably doing something very physiological in this case, by relieving anxiety. I would say that sugar pills would be a lot cheaper and save us money, but I don’t think we need more sugar either. Maybe, we should go Germany’s route and prescribe St. John’s Wort for mild depression?

• 10. Hydrochlorothiazide (various brand names) lowers blood pressure — 47.8 million
• 9. Generic Glucophage (metformin) diabetes drug — 48.3 million
• 8. Amoxicillin (various brand names) antibiotic — 52.3 million
• 7. Azithromycin (brand names include Z-Pak and Zithromax), antibiotic — 52.6 million
• 6. Generic Prilosec (omeprazole), antacid drug — 53.4 million (does not include over-the-counter sales)
• 5. Generic Norvasc (amlodipine besylate), angina/blood pressure drug — 57.2 million
• 4. Generic Synthroid (levothyroxine sodium), synthetic thyroid hormone — 70.5 million
• 3. Lisinopril (brand names include Prinivil and Zestril), blood pressure drug — 87.4 million
• 2. Generic Zocor (simvastatin), cholesterol-lowering statin drug — 94.1 million
• 1. Hydrocodone (combined with acetaminophen), opiate/painkiller — 131.2 million

This list doesn’t contain any psychiatric drugs–Xanax just barely misses the cut–but the #1 drug, hydrocodone, is psychoactive. However, while our #1 psychiatric drug did not make it into the top 10 most prescribed, our #8 drug, the atypical antipsychotic Seroquel clocks in at #6 on the drugs we spend the most money on (shown bellow).

Also of note, is the #1 most prescribed drug for teenagers. Can you guess what it is? Methylphenidate, Ritalin, the ADHD medicine. I’m most surprised it’s not adderall at this point.

According to ABC news: “The United States makes up only 4.6 percent of the world’s population, but consumes 80 percent of its opioids — and 99 percent of the world’s hydrocodone, the opiate that is in Vicodin.” Our use of hydrocodone and other opiate painkillers has many issues: such as diversion and abuse and use as a bandage in chronic pain or injury instead of treating underlying issues (where it may even make pain worse in the long term). Another startling new trend, is the spike in newborns born dependent on opiates:

The best sellers are often generic drugs, so it is also interesting to see where “big pharma” is making the most money:

Top 10 drug we spend the most money on in the United States overall (according to IMS Institute for Healthcare Informatics in 2011)

• 10. Epogen, injectable anemia drug — $3.3 billion
• 9. Actos, diabetes drug — $3.5 billion
• 8. Crestor, cholesterol-lowering statin drug — $3.8 billion
• 7. Singulair, oral asthma drug — $4.1 billion
• 6. Seroquel, antipsychotic drug — $4.4 billion
• 5. Abilify, antipsychotic drug — $4.6 billion
• 4. Advair Diskus, asthma inhaler — $4.7 billion
• 3. Plavix, blood thinner — $6.1 billion
• 2. Nexium, antacid drug — $6.3 billion
• 1. Lipitor, cholesterol-lowering statin drug — $7.2 billion

Note the atypical antipsychotics Seroquel and Abilities. One meta-analysis of antipsychotics, showed they have questionable benefit over the now-generic typical antipsychotics, and were not a cost-effective answer. The studies analyzed all suffer from the same difficulties that genetics studies of schizophrenia do, because patients are so heterogeneous and diagnoses are somewhat subjective. Atypical prescriptions are probably too high, due to advertising and “newer is better” kind of thinking, but because the disorders are heterogeneous, I’m glad that we have more drugs to choose from and try out with individual patients.

Also, I’m also shocked that antacid drugs can make that much money, but I guess it’s in a different ballpark than Tums.

References / Further Reading
Turner, E. H., Matthews, A. M., Linardatos, E., Tell, R. A., & Rosenthal, R. (2008). Selective Publication of Antidepressant Trials and Its Influence on Apparent Efficacy. New England Journal of Medicine, 358(3), 252-260. Massachusetts Medical Society. doi:10.1056/NEJMsa065779

Hanrahan, P., Luchins, D. J., Fabian, R., & Tolley, G. (2006). Cost-effectiveness of atypical antipsychotic medications versus conventional medication. Expert Opinion on Pharmacotherapy, 7(13), 1749-1758. Expert Opinion. doi:10.1517/14656566.7.13.1749

Julius Axelrod

More recently, scientists discovered an evolutionarily recent nonsynonomous single-nucleotide polymorphism (SNP) in the protein-coding portion of the COMT gene–Val¹⁵⁸Met or rs4680. This means that some people carry a version of the gene that differs by a single DNA basepair and alters the 158th amino acid in the protein, changing it from valine to methionine.

Just because an amino acid has been altered, doesn’t mean there will necessary be a functional change in the protein, that has to be studied explicitly, but in this case it was dramatic.

Scientists have studied the Val¹⁵⁸Met polymorphism and found dramatic effects in its enzymatic activity, expression levels, and behavioral phenotypes for its carriers as well with influences on subjective well-being, emotional processing, and possibly even dopamine-related diseases such as schizophrenia and Parkinsons. It is an extremely well-studied polymorphism with 165 papers referencing it on pubmed.

COMT Val¹⁵⁸Met’s biochemical effects

When scientists transfected the Met polymporphism is into cultured cells, protein expression decreased, and it’s overall enzymatic activity greatly decreased. When they controlled for transfection efficiency using pSV-β-galactosidase (though I am not familiar with this technique and how good of a control it is), they saw a 70-90% decrease in immunoreactive protein staining for COMT staining, and a 40% decrease in enzymatic activity measured by the amount of isotopically labled methyl groups were added to 3-4-dihydroxybenzoic acid (Shield et al., 2003). Of course, you always want to study things in as physiological of conditions as possible. Chen et al. (free fultext) did a similar experiment at body temperature in post-mortem human DLPFC tissue and also showed a 40% decrease in COMT enzymatic activity.

So great, the COMT Val/Met polymorphism has robust biochemical effects in the relatively well-characterized and obviously important dopamine pathway, but does it have measurable phenotypic effects in humans?

COMT Val¹⁵⁸Met’s human phenotypic effects: card sorting, pot smoking, and happiness

In 2001, Egan et al. showed that the Val/Met polymorphism can effect frontal lobe function. They studied 175 patients with schizophrenia, 219 unaffected siblings, and 55 controls. COMT genotype predicted preservation in the Wisconson Card Sorting (WCS) task (p=.001).

WCS is a neuropsychological test, measuring subject’s “set-shifting,” cognitive flexibility, or executive function ability. The experimenter shows the subject a card, and subjects must choose which pile to place the card into. The only feedback the experimenter gives to subjects is whether they sorted a card correctly or incorrectly, and from this feedback they must learn the sorting rule on their own. At some point during the trial, the experimenter changes the sorting rule , without the subjects being notified. Perseverance errors are made, when the subject continues to sort by the first rule they learned and ignore the new feedback they are getting. Schizophrenics and patients with damage to the dorsal-lateral prefrontal cortex (DLPFC) perform poorly on this task; they often perseverate and learn the second rule more slowly than controls. (I’ve previously written about the DLPFC’s involvement in economic decisions.)

Here’s one of the really interesting parts. The low activity Val/Met polymorphism, which raises dopamine levels, ENHANCED cognitive performance. This may seem counter intuitive if like me you had at one point learned the over-simplified dopamine hypothesis that basically went: dopamine antagonists work as antipsychotics, therefore schizophrenics have too much dopamine. Of course, the brain is never that simple and location is important. According to current consensus, schizophrenics are often hypodopaminergic in the frontal cortex–the most-involved region in executive function tasks like the WCS–and hyperdopaminergic in other regions such as the striatum. Interestingly, giving schizophrenics dopamimetic drugs like cocaine and amphetamines actually improves their performance on this task.

While COMT is expressed in most of the brain, it may have a stronger effect in the prefrontal cortex. This is supported experimentally by the fact that COMT knockout mice (that do not express the gene at all) show increases in dopamine in the prefrontal cortex but not the striatum (Gogos 1998). Theoretically, it is supported by the observation that the PFC has much lower levels of dopamine transporter (which has a 1,000-fold higher affinity for dopamine than does COMT). So while in the striatum, the effect of the dopamine transporter probably dominates, internalizing dopamine where it is broken down by the intracellular enzyme mono amine oxidase (MAO), in the PFC far less dopamine is being internalized and far more is being broken down in synaptic or parasynaptic regions by COMT, which acts extracellularly.

COMT Val¹⁵⁸Met Marijuana and Schizophrenia

Caspi’s 2005 longitudinal cohort study of over 953 caucasian NZ children, were followed until they were 26-years-old, and showed that children who carried the COMT val158 allele and used cannabis before age 18 were more likely to exhibit psychotic symptoms or develop schizophreniform disorder. Cannabis use had no influence on psychosis in individuals with two methionine alleles.

Of the cohort, 1% of the group met DSM IV criteria for schizophrenia (symptom duration > 6 months), and another 2.6% for schizophreniform disorder (i.e., symptom duration from 1–6 months). The cohort was tested for broader pyschosis-like measures, and 13% reported >1 non-drug-related hallucinatory experience, and 21% reported >1 delusional belief symptom (8% reported both and 26% reported either). These numbers may seem scarily high, but similar numbers are reported in studies of the North American population as well.

Using the regression:

Psychosis=b0 + b1(COMT) + b2(adolescent – onset cannabis use) + b3(COMT × adolescent-onset cannabis use)

there was a significant, but not super-robust interaction on the additive scale between COMT and cannabis use before age 18 for predicting schizophreniform disorder (χ²(1) = 4.5, p = .034) and evidence of hallucinatory experiences (χ²(1) 4.9, p = .027), but not for evidence of delusional beliefs (χ²(1) = .73, p = .39).

However, these findings were not supported by Zammit’s 2007 study of 493 schizophrenic patients’ COMT genes (among others)  and their interactions with cannabis use. The study found no  association between Val¹⁵⁸Met genotype and cannabis use in our sample of 493 persons with schizophrenia. (And I guess, if the Val allele x marijuana environmental interaction was causative of schizophrenia, you’d expect a larger percentage of the smokers with schizophrenia to have the allele. Although they claim they should have enough statistical power to replicate the interaction, they admit it is not the best design to assess the gene x environment interaction.)

Other studies have claimed that the Val/Met polymorphism is a risk for schizophrenia in and of itself, but while the region does have some signal in genome wide association studies (GWAS) of the disease, the signal is not very strong, so any association is unlikely to be big. Therefore, if there is a strong association, it will likely involve a gene x gene interaction or gene x environment interaction.

COMT has been looked at as a candidate gene in schizophrenia and psychosis, because of the involvement of dopamine in those diseases. Also, COMT it is one of the genes where a copy is lost in the 22q11.2 deletion syndrome, also known as DiGeorge Syndrome or VCS, which increases the relative risk of schizophrenia from around 1%, to around 20-30%.

COMT Val¹⁵⁸Met and Pleasure

In my opinion, one of the most intriguing findings about this polymorphism is its apparent effects on the experience of pleasure. Not only does the met polymorphism seems to improve prefrontal cortex function, and possibly decreases psychosis risk, it actually makes people report better well-being.

Using a cool psychological technique called experience sample monitoring (ESM), Wichers et al. 2008 genotyped 492 subjects and gave them digital wristwatches and self-assessment forms. For 5 days, the watches would beep at a random time in ten blocks between 7:30 and 22:30. So for example, the watch might beep at 8:37, then 11:14, and so forth throughout the day, and at each beep the subject was told to record their “thoughts, current context (activity, persons present, and location), appraisals of current situation and mood.”

“Reward experience on the continuum of event appraisal stratified by COMT genotype (event reference category is ‘neutral’).” Wichers (2007) Neuropsychopharmacology

Subjects with the met polymorphism reported more pleasure from what should have been equally pleasurable activities, and the effects were got bigger the more pleasurable an event was.

This made me curious about COMT’s possible relationship to depression. However, the first two studies I found in a very haphazard literature review were the opposite of what I expected, with the Met allele being associated to postpartum depression and depression in men (Comasco 2011) and (Åberg 2011). However, perhaps this was to be expected as pleasure and happiness can be very different things, and antidepressants are thought to work through serotonin and norepinephrine pathways, not dopamine pathways (though COMT will effect NE levels).

So what genotype are you?

The evolutionarily recent Met polymorphism isn’t rare by any means. Though allele frequency varies by geographic ancestry–about 12% of the overall population sampled is homozygous for the Met allele, and another 42% carry one copy (see refSNP). If you really must know your genotype, it is measured in the SNP panel done by 23 and me. I think, I’m going to try to hold out for the thousand dollar genome and then get myself sequenced, or see if I can weasel my way into the control group (or experimental group) of some study.

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Edit: Since this post has been popular–for my lowly blog anyways ; ) –I wanted to add a bit of background:

If you have any opinions about gene candidate studies, GWAS, reductionist genetics, neurogenetics, etc., or disagree with anything I’ve written here, please leave a comment (especially if it’s snarky.)

Also, if you’ve read this far, you may be intersted in my other posts genetics posts:

Genoeconomics – Can genetic variation predict economic decisions?

New sequencing study links autism to FMRP, the gene disrupted in fragile X syndrome and a regulator of synaptic plasticity

Mirror Touch Synesthesia and the Genetics of Synesthesia

Genetics of Sleep – How much do you need?

Epigenetics and The Brain — 5-hydroxy-methocytosines

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References:

Shield, A. J., Thomae, B. A., Eckloff, B. W., Wieben, E. D., & Weinshilboum, R. M. (2003). Human catechol O-methyltransferase genetic variation: gene resequencing and functional characterization of variant allozymes. Mol Psychiatry, 9(2), 151-160. Nature Publishing Group. Retrieved from http://dx.doi.org/10.1038/sj.mp.4001386

Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., Goldman, D., et al. (2001). Effect of COMT Val108/158 Met genotype on frontal  lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences , 98 (12 ), 6917-6922. doi:10.1073/pnas.111134598

Gogos, J. A., Morgan, M., Luine, V., Santha, M., Ogawa, S., Pfaff, D., & Karayiorgou, M. (1998). Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proceedings of the National Academy of Sciences , 95 (17 ), 9991-9996. doi:10.1073/pnas.95.17.9991

Avshalom Caspi, Terrie E. Moffitt, Mary Cannon, Joseph McClay, Robin Murray, Ian W. Craig, et al. (2005). Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction, Biological Psychiatry, 57(10),  0006-3223. doi:10.1016/j.biopsych.2005.01.026.

ZAMMIT, S., SPURLOCK, G., WILLIAMS, H., NORTON, N., WILLIAMS, N., O’DONOVAN, M. C., & OWEN, M. J. (2007). Genotype effects of CHRNA7, CNR1 and COMT in  schizophrenia: interactions with tobacco and cannabis use . The British Journal of Psychiatry , 191 (5 ), 402-407. doi:10.1192/bjp.bp.107.036129

Wichers, M., Aguilera, M., Kenis, G., Krabbendam, L., Myin-Germeys, I., Jacobs, N., Peeters, F., et al. (2007). The Catechol-O-Methyl Transferase Val158Met Polymorphism and Experience of Reward in the Flow of Daily Life. Neuropsychopharmacology, 33(13), 3030-3036. American College of Neuropsychopharmacology. Retrieved from http://dx.doi.org/10.1038/sj.npp.1301520

Comasco, E., Sylvén, S. M., Papadopoulos, F. C., Sundström-Poromaa, I., Oreland, L., & Skalkidou, A. (2011). Postpartum depression symptoms:  a case–control study on monoaminergic functional polymorphisms and environmental stressors. Psychiatric Genetics, 21(1). Retrieved from http://journals.lww.com/psychgenetics/Fulltext/2011/02000/Postpartum_depression_symptoms___a_case_control.4.aspx

Elin Åberg, Andrés Fandiño-Losada, Louise K. Sjöholm, Yvonne Forsell, Catharina Lavebratt (2011) The functional Val158Met polymorphism in catechol-O-methyltransferase (COMT) is associated with depression and motivation in men from a Swedish population-based study, Journal of Affective Disorders, Volume 129, Issues 1–3,  Pages 158-166, ISSN 0165-0327, 10.1016/j.jad.2010.08.009.

Podcasts:

Podcasts have gotten me through a lot of boring lab work, and introduced me to and piqued my interest in many topics. My top 3 podcasts (in alphabetic order):

1. Brain Science Podcast – Hosted by an ER doctor, Ginger Campbell, who does a great job of getting big name neuroscientists, talking in depth on a topic, but keeping everything very accessible and easy to understand.  The tagline for the show is the wonderful “The show for everyone who has a brain.” I find it especially good for finding books, and getting introduced to schools of psychology out neuroscience I hadn’t previously heard of. I also love that Ginger repeats and clarifies important points in the middle and end of episodes and always asks the guests to give advice to students interest in neuroscience. The website also features annotated transcripts of the episodes if you’d prefer to keep things occipital. Monthly episodes ~1 hr.

2. Neuropod – Nature’s official neuroscience podcast hosted by neuroscience journalist Kerri Smith. Each episode is around a half hour and usually features 3-4 pieces interviewing authors of recent papers and reviews. (The website also has links to the papers if they peak your interest.) The whole format is better produced than many podcasts and resembles feature pieces on public radio. Monthly episodes ~30 minutes.

3. Neuroscientist’s Talk Shop – As the name implies this one is a little more intense, speakers will assume you are at least a neuroscience graduate student, though I think you can still get a lot out of it, even if you aren’t. It usually has a more computational, electrophysiologal, and information processing slant. Each episode consists of an informal discussion between a few of University of San Antonio’s professors. They are all great speakers and it can often be a lively and funny discussion. I like that they are willing to speculate on topics (though like any good scientists, they make it more than clear when they are speculating). It’s a great way to see how professional neuroscientists think and talk. Frequency varies 1-3 weeks during the school year ~45 min.

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Also, if you want more media check out these great psychiatric genetics lectures, and  my post on top neuroscience blogs,

Despite having cared for laboratory mice for years, I’m wowed by the complexity of this task! The trainer’s site: http://mouse-agility.com/ describes the animals living conditions and training method.

The trainer keeps the mice housed in groups of 3-4 females, in 3-dimensional cages such as a remodeled cupboard, or:

a pyramid of different-sized tables, the several floors interestingly arranged and connected by ropes or ladders – this will keep them fit in all respects. Another advantage of this husbandry is the perfect airing, the good chance to watch your pets and the direct contact to them for the lack of cage bars or glass… To supply their need for digging, I use to place a few litter-filled boxes onto the tables, as well as some bigger tubs beneath them, used as their “basement”.

Starting at 4 weeks, the mice are trained with “clicker training,” an operant conditioning method developed by students of B.F. Skinner. In clicker training, positive reinforcement of behavior with food, is accompanied with a stereotyped auditory cue such as a click. Repeated pairing turns the click into a conditioned reinforcer, that can more inform the animal what behavior they are being rewarded with greater temporal precision,  allowing faster and more complicated training. Using the process psychologists call shaping, mice are trained to do progressively longer and harder tasks.

Mice can be difficult to train with this method because they are naturally cautious and anxious creatures and can be frightened by the noise of the clicker or presence of a trainer. They are also trained using a random reinforcement paradigm, where rewards are not always given at the end of a trial and rewards vary between types of food and caressing.

One of the problems with using mice in experiments (and a large reason why rats are used, despite the sophistication of genetic manipulation in mice), is that they are hard to train to do complex tasks. I don’t know to what extent clicker training and shaping is used by experimenters, but I doubt it is widespread. I would guess that it’s use can extend beyond simple operant conditioning and be used to inform the mice of the relavent cues required for the task. Perhaps using clicker training or by collaborating with expert animal trainers outside of scientific settings we could finally come up with tests of general intelligence, task-shifting,  etc., that could then be manipulated genetically in mice.

The connectome  is a map of all neural connections in a brain, which I believe only currently exists for the flatworm C. Elegans. Seung’s group and collaborators are working using serial electron microscopy, and partially automated EM analysis and the crowdsourcing site eyewire  to reconstruct parts of the mouse retina, with the hope of steadily improving technologies to map larger and larger areas, eventually reconstructing an entire mouse brain, and then human brains.

If the technique ever becomes feasible for human brains, we will be able to test for connectopathies in various diseases (psychiatric diseases caused by theorized miswiring of areas of the brain). Seung also argues that the connectome may be the best physiological correlate for the essence of what we consider ourselves–it is formed by genetics and experience, and is relatively static but constantly changing–just like our personalities, habits, dreams, and desires.

I really want to check out Seung’s new book, Connectome: How the Brain’s Wiring Makes Us Who We Are. Seung is a great presenter, so I recommend you watch the videos or listen to the podcast below:

Sebastian Seung on Brain Science Podcast

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You may also be interested in my post: How many neurons do we really have? (And why we might have 10x fewer glia than we previously thought.)

But how exactly do you find the most popular blog? There are blog ranking lists, top results on google, and lists of expert recommendations. Half the ones you find haven’t been updated in over a year.

Here I’ve analyzed some of these listings, and put my personal recommendations of up to date quality blogs in bold. (Updated June 2012.)

List I – Google Reader’s Top Results for Neuroscience Blogs or Neuro Blogs

1. Mind Hacks - Neuroscience and psychology tricks to find out what’s going on inside your brain. Features cool case studies, links to interesting articles, and analysis of the popular presses coverage of psychology issues. Most posts by Vaughan Bell, senior research fellow at the Institute of Psychiatry, King’s College London, with occassional offerings from Tom Stafford, Lecturer in Psychology and Cognitive Science in the Department of Psychology, University of Sheffield.

2. Action Potential - A Nature.com blog that is updated almost weekly. Similar in style to what I want to achieve, this blog lays out long summaries of papers recently published in nature, reports on conferences. Highly Reccomended. I really hope we start seeing more of this kind of blog.

3. Law and Neuroscience Blog - Blog where MacArthur Foundation Researchers on Law and Neuroscience can post about how Neuroscience is influencing (or should be influencing) law.

4. NeuroSkeptic - A UK neuroscientist’s skeptical look at his own field, and beyond.

5. Neuropathology Blog - Brian E. Moore, MD, a neuropathologist in the US,  discusses the practice of neuropathology, tumors, anatomy, neurodegenerative disease, muscle and nerve disorders, and more.

List II – Most Popular Neuroscience Blogs according to Networked Blogs Neuroscience Rankings – This is a site I discovered while researching this post. Networked Blogs allows you to find new blogs, follow them, and read all of your blogs in one place. Conveniently uses Facebook login. (Follow me!)

1. Neurophilosophy - A great blog for keeping up with a wide birth of neuroscience news. Maintained by an active blogger, tweeter, and ex-molecular and developmental neurobiologist Mo Costandi. On Neurophilosophy, you can find accurate articles about interesting new findings long before they are covered by other blogs.

2. Psychology Corner - Blog by a Romanian clinical psychologist and psychotherapist Lucia Grosaru. I’d like to see more updates and more coverage of scientific articles, but popular articles like: “Toddlers and children beauty pageants – Risk factors for severe psychological turmoils” and “10 (Psychological) Reasons why we like Dexter Morgan” engages people and gets them commenting in a way I haven’t managed to.

3. NeuroLogica - You may also know the accomplished Yale Neurologist Steve Novella from his podcast The Skeptic’s Guide to the Universe, his other blogs, or lectures with the Teaching Company. For such an accomplished busy man, Novella keeps his blog regularly updated with articles about new scientific findings. What really sets this blog apart is how Novella uses his background knowledge to frame the study in it’s surrounding body of work, explain why he finds it interesting, and talk about the future of the field.

4. Snow Drop - This blog’s appearance in the top 5 demonstrates the dangers of democracy, and a need for the blogging community to regulate itself better. This blog is clearly spam to sell the author’s rehabilitation programs. For example: the “author’s” 2012 article The Importance of Zinc is uncredited copy-pasta plagiarism of this 2006 eurekalert press release.  I know very little about neurodevelopmental consultant Andrew Brereton, who says he became interested in neuroscience and child development after his son was diagnosed with cerebral palsy, but his lack of integrity makes me skeptical about his claims, and I wonder how legitimate his therapy is.

5. Neuromarca - Spanish-language neuromarketing blog. Si quieres leer de neuromarketing esto es tu blog! And if you want to read it in english, google chrome’s translate feature will do a good enough job. Sergio Monge Benito’s quality blogposts on an area outside my main interests and expertise, but a good way to learn about practical applications of neuroscience to a field with little exposure in conventional neuroscience academia.

List III – Researchblogging.org’s 2010 Best Neuroscience Blogs (most recent awards)

Previously mentioned Neuroskeptic, and Neurophilosophy were in the top overall blogs.

Winner for Best Neuroscience Blog: Neurotopia - no longer updated, but interesting to look through the archives

Other Finalists:

Neurocritic - Interesting blog with diagrams and links to primary literature.

Quantum Lobe Chronicles - William Lu’s blog about Psychology, neuroscience, philosophy, quantum physics. Barely updated anymore.

Neurodojo - A neuroethologist’s blog less about neuroethology and more about blogging, the internet, sociology of science, and random stuff.

Wiring the Brain -  Brain wiring during development and what happens when it goes wrong. Good, focused blog, with diagrams and references to primary literature.

Talking Brains - Greg Hickok and David Poeppel–Professors at UC Irvine and NYU–blog on the neural organization of language. Essays, comments on new papers, and job openings. I like the idea of a small collaborative blog like this–always having someone to bounce ideas off of, more writers makes updates more consistent, but it’s not too anonymous or dilute. (If anyone is interested in merging blogs or contributing to NeuroAmer let me know. I haven’t thought about it too seriously.)

Brain Blogger - A collaborative blogging effort supported by the  Global Neuroscience Initiative Foundation (GNIF), Brain Blogger has over 80 contributors including neurosurgeons, psychotherapists, forensic psychologists, registered nurses, clinical pharmacists, patient advocates, and general citizens concerned about neurological and mental health.

List IV Blogrank’s Top Mental Health - Uses a 20-factor formula to rate blogs and displays some stats for many sites such as number of visitors and RSS subscribers. Unfortunately doesn’t have a category for neuroscience, so I scrolled through and found the top 5 neuroscience-y blogs. These blogs are more on the human experience side than on the science side, but its important for even the most basic neuroscientists to understand the impact of mental health and psychiatric disease.

1. Autism Learning Felt - This blog is written by Tammy L., the stay-at-home mother of a 15-year-old girl with autism. She describes the blog as P.R.-friendly, meaning she’ll reviews of all types of products that can be related to children with autism or moms. Reviews don’t seem too critical, but aren’t saccharine either, just straight-up descriptions of products. A good window into the types of commercially available products for children with autism.

2. The Secret Life of a Manic Depressive - A mental health activist’s blog chronicling her diagnosis of bipolar disorder and body dysmorphic disorder, and navigating the mental health care system in the UK. The writer has written for One in Four magazine, BBC Ouch, the Guardian, Independent and the Observer.

3. Storied Mind – Recover Life From Depression - John Folk-Williams’ blog to share the ideas, stories and information that have him get over depression and restart his life. Pop-psychology advice.

To be honest, not much from this list really impressed me, so I moved on.

Also, check out my post: Beyond Blogs – Keep up with neuroscience through podcasts. More posts will be coming soon with similar analysis for the most popular psychology blogs, most popular biology blogs, and most popular genetics blogs.

If anyone has recommendations for good neuroscience blogs that are consistently updated or tools to find them, please post them below or shoot me an email.