Controlling fear by modifying DNA

April 28, 2014
Controlling fear by modifying DNA
Neuroscientists from The University of Queensland’s Queensland Brain Institute may have found a way to silence the gene that feeds fear.

(Medical Xpress)—For many people, fear of flying or of spiders skittering across the lounge room floor is more than just a momentary increase in heart rate and a pair of sweaty palms.

It's a hard-core phobia that can lead to crippling anxiety, but an international team of researchers, including neuroscientists from The University of Queensland's Queensland Brain Institute (QBI), may have found a way to silence the gene that feeds this fear.

QBI senior research fellow Dr Timothy Bredy said the team had shed new light on the processes involved in loosening the grip of fear-related memories, particularly those implicated in conditions such as phobia and .

Dr Bredy said they had discovered a novel mechanism of gene regulation associated with , an inhibitory learning process thought to be critical for controlling fear when the response was no longer required.

"Rather than being static, the way genes function is incredibly dynamic and can be altered by our daily life experiences, with emotionally relevant events having a pronounced impact," Dr Bredy said.

He said that by understanding the fundamental relationship between the way in which DNA functions without a change in the underlying sequence, future targets for therapeutic intervention in fear-related could be developed.

"This may be achieved through the selective enhancement of memory for fear extinction by targeting genes that are subject to this novel mode of epigenetic regulation," he said.

Mr Xiang Li, a PhD candidate and the study's lead author, said fear extinction was a clear example of rapid behavioural adaptation, and that impairments in this process were critically involved in the development of fear-related anxiety disorders.

"What is most exciting is that we have revealed an epigenetic state that appears to be quite specific for fear extinction," Mr Li said.

Dr Bredy said this was the first comprehensive analysis of how fear extinction was influenced by modifying DNA.

"It highlights the adaptive significance of experience-dependent changes in the chromatin landscape in the adult brain," he said.

The collaborative research is being done by a team from QBI, the University of California, Irvine, and Harvard University.

The study was published this month in the Proceedings of the National Academy of Sciences.

Explore further: Regulating the formation of fear extinction memory

More information: Xiang Li, Wei Wei, Qiong-Yi Zhao, Jocelyn Widagdo, Danay Baker-Andresen, Charlotte R. Flavell, Ana D'Alessio, Yi Zhang, and Timothy W. Bredy. "Neocortical Tet3-mediated accumulation of 5-hydroxymethylcytosine promotes rapid behavioral adaptation." PNAS 2014 ; published ahead of print April 22, 2014, DOI: 10.1073/pnas.1318906111

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JVK
1 / 5 (1) Apr 28, 2014
This is the critical link from the epigenetic landscape to the physical landscape of DNA in the organized genome of species that must acquire a specific nutrient via dietary intake. That fact links nutrient-dependent changes in the microRNA/messenger RNA balance from DNA methylation to genomic stability via alternative splicings of pre-mRNA; amino acid substitutions, and the conserved molecular mechanisms that link sensing and signaling to the pheromone-controlled physiology of reproduction in species from microbes to man.

Population geneticists and evolutionary theorists must not have seen this coming or they would already have quit trying to explain away ecological adaptations with their pseudoscientific nonsense about mutations, natural selection, and evolution. Here we have serious scientists, such as Dr. Bredy, who have instead been working on experience-dependent nutrient-dependent epigenetic effects that underlie what is known about transgenerational epigenetic inheritance.
anonymous_9001
5 / 5 (1) Apr 28, 2014
Instead of assuming what Brady believes or doesn't believe and making a fool of yourself, contact him.
JVK
1 / 5 (1) Apr 28, 2014
I made no assumptions; I'm familiar with his past work and understand biologically-based cause and effect involving 5hmcs and nutrient-dependent cell type differentiation. See for example:

Dynamic DNA methylation: a prime candidate for genomic metaplasticity and behavioral adaptation http://www.scienc...12001671

As I've repeatedly told you to no avail -- because you are an anonymous fool who believes in a ridiculous theory -- nutrient-dependent pheromone-controlled ecological adaption (e.g., the antithesis of mutation-driven evolution) is supported by experimental evidence and exemplified in the diversity of species from microbes to man.

Nutrient-dependent/pheromone-controlled adaptive evolution: a model.
http://www.ncbi.n...24693353
anonymous_9001
5 / 5 (2) Apr 28, 2014
I made no assumptions


Blatantly false.

Just because his research focuses on epigenetics doesn't mean he denies mutation and natural selection.

Just because microbiologists study and write about microbes exclusively doesn't mean they don't believe elephants exist. That's the sort of logic you're using here.
russell_russell
not rated yet Apr 28, 2014
From the Abstract -

5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation have not been fully elucidated. Moreover, although the ten-eleven translocation (Tet) family of enzymes is known to be essential for converting methylated DNA to 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC capture together with high-throughput DNA sequencing on individual mice, we show that fear extinction, an important form of reversal learning, leads to a dramatic genome-wide redistribution of 5-hmC within the infralimbic prefrontal cortex.

Wonderful research. I disagree with "reversal learning".
Everything is recorded. Detrimental 'recordings' still have the same cues.
What is isolated undergoes "pruning
russell_russell
not rated yet Apr 28, 2014
The cues remain the same. The newly learned and recorded - as stated - is favored now from the redistributed 5-hmc stemming from the methylated DNA. The cues access "the paths most traveled" - paths to the isolated (from redistributed 5-hmC) undergo atrophy.
anonymous_9001
5 / 5 (2) Apr 28, 2014
My prompt to Dr. Bredy:

I have encountered somebody that claims your focus on epigenetics means that you deny the contribution of mutation and natural selection to evolution. Could I get a brief statement on that?


His response:

http://i.imgur.com/Cg9wDGl.jpg

For emphasis:

gene mutations aren't the whole story driving natural selection


Meaning they still are part of the story, in conjunction with epigenetic mechanisms.

And:

they (epigenetic mechanisms) also play a role in evolution


Also. Not exclusively.
JVK
1 / 5 (1) Apr 28, 2014
The anonymous fool still wants mutations to somehow be involved despite no experimental evidence and the biophysical constraints. And he still wants to play the anonymity card while eliciting comments from others that only partially address whats currently available in the extant literature on biologically based cause and effect.

"Oxidation of 5-methyl cytosine (5Mc) to 5-hydroxy mC (5hmC) is considered the main pathway in removing the methyl tags from the genome, but in the brain increased levels of 5hmC in gene bodies have been shown to correlate with transcriptional activation [48]."

The link between nutrient uptake, 5hmC, learning and behavior is as clear when it involves food odors as when learning and behavior are associated with social odors called pheromones that control the nutrient-dependent physiology of reproduction.

The link includes what is known about the role of 5hmc in cell type differentiation in individuals of vertebrates and invertebrates.
JVK
1 / 5 (1) Apr 28, 2014
"The accumulation of these [Tet-linked] DNA base modifications may have different effects depending on whether they occur at single bases within key binding motifs, which would suggest a role in regulating transcription factor activity, and potentially alternative splicing, or if they are more broadly distributed, the pattern of accumulation may be indicative of a role in the regulation of DNA structure or chromatin looping (39)." http://www.pnas.o...abstract

Base pair flipping, alternative splicings of pre-mRNA and de novo Creation of olfactory receptor genes establish the link from the epigenetic landscape to the physical landscape of DNA via methylation in the birds and the bees (and in what is now central China). Biophysical constraints prevent beneficial mutations. It's as simple as that and only an anonymous fool would continue to try and complicate it without providing any experimental evidence to support his claims.
anonymous_9001
5 / 5 (1) Apr 28, 2014
His response directly contradicts you and you brush it off as insignificant. I'd expect nothing less.
Sinister1812
5 / 5 (1) Apr 29, 2014
If this becomes a reality, these findings would be a breakthrough for things like social anxiety and agoraphobia.
JVK
2 / 5 (2) Apr 29, 2014
If this becomes a reality...


If WHAT b.e.c.o.m.e.s a reality? What makes you think it is not already the reality of what is known about physics, chemistry and conserved molecular mechanisms that link biologically based cause and effect in species from microbes to man?

I quoted from the article by Bredy's group: "The accumulation of these [Tet-linked] DNA base modifications may have different effects depending on whether they occur at single bases within key binding motifs, which would suggest a role in regulating transcription factor activity, and potentially alternative splicing..."

We detailed the role of alternative splicings of pre-mRNA in our 1996 Hormones and Behavior review: From fertilization to adult sexual behavior http://www.ncbi.n.../9047261

What we see now is how quickly the processes that lead from sensory input to ecological adaptations can occur and lead to fixation and transgenerational epigenetic inheritance.
JVK
1 / 5 (1) Apr 29, 2014
His response directly contradicts you and you brush it off as insignificant.
Your comments are insignificant and your question to him included no model of mutation-driven evolution for comparison. If there were a model, it could be compared to the facts exemplified in this report, which is another refutation of pseudoscientific nonsense.

http://www.biomed...4/15/305
"...after stringent quality filtering using information from zebra finch and chicken, the best-annotated avian genome assemblies, we can state that the core set of transcribed house finch sequences comprises almost 10,000 unique genes. This set of genes is an invaluable resource for forthcoming efforts aimed at pinpointing the genetic basis of evolutionarily important traits in the house finch, such as resistance to Mycoplasma gallisepticum [17,24,25,31] and the intensity of plumage redness in males [8,18,21,22]."

Ecologically-adapted gene sets are nutrient-dependent and pheromone-controlled.
anonymous_9001
5 / 5 (1) Apr 29, 2014
It doesn't matter if my question included a model. He doesn't believe what you claimed he believes. He recognizes the contribution of mutation after you said he wouldn't. That's all there is to it.
JVK
1 / 5 (1) Apr 30, 2014
http://www.nature...746.html
Maternal nutrition at conception modulates DNA methylation of human metastable epialleles

The link to one-carbon metabolism and methylation eliminates any chance that intelligent researchers will continue to tout mutation-driven evolution or include natural selection of anything except food in their models of species diversity.

Only anonymous fools will be left to tout their pseudoscientific nonsense while everyone else learns that ecologically-adapted gene sets are nutrient-dependent and pheromone-controlled.
Sinister1812
not rated yet Apr 30, 2014
If WHAT b.e.c.o.m.e.s a reality? What makes you think it is not already the reality of what is known about physics, chemistry and conserved molecular mechanisms that link biologically based cause and effect in species from microbes to man?


What I meant is that I don't see any therapists doing this today, to treat anxiety. Wasn't saying it wasn't possible (it obviously is!).
anonymous_9001
5 / 5 (1) Apr 30, 2014
The link to one-carbon metabolism and methylation eliminates any chance that intelligent researchers will continue to tout mutation-driven evolution or include natural selection of anything except food in their models of species diversity.


Clearly not, given Bredy's response. You called him a serious scientist, yet he still acknowledges mutation and natural selection. Check and mate.
JVK
1 / 5 (1) Apr 30, 2014
The link from nutrient uptake to DNA methylation and species diversity via de novo creation of experience-dependent olfactory receptor genes, which underlie the differentiation of other cell types, is clear from the level of one-carbon metabolism on up and from the epigenetic effects of nutrients that metabolize to species-specific pheromones that enable species diversity via control of reproduction from the top down.

Whatever you think anyone else acknowledges about mutation and natural selection is irrelevant unless mutations and natural selection can be linked from ecological variation to ecological adaptations manifested in morphological and behavioral phenotypes. There is no such thing as evolution of morphological phenotypes without evolution of behavioral phenotypes, which is why DNA methylation and ecological adaptation have replaced the pseudoscientific nonsense of mutation-driven evolution.
JVK
1 / 5 (1) Apr 30, 2014
See the comments section at http://journal.fr...127/full for more information on how Bredy's works pertain to the works of others that link nutrient-dependent DNA methylation to pheromone-controlled species diversity.
anonymous_9001
not rated yet May 03, 2014
See the comments section at http://journal.fr...127/full for more information on how Bredy's works pertain to the works of others that link nutrient-dependent DNA methylation to pheromone-controlled species diversity.


Except for those cases in which people (me) contact Bredy directly to see that he supports both what you put forward and what you deny. Embarrassing, isn't it?
JVK
not rated yet May 03, 2014
People like you cannot understand the difference between a mutation and an ecological adaptation, which makes anything I say go in one of your ears and out the other -- except when your confused brain gets in the way and you pose questions to others who confuse you even further because you are an anonymous fool who has been taught to believe in pseudoscientific nonsense. See for comparison:

http://medicalxpr...firstCmt
anonymous_9001
not rated yet May 04, 2014
If you would like to pose your own questions to Bredy, go right ahead. Nobody's stopping you. As of right now, however, I have shown he has no qualms about the role of mutation in generating genotypic variation.
JVK
not rated yet May 04, 2014
I wrote: "People like you cannot understand the difference between a mutation and an ecological adaptation..."

There is no reason to keep reasserting that fact. The need is to show how mutations generate benefits via whatever conserved molecular mechanisms link them to biophysically contrained ecological adaptations.

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