Unraveling oxytocin – is it nature’s medicine?

This 2020 review attempted to consolidate thousands of research papers on oxytocin:

“Chemical properties of oxytocin make this molecule difficult to work with and to measure. Effects of oxytocin are context-dependent, sexually dimorphic, and altered by experience. Its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.

Widely used medical interventions i.e.:

  • Exogenous oxytocin, such as Pitocin given to facilitate labor;
  • Opioid medications that block the oxytocin system; or
  • Cesarean sections that alter exposure to endogenous oxytocin

have lasting consequences for the offspring and/or mother.

Such exposures hold the potential to have epigenetic effects on the oxytocin systems, including changes in DNA methylation. These changes in turn would have lasting effects on the expression of receptors for oxytocin, leaving individuals differentially able to respond to oxytocin and also possibly to the effects of vasopressin.

Regions with especially high levels of OXTR [oxytocin receptor gene] are:

  • Various parts of the amygdala;
  • Bed nucleus of the stria terminalis;
  • Nucleus accumbens;
  • Brainstem source nuclei for the autonomic nervous system;
  • Systems that regulate the HPA axis; as well as
  • Brainstem tissues involved in pain and social attention.

Oxytocin protects neural cells against hypoxic-ischemic conditions by:

  • Preserving mitochondrial function;
  • Reducing oxidative stress; and
  • Decreasing a chromatin protein that is released during inflammation

which can activate microglia through the receptor for advanced glycation end products (RAGE). RAGE acts as an oxytocin-binding protein facilitating the transport of oxytocin across the blood-brain barrier and through other tissues.

Directionality of this transport is 5–10 times higher from the blood to the brain, in comparison with brain to blood transport. Individual differences in RAGE could help to predict cellular access to oxytocin and might also facilitate access to oxytocin under conditions of stress or illness.

Oxytocin and vasopressin and their receptors are genetically variable, epigenetically regulated, and sensitive to stressors and diet across the lifespan. As one example, salt releases vasopressin and also oxytocin.

Nicotine is a potent regulator of vasopressin. Smoking, including prenatal exposure of a fetus, holds the potential to adjust this system with effects that likely differ between males and females and that may be transgenerational.

Relative concentrations of endogenous oxytocin and vasopressin in plasma were associated with:

These studies support the usefulness of measurements of both oxytocin and vasopressin but leave many empirical questions unresolved.

The vast majority of oxytocin in biosamples evades detection using conventional approaches to measurement.”

https://pharmrev.aspetjournals.org/content/pharmrev/72/4/829.full.pdf “Is Oxytocin Nature’s Medicine?”

I appreciated efforts to extract worthwhile oxytocin research from countless poorly performed studies, research that wasted resources, and research that actually detracted from science.

I was disappointed that at least one of the reviewers didn’t take this review as an opportunity to confess their previous wastes like three flimsy studies discussed in Using oxytocin receptor gene methylation to pursue an agenda.

Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.

Although these reviewers didn’t provide concrete answers to many questions, they highlighted promising research areas, such as:

  • Improved approaches to oxytocin measurements;
  • Prenatal epigenetic experience associations with oxytocin and OXTR; and
  • Possible transgenerational transmission of these prenatal epigenetic experiences.

An environmental signaling paradigm of aging

To follow up A rejuvenation therapy and sulforaphane, the study’s lead laboratory researcher – Dr. Harold Katcher – provided evidence for an environmental signaling paradigm of aging in this 2015 paper:

“The age-phenotype of a cell or organ depends on its environment and not its history.

Organ dysfunction is not the cause of aging, but is the result of its milieu. Therefore, the aged milieu is the cause. Though it has been thought that the aging immune system is the cause of aging, it can seen to be the result of aging.

The systemic milieu of an organism sets the age-phenotype of its cells, tissues and organs. Cells and organs secrete factors into the blood, which are determined by the age-phenotype and repair-states of those cells and organs. The presence and concentrations of these blood-borne factors determine the age-phenotype of cells and organs.

Here we must be a bit more speculative. Changes in the concentrations of factors present in the blood, rather than their presence or absence, determines age-phenotype.

Interactions between disparate levels of the body’s hierarchy establish a consensus age-phenotype for cells and organs, and this largely occurs via the bloodstream. There appear to be positive factors that promote youthful age-phenotypes and negative factors that promote the aged phenotypes.

We readily consider development as a ‘program’, and it seems clear that we must consider post-adult development as ‘programmed’ as well. But if there is a program it is neither in the genes nor the chromatin, but in the interaction of complex, interconnected systems spanning the hierarchical levels.

If these aforementioned principles are correct, it should be easy to verify. If so, then whole organism rejuvenation might require little more than changing the concentrations of all age-determining molecules of the bloodstream and the various stem cell niche environments to youthful levels for a time sufficient to cause rejuvenation at the cellular level.

Once cells start secreting factors appropriate to their new, younger age-phenotypes, cognate changes should propagate through the hierarchical levels.

The analogy to the workings of a mechanical clock is not very exact. ‘Gears’ represent the individual aging clocks, both cellular and organic (shown at different levels within the mechanism) which interact, ultimately resulting in the organismic age, i.e. the ‘body clock’, represented by the ‘hour hand’ (no minute hand is shown).

In mammals, the readout of the clock corresponds to the age-related composition of the blood plasma. In this model, moving the hour hand backwards should result in a turning back of the composite clocks as well – a result obtain[ed] when induction to pluripotence is used to reset the cellular clocks.

Apart from being slowed down or sped up, the body clock can also be reset. Organisms, organs, and their cells can be reset to different age-phenotypes depending on their environment.

We know that old transplanted tissues and organs can regain function and live for the entire life of the younger host at least in rodents. We must suppose that age-phenotype changes must have taken place at the cellular level to allow this.

Rejuvenation cannot be explained on the basis that aging represents the accumulation of irreparable cellular damage.

None of these principles is rigorously established as such, but all are supported by experimental evidence.”

http://www.eurekaselect.com/130538/article “Towards an Evidence-based Model of Aging”

Here are some of his responses to comments on the blog post that first curated his current research:

“We’ve (scientists), spent the past 70 years trying to definitively prove the commonsense ‘wear and tear’ theories and have not succeeded. So I tried something different, looking at the results of experiments.

This is not based on ‘theory’ (say mitochondrial aging or ‘wear and tear’) but on experimental evidence. Theory comes in explaining our results, not achieving them. There is a theory becoming clear, one very different from the commonsense view of ‘wear and tear’ aging.

We haven’t examined the immune response. All that we know for sure is that the chronic inflammation of aging stopped. I can definitively say that chronic inflammation due to aging can be reversed with factors present in young blood.

There are amazing things that Big Pharma won’t touch as there’s not enough profit in them (they can’t be patented). So I guess we’re somewhat the same, but we know what to do and have proven it – for us, it’s not the money. However, money allows you to do things.

Being 75 myself puts a time-frame around the project. We plan to propose its use for the diseases of aging – eventually, everyone will use it. It will end up changing humanity. As people already seem to have too much free time to begin with, what will people do with those extra years they will be given?”

Sections 3 “Aging Manifestations that Have Hitherto Been Proposed as the Causes of Aging are the Consequences of Aging” and 10 “Several Factors ‘Conspire’ to Promote Inflammation in Old Mammalian Bodies, Inflammation Leads to Several Diseases of Aging and Perhaps to Aging Itself” were especially informative.

The former section discussed cells that were capable of making repairs but didn’t make repairs, with aging being the consequence of this behavior. The latter reviewed topics of the current study such as senescence, IL-6, NF-κB, and C-reactive protein in terms of feedback loops.

See Reevaluate findings in another paradigm for comparisons of Section 6 with another view of hypothalamic aging.

Work your voluntary muscles today

This 2020 review by the Aging as a disease research group highlighted their specialty:

“A theory that fits both the aging and the rejuvenation data suggests that aging is caused primarily by the functional (and notably, experimentally reversible) inactivation of resident stem cells, which precipitates deteriorated tissue maintenance and repair and leads to the loss of organ homeostasis.

The damaged and unrepaired tissues suffer changes in their biochemistry, including the molecular crosstalk with resident stem cells, which further inhibits productive, regenerative responses. The inflammatory and fibrotic secretome can then propagate systemically, affecting the entire organism.

Skeletal muscle accounts for almost 40% of the total adult human body mass. This tissue is indispensable for vital functions such as respiration, locomotion, and voluntary movements and is among the most age-sensitive in mammals.

Muscle is capable of active repair in response to daily wear and tear, intense exercises, or injuries. Muscle regeneration relies on the adult muscle stem cells, also called satellite cells.

Rather than a significant decline in the total number with age, most of the data support a dramatic lack of activation of muscle stem cells after injury and a concomitant lack in the formation of progenitors that are needed for repair.

Multiple experimental approaches have been used for tissue rejuvenation and/or systemic rejuvenation; these include ablation of senescent cells and re-calibration of key signaling pathways that are needed for productive stem cell responses. To test the success in experimental rejuvenation, 1-4 approaches are typically applied, and skeletal muscle is well-suited for assaying each one.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7007696/ “Skeletal muscle as an experimental model of choice to study tissue aging and rejuvenation”

The review had a short section on inflammation details. Not enough, and there’s no tissue repair. Continuing unchecked is a systemic issue that led the reviewers to their paradigm of aging as a disease.

The review concluded with a subject that’s taught in high school, and should be understood at least before college graduation. It’s curious that an item like sample size required emphasis. Maybe research that doesn’t adhere to basics is a current issue?

Aging as a disease

This 2020 interview was with UC Berkeley researchers:

“Lack of cure goes hand in hand with inability to accept that this [aging] is disease. For example, there was some resistance to accept tuberculosis as the actual disease. When there was no antibiotics or cure against it, people tended to discard it and said, oh, it’s just nerves, you need to go to a sanatorium and relax.

It used to be that, please do not diagnose that there’s bacterial meningitis, because there is no cure. Whatever else you can come up with, do it first. Now, diagnose it as fast as possible, so we can put patients on antibiotics immediately. My prediction is that the same will happen to aging.

We and others have demonstrated that you can, from the outside, either by some signal or blood therapy, parabiosis, something like that, some intervention, jump-start the aged resident stem cells in the tissue and get them to behave as, by whatever means you’re measuring it, young or a lot closer to young than they would normally be. The intrinsic capacity of them to act that way is there.

As we grow old, the environment of differentiated niche stem cells does not provide productive instruction. It provides counterproductive instruction, which, overall, tells them just to remain quiescent and do nothing.

It’s not a program to kill you. It’s the lack of a program to keep you young and healthy for longer than 90 years.

If your program was that whenever you’re a damaged, differentiated cell, you simply trigger apoptosis and activate stem cells to make new cells, we would live much longer and healthy. The program right now is to resist being dead and replaced as much as you can for as long as you can.

So cells produce too much TGF beta [transforming growth factor-β] because it helps them to keep functioning even when they’re damaged. That too much TGF beta, ironically, inhibits resident stem cells, so they are not replacing old cells with new ones. It’s almost like you have old bureaucrats that are running an organization and do not want to be replaced.

Our thoughts are probably different from most people, because we go to the data and the data show that they’re not really fully what authors wrote in the abstract or conclusion. When you look at that, my thought is that much more work needs to be done before it [partial cellular reprogramming] could be even thought to be commercialized.”

https://www.lifespan.io/news/apheresis-with-profs-irina-michael-conboy/ “Irina & Michael Conboy – Resetting Aged Blood to Restore Youth”

Keep in mind that although the interviewers’ organization had changed, their advocacy position as displayed in A blood plasma aging clock persisted. One of the interviewees is on the scientific advisory board of the interviewers’ organization, and they also have an interest in downgrading competing approaches.

Despite the caveats, this interview was these researchers’ perspective in their decades-long investigations of aging. I included the graphic and below quote from Organismal aging and cellular senescence to note how their paradigm compared with other aging researchers:

“In our view, recent evidence that

  • Senescence is based on an unterminated developmental growth program and the finding that
  • The concept of post-mitotic senescence requires the activation of expansion, or ‘growth’ factors as a second hit,

favor the assumption that aging underlies a grating of genetic determination similarly to what is summarized above under the pseudo-programmed causative approach.”

Clearing out the 2019 queue of interesting papers

I’m clearing out the below queue of 27 studies and reviews I’ve partially read this year but haven’t taken the time to curate. I have a pesky full-time job that demands my presence elsewhere during the day. :-\

Should I add any of these back in? Let’s be ready for the next decade!

Early life

https://link.springer.com/article/10.1007/s12035-018-1328-x “Early Behavioral Alterations and Increased Expression of Endogenous Retroviruses Are Inherited Across Generations in Mice Prenatally Exposed to Valproic Acid” (not freely available)

https://www.sciencedirect.com/science/article/pii/S0166432818309392 “Consolidation of an aversive taste memory requires two rounds of transcriptional and epigenetic regulation in the insular cortex” (not freely available)

https://www.nature.com/articles/s41380-018-0265-4 “Intergenerational transmission of depression: clinical observations and molecular mechanisms” (not freely available)


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454089/ “Epigenomics and Transcriptomics in the Prediction and Diagnosis of Childhood Asthma: Are We There Yet?”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6628997/Placental epigenetic clocks: estimating gestational age using placental DNA methylation levels”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770436/ “Mismatched Prenatal and Postnatal Maternal Depressive Symptoms and Child Behaviours: A Sex-Dependent Role for NR3C1 DNA Methylation in the Wirral Child Health and Development Study”

https://www.sciencedirect.com/science/article/pii/S0889159119306440 “Environmental influences on placental programming and offspring outcomes following maternal immune activation”

https://academic.oup.com/mutage/article-abstract/34/4/315/5581970 “5-Hydroxymethylcytosine in cord blood and associations of DNA methylation with sex in newborns” (not freely available)

https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/JP278270 “Paternal diet impairs F1 and F2 offspring vascular function through sperm and seminal plasma specific mechanisms in mice”

https://onlinelibrary.wiley.com/doi/full/10.1111/nmo.13751 “Sex differences in the epigenetic regulation of chronic visceral pain following unpredictable early life stress” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6811979/ “Genome-wide DNA methylation data from adult brain following prenatal immune activation and dietary intervention”

https://link.springer.com/article/10.1007/s00702-019-02048-2miRNAs in depression vulnerability and resilience: novel targets for preventive strategies”

Later life

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543991/ “Effect of Flywheel Resistance Training on Balance Performance in Older Adults. A Randomized Controlled Trial”

https://www.mdpi.com/2411-5142/4/3/61/htm “Eccentric Overload Flywheel Training in Older Adults”

https://www.nature.com/articles/s41577-019-0151-6 “Epigenetic regulation of the innate immune response to infection” (not freely available)

https://link.springer.com/chapter/10.1007/978-981-13-6123-4_1 “Hair Cell Regeneration” (not freely available)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422915/Histone Modifications as an Intersection Between Diet and Longevity”

https://www.sciencedirect.com/science/article/abs/pii/S0306453019300733 “Serotonin transporter gene methylation predicts long-term cortisol concentrations in hair” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0047637419300338 “Frailty biomarkers in humans and rodents: Current approaches and future advances” (not freely available)

https://onlinelibrary.wiley.com/doi/full/10.1111/pcn.12901 “Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627480/ “In Search of Panacea—Review of Recent Studies Concerning Nature-Derived Anticancer Agents”

https://www.sciencedirect.com/science/article/abs/pii/S0028390819303363 “Reversal of oxycodone conditioned place preference by oxytocin: Promoting global DNA methylation in the hippocampus” (not freely available)

https://www.futuremedicine.com/doi/10.2217/epi-2019-0102 “Different epigenetic clocks reflect distinct pathophysiological features of multiple sclerosis”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834159/ “The Beige Adipocyte as a Therapy for Metabolic Diseases”

https://www.sciencedirect.com/science/article/abs/pii/S8756328219304077 “Bone adaptation: safety factors and load predictability in shaping skeletal form” (not freely available)

https://www.nature.com/articles/s41380-019-0549-3 “Successful treatment of post-traumatic stress disorder reverses DNA methylation marks” (not freely available)

https://www.sciencedirect.com/science/article/abs/pii/S0166223619301821 “Editing the Epigenome to Tackle Brain Disorders” (not freely available)

Using oxytocin receptor gene methylation to pursue an agenda

A pair of 2019 Virginia studies involved human mother/infant subjects:

“We show that OXTRm [oxytocin receptor gene DNA methylation] in infancy and its change is predicted by maternal engagement and reflective of behavioral temperament.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6795517 “Epigenetic dynamics in infancy and the impact of maternal engagement”

“Infants with higher OXTRm show enhanced responses to anger and fear and attenuated responses to happiness in right inferior frontal cortex, a region implicated in emotion processing through action-perception coupling.

Infant fNIRS [functional near-infrared spectroscopy] is limited to measuring responses from cerebral cortex. It is unknown whether OXTR is expressed in the cerebral cortex during prenatal and early postnatal human brain development.”

https://www.sciencedirect.com/science/article/pii/S187892931830207X “Epigenetic modification of the oxytocin receptor gene is associated with emotion processing in the infant brain”

Both studies had weak disclosures of limitations on their findings’ relevance and significance. The largest non-disclosed contrary finding was from the 2015 Early-life epigenetic regulation of the oxytocin receptor gene:

These results suggest that:

  • Blood Oxtr DNA methylation may reflect early experience of maternal care, and
  • Oxtr methylation across tissues is highly concordant for specific CpGs, but
  • Inferences across tissues are not supported for individual variation in Oxtr methylation.

That rat study found that blood OXTR methylation of 25 CpG sites couldn’t accurately predict the same 25 CpG sites’ OXTR methylation in each subject’s hippocampus, hypothalamus, and striatum (which includes the nucleus accumbens) brain areas. Without significant effects in these limbic system structures, there couldn’t be any associated behavioral effects.

But CpG site associations and correlations were deemed good in the two current studies because they cited:

“Recent work in prairie voles has found that both brain- and blood-derived OXTRm levels at these sites are negatively associated with gene expression in the brain and highly correlated with each other.”

https://www.sciencedirect.com/science/article/pii/S0306453018306103 “Early nurture epigenetically tunes the oxytocin receptor”

The 2018 prairie vole study – which included several of the same researchers as the two current studies – found four nucleus accumbens CpG sites that had high correlations to humans. Discarding one of these CpG sites allowed their statistics package to make a four-decimal place finding:

“The methylation state of the blood was also associated with the level of transcription in the brain at three of the four CpG sites..whole blood was capable of explaining 94.92% of the variance in Oxtr DNA methylation and 18.20% of the variance in Oxtr expression.”

Few limitations on the prairie vole study findings were disclosed. Like the two current studies, there wasn’t a limitation section that placed research findings into suitable contexts. So readers didn’t know researcher viewpoints on items such as:

  • What additional information showed that 3 of the 30+ million human CpGs accurately predicted specific brain OXTR methylation and expression from saliva OXTR methylation?
  • What additional information demonstrated how “measuring responses from cerebral cortex” although “it is unknown whether OXTR is expressed in the cerebral cortex” provided detailed and dependable estimates of limbic system CpG site OXTR methylation and expression?
  • Was the above 25-CpG study evidence considered?

Further contrast these three studies with a typical, four-point, 285-word limitation section of a study like Prenatal stress heightened adult chronic pain. The word “limit” appeared 6 times in that pain study, 3 times in the current fNIRS study, and 0 times in the current maternal engagement and cited prairie vole studies.

Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.

Caloric restriction’s epigenetic effects

This 2019 US review subject was caloric restriction (CR) without malnutrition:

“Cellular adaptation that occurs in response to dietary patterns can be explained by alterations in epigenetic mechanisms such as DNA methylation, histone modifications, and microRNA. Epigenetic reprogramming of the underlying chronic low-grade inflammation by CR can lead to immuno-metabolic adaptations that enhance quality of life, extend lifespan, and delay chronic disease onset.

Short- and long-term CRs produce significant changes in different tissues and across species, in some animal models even with sex-specific effects. Early CR onset may cause a different and even an opposite effect on physiological outcomes in animal models such as body weight.”

https://academic.oup.com/advances/article-abstract/10/3/520/5420411 “Epigenetic Regulation of Metabolism and Inflammation by Calorie Restriction” (not freely available)

1. The review didn’t present evidence to equate survival (left axis) with methylation drift (right axis) per the above graphic. Methylation drift should point in the opposite direction of survival, if anything.

2. No mention was made of the epigenetic clock method of measuring age acceleration, although it’s been available since 2013 and recent diet studies have used it. The sole citation of an age acceleration study was from 2001, which was unacceptable for a review published in 2019.

3. The review provided many cellular-level details about the subject. However, organism-level areas weren’t sufficiently evidenced:

A. Arguments for an effect usually include explanations for no effect as well as opposite effects. The reviewers didn’t provide direct evidence for why, if caloric restriction extended lifespan, caloric overabundance produced shorter lifespans.

B. Caloric restriction evidence was presented as if only it was responsible for organism-level effects. Other mechanisms may have been involved.

An example of such a mechanism was demonstrated in a 2007 rodent study Reduced Oxidant Stress and Extended Lifespan in Mice Exposed to a Low Glycotoxin Diet which compared two 40%-calorie-restricted diets.

The calories and composition of both diets were identical. However, advanced glycation end product (AGE) levels were doubled in standard chow because heating temperatures were “sufficiently high to inadvertently cause standard mouse chow to be rich in oxidant AGEs.”

The study found that a diet with lower chow heating temperatures increased lifespan and health span irrespective of caloric restriction!

  • The low-AGE calorie-restricted diet group lived an average of 15% longer (>20 human equivalent years) than the CR group.
  • 40% of the low-AGE calorie-restricted diet group were still alive when the last CR group member died.
  • The CR group also had significantly more: 1) oxidative stress damage; 2) glucose and insulin metabolism problems; and 3) kidney, spleen, and liver injuries.

A drug that countered effects of a traumatizing mother

This 2019 US rodent study concerned transmitting poor maternal care to the next generation:

“The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. Infant experiences with a caregiver have lifelong behavioral consequences.

Maternal behavior is a complex behavior requiring the recruitment of multiple brain regions including the nucleus accumbens, bed nucleus of the stria terminalis, ventral tegmental area, prefrontal cortex, amygdala, and medial preoptic area. Dysregulation within this circuitry can lead to altered or impaired maternal responsiveness.

We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring.

  1. We replicate that dams with a history of maltreatment mistreat their own offspring.
  2. We show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring.
  3. We show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care.
  4. We show altered methylation and gene expression in maltreated dams normalized by zebularine.

These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.”

“Maternal behavior is an intergenerational behavior. It is important to establish the neurobiological underpinnings of aberrant maternal behavior and explore treatments that can improve maternal behavior to prevent the perpetuation of poor maternal care across generations.”

The study authors demonstrated intergenerational epigenetic effects, and missed an opportunity to also investigate transgenerational epigenetically inherited effects. They cited reference 60 for the first part of the above quotation, but the cited reviewer misused the transgenerational term by applying it to grand-offspring instead of the great-grand-offspring.

There were resources available to replicate the study authors’ previous findings, which didn’t show anything new. Why not use such resources to uncover evidence even more applicable to humans by extending experiments to great-grand-offspring that would have no potential germline exposure to the initial damaging cause?

Could a study design similar to A limited study of parental transmission of anxiety/stress-reactive traits have been integrated? That study’s thorough removal of parental behavior would be an outstanding methodology to confirm by falsifiability whether parental behavior is both an intergenerational and a transgenerational epigenetic inheritance mechanism.

Rodent great-grand-offspring can be studied in < 9 months. It takes > 50 years for human studies to reach the great-grand-offspring transgenerational generation.

  • Why not attempt to “prevent the perpetuation of poor maternal care across generations?”
  • Isn’t it a plausible hypothesis that humans “with a history of maltreatment mistreat their own offspring?”
  • Isn’t it worth the extra effort to extend animal research to investigate this unfortunate chain?

https://www.nature.com/articles/s41598-019-46539-4 “Pharmacological manipulation of DNA methylation normalizes maternal behavior, DNA methylation, and gene expression in dams with a history of maltreatment”

Our brains are shaped by our early environments

This 2019 McGill paper reviewed human and animal studies on brain-shaping influences from the fetal period through childhood:

“In neonates, regions of the methylome that are highly variable across individuals are explained by the genotype alone in 25 percent of cases. The best explanation for 75 percent of variably methylated regions is the interaction of genotype with different in utero environments.

A meta-analysis including 45,821 individuals with attention-deficit/hyperactivity disorder and 9,207,363 controls suggests that conditions such as preeclampsia, Apgar score lower than 7 at 5 minutes, breech/transverse presentations, and prolapsed/nuchal cord – all of which involve some sort of poor oxygenation during delivery – are significantly associated with attention-deficit/hyperactivity disorder. The dopaminergic system seems to be one of the brain systems most affected by perinatal hypoxia-ischemia.

Exposure to childhood trauma activates the stress response systems and dysregulates serotonin transmission that can adversely impact brain development. Smaller cerebral, cerebellar, prefrontal cortex, and corpus callosum volumes were reported in maltreated young people as well as reduced hippocampal activity.

Environmental enrichment has a series of beneficial effects associated with neuroplasticity mechanisms, increasing hippocampal volume, and enhancing dorsal dentate gyrus-specific differences in gene expression. Environmental enrichment after prenatal stress decreases depressive-like behaviors and fear, and improves cognitive deficits.”

The reviewers presented strong evidence until the Possible Factors for Reversibility section, which ended with the assertion:

“All these positive environmental experiences mentioned in this section could counterbalance the detrimental effects of early life adversities, making individuals resilient to brain alterations and development of later psychopathology.”

The review’s penultimate sentence recognized that research is seldom done on direct treatments of causes:

“The cross-sectional nature of most epigenetic studies and the tissue specificity of the epigenetic changes are still challenges.”

Cross-sectional studies won’t provide definitive data on cause-and-effect relationships.

The question yet to be examined is: How can humans best address these early-life causes to ameliorate their lifelong effects?

https://onlinelibrary.wiley.com/doi/full/10.1111/dmcn.14182 “Early environmental influences on the development of children’s brain structure and function” (not freely available)

Epigenetic factors affecting female rat sexual behavior

This 2018 Baltimore/Montreal rodent study found:

“If sexually naïve females have their formative sexually rewarding experiences paired with the same male, they will recognize that male and display mate-guarding behavior towards him in the presence of a female competitor. Female rats that display mate-guarding behavior also show enhanced activation of oxytocin and vasopressin neurons in the supraoptic and paraventricular hypothalamic nucleus.

We examined the effect of a lysine-specific demethylase-1 inhibitor to block the action of demethylase enzymes and maintain the methylation state of corresponding genes. Female rats treated with the demethylase inhibitor failed to show any measure of mate guarding, whereas females treated with vehicle displayed mate guarding behavior. Demethylase inhibitor treatment also blocked the ability of familiar male cues to activate oxytocin and vasopressin neurons, whereas vehicle-treated females showed this enhanced activation.”

General principles and their study-specific illustrations were:

Histone modifications are a key element in gene regulation through chromatin remodeling. Histone methylation / demethylation does not have straightforward transcriptional outcomes as do other histone modifications, like acetylation, which is almost invariably associated with transcriptional activation.

What is of vital importance in regards to histone methylation / demethylation is the pattern of methylation that is established. Patterns of methylation incorporate both methylated and demethylated residues, and are what ultimately play a role in transcriptional outcomes.

In the present study, inhibiting LSD1 demethylase enzymes disrupted the ability of cells to properly establish histone methylation / demethylation patterns, thus creating a deficit in the cells’ ability to transcribe the gene products necessary for the enhanced induction of OT, AVP, and the subsequent mate-guarding behaviors we observed. This study is the first to demonstrate a definitive role of epigenetic histone modifications in a conditioned sexual response.”

https://www.sciencedirect.com/science/article/pii/S0031938418303421 “Inhibition of lysine-specific demethylase enzyme disrupts sexually conditioned mate guarding in the female rat” (not freely available)

Epigenetic variations in metabolism

This 2018 German review was comprehensive for its subject, epigenetic control of variation and stochasticity in metabolic disease. I’ll focus on one aspect, phenotypic variation:

“Phenotypic [Mendelian] variation can result both from gain- and loss-of-function mutations. Because of the extreme interconnectivity of cell regulatory networks, even at the cellular level, predicting the impact of a sequence variant is difficult as the resultant variation acts:

  • In the context of all other variants and
  • Their potential additive, synergistic and antagonistic interactions.

This phenomenon is known as epistasis.

∼98.5% of our genome is non-protein-coding: it is pervasively transcribed, and its transcripts can support regulatory function. Among the best functionally characterized non-coding RNAs (ncRNAs) arising from these sequences are microRNAs (miRNAs).

Environmental [non-Mendelian] variation or ‘stimuli’ occurring during critical windows of susceptibility can elicit lifelong alterations in an individual’s phenotype. Intergenerational metabolic reprogramming [in fruit flies] results from global alterations in chromatin state integrity, particularly from reduced H3K27me3 and H3K9me3 [histone] domains.

The broad variation of fingerprints in humans is thought to depend to a large degree on stochastic variation in mechanical forces. These clear examples of inducible multi-stable or stochastic variation highlight how little we know about the landscape of potential phenotypic variation itself.

Consensus estimates of heritability for obesity and T2D are ∼70% and ∼35% respectively. The remaining, unexplained component is known to involve gene–environment interactions as well as non-Mendelian players.”

Although the above graphic displays transgenerational inheritance for humans, the reviewers didn’t cite any human studies that adequately demonstrated causes for and effects of transgenerational epigenetic inheritance.

I’ve read the cited Swedish and Dutch studies. Their designs, methods, and “correlate with” / “was associated with” results didn’t provide incontrovertible evidence from the F0 great-grandparents, F1 grandparents, F2 parents, and F3 children. It’s necessary to thoroughly study each generation to confirm definitive transgenerational epigenetic inheritance causes and effects.

As noted in How to hijack science: Ignore its intent and focus on the 0.0001%, there aren’t any such published studies to cite. Researchers urgently need to do this human research, and stop using these poor substitutes [1] to pretend there are already adequately evidenced transgenerational epigenetic inheritance human results.

I downgraded the review for treating research of this and other subjects as faits accomplis. It’s opposite ends of the evidential spectrum to state “how little we know about the landscape of potential phenotypic variation,” and in the same review, speciously extrapolate animal experiments into putative human results.

https://www.sciencedirect.com/science/article/pii/S2212877818301984 “Epigenetic control of variation and stochasticity in metabolic disease”

[1] As an example of the poor substitutes for evidence, a researcher referred me to the 2013 “Transgenerational effects of prenatal exposure to the 1944–45 Dutch famine” which is freely available at https://obgyn.onlinelibrary.wiley.com/doi/full/10.1111/1471-0528.12136 as a study finding human transgenerational epigenetic inheritance.

The Methods section showed:

  • The study’s non-statistical data was almost all unverified self-reports by a self-selected sample of the F2 generation, average age 37.
  • No detailed physical measurements or samples were taken of them, nor of the F1 generation, nor of the F0 generation, all of which are required as baselines for any transgenerational epigenetic inheritance findings.
  • No detailed physical measurements or samples were taken of the F3 generation, which is the generation that may provide transgenerational evidence if the previous generations also have detailed physical baselines.

The study’s researchers drew enough participants (360) such that their statistics package allowed them to impute and assume into existence a LOT of data. But the scientific method constrained them to make factual statements of what the evidence actually showed. They admitted:

“In conclusion, we did not find a transgenerational effect of prenatal famine exposure on the health of grandchildren in this study.”

Yet this study is somehow cited for evidence of human transgenerational epigenetically inherited causes and effects!

Resiliency in stress responses

This 2018 US Veterans Administration review subject was resiliency and stress responses:

Neurobiological and behavioral responses to stress are highly variable. Exposure to a similar stressor can lead to heterogeneous outcomes — manifesting psychopathology in one individual, but having minimal effect, or even enhancing resilience, in another.

We highlight aspects of stress response modulation related to early life development and epigenetics, selected neurobiological and neurochemical systems, and a number of emotional, cognitive, psychosocial, and behavioral factors important in resilience.”

The review cited studies I’ve previously curated:

There were two things I didn’t understand about this review. The first was why the paper isn’t freely available. It’s completely paid for by the US taxpayer, and no copyright is claimed. I recommend contacting the authors for a copy.

The second was why the VA hasn’t participated in either animal or human follow-on studies to the 2015 Northwestern University GABAergic mechanisms regulated by miR-33 encode state-dependent fear. That study’s relevance to PTSD, this review’s subject, and the VA’s mission is too important to ignore. For example:

“Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar.

“It’s difficult for therapists to help these patients,” Radulovic said, “because the patients themselves can’t remember their traumatic experiences that are the root cause of their symptoms.”

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”

I curated the research in A study that provided evidence for basic principles of Primal Therapy. These researchers have published several papers since then. Here are the abstracts from three of them:

Experimental Methods for Functional Studies of microRNAs in Animal Models of Psychiatric Disorders

“Pharmacological treatments for psychiatric illnesses are often unsuccessful. This is largely due to the poor understanding of the molecular mechanisms underlying these disorders. We are particularly interested in elucidating the mechanism of affective disorders rooted in traumatic experiences.

To date, the research of mental disorders in general has focused on the causal role of individual genes and proteins, an approach that is inconsistent with the proposed polygenetic nature of these disorders. We recently took an alternative direction, by establishing the role of miRNAs in the coding of stress-related, fear-provoking memories.

Here we describe in detail our work on the role of miR-33 in state-dependent learning, a process implicated in dissociative amnesia, wherein memories formed in a certain brain state can best be retrieved if the brain is in the same state. We present the specific experimental approaches we apply to study the role of miRNAs in this model and demonstrate that miR-33 regulates the susceptibility to state-dependent learning induced by inhibitory neurotransmission.”

Neurobiological mechanisms of state-dependent learning

“State-dependent learning (SDL) is a phenomenon relating to information storage and retrieval restricted to discrete states. While extensively studied using psychopharmacological approaches, SDL has not been subjected to rigorous neuroscientific study.

Here we present an overview of approaches historically used to induce SDL, and highlight some of the known neurobiological mechanisms, in particular those related to inhibitory neurotransmission and its regulation by microRNAs (miR).

We also propose novel cellular and circuit mechanisms as contributing factors. Lastly, we discuss the implications of advancing our knowledge on SDL, both for most fundamental processes of learning and memory as well as for development and maintenance of psychopathology.”

Neurobiological correlates of state-dependent context fear

“Retrieval of fear memories can be state-dependent, meaning that they are best retrieved if the brain states at encoding and retrieval are similar. Such states can be induced by activating extrasynaptic γ-aminobutyric acid type A receptors (GABAAR) with the broad α-subunit activator gaboxadol. However, the circuit mechanisms and specific subunits underlying gaboxadol’s effects are not well understood.

Here we show that gaboxadol induces profound changes of local and network oscillatory activity, indicative of discoordinated hippocampal-cortical activity, that were accompanied by robust and long-lasting state-dependent conditioned fear. Episodic memories typically are hippocampus-dependent for a limited period after learning, but become cortex-dependent with the passage of time.

In contrast, state-dependent memories continued to rely on hippocampal GABAergic mechanisms for memory retrieval. Pharmacological approaches with α- subunit-specific agonists targeting the hippocampus implicated the prototypic extrasynaptic subunits (α4) as the mediator of state-dependent conditioned fear.

Together, our findings suggest that continued dependence on hippocampal rather than cortical mechanisms could be an important feature of state-dependent memories that contributes to their conditional retrieval.”

Here’s an independent 2017 Netherlands/UC San Diego review that should bring these researchers’ efforts to the VA’s attention:

MicroRNAs in Post-traumatic Stress Disorder

“Post-traumatic stress disorder (PTSD) is a psychiatric disorder that can develop following exposure to or witnessing of a (potentially) threatening event. A critical issue is to pinpoint the (neuro)biological mechanisms underlying the susceptibility to stress-related disorder such as PTSD, which develops in the minority of ~15% of individuals exposed to trauma.

Over the last few years, a first wave of epigenetic studies has been performed in an attempt to identify the molecular underpinnings of the long-lasting behavioral and mental effects of trauma exposure. The potential roles of non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) in moderating or mediating the impact of severe stress and trauma are increasingly gaining attention. To date, most studies focusing on the roles of miRNAs in PTSD have, however, been completed in animals, using cross-sectional study designs and focusing almost exclusively on subjects with susceptible phenotypes.

Therefore, there is a strong need for new research comprising translational and cross-species approaches that use longitudinal designs for studying trajectories of change contrasting susceptible and resilient subjects. The present review offers a comprehensive overview of available studies of miRNAs in PTSD and discusses the current challenges, pitfalls, and future perspectives of this field.”

Here’s a 2017 Netherlands human study that similarly merits the US Veterans Administration’s attention:

Circulating miRNA associated with posttraumatic stress disorder in a cohort of military combat veterans

“Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced.

PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.”

See the below comments for reasons why I downgraded this review’s rating.

https://link.springer.com/article/10.1007/s11920-018-0887-x “Stress Response Modulation Underlying the Psychobiology of Resilience” (not freely available)

The lifelong impact of maternal postpartum behavior

This 2018 French/Italian/Swiss rodent study was an extension of the work done by the group of researchers who performed Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies and Treating prenatal stress-related disorders with an oxytocin receptor agonist:

“Reduction of maternal behavior [nursing behavior, grooming, licking, carrying pups] was predictive of behavioral disturbances in PRS [prenatally restraint stressed] rats as well as of the impairment of the oxytocin and its receptor gene expression.

Postpartum carbetocin [an oxytocin receptor agonist unavailable in the US] corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior.

Moreover, postpartum carbetocin had an anti-stress effect on HPA [hypothalamic-pituitary-adrenal] axis activity in the adult PRS progeny and increased hippocampal mGlu5 [type 5 metabotropic glutamate] receptor expression in aging.

Early postpartum carbetocin administration to the dam enhances maternal behavior and prevents all the pathological outcomes of PRS throughout the entire lifespan of the progeny..proves that the defect in maternal care induced by gestational stress programs the development of the offspring.

This chart from Figure 4 summarized the behavioral performance of aged adult male progeny in relation to the experimental variables of:

  1. Stress administered to the mothers three times daily every day during the second half of pregnancy up until delivery; and
  2. The effects on the mothers’ behavior of daily carbetocin administration during postpartum days 1 through 7.

The symbols denote which of these relationships had statistically significant effects:

  • “* p [Pearson’s correlation coefficient] < 0.05 PRS-Saline vs. CONT-Saline;
  • # p < 0.05 PRS-Carbetocin vs. the PRS-Saline group.”

There are many interesting aspects to this study. Ask the corresponding coauthor Dr. Sara Morley-Fletcher at sara.morley-fletcher@univ-lille1.fr for a copy.

One place the paper referenced the researchers’ previous studies was in this context:

“Postpartum carbetocin administration reversed the same molecular and behavioral parameters in the hippocampus, as does adult chronic carbetocin treatment, i.e. it led to a correction of the HPA axis negative feedback mechanisms, stress and anti-stress gene expression, and synaptic glutamate release. The fact that postpartum carbetocin administration [to the stressed mothers in this study] had the same effect [on the PRS infants in this study] as adult carbetocin treatment [to the PRS offspring in the previous study] indicates a short-term effect of carbetocin when administered in adulthood and a reprogramming (long-term) effect lasting until an advanced age when administered in early development.”

This group’s research seems to be constrained to treatments of F0 and F1 generations. What intergenerational and transgenerational effects would they possibly find by extending research efforts to F2 and F3 generations?

As the study may apply to humans:

The study demonstrated that stresses during the second half of pregnancy had lifelong impacts on both the mothers’ and offsprings’ biology and behavior. Studies and reviews that attribute similar human biological and behavioral conditions to unknown causes, or shuffle them into the black box of individual differences, should be recognized as either disingenuous or insufficient etiological investigations.

The study showed that prevention of gestational stress was a viable strategy. The control group progeny’s biology and behavior wasn’t affected by carbetocin administration to their mothers because neither they nor their mothers had experience-dependent epigenetic deficiencies.

The study demonstrated a biological and behavioral cure for the PRS offspring by changing their stressed mothers’ behaviors during a critical period of their development. The above excerpt characterized improving the mothers’ behaviors as a long-term cure for the PRS descendants, as opposed to the short-term cure of administering carbetocin to the PRS children when they were adults.

What long-term therapies may be effective for humans who had their developmental trajectories altered by their mothers’ stresses during their gestation, or who didn’t get the parental care they needed when they needed it?

https://www.sciencedirect.com/science/article/pii/S0161813X18301062 “Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance” (not freely available)

Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies

This 2018 French/Italian/Swiss rodent study used a prenatally restraint stressed (PRS) model to create problems that could be resolved by various chemicals:

“S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties.

Most of studies examining the antidepressant effects of new molecules are carried out using behavioral tests performed in unstressed animals.

Corticosterone-treated mice and rats exposed to chronic stress are models that do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period. The PRS rat model is characterized by a prolonged corticosterone response to stress and by abnormal behavior.

All the behavioral alterations induced by PRS were corrected by chronic S 47445 administration at both doses.”

The paper included a section comparing S 47445 to ketamine:

“Ketamine, however, causes severe cognitive impairment and psychotomimetic [mimics the symptoms of psychosis, reference not freely available] effects that are direct consequences of the prolonged inhibition of NMDA receptors in cortical and hippocampal interneurons, and seriously limit the chronic administration of the drug in the clinical setting. [reference not freely available]

S 47445 by inducing a direct activation of AMPARs displayed an antidepressant activity without the adverse effect of ketamine. Indeed, contrary to ketamine, S 47445 presented no psychotomimetic effects and induced no occurrence of spontaneous epileptic seizures. [reference freely available] Moreover, S 47445 also presented pro-cognitive properties.”

Compare the above with this April 2018 Chicago Tribune story that had opinions with no linked references:

“ketamine, an anesthetic used to sedate both people and animals before surgery. It’s also a notorious street drug, abused by clubgoers seeking a trancelike, hallucinatory high. But in recent years, numerous studies have found that ketamine can be an effective and speedy treatment for people with depression.”

Which coverage better informed us?

Treating prenatal stress-related disorders with an oxytocin receptor agonist was performed by several of this paper’s coauthors. One references to it was:

“We have already reported that depolarization-evoked glutamate release in the ventral hippocampus is negatively correlated with risk-taking behavior of PRS rats, and that such correlation can be corrected by chronic treatment with monoaminergic/ melatoninergic antidepressants or oxytocin receptor agonist. Thus, an impairment of glutamatergic transmission in the ventral hippocampus lies at the core of the pathological phenotype of PRS rats.”

Looking at the above graphic of the experimental design, I’m not sure why the term perinatal (occurring during or pertaining to the phase surrounding the time of birth) was used in the paper’s title and content to describe the stress period. The pregnant females were stressed three times every day during the second half of pregnancy up until delivery, so the prenatal (previous to birth) term was more applicable.

So, how does this study help humans?

One takeaway is to avoid stressing pregnant mothers-to-be if her children will be expected to become adults without cognitive, emotional, and behavioral problems.

The study demonstrated one way prenatal events cause lifelong effects. The PRS model provides another example of why it’s useless to ask adult humans to self-report causes of epigenetic problems in their lives when these originated before birth, during infancy, or in early childhood, well before humans develop sufficient cognitive capability to recognize such situations. It’s incomprehensible that this unreliable paradigm is still given significant weight in stress studies, especially when experimental designs:

“Do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period.”

Also, a relevant difference between humans and PRS rats is that we can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments such as those mentioned above.

https://www.sciencedirect.com/science/article/pii/S0028390818301291 “The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats” (not freely available) Thanks to coauthors Stefania Maccari and Dr. Jerome Mairesse for providing a copy.

How to cure the ultimate causes of migraines?

Most of the spam I get on this blog comes in as ersatz comments on The hypothalamus couples with the brainstem to cause migraines. I don’t know what it is about the post that attracts internet bots.

The unwanted attention is too bad because the post represents a good personal illustration of “changes in the neural response to painful stimuli.” Last year I experienced three three-day migraines in one month as did the study’s subject. This led to me cycling through a half-dozen medications in an effort to address the migraine causes.

None of the medications proved to be effective at treating the causes. I found one that interrupted the progress of migraines – sumatriptan, a serotonin receptor agonist. I’ve used it when symptoms start, and the medication has kept me from having a full-blown migraine episode in the past year.

1. It may be argued that migraine headache tendencies are genetically inherited. Supporting personal evidence is that both my mother and younger sister have migraine problems. My father, older sister, and younger brother didn’t have migraine problems. Familial genetic inheritance usually isn’t the whole story of diseases, though.

2. Migraine headaches may be an example of diseases that are results of how humans have evolved. From Genetic imprinting, sleep, and parent-offspring conflict:

“Evolutionary theory predicts: that which evolves is not necessarily that which is healthy.

Why should pregnancy not be more efficient and more robust than other physiological systems, rather than less? Crucial checks, balances and feedback controls are lacking in the shared physiology of the maternal–fetal unit.

Both migraine causes and effects may be traced back to natural lacks of feedback loops. These lacks demonstrate that such physiological feedback wasn’t evolutionarily necessary in order for humans to survive and reproduce.

3. Examples of other processes occurring during prenatal development that also lack feedback loops, and their subsequent diseases, are:

A. Hypoxic conditions per Lack of oxygen’s epigenetic effects are causes of the fetus later developing:

  • “age-related macular degeneration
  • cancer progression
  • chronic kidney disease
  • cardiomyopathies
  • adipose tissue fibrosis
  • inflammation
  • detrimental effects which are linked to epigenetic changes.”

B. Stressing pregnant dams per Treating prenatal stress-related disorders with an oxytocin receptor agonist caused fetuses to develop a:

and abnormalities:

  • in social behavior,
  • in the HPA response to stress, and
  • in the expression of stress-related genes in the hippocampus and amygdala.”

1. What would be a treatment that could cure genetic causes for migraines?

I don’t know of any gene therapies.

2. What treatments could cure migraines caused by an evolved lack of feedback mechanisms?

We humans are who we have become, unless and until we can change original causes. Can we deal with “changes in the neural response to painful stimuli” without developing hopes for therapies or technologies per Differing approaches to a life wasted on beliefs?

3. What treatments could cure prenatal epigenetic causes for migraines?

The only effective solution I know of that’s been studied in humans is to prevent adverse conditions like hypoxia from taking place during pregnancy. The critical periods of our physical development are over once we’re adults, and we can’t unbake a cake.

Maybe science will offer other possibilities. Maybe researchers could do more than their funding sponsors expect?