Cortisol

Epigenetic stress effects in preterm infants

gettingwell4 4-5 stars Advanced knowledge, Brain development, Brain hemispheres, Cerebrum, Cortisol, Epigenetics, Glutamate, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress , , , , , ,

This 2017 Italian review selected 9 human studies on the epigenetic effects of:

“One of the major adverse events in human development. Preterm infants are hospitalized in the Neonatal Intensive Care Unit where they are exposed to life-saving yet pain-inducing procedures and to protective care.”

Highlights of the referenced studies included:

  • “Early exposure to adverse events during the third trimester of pregnancy is capable to alter the epigenetic status of imprinted and placenta-related genes which have relevant implications for fetal development and preterm infants’ HPA [hypothalamic–pituitary–adrenal] stress reactivity during infancy.”
  • “There was an association between DNAm [DNA methylation] and white matter tract tissue integrity and shape inferred from dMRI [diffusion MRI], suggesting that epigenetic variation may contribute to the cerebral phenotype of preterm birth.”

Limitations of the referenced studies included:

  • “A multiple sampling design that includes parental samples, placental tissue, cord blood and extends across the life-course would be required to investigate the relative contributions of in utero and postnatal exposures to changes in DNAm, and the extent to which preterm birth leaves a legacy on the methylome.”
  • Saliva, blood, and other tissues’ DNA methylation may not produce valid links to brain tissue DNA methylation of the same gene, which may hamper conclusive inferences about behavior, etc.

http://www.sciencedirect.com/science/article/pii/S0149763417302117 “Preterm Behavioral Epigenetics: A systematic review” (not freely available)

http://www.nature.com/tp/journal/v6/n1/full/tp2015210a.html “Epigenomic profiling of preterm infants reveals DNA methylation differences at sites associated with neural function” (one of the studies selected, quoted above)

The hypothalamus couples with the brainstem to cause migraines

gettingwell4 4-5 stars Advanced knowledge, Brain development, Brain hemispheres, Brainstem, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Lower brain, Neurochemicals, Oxytocin, Stress

This 2016 German human study with one subject found:

“The hypothalamus to be the primary generator of migraine attacks which, due to specific interactions with specific areas in the higher and lower brainstem, could alter the activity levels of the key regions of migraine pathophysiology.”

The subject underwent daily fMRI scans, and procedures to evoke brain activity. She didn’t take any medications, and suffered three migraine attacks during the 31-day experimental period.

Neuroskeptic commented:

“The dorsal pons has previously been found to be hyperactive during migraine. It’s been dubbed the brain’s ‘migraine generator.’ Schulte and May’s data suggest that this is not entirely true – rather, it looks like the hypothalamus may be the true generator of migraine, while the brainstem could be a downstream mediator of the disorder.

A hypothalamic origin of migraines would help to explain some of the symptoms of the disorder, such as changes in appetite, that often accompany the headaches.”

The above graphic looks to me like the result of feedback mechanisms that either didn’t exist or inadequately handled the triggering event. Other examples of the hypothalamus lacking feedback or being involved in a deviated feedback loop include:

There are many unanswered questions with a one-person study, of course. Addressing the cause of this painful condition would find out when, where, and how a person’s hypothalamus became modified to express migraine tendencies.

I’d guess that migraine tendencies may appear as early as the first trimester of pregnancy, given that a highly functional hypothalamus is needed for survival and development in our earliest lives. Gaining as much familial and historical information as possible from the person would be necessary steps in therapies that address migraine causes.

http://blogs.discovermagazine.com/neuroskeptic/2016/05/22/pinpointing-origins-of-migraine/ “Pinpointing the Origins of Migraine in the Brain”

https://academic.oup.com/brain/article/139/7/1987/2464241 “The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks”

As mentioned in How to cure the ultimate causes of migraines? comments are turned off for this post due to it somehow becoming a magnet for spammers. Readers can comment on that post instead.

A one-sided review of stress

gettingwell4 0-1 star Wasted resources, Amygdala, Brain development, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Oxytocin, Primal Therapy, Serotonin, Stress, Vasopressin , , , , ,

The subject of this 2016 Italian/New York review was the stress response:

“The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical [HPA] axis and the consequent release of corticosteroid hormones, is indeed aimed at promoting metabolic, functional, and behavioral adaptations. However, behavioral stress is also associated with fast and long-lasting neurochemical, structural, and behavioral changes, leading to long-term remodeling of glutamate transmission, and increased susceptibility to neuropsychiatric disorders.

Of note, early-life events, both in utero and during the early postnatal life, trigger reprogramming of the stress response, which is often associated with loss of stress resilience and ensuing neurobehavioral (mal)adaptations.”

The reviewers’ intentional dismissal of the role of GABA in favor of the role of glutamate was a key point:

“The changes in neuronal excitability and synaptic plasticity induced by stress are the result of an imbalance of excitatory (glutamatergic) and inhibitory (GABAergic) transmission, leading to long-lasting (mal)adaptive functional modifications. Although both glutamate and GABA transmission are critically associated with stress-induced alteration of neuronal excitability, the present review will focus on the modulation of glutamate release and transmission induced by stress and glucocorticoids.”

No particular reason was given for this bias. I inferred from the review’s final sentence that the review’s sponsors and funding prompted this decision:

“In-depth studies of changes in glutamate transmission and dendrite remodeling induced by stress in early and late life will help to elucidate the biological underpinnings of the (mal)adaptive strategies the brain adopts to cope with environmental challenges in one’s life.”

The bias led to ignoring evidence for areas the reviewers posed as needing further research. An example of relevant research the reviewers failed to consider was the 2015 Northwestern University study I curated in A study that provided evidence for basic principles of Primal Therapy that found:

“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.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812483/ “Stress Response and Perinatal Reprogramming: Unraveling (Mal)adaptive Strategies”

Epigenetic contributions to hypertension

gettingwell4 4-5 stars Advanced knowledge, Cortisol, Epigenetics, Neurochemicals, Stress ,

This 2016 Australian review subject was epigenetic contributions to hypertension:

“Hypertension (HT) affects more than 1 billion people globally and is a major risk factor for stroke, chronic kidney disease, and myocardial infarction.

Essential hypertension (EH) is a complex, polygenic condition with no single causative agent. There is increasing evidence that epigenetic modifications are as important as genetic predisposition in the development of EH.

Many epigenetic studies are, however, limited by the fact that only blood is studied rather than the effector tissues. The utility of blood methylation status in epigenetic research is yet to be determined. Furthermore, the polygenic complexity of HT and the limited knowledge on some of the non-coding RNAs makes it more challenging to decipher the exact mechanisms involved.”

The review had sections for hypertension studies on DNA methylation, histone modification, and microRNA/other non-coding RNA types. Here’s a sample of the findings:

“HSD11B2-mediated degradation of cortisol to cortisone is disrupted when the promoter region of the HSD11B2 gene is hypermethylated. The resulting imbalance in the active metabolites of cortisol and cortisone, tetrahydrocortisol, and tetrahydocortisone, respectively, promotes the onset of HT.

Histone modification affecting arterial pressure levels has been documented in a variety of human and animal tissues, including vascular smooth muscle. Vascular oxidative stress can contribute to endothelial dysfunction—a hallmark of HT—and the development of HT.

Two miRNAs (has-miR-181a and has-miR-663) with the ability to bind to the 3′ UTR of renin mRNA were found to be under-expressed in EH. These miRNAs were able to regulate the expression of a reporter gene and renin-mRNA itself, which explains over-expression of renin mRNA seen in EH kidney.”

The publisher, International Journal of Molecular Sciences, makes ALL of its articles open access. Another of its requirements is:

“The full experimental details must be provided so that the results can be reproduced.”

There also aren’t artificial limitations on either the length of the study or the number of supplementary files.

http://www.mdpi.com/1422-0067/17/4/451/htm “Epigenetic Modifications in Essential Hypertension”

Problematic research into epigenetic effects of paternal stress on male offspring

gettingwell4 0-1 star Wasted resources, Cortisol, Epigenetics, Neurochemicals, Stress ,

This 2016 Chinese rodent study and its accompanying commentary Don’t stress dad — it’s bad for your kids’ health were caught up in an agenda.

The first problem I noticed was that the hyperglycemic effects found only in the male offspring weren’t consistently labelled as sex-specific. Try to find that fact in the paywalled commentary with its intentionally misleading headline, or in the news coverage with headlines such as “Stressed mouse dads give their offspring high blood sugar.”

That the effects were male-only was briefly noted in the study, yet “male” was absent from the “stress-F1 mice” label used after the initial mention.

2015年12月22日-陆炎模式图单独导出-v2

The researchers provided no mechanisms that plausibly linked the effects to offspring sex. There was plenty of time between the May 3, 2015 submission and the February 18, 2016 publication to clarify this and other items. I wonder what the reviewer noted.

The second problem was that the highest number of male “stress-F1 mice” tested was only six. I didn’t see any disclosures of what led to the scarcity of subjects, or of the likely impact of using so few.

A related limitation was that the male “stress-F1 mice” were killed as young adults. Whether or not the hyperglycemic effects carried through to old age or to another generation wasn’t determined.

I’m leery of studies like this one that didn’t have a Limitations section, and especially so when the news coverage overlooked obvious limitations. It was difficult to place the findings in a context other than promoting that a male’s stress may also adversely affect their offspring.

One of the problems that research caught up in an agenda create is that non-headline findings are overlooked. Other than sex-specific effects, the study found that the putative preconception cause of hyperglycemia didn’t cause other symptoms:

  • “No significant growth defects were observed in male offspring from stress-F0 fathers (stress-F1 mice) during their early lives.
  • Insulin sensitivity was not changed in stress-F1 mice.
  • Serum glucagon, leptin, and pro-inflammatory cytokines (tumor necrosis factor α [TNFα], interleukin-6 [IL-6]) were unaffected.
  • Body weight, food intake, locomotor activity, CO2 production, O2 consumption, and respiratory exchange ratios also remained unchanged.
  • Liver weight, liver weight/body weight ratios, hepatic triglyceride content, and the histological phenotypes were also comparable.
  • The methylation pattern and expression of microRNAs were not affected in the fetal brains of stress-F1 mice.”

The handling of the study reminded me of Transgenerational epigenetic programming with stress and microRNA where most of the news coverage similarly focused on it being a male’s stress, not a female’s, that affected the developing embryo. The important part lost from news coverage of that study was it demonstrated how a damaging influence can begin immediately after conception, but the symptoms didn’t present until adulthood!

http://www.sciencedirect.com/science/article/pii/S1550413116300067 “Paternal Psychological Stress Reprograms Hepatic Gluconeogenesis in Offspring”

The current paradigm of child abuse limits pre-childhood causal research

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As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments for causes of your symptoms?

Such information wasn’t available in this 2016 Miami review of the effects of child abuse. The review laid out the current paradigm mentioned in Grokking an Adverse Childhood Experiences (ACE) score, one that limits research into pre-childhood causes for later-life symptoms.

The review’s goal was to describe:

“How numerous clinical and basic studies have contributed to establish the now widely accepted idea that adverse early life experiences can elicit profound effects on the development and function of the nervous system.”

The hidden assumptions of almost all of the cited references were that these distant causes could no longer be addressed. Aren’t such assumptions testable today?

As an example, the Discussion section posed the top nine “most pressing unanswered questions related to the neurobiological effects of early life trauma.” In line with the current paradigm, the reviewer assigned “Are the biological consequences of ELS [early life stress] reversible?” into the sixth position.

If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of damage would also reverse damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

The review also demonstrated how the current paradigm of child abuse misrepresented items like telomere length and oxytocin. Researchers on the bandwagon tend to forget about the principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

That single experiment for telomere length arrived in 2016 with Using an epigenetic clock to distinguish cellular aging from senescence. The review’s seven citations for telomere length that all had findings “associated with” or “linked to” child abuse should now be viewed in a different light.

The same light shone on oxytocin with Testing the null hypothesis of oxytocin’s effects in humans and Oxytocin research null findings come out of the file drawer. See their references, and decide for yourself whether or not:

“Claimed research findings may often be simply accurate measures of the prevailing bias.”

http://www.cell.com/neuron/fulltext/S0896-6273%2816%2900020-9 “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Epigenetic regulation of natural killer cells

gettingwell4 2-3 stars Required further work, Cortisol, Epigenetics, Immune system, Neurochemicals, Stress ,

This 2016 German review focused on how epigenetic processes affected the natural killer cell part of the immune system:

“Natural killer (NK) cells recognize and eliminate tumor- and virus-infected cells, parasites as well as certain types of bacteria. NK cell activity is related to a complex interaction of activating and inhibiting receptors on the NK cell surface.

During the development of HPCs [hemopoietic progenitor cells] to mature NK cells, the DNA demethylation of KIR [killer cell immunoglobin-like receptors] genes leads to KIR expression. But DNA methylation does not just determine which KIR gene is expressed, it also determines which allele expresses the KIR gene. KIR genes are also regulated by microRNA.

KIR genes exhibit highly similar histone acetylation signatures, which are typically found in expressed genes. This fact puts the KIR genes into a state of readiness for transcription which is depending on the DNA methylation as critical epigenetic modification in the regulation of KIR gene expression.

Epigenetic modifications have been reported to be involved in the expression of NKG2D, which is one the most important activating NK cell receptor.”

The reviewers included a section on NK cell activity and external stimuli. They summarized:

“The significance of the described findings is limited by study designs. Although human NK cells were frequently used, in most cases treatment took place in ex vivo experiments.”

The reviewers also provided a good three-paragraph explanation of general epigenetic mechanisms.

http://www.mdpi.com/1422-0067/17/3/326/htm “Natural Killer Cells—An Epigenetic Perspective of Development and Regulation”

Beneficial epigenetic effects of mild stress with social support during puberty

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This 2016 Pennsylvania rodent study found:

“Stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase resilience to age-related cognitive decline in females.

These findings are actually consistent with previous studies showing that some amount of adversity, or adversity under more favorable circumstances such as social support or a protective gene polymorphism, provides a measure of ‘grit’ in coping with later life challenges.

Our findings provide a unique perspective on this relationship, as they highlight the important link between experience during the pubertal window and cognitive health during aging.”

These researchers made efforts to further investigate causes of unexpected results, such as:

“Peripubertal stress alone did not significantly alter Barnes maze performance in aging compared to aged Controls. Mice that had experienced stress with concurrent social support (CVS + SI) actually performed better than Control aged mice, specifically in learning the reversal task faster.

Peripubertal stress had no effect on corticosterone levels in response to an acute restraint stress or in sensorimotor gating and baseline startle reactivity.”

Their investigations led to epigenetic findings:

“Consistent with our behavioral findings, stress in the context of social interaction resulted in long-term reprogramming of gene expression in the PFC [prefrontal cortex]. While there were no differentially expressed genes between Control and CVS females, there were 88 genes that were significantly different between Control and CVS + SI groups. Of genes that were downregulated, a large portion (23 genes; 35%) were microRNAs.

We found that the PFC transcriptome of CVS + SI aged females was significantly enriched for predicted targets of the 23 microRNAs that were downregulated in the PFC in these mice. This suggests that microRNAs represent a mode of regulation capable of enacting far-reaching programmatic effects, and are a critical epigenetic gene expression regulatory mechanism.”

Applicability to humans was suggested by associations such as:

“A single microRNA can target more than a hundred different mRNA targets, and more than 45,000 conserved microRNA binding sites have been annotated in the 3′ UTR of 60% of human genes.”

A few limitations were noted:

“Given that mice at this age (1 year) are commonly compared to ‘late middle aged’ humans, later aging time points may yield differences in this group. Alternatively, it is possible that there was an effect of peripubertal stress that was not long-lasting due to the mild nature of our chronic stress model.

To include early neglect as a part of the stressor experience, CVS females were weaned one week earlier (PN21) than Control and CVS + SI mice. Addition of stress of this earlier weaning likely poses a significant contribution to programming of the PFC.”

One of the study coauthors was also a coauthor of:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870871/ “Peripubertal stress with social support promotes resilience in the face of aging”

Epigenetic effects of diet, and reversing DNA methylation

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This 2015 French review focused on:

“The role of maternal health and nutrition in the initiation and progression of metabolic and other disorders.

The effects of various in utero exposures and maternal nutritional status may have different effects on the epigenome. However, critical windows of exposure that seem to exist during development need to be better defined.

The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course.”

The reviewer used the term “transgenerational” to refer to effects that were more appropriately termed parental or intergenerational. Per the definition in A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply there needed to be evidence in at least the next 2 male and/or 3 female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

The review had separate sections for animal and human studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663595/ “Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood”

I arrived at the above review as a result of it citing the 2014 Harvard Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. I’ll quote a few items from that review’s informative “Role of DNA demethylation in neural development” section:

“Distinct parts of mammalian brains, including frontal cortex, hippocampus, and cerebellum, all exhibit age-dependent acquisition of 5hmC [an oxidized derivative of 5mC [methylation of the fifth position of cytosine]].

In fact, the genome of mature neurons in adult central nervous system contains the highest level of 5hmC of any mammalian cell-type (~40% as abundant as 5mC in Purkinje neurons in cerebellum). These observations indicate that 5mC oxidation and potentially DNA demethylation may be functionally important for neuronal differentiation and maturation processes.

A comprehensive base-resolution analyses of 5mC and 5hmC in mammalian frontal cortex in both fetal and adult stages indicate that non-CpG methylation (mCH) and CpG hydroxymethylation (hCG) drastically build up in cortical neurons after birth, coinciding with the peak of synaptogenesis and synaptic pruning in the cortex. This study demonstrated that mCH could become a dominant form of cytosine modifications in adult brains, accounting for 53% in adult human cortical neuronal genome.

In mature neurons, intragenic mCH is preferentially enriched at inactive non-neuronal lineage-specific genes, indicating a role in negative regulation of the associated transcripts. By contrast, genic hCG is positively correlated with gene expression levels.”

What’s the underlying question for every brain study to answer?

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Beliefs, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Testosterone, Thalamus , , , , , ,

Is the underlying question for every brain study to answer:

  • How do our brains internally represent the external world?

Is it:

  • How did we learn what we know?
  • How do we forget or disregard what we’ve learned?
  • What keeps us from acquiring and learning newer or better information?

How about:

  • What affects how we pay attention to our environments?
  • How do our various biochemical states affect our perceptions, learning, experiences, and behavior?
  • How do these factors in turn affect our biology?

Or maybe:

  • Why do we do what we do?
  • How is our behavior affected by our experiences?
  • How did we become attracted and motivated toward what we like?
  • How do we develop expectations?
  • Why do we avoid certain situations?

Not to lose sight of:

  • How do the contexts affect all of the above?
  • What happens over time to affect all of the above?

This 2015 UCLA paper reviewed the above questions from the perspective of Pavlovian conditioning:

“The common definition of Pavlovian conditioning, that via repeated pairings of a neutral stimulus with a stimulus that elicits a reflex the neutral stimulus acquires the ability to elicit that the reflex, is neither accurate nor reflective of the richness of Pavlovian conditioning. Rather, Pavlovian conditioning is the way we learn about dependent relationships between stimuli.

Pavlovian conditioning is one of the few areas in biology in which there is direct experimental evidence of biological fitness.”

The most important question unanswered by the review was:

  • How can its information be used to help humans?

How can Pavlovian conditioning answer: What can a human do about the thoughts, feelings, behavior, epigenetic effects – the person – the phenotype – that they’ve been shaped into?

One example of the unanswered question: the review pointed out in a section about fear extinction that this process doesn’t involve unlearning. Fear extinction instead inhibits the symptoms of fear response. The fear memory is still intact, awaiting some other context to be reactivated and expressed.

How can this information be used to help humans?

  • Is inhibiting the symptoms and leaving the fear memory in place costless with humans?
  • Or does this practice have both potential and realized adverse effects?
  • Where’s the human research on methods that may directly address a painful emotional memory?

One relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is that a person continues to be their conditioned self until they address the sources of their pain. A corollary is that efforts to relieve symptoms seldom address causes.

How could it be otherwise? A problem isn’t cured by ameliorating its effects.

http://cshperspectives.cshlp.org/content/8/1/a021717.full “The Origins and Organization of Vertebrate Pavlovian Conditioning”

Use it or lose it: the interplay of new brain cells, age, and activity

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres, Testosterone , , , ,

This 2015 German review was of aging and activity in the context of adult neurogenesis:

“Adult neurogenesis might be of profound functional significance because it occurs at a strategic bottleneck location in the hippocampus.

Age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis, because adult neurogenesis is neuronal development under the conditions of the adult brain.

The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes (e.g., in cell or synapse numbers), but emerge on a systems level and above when an organism ages. With respect to adult neurogenesis, only one multilevel experiment including morphology and behavior has been conducted, and, even in that study, only three time points were investigated.

In old age, adult neurogenesis occurs at only a small fraction of the level in early adulthood. The decline does not seem to be ‘regulated’ but rather the by-product of many age-related changes of other sorts.

From a behavioral level down to a synaptic level, activity increases adult neurogenesis. This regulation does not seem to occur in an all-or-nothing fashion but rather influences different stages of neuronal development differently. Both cell proliferation and survival are influenced by or even depend on activity.

The effects of exercise and environmental enrichment are additive, which indicates that increasing the potential for neurogenesis is sufficient to increase the actual use of the recruitable cells in the case of cognitive stimulation. Physical activity would not by itself provide specific hippocampus-relevant stimuli that induce net neurogenesis but be associated with a greater chance to encounter specific relevant stimuli.

Adult hippocampal neurogenesis might contribute to a structural or neural reserve that if appropriately trained early in life might provide a compensatory buffer of brain plasticity in the face of increasing neurodegeneration or nonpathological age-related functional losses. There is still only limited information on the activity-dependent parameters that help to prevent the age-dependent decrease in adult neurogenesis and maintain cellular plasticity.

The big question is what the functional contribution of so few new neurons over so long periods can be. Any comprehensive concept has to bring together the acute functional contributions of newly generated, highly plastic neurons and the more-or-less lasting changes they introduce to the network.”

I’ve quoted quite a lot, but there are more details that await your reading. A few items from the study referenced in the first paragraph above:

“The hippocampus represents a bottleneck in processing..adult hippocampal neurogenesis occurs at exactly the narrowest spot.

We have derived the theory that the function of adult hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty..a mechanism for preparing the hippocampus for processing greater levels of complexity.”

The role of the hippocampus in emotion was ignored as it so often is. The way to address many of the gaps mentioned by the author may be to Advance science by including emotion in research.

For example, from the author’s The mystery of humans’ evolved capability for adults to grow new brain cells:

“Adult neurogenesis is already effective early in life, actually very well before true adulthood, and is at very high levels when sexual maturity has been reached. Behavioral advantages associated with adult neurogenesis must be relevant during the reproductive period.”

When human studies are designed to research how “behavioral advantages associated with adult neurogenesis must be relevant” what purpose does it serve to exclude emotional content?

http://cshperspectives.cshlp.org/content/7/11/a018929.full “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”

Early-life epigenetic regulation of the oxytocin receptor gene

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This 2015 US/Canadian rodent study investigated the effects of natural variation in maternal care:

“The effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr [oxytocin receptor gene] across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus).

Rats reared by high licking-grooming (HL) and low licking-grooming (LL) rat dams exhibited differences across study outcomes:

  • LL offspring were more active in behavioral arenas,
  • Exhibited lower body mass in adulthood, and
  • Showed reduced corticosterone responsivity to a stressor.

Oxtr DNA methylation was significantly lower at multiple CpGs in the blood of LL versus HL males, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region.

Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in DNA methylation relative to these global patterns was not consistent across tissues.

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.

nonsignificance

Individual DNA methylation values were not correlated across brain tissues, despite tissue concordance at the group level.

For each CpG, we computed the Pearson correlation coefficient r between methylation values for matched samples in pairs of brain regions (bars). Dark and light shaded regions represent 95% and 99% thresholds, respectively, of distributions of possible correlation coefficients determined from 10,000 permutations of the measured values among the individuals. These distributions represent the null hypothesis that an individual DNA methylation value in one brain region does not help to predict the value in another region in the same animal.

(A) Correlations based on pyrosequencing data for matched samples passing validation in both hippocampus (HC) and hypothalamus (Hypo). Correlations for individuals at each CpG were either weak (.2 < r < .3) or absent (r < .2), and none were significant, even prior to correction for multiple comparisons.

(B) Correlations for matched samples passing validation in both hippocampus and striatum (Str). Two correlations (CpG 1 and 11) were individually significant prior to but not following correction, and this result could be expected by chance.

Correlations between hippocampus and blood (described in the text) yielded similar results, and no particular CpG yielded consistently high correlation across multiple tissues.”

The study focused on whether or not an individual’s experience-dependent oxytocin receptor gene DNA methylation in one of the four studied tissues could be used to infer a significant effect in the three other tissues. The main finding was NO, it couldn’t!

The researchers’ other findings may have been strengthened had they also examined causes for the observed effects. The “natural variation in maternal licking and grooming” developed from somewhere, didn’t it?

The subjects’ mothers were presumably available for the same tests as the subjects, but nothing was done with them. Investigating at least one earlier generation may have enabled etiologic associations of “the effects of early life rearing experience” and “individual variation in DNA methylation.”

https://www.sciencedirect.com/science/article/abs/pii/S0018506X1500118X “Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats” (not freely available)

Chronic pain causes epigenetic changes in the brain and immune system

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This 2015 Canadian rodent study by McGill researchers found:

“The critical involvement of DNA methylation in chronic pain. We show that in the PFC [prefrontal cortex], a brain region strongly implicated in chronic pain, a stunning number of promoters [control gene expression] are differentially methylated 9 months after injury. These changes are distant both in time and space from the original injury.

The changes in DNA methylation are highly organized in functional pathways that have been implicated in pain such as dysregulation of dopaminergic, glutamatergic, opioid and serotoninergic systems and important signaling and inflammatory pathways.

Genome-wide DNA methylation modifications of T cells [circulating white blood cells that control immune response] are also associated with nerve injury.

Most of the promoters (72%) identified as differentially methylated in T cells after nerve injury were also affected in the brain. While the methylation profiles in some of these modules were affected in the same direction in the brain and the T cells, others went in opposite direction. This is consistent with the idea that the brain and the immune system play different roles in chronic pain.

These data suggest that:

  • Persistent pain is associated with broad and highly organized organism-wide changes in DNA methylation, including two critical biological systems: the central nervous and immune systems.
  • This work also provides a possible mechanistic explanation for commonly observed comorbidities observed in chronic pain (i.e anxiety, depression).
  • Finally, the sheer magnitude of the impact of chronic pain, particularly in the prefrontal cortex, illustrates the profound impact that living with chronic pain exerts on an individual.”

http://www.nature.com/articles/srep19615 “Overlapping signatures of chronic pain in the DNA methylation landscape of prefrontal cortex and peripheral T cells”

The news coverage focused on how the study’s findings may lead to non-invasive DNA methylation measurements of chronic pain as well as treatments of the effects. I’d argue that the researchers’ concluding statement of the Discussion section deserved the most focus:

“Beyond the example of chronic pain, the robust and highly organized DNA methylation changes seen here in response to nerve injury provides some of the strongest evidence to date that experience effects DNA methylation landscapes at large distances in time and space.”

The study provided “some of the strongest evidence to date” that experiences caused widespread, long-lasting epigenetic changes. Given experiences’ etiologic functions, research with working hypotheses that experiences may also reverse epigenetic changes should be green-lighted.

“DNA methylation landscapes at large distances in time and space” warrant systematic examination of how experiential epigenetic changes during early life may be reversed by experiential therapies later in life. In the current year, there’s sufficient evidence for modifying research goals to primarily address causes, not just effects.

Lifelong effects of stress

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A 2016 commentary A trilogy of glucocorticoid receptor actions that included two 2015 French rodent studies started out:

“Glucocorticoids (GCs) belong to a class of endogenous, stress-stimulated steroid hormones. They have wide ranging physiologic effects capable of impacting metabolism, immunity, development, stress, cognition, and arousal.

GCs exert their cellular effects by binding to the GC receptor (GR), one of a 48-member (in humans) nuclear receptor superfamily of ligand-activated transcription factors.”

The French studies were exceedingly technical. The first GR SUMOylation and formation of an SUMO-SMRT/NCoR1-HDAC3 repressing complex is mandatory for GC-induced IR nGRE-mediated transrepression:

“GCs acting through binding to the GR are peripheral effectors of circadian and stress-related homeostatic functions fundamental for survival.

Unveils, at the molecular level, the mechanisms that underlie the GC-induced GR direct transrepression function mediated by the evolutionary conserved inverted repeated negative response element. This knowledge paves the way to the elucidation of the functions of the GR at the submolecular levels and to the future educated design and screening of drugs, which could be devoid of undesirable debilitating effects on prolonged GC therapy.”

The companion study Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex stated:

“GCs have been widely used to combat inflammatory and allergic disorders. However, multiple severe undesirable side effects associated with long-term GC treatments, as well as induction of glucocorticoid resistance associated with such treatments, limit their therapeutic usefulness.”

Even when researchers study causes, they often justify their efforts in terms of outcomes that address effects. Is an etiologic advancement in science somehow unsatisfactory in and of itself?

Once in a while I get a series of personal revelations while reading scientific publications. Paradoxically, understanding aspects of myself has seldom been sufficient to address historical problems.

Thoughts are only where some of the effects of problems show up, and clarifying my understanding can – at most – tamp down these effects. The causes are elsewhere, and addressing them at the source is what ultimately needs to happen.

A few glucocorticoid-related items to ponder:

  • How has stress impacted my life? When and where did it start?
  • Why do I feel wonderful after taking prednisone or other anti-inflammatories? What may be the originating causes of such effects?
  • Why have prolonged periods of my life been characterized by muted responses to stress? How did I get that way?
  • Have I really understood why I’ve reflexively put myself into stressful situations? What will break me out of that habit?
  • Why do the feelings I experience while under stressful situations feel familiar? Does my unconsciousness of their origins have something to do with “homeostatic functions fundamental for survival?”
  • Why haven’t I noticed that symptoms of stress keep showing up in my life? There are “physiologic effects capable of impacting metabolism, immunity,” etc. but I don’t do something about it?
  • How else may stress impact my biology? Brain functioning? Ideas and beliefs? Behavior?

Treating prenatal stress-related disorders with an oxytocin receptor agonist

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This 2015 French/Italian rodent study found:

“Chronic systemic treatment with carbetocin [unavailable in the US] in PRS [prenatally restraint stressed] rats corrected:

  • the defect in glutamate release,
  • anxiety– and depressive-like behavior,

and abnormalities:

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

These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life.”

carbetocin

The adult male subjects were:

“PRS rats..the offspring of dams exposed to repeated episodes of restraint stress during pregnancy.

These rats display anxiety- and depressive-like behaviors and show an excessive glucocorticoid response to acute stress, which is indicative of a dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis caused by an impaired hippocampal glucocorticoid negative feedback.

PRS rats show a selective reduction in glutamate release in the ventral hippocampus.”

The researchers cited several other studies they have performed with the PRS phenotype. In the current study:

“Carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala.

Carbetocin displayed a robust therapeutic activity in PRS rats, but had no effect in unstressed rats, therefore discriminating between physiological and pathological conditions.”

The PRS phenotype showed the ease with which a child can be epigenetically changed – even before they’re born – to be less capable over their entire life. Just stress the pregnant mother-to-be.

https://www.sciencedirect.com/science/article/abs/pii/S0306453015002395 “Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats” (not freely available) Thanks to coauthor Dr. Eleonora Gatta for providing the full study.