Limbic system

An emotional center of our brains

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This 2018 McGill/UC San Diego rodent study subject was the dentate gyrus area of the hippocampus:

“Early life experience influences stress reactivity and mental health through effects on cognitive-emotional functions that are, in part, linked to gene expression in the dorsal and ventral hippocampus. The hippocampal dentate gyrus (DG) is a major site for experience-dependent plasticity associated with sustained transcriptional alterations, potentially mediated by epigenetic modifications.

Peripubertal environmental enrichment increases hippocampal volume and enhances dorsal DG-specific differences in gene expression. Overall, our transcriptome and DNA methylation data support a model of regional and environmental effects on the molecular profile of DG neurons.”

The study thoroughly investigated several areas. I’ll quote a few parts with the section heading.

Introduction:

“The dorsal hippocampus, corresponding to the posterior hippocampus in primates, associates closely with cognitive functions and age-related cognitive impairments. In contrast, the ventral hippocampus, (anterior region in primates) is implicated in the regulation of emotional states and vulnerability for affective disorders. This functional specialization is reflected in patterns of gene expression.”

Results subsections:

“Environmental enrichment promotes hippocampal neurogenesis – hippocampal volume is enlarged in mice raised in an enriched environment (EE) compared with standard housing (SH) in both the dorsal and ventral poles. EE also associates with >60% more newborn neurons.

Specialization of gene expression in dorsal and ventral DG – Gene expression was more affected by EE in dorsal than ventral DG, and dorsal DG has twice as many differentially-expressed genes.

DNA methylation differences between dorsal and ventral DG – Each of the three forms of methylation [CpG, non-CpG, and hmC (hydroxymethylation)] exhibited a distinct genomic distribution in dorsal and ventral DG. A key advantage of whole-genome DNA methylation profiling is the ability to identify differentially methylated regions (DMRs), often far from any gene body, that mark tissue-specific gene regulatory elements.

This strong bias, with ~40-fold more hypomethylated regions in the dorsal DG, contrasts with the balanced number of differentially expressed genes in dorsal and ventral DG, suggesting an asymmetric role for DNA methylation in region-specific gene regulation. Despite their small number, ventral hypomethylated DMRs marked key developmental patterning transcription factors..which are linked to the proliferation, maintenance and survival of neural stem cells.

DNA methylation correlates with repression at some genes – CG and non-CG DNA methylation are associated with reduced gene expression, while hmC associates with increased expression. Dorsal DMRs were also enriched at genes that were up- and down-regulated in EE, although over half of dorsal up-regulated genes, and >98.5% of ventral up-regulated genes, contained no DMRs that could explain their region-specific differential expression.”

Discussion:

  • “a The cell stages occurring within the subgranular zone of the dentate gyrus are shown together with a schematic illustration of possible relative proportions consistent with our data. RGL Radial glia-like progenitor, NSC Neural stem cell.
  • b Key genes associated with the RGL stage are up-regulated in ventral DG relative to dorsal DG.
  • c We propose that mCH [non-CpG methylation] accumulates mainly in mature neurons.”

Why do human brain studies that include the hippocampus overwhelmingly ignore its role in our emotions? For example, the researchers of Advance science by including emotion in research could find only 397 suitable studies performed over 22 years from 1990 to 2011. There were tens or hundreds of times more human brain studies done during the same period that intentionally excluded emotional content!

The current rodent study provided physiological bases for dialing back the bias of human brain research focused exclusively on cognitive functions without also investigating attributes of emotional processing. Let’s see human studies designed to correct this recurring deficiency.

https://www.nature.com/articles/s41467-017-02748-x “Environmental enrichment increases transcriptional and epigenetic differentiation between mouse dorsal and ventral dentate gyrus”

Non-CpG DNA methylation

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This 2017 Korean review compared and contrasted CpG and non-CpG DNA methylation:

“Non-CpG methylation is restricted to specific cell types, such as pluripotent stem cells, oocytes, neurons, and glial cells. Accumulation of methylation at non-CpG sites and CpG sites in neurons seems to be involved in development and disease etiology.

Non-CpG methylation is established during postnatal development of the hippocampus and its levels increase over time. Similarly, non-CpG methylation is scarcely detected in human fetal frontal cortex, but is dramatically increased in later life. This increase in non-CpG methylation occurs simultaneously with synaptic development and increases in synaptic density.

In contrast, CpG methylation occurs during early development and does not increase over time.

Neurons have considerably higher levels of non-CpG methylation than glial cells. The human male ES [embryonic stem] cell line (H1) is more highly methylated than the female ES cell line (H9).

Among the different types of non-CpG methylation (CpA [adenosine], CpT [thymine], and CpC [another cytosine]), methylation is most common at CpA sites. For instance, in human iPS [induced pluripotent stem] cells, 5mCs are found in approximately 68.31%, 7.81%, 1.99%, and 1.05% of CpG, CpA, CpT, and CpC sites, respectively.”

The reviewers’ referenced statement:

“CpG methylation occurs during early development and does not increase over time.”

was presented outside of its context. The 2013 cited source’s statement was restricted to “selected loci” in the rodent hippocampus:

“Consistent with a recent study of the cortex, time-course analyses revealed that CpH [non-CpG] methylation at the selected loci was established during postnatal development of the hippocampus and was then present throughout life, whereas CpG methylation was established during early development.”

Epigenetic study methodologies improved in 2017 had more information on CpA methylation.

http://www.mdpi.com/2073-4425/8/6/148/htm “CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function”

DNA methylation and childhood adversity

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This 2017 Georgia human review covered:

“Recent studies, primarily focused on the findings from human studies, to indicate the role of DNA methylation in the associations between childhood adversity and cardiometabolic disease in adulthood. In particular, we focused on DNA methylation modifications in genes regulating the hypothalamus-pituitary-adrenal axis as well as the immune system.”

Recommendations in the review’s Epigenetics inheritance and preadaptation theory section included:

“Twin studies offer another promising design to explore the mediation effect of DNA methylation between child adversity and cardiometabolic outcomes..which could rule out heterogeneity due to genetic and familia[l]r environmental confounding.”

As it so happened, the below 2018 study provided some evidence.

http://www.sciencedirect.com/science/article/pii/S0167527317352762 “The role of DNA methylation in the association between childhood adversity and cardiometabolic disease” (not freely available) Thanks to lead author Dr. Guang Hao for providing the full study.

This 2018 UK human study:

“Tested the hypothesis that victimization is associated with DNA methylation in the Environmental Risk (E-Risk) Longitudinal Study, a nationally representative 1994-1995 birth cohort of 2,232 twins born in England and Wales and assessed at ages 5, 7, 10, 12, and 18 years. Multiple forms of victimization were ascertained in childhood and adolescence (including physical, sexual, and emotional abuse; neglect; exposure to intimate-partner violence; bullying; cyber-victimization; and crime).

Hypothesis-driven analyses of six candidate genes in the stress response (

  1. NR3C1 [glucocorticoid receptor],
  2. FKBP5 [a regulator of the stress hormone system],
  3. BDNF [brain-derived neurotrophic factor],
  4. AVP [arginine vasopressin],
  5. CRHR1 [corticotropin-releasing hormone receptor 1],
  6. SLC6A4 [serotonin transporter]

) did not reveal predicted associations with DNA methylation.

Epigenetic epidemiology is not yet well matched to experimental, nonhuman models in uncovering the biological embedding of stress.”

One of the sad findings was that as the types of trauma inflicted by other people on the subjects increased, so did the percentage of subjects who hurt themselves by smoking. Two-thirds of teens who reported three or more of the seven adolescent trauma types also smoked by age 18:

Polyvictimization

Self-harming behaviors other than smoking weren’t considered.

Another somber finding was:

“Childhood sexual victimization is associated with stable DNA methylation differences in whole blood in young adulthood. These associations were not observed in relation to sexual victimization in adolescence.”

The researchers guided future studies regarding the proxy measurements of peripheral blood DNA methylation:

“The vast majority of subsequent human studies, including the present one, have relied on peripheral blood. This choice is expedient, but also scientifically reasonable given the aim of detecting effects on stress-related physical health systems that include peripheral circulating processes (immune, neuroendocrine).

But whole blood is heterogeneous, and although cell-type composition can be evaluated and controlled, as in the present study, it does raise the question of whether peripheral blood is a problematic surrogate tissue for research on the epigenetics of stress.

Comparisons of methylomic variation across blood and brain suggest that blood-based EWAS may yield limited information relating to underlying pathological processes for disorders where brain is the primary tissue of interest.”

1. The comment on “epigenetic epidemiology” overstated the study’s findings because the epigenetic analysis, although thorough, was limited to peripheral blood DNA methylation. Other consequential epigenetic effects weren’t investigated, such as histone modifications and microRNA expression.

2. An unstated limitation was that the DNA methylation analyses were constrained by budgets. Studies like The primary causes of individual differences in DNA methylation are environmental factors point out restrictions in the methodology:

“A main limitation with studies using the Illumina 450 K array is that the platform only covers ~1.5 % of overall genomic CpGs, which are biased towards promoters and strongly underrepresented in distal regulatory elements, i.e., enhancers.

WGBS [whole-genome bisulfite sequencing] offers single-site resolution CpG methylation interrogation at full genomic coverage.

Another advantage of WGBS is its ability to access patterns of non-CpG methylation.”

I’d expect that in the future, researchers with larger budgets would reanalyze the study samples using other techniques.

3. The researchers started and ended the study presenting their view of human “embedding of stress” as a fact rather than a paradigm. Epigenetic effects of early life stress exposure compared and contrasted this with another substantiated view.

4. The study focused on the children’s intergenerational epigenetic effects. An outstanding opportunity to advance science was missed regarding transgenerational epigenetic inheritance:

  • Wouldn’t the parents’ blood samples and histories – derived from administering the same questionnaires their twins answered at age 18 – likely provide distant causal evidence for some of the children’s observed effects?
  • And lay the groundwork for hypotheses about aspects of future generations’ physiologies and behaviors?

https://ajp.psychiatryonline.org/doi/full/10.1176/appi.ajp.2017.17060693 “Analysis of DNA Methylation in Young People: Limited Evidence for an Association Between Victimization Stress and Epigenetic Variation in Blood” (not freely available) Thanks to coauthor Dr. Helen Fisher for providing the full study.

Can researchers make a difference in their fields?

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The purpose and finding of this 2017 UK meta-analysis of human epigenetics and cognitive abilities was:

“A meta-analysis of the relationship between blood-based DNA methylation and cognitive function.

We identified [two] methylation sites that are linked to an aspect of executive function and global cognitive ability. The latter finding relied on a relatively crude cognitive test..which is commonly used to identify individuals at risk of dementia.

One of the two CpG sites identified was under modest genetic control..there are relatively modest methylation signatures for cognitive function.”

The review’s stated limitations included:

“It is, of course, possible that a reliable blood-based epigenetic marker of cognitive function may be several degrees of separation away from the biological processes that drive cognitive skills.

There are additional limitations of this study:

  • A varying number of participants with cognitive data available for each test;
  • Heterogeneity in relation to the ethnicity and geographical location of the participants across cohorts; and
  • Relating a blood-based methylation signature to a brain-based outcome.

A 6-year window [between ages 70 and 76] is possibly too narrow to observe substantial changes in the CpG levels.”

All of these limitations were known before the meta-analysis was planned and performed. Other “possible” limitations already known by the 47 coauthors include those from Genetic statistics don’t necessarily predict the effects of an individual’s genes.

The paper referenced studies to justify the efforts, such as one (cited twice) coauthored by the lead author of A problematic study of DNA methylation in frontal cortex development and schizophrenia:

“Epigenome-wide studies of other brain-related outcomes, such as schizophrenia, have identified putative blood-based methylation signatures.”

Was this weak-sauce meta-analysis done just to plump up 47 CVs? Why can’t researchers investigate conditions that could make a difference in their fields?

Was this meta-analysis done mainly because the funding was available? I’ve heard that the primary reason there are papers like the doubly-cited one above is that the US NIMH funds few other types of research outside of their biomarker dogma.

The opportunity costs of this genre of research are staggering. Were there no more productive topics that these 47 scientists could have investigated?

Here are a few more-promising research areas where epigenetic effects can be observed in human behavior and physiology:

I hope that the researchers value their professions enough to make a difference with these or other areas of their expertise. And that sponsors won’t thwart researchers’ desires for difference-making science by putting them into endless funding queues.

https://www.nature.com/articles/s41380-017-0008-y “Meta-analysis of epigenome-wide association studies of cognitive abilities”

Make consequential measurements in epigenetic studies

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The subject of this 2017 Spanish review was human placental epigenetic changes:

“39 papers assessing human placental epigenetic signatures in association with either

  • (i) psychosocial stress,
  • (ii) maternal psychopathology,
  • (iii) maternal smoking during pregnancy, and
  • (iv) exposure to environmental pollutants,

were identified.

Their findings revealed placental tissue as a unique source of epigenetic variability that does not correlate with epigenetic patterns observed in maternal or newborn blood.“

Each study’s confounders were summarized by a column in Table 1. Some of the reviewers’ comments included:

“33 out of 39 papers reviewed (85%) reported significant associations between either placental DNA methylation or placental miRNA expression and exposure to any of the risk factors assessed. However, the methodological heterogeneity present throughout the studies reviewed does not allow meta-analytic exploration of reported findings.

Heterogeneity regarding the origin of biological tissues analyzed confounds the replicability and validity of reported findings and their potential synthesis.”

Sponsors and researchers really have to take their work seriously if the developmental origins of health and disease hypothesis can advance to a well-evidenced theory. Study designers should:

  1. Sample consequential dimensions. “There were no studies examining histone modifications.” Why were there no human studies in this important category of epigenetic changes in the placenta, the “barrier protecting the fetus“?
  2. Correct methodological deficiencies in advance. Eliminate insufficiencies like “Once collected, processing and storage of placental samples also differed across studies and was not reported in all of them.”
  3. Stop using convenient but non-etiologic proxy assays such as global methylation. How can a study advance the DOHaD hypothesis if everyone knows ahead of time that its outcome will be yet another finding that epigenetic changes “are associated with” non-causal factors?
  4. Forget about non-biological measurements like educational attainment per Does a societal mandate cause DNA methylation?.

Every human alive today has observable lasting epigenetic effects caused by environmental factors during the earliest parts of our lives, and potentially even before we’re conceived. Isn’t this sufficient rationale to expect serious efforts by research sponsors and designers?

https://www.sciencedirect.com/science/article/pii/S0892036217301769 “The impact of prenatal insults on the human placental epigenome: A systematic review” (click the Download PDF link to read the paper)

Epigenetics research and evolution

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This 2017 UK essay was a longish review of how epigenetics and other research has informed evolutionary theory:

“There are several processes by which directed evolutionary change occurs – targeted mutation, gene transposition, epigenetics, cultural change, niche construction and adaptation.

Evolution is an ongoing set of iterative interactions between organisms and the environment. Directionality is introduced by the agency of organisms themselves.”

A few takeaway items concerned:

“It is of course the functional phenotype that is ‘seen’ by natural selection. DNA sequences are not directly available for selection other than through their functional consequences.

The comparative failure of genome-wide association studies to reveal very much about the genetic origins of health and disease is one of the most important empirical findings arising from genome sequencing.

Environmental epigenetic impacts on biology and disease include:

  • Worldwide differences in regional disease frequencies
  • Low frequency of genetic component of disease as determined with genome wide association studies (GWAS)
  • Dramatic increases in disease frequencies over past decades
  • Identical twins with variable and discordant disease frequency
  • Environmental exposures associated with disease
  • Regional differences and rapid induction events in evolution“

The above list was from the cited 2016 review “Developmental origins of epigenetic transgenerational inheritance” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933018

Further points about behavior’s role in evolution:

“Differential mutation rates are not essential to enable organisms to guide their own evolution.

If organisms have agency and, within obvious limits, can choose their lifestyles, and if these lifestyles result in inheritable epigenetic changes, then it follows that organisms can at least partially make choices that can have long-term evolutionary impact.”

These discussions provided support for the central question of The PRice “equation” for individually evolving: Which equation describes your life?:

“Applying the “How does a phenotype influence its own change?” question to a person:

How can a person remedy their undesirable traits – many of which are from their ancestral phenotype – and acquire desirable traits?”

http://www.mdpi.com/2079-7737/6/4/47/htm “Was the Watchmaker Blind? Or Was She One-Eyed?”

Epigenetic study methodologies improved in 2017

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Let’s start out 2018 paying more attention to advancements in science that provide sound empirical data and methodology. Let’s ignore and de-emphasize studies and reviews that aren’t much more than beliefs couched in models and memes, whatever their presumed authority.

Let sponsors direct researchers to focus on ultimate causes of diseases. Let’s put research of treatments affecting causes ahead of those that only address symptoms.

Here are two areas of epigenetic research that improved in 2017.

Improved methodologies enabled DNA methylation studies of adenine, one of the four bases of DNA, to advance, such as this 2017 Wisconsin/Minnesota study N6-methyladenine is an epigenetic marker of mammalian early life stress:

“6 mA is present in the mammalian brain, is altered within the Htr2a gene promoter by early life stress and biological sex, and increased 6 mA is associated with gene repression. These data suggest that methylation of adenosine within mammalian DNA may be used as an additional epigenetic biomarker for investigating the development of stress-induced neuropathology.”

Most DNA methylation research is performed on the cytosine and guanine bases.

Other examples of improved methodologies were discussed in this 2017 Japanese study Genome-wide identification of inter-individually variable DNA methylation sites improves the efficacy of epigenetic association studies:

“A strategy focusing on CpG sites with high DNA methylation level variability may attain an improved efficacy..estimated to be 3.7-fold higher than that of the most frequently used strategy.

With ~90% coverage of human CpGs, whole-genome bisulfite sequencing (WGBS) provides the highest coverage among the currently available DNAm [DNA methylation] profiling technologies. However, because of its high cost, it is presently infeasible to apply WGBS to large-scale EWASs [epigenome-wide association studies], which require DNAm profiling of hundreds or thousands of subjects. Therefore, microarrays and targeted bisulfite sequencing are currently practicable for large-scale EWASs and thus, effective strategies to select target regions are essentially needed to improve the efficacy of epigenetic association studies.

DNAm levels measured with microarrays are invariable for most CpG sites in the study populations. As invariable DNAm signatures cannot be associated with exposures, intermediate phenotypes, or diseases, current designs of probe sets are inefficient for blood-based EWASs.”

How to cure the ultimate causes of migraines?

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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?

Differing approaches to a life wasted on beliefs

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Let’s start by observing that people structure their lives around beliefs. As time goes on, what actions would a person have taken to ward off non-confirming evidence?

One response may be that they would engage in ever-increasing efforts to develop new beliefs that justified how they spent their one precious life’s time so far.

Such was my take on beliefs embedded in https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5684598/pdf/PSYCHIATRY2017-5491812.pdf “Epigenetic and Neural Circuitry Landscape of Psychotherapeutic Interventions”:

“Animal models have shown the benefits of continued environmental enrichment (EE) on psychopathological phenotypes, which carries exciting translational value.

This paper posits that psychotherapy serves as a positive environmental input (something akin to EE).”

The author conveyed his belief that wonderful interventions were going to happen in the future. However, when scrutinized, most human studies have demonstrated NULL effects of psychotherapeutic interventions on causes. Without sound evidence that treatments affect causes, his belief seemed driven by something else.

The author cited findings of research like A problematic study of oxytocin receptor gene methylation, childhood abuse, and psychiatric symptoms as supporting external interventions to tamp down symptoms of patients’ presenting problems. Did any of the 300+ cited references concern treatments where patients instead therapeutically addressed their problems’ root causes?

For an analogous religious example, a person’s belief caused him to spend years of his life trying to convince men to act so that they could get their own planet after death, and trying to convince women to latch onto men who had this belief. A new and apparently newsworthy belief developed from his underlying causes:

“The founder and CEO of neuroscience company Kernel wants “to expand the bounds of human intelligence.” He is planning to do this with neuroprosthetics; brain augmentations that can improve mental function and treat disorders. Put simply, Kernel hopes to place a chip in your brain.

He was raised as a Mormon in Utah and it was while carrying out two years of missionary work in Ecuador that he was struck by what he describes as an “overwhelming desire to improve the lives of others.”

He suffered from chronic depression from the ages of 24 to 34, and has seen his father and stepfather face huge mental health struggles.”

https://www.theguardian.com/small-business-network/2017/dec/14/humans-20-meet-the-entrepreneur-who-wants-to-put-a-chip-in-your-brain “Humans 2.0: meet the entrepreneur who wants to put a chip in your brain”

The article stated that he had given up Mormonism. There was nothing to suggest, though, that he had therapeutically addressed any underlying causes for his misdirected thoughts, feelings, and behavior.

So he developed other beliefs instead.

What can people do to keep their lives from being wasted on beliefs? As mentioned in What was not, is not, and will never be:

“The problem is that spending our time and efforts on these ideas, beliefs, and behaviors won’t ameliorate their motivating causes. Our efforts only push us further away from our truths, with real consequences: a wasted life.”

The goal of the therapeutic approach advocated by Dr. Arthur Janov’s Primal Therapy is to remove the force of presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.

Epigenetic effects of microRNA on fetal heart development

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This 2017 Australian review’s subject was epigenetic impacts involving microRNA in adverse intrauterine environments, and how these affected fetal heart tissue development:

“We describe how an adverse intrauterine environment can influence the expression of miRNAs (a sub-set of non-coding RNAs) and how these changes may impact heart development. Potential consequences of altered miRNA expression in the fetal heart include; Hypoxia inducible factor (HIF) activation, dysregulation of angiogenesis, mitochondrial abnormalities and altered glucose and fatty acid transport/metabolism.

This feedback network between miRNAs and other epigenetic pathways forms an epigenetics–miRNA regulatory circuit that organizes the whole gene expression profile. The human heart encodes over 700 miRNAs.”

A 2016 review Lack of oxygen’s epigenetic effects also provided a details about hypoxia. Those reviewers importantly pointed out the natural lack of a feedback mechanism to the HIF-1α signaling source, and how this evolutionary lack contributed to diseases.

http://www.mdpi.com/1422-0067/18/12/2628/htm “Adverse Intrauterine Environment and Cardiac miRNA Expression”

Do you have your family’s detailed medical histories?

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Imagine that you were a parent who puzzled over the mystery of your pre-teen daughter’s hyperactive behavior. Without detailed family medical histories, would anyone recognize this as a preprogammed phenotype?

Could anyone trace the daughter’s behavior back to her maternal great-grandmother being treated with glucocorticoids near the end of the second trimester of carrying her grandfather?

Such was a finding of a 2017 Canadian guinea pig study that was undertaken to better inform physicians of the transgenerationally inherited epigenetic effects of glucocorticoid treatments commonly prescribed during human pregnancies:

“This study presents the first evidence that prenatal treatment with sGC [synthetic glucocorticoid] results in transgenerational paternal transmission of hyperactivity and altered hypothalamic gene expression through three generations of young offspring. Female offspring appear to be more sensitive than male offspring to the programming effects of sGC, which suggests an interaction between sGC and sex hormones or sex-linked genes. Paternal transmission to F3 strongly implicates epigenetic mechanisms in the process of transmission, and small noncoding RNAs likely play a major role.”

Some details of the study included:

Veh[icle] was the control group initially treated with saline.

The study was informative and conclusive for the aspects studied. From the Methods section:

“Data from same-sex littermates were meaned to prevent litter bias. Sample sizes (N) correspond to independent litters, and not to the total number of offspring across all litters.

Power analyses based on previous studies determined N ≥ 8 sufficient to account for inter-litter variability and detect effects in the tests performed.”

https://www.nature.com/articles/s41598-017-11635-w “Prenatal Glucocorticoid Exposure Modifies Endocrine Function and Behaviour for 3 Generations Following Maternal and Paternal Transmission”

An update on brain zapping

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This 2017 general-audience article entitled Ultrasound for the brain provided a hyped update on brain zapping:

“Ultrasound could potentially treat other movement disorders, as well as depression, anxiety and a host of intract­able neuropsychiatric disorders..

This could be a breakthrough..

Researchers hope one day to help people with neuropsychiatric conditions by repairing or resetting the relevant neural pathways..

The potential advantages, especially for deep brain areas, are huge..”

Though not the main thrust of the article, another potential use of ultrasound would be to activate drugs delivered to a specific area, as this image portrays:

Vanderbilt University was again at the forefront of brain zapping, as noted in What’s an appropriate control group for a schizophrenia study? for example. I hope the disclosures for subjects participating in Vanderbilt’s brain-zapping studies made it clear that:

“At high intensities, such as those used to relieve essential tremor, ultrasound’s effects are largely thermal: the tissue heats up and cells die.”

Comments are disabled because this post has somehow become a target for spammers. Readers can click the above control group link to comment.

One example of how experience changes the brain

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This 2017 California rodent study found:

“Neural representations within the mouse hypothalamus, that underlie innate social behaviours, are shaped by social experience.

In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male versus female conspecifics [members of the same species]. However, in inexperienced adult males, male and female intruders activated overlapping neuronal populations.

Sex-specific neuronal ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not to mount or attack conspecifics, ensemble divergence did not occur. However, 30 minutes of sexual experience with a female was sufficient to promote the separation of male and female ensembles.

These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviours. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a ‘hard-wired’ system.”

Hat tip to Neuroskeptic for both alerting me to the study and simplifying its overly-dense graphics.

http://www.nature.com/nature/journal/v550/n7676/full/nature23885.html “Social behaviour shapes hypothalamic neural ensemble representations of conspecific sex” (not freely available)

“Transgenerationally” inherited epigenetic effects of fetal alcohol exposure

gettingwell4 2-3 stars Required further work, Acetylcholine, Brain development, Cerebrum, Epigenetics, Hippocampus, Limbic system, Memory, Neurochemicals , , , , , ,

The fourth paper of Transgenerational epigenetic inheritance week was a 2016 German rodent study of of improperly-termed “transgenerational” epigenetic effects of alcohol:

“We investigated 2 generations of offspring born to alcohol-treated mothers. Here, we show that memory impairment and reduced synthesis of acetylcholine occurs in both F1 (exposed to ethanol in utero) and F2 generation (never been exposed to ethanol). Effects in the F2 generation are most likely consequences of transgenerationally transmitted epigenetic modifications in stem cells induced by alcohol.

The results further suggest an epigenetic trait for an anticholinergic endophenotype associated with cognitive dysfunction which might be relevant to our understanding of mental impairment in neurodegenerative disorders such as Alzheimer’s disease and related disorders.”

F0 generation mothers modeled human fetal alcohol syndrome. They were exposed to ethanol gradually up to 20%, then mated. The 20% ethanol intake level was maintained until the F1 generation pups were born, then gradually diminished to 0%. After a ten-day wait, an eight-week handling and shaping period started, followed by five weeks of behavioral testing.

The F1 children and F2 grandchildren started an eight-week handling and shaping period after young adulthood, followed by five weeks of behavioral testing. The F1 children were mated after behavioral testing.

The F0 parents showed no significant differences in working memory and reference memory compared with controls. Both the F1 children and F2 grandchildren were significantly impaired in the same tests compared with controls, with the F1 children performing worse than the F2 grandchildren. No sex-dependent differences were noted.

After behavioral impairments due to intergenerational epigenetic modifications were established, the F2 grandchildren received treatments to ascertain the contribution of cholinergic dysfunction in their behavioral impairments. It was confirmed, as an acetylcholine esterase inhibitor that crosses the blood-brain barrier almost completely erased working-memory and reference-memory performance deficits.

Items in the Discussion section included:

  • A dozen studies from 2014-2016 were cited for epigenetic mechanisms of inheritance stemming from parental alcohol consumption; and
  • Transgenerational inheritance of alcohol-induced neurodevelopmental deficits may involve epigenetic mechanisms that are resistant to developmental clearance.

As argued in Transgenerational effects of early environmental insults on aging and disease and A review of epigenetic transgenerational inheritance of reproductive disease, testing of F3 great-grandchildren was needed in order to establish transgenerational vs. intergenerational results. A F3 generation necessarily controls for the variable of F2 direct germline exposure.

http://www.neurobiologyofaging.org/article/S0197-4580(16)30303-7/pdf “Transgenerational transmission of an anticholinergic endophenotype with memory dysfunction” (not freely available)

Transgenerational pathological traits induced by prenatal immune activation

gettingwell4 2-3 stars Required further work, Amygdala, Brain development, Epigenetics, Glutamate, Immune system, Limbic system, Neurochemicals, Stress , , , , , , ,

The third paper of Transgenerational epigenetic inheritance week was a 2016 Swiss rodent study of immune system epigenetic effects:

“Our study demonstrates for, we believe, the first time that prenatal immune activation can negatively affect brain and behavioral functions in multiple generations. These findings thus highlight a novel pathological aspect of this early-life adversity in shaping disease risk across generations.”

The epigenetic effects noted in the initial round of experiments included:

  • F1 child and F2 grandchild impaired sociability;
  • F1 and F2 abnormal fear expression;
  • F1 but not F2 sensorimotor gating deficiencies; and
  • F2 but not F1 behavioral despair associated with depressive-like behavior.

These transgenerational effects emerged in both male and female offspring. The prenatal immune activation timing corresponded to the middle of the first trimester of human pregnancy.

The effects were found to be mediated by the paternal but not maternal lineage. The researchers didn’t develop a maternal lineage F3 great-grandchild generation.

The next round of experiments done with the paternal lineage F3 great-grandchildren noted these epigenetic effects:

  • The F3 great-grandchildren had impaired sociability, abnormal fear expression and behavioral despair; and
  • The F3 great-grandchildren had normal sensorimotor gating.

Since the first round of tests didn’t show sex-dependent effects, the F3 great-grandchildren were male-only to minimize the number of animals.

Samples of only the amygdalar complex were taken to develop findings of transcriptomic effects of prenatal immune activation.

Items in the Discussion section included:

  1. The F2 grandchild and F3 great-grandchild generations’ phenotype of impaired sociability, abnormal fear expression and behavioral despair demonstrated that prenatal immune activation likely altered epigenetic marks in the germ line of the F1 children which resisted erasure and epigenetic reestablishment during germ cell development.
  2. Abnormal F1 child sensorimotor gating followed by normal F2 grandchild and F3 great-grandchild sensorimotor gating demonstrated that prenatal immune activation may also modify somatic but not germ cells.
  3. Non-significant F1 child behavioral despair followed by F2 grandchild and F3 great-grandchild behavioral despair demonstrated that prenatal immune activation may modify F1 germ cells sufficiently to develop a transgenerational phenotype, but unlike item 1 above, somatic cells were insufficiently modified, and the phenotype skipped the F1 children.
  4. Studies were cited that prenatal immune activation later in the gestational process may produce different effects.

The initial round of experiments wasn’t definitive for the maternal lineage. As argued in Transgenerational effects of early environmental insults on aging and disease and A review of epigenetic transgenerational inheritance of reproductive disease, testing of maternal lineage F3 great-grandchildren was needed to control for the variable of direct F2 grandchild germ-line exposure.

Also, effects that didn’t reach statistical significance in the maternal lineage F1 children and F2 grandchildren may have been different in the F3 great-grandchildren. The researchers indirectly acknowledged this lack by noting that these and other effects of immune challenges in a maternal lineage weren’t excluded by the study.

https://www.nature.com/mp/journal/v22/n1/pdf/mp201641a.pdf “Transgenerational transmission and modification of pathological traits induced by prenatal immune activation” (not freely available)

The study’s lead researcher authored a freely-available 2017 review that placed this study in context and provided further details from other studies:

http://www.nature.com/tp/journal/v7/n5/full/tp201778a.html “Epigenetic and transgenerational mechanisms in infection-mediated neurodevelopmental disorders”