Experience-induced transgenerational programming of neuronal structure and functions

The second paper of Transgenerational epigenetic inheritance week was a 2017 German/Israeli review focused on:

“The inter- and transgenerational effects of stress experience prior to and during gestation..the concept of stress-induced (re-)programming in more detail by highlighting epigenetic mechanisms and particularly those affecting the development of monoaminergic transmitter systems, which constitute the brain’s reward system..we offer some perspectives on the development of protective and therapeutic interventions in cognitive and emotional disturbances resulting from preconception and prenatal stress.”

The reviewers noted that human studies have difficulties predicting adult responses to stress that are based on gene expression and early life experience. Clinical studies that experimentally manipulate the type, level and timing of the stressful exposure aren’t possible. Clinical studies are also predicated on the symptoms being recognized as disorders and/or diseases.

The researchers noted difficulties in human interventions and treatments. Before and during pregnancy, and perinatal periods are where stress effects are largest, but current human research hasn’t gathered sufficient findings to develop practical guidelines for early intervention programs.


I’m not persuaded by arguments that cite the difficulties of performing human research on transgenerational epigenetic inheritance. There are overwhelming numbers of people who have obvious stress symptoms: these didn’t develop in a vacuum.

Researchers:

  • Design human studies to test what’s known from transgenerational epigenetic inheritance animal studies that will include documenting the subjects’ detailed histories with sufficient biometric samples and data obtained from their lineage.
  • Induce the subjects to at least temporarily avoid what’s harmful for them and/or the offspring, in favor of what’s beneficial.
  • Document the subjects’ actions with history and samples.

I acknowledge that economic incentives may not be enough to get people to participate. I’m familiar with a juvenile sickle-cell study that didn’t get enough subjects despite offering free transportation and hundreds of dollars per visit. The main problem seemed to be that the additional income would be reported and threaten the caregiver’s welfare benefits.

Stop whining that your jobs are difficult, researchers. Society doesn’t owe you a job. Earn it – get yourself and the people in your organization motivated to advance science.

http://www.sciencedirect.com/science/article/pii/S014976341630731X “Experience-induced transgenerational (re-)programming of neuronal structure and functions: Impact of stress prior and during pregnancy” (not freely available)

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Epigenetic effects of early life stress exposure

This 2017 Netherlands review subject was the lasting epigenetic effects of early-life stress:

“Exposure to stress during critical periods in development can have severe long-term consequences..One of the key stress response systems mediating these long-term effects of stress is the hypothalamic-pituitary-adrenal (HPA) axis..early life stress (ELS) exposure has been reported to have numerous consequences on HPA-axis function in adulthood.

ELS is able to “imprint” or “program” an organism’s neuroendocrine, neural and behavioral responses to stress..research focuses along two complementary lines.

Firstly, ELS during critical stages in brain maturation may disrupt specific developmental processes (by altered neurotransmitter exposure, gene transcription, or neuronal differentiation), leading to aberrant neural circuit function throughout life..

Secondly, ELS may induce modifications of the epigenome which lastingly affect brain function..These epigenetic modifications are inducible, stable, and yet reversible, constituting an important emerging mechanism by which transient environmental stimuli can induce persistent changes in gene expression and ultimately behavior.”

In early life, the lower brain and limbic system brain structures are more developed and dominant, whereas the cerebrum and other brain structures are less developed (use the above graphic as a rough guide). Stress and pain generally have a greater impact on the fetus, then the infant, and then the adult.


The reviewers cited 50+ studies from years 2000-2015 in the “Early Life Stress Effects in a “Matching” Stressful Adult Environment” section to argue for the match/mismatch theory:

“Encountering ELS prepares an organism for similar (“matching”) adversities during adulthood, while a mismatching environment results in an increased susceptibility to psychopathology, indicating that ELS can exert either beneficial or disadvantageous effects depending on the environmental context.

Initial evidence for HPA-axis hypo-reactivity is observed for early social deprivation, potentially reflecting the abnormal HPA-axis function as observed in post-traumatic stress disorder.

Interestingly, experiencing additional (chronic) stress in adulthood seems to normalize these alterations in HPA-axis function, supporting the match/mismatch theory.”

Evidence for this theory was contrasted with the allostatic load theory presented in, for example, How one person’s paradigms regarding stress and epigenetics impedes relevant research.


The review mainly cites evidence from rodent studies that mismatched reactions in adulthood may be consequences of early-life events. These events:

“..imprint or program an organism’s neuroendocrine, neural and behavioral responses..leading to aberrant neural circuit function throughout life..which lastingly affect brain function..”

Taking this research to a personal level:

  • Have you had feelings that you were unsafe, although your environment was objectively safe?
  • Have you felt uneasy when people are nice to you?
  • Have you felt anxious when someone pays attention to you, even after you’ve acted to gain their attention?

I assert that mismatched human feelings are one form of mismatched reactions. As such, they may be interpreted as consequences of early-life experiences, and indicators of personal truths.

If researchers can let go of their biases and Advance science by including emotion in research, they may find that human subjects’ feelings produce better evidence for what actually happened during the subjects’ early lives than do standard scientific methods of:

Incorporating this evidence may bring researchers closer to backwardly predicting the major insults to an individual that knocked their development processes out of normally robust pathways and/or induced “persistent changes in gene expression and ultimately behavior.”

https://www.frontiersin.org/articles/10.3389/fncel.2017.00087/full “Modulation of the Hypothalamic-Pituitary-Adrenal Axis by Early Life Stress Exposure”


I discovered this review as a result of it being cited in http://www.sciencedirect.com/science/article/pii/S1084952117302884 “Long-term effects of early environment on the brain: Lesson from rodent models” (not freely available)

How one person’s paradigms regarding stress and epigenetics impedes relevant research

This 2017 review laid out the tired, old, restrictive guidelines by which current US research on the epigenetic effects of stress is funded. The reviewer rehashed paradigms circumscribed by his authoritative position in guiding funding, and called for more government funding to support and extend his reach.

The reviewer won’t change his beliefs regarding individual differences and allostatic load since he helped to start those memes. US researchers with study ideas to develop evidence beyond such memes may have difficulties finding funding.

Here’s one example of the reviewer’s restrictive views taken from the Conclusion section:

Adverse experiences and environments cause problems over the life course in which there is no such thing as “reversibility” (i.e., “rolling the clock back”) but rather a change in trajectory [10] in keeping with the original definition of epigenetics [132] as the emergence of characteristics not previously evident or even predictable from an earlier developmental stage. By the same token, we mean “redirection” instead of “reversibility”—in that changes in the social and physical environment on both a societal and a personal level can alter a negative trajectory in a more positive direction.”

What would happen if US researchers proposed tests of his “there is no such thing as reversibility” axiom? To secure funding, his sphere of influence would probably steer the prospective studies’ experiments toward altering “a negative trajectory in a more positive direction” instead. An example of his influence may be found in the press release of Familiar stress opens up an epigenetic window of neural plasticity where the lead researcher stated a goal of:

“..not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I found nothing in citation [10] (of which the reviewer is a coauthor) where the rodent study researchers even attempted to directly reverse the epigenetic changes! The researchers under his guidance simply asserted:

“..a history of stress exposure can permanently alter gene expression patterns in the hippocampus and the behavioral response to a novel stressor”

without making any therapeutic efforts to test the permanence assumption! Never mind that researchers outside the reviewer’s sphere of influence have done exactly that. In any event, citation [10] didn’t support an “there is no such thing as reversibility” axiom.

The reviewer also implied that humans respond just like lab rats and can be treated as such. Notice that the above graphic conflated rodent and human behaviors. Further examples of this inappropriate merger of behaviors are in the Conclusion section.


What may be a more promising research approach to human treatments of the epigenetic effects of stress now that it’s 2017? I pointed out in The current paradigm of child abuse limits pre-childhood causal research:

“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 the damage would also reverse the 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 human treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?”

http://journals.sagepub.com/doi/full/10.1177/2470547017692328 “Neurobiological and Systemic Effects of Chronic Stress”

Epigenetic stress effects in preterm infants

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)

A limited study of parental transmission of anxiety/stress-reactive traits

BehavioralTraitsThis 2016 New York rodent study found:

“Parental behavioural traits can be transmitted by non-genetic mechanisms to the offspring.

We show that four anxiety/stress-reactive traits are transmitted via independent iterative-somatic and gametic epigenetic mechanisms across multiple generations.

As the individual traits/pathways each have their own generation-dependent penetrance and gender specificity, the resulting cumulative phenotype is pleiotropic. In the context of genetic diseases, it is typically assumed that this phenomenon arises from individual differences in vulnerability to the various effects of the causative gene. However, the work presented here reveals that pleiotropy can be produced by the variable distribution and segregated transmission of behavioural traits.”


A primary focus was how anxiety was transmitted from parents to offspring:

“The iterative propagation of the male-specific anxiety-like behaviour is most compatible with a model in which proinflammatory state is propagated from H [serotonin1A receptor heterozygote F0] to F1 [children] females and in which the proinflammatory state is acquired by F1 males from their H mothers, and then by F2 [grandchildren] males from their F1 mothers.

We propose that increased levels of gestational MIP-1β [macrophage inflammatory protein 1β] in H and F1 mothers, together with additional proinflammatory cytokines and bioactive proteins, are required to produce immune system activation in their newborn offspring, which in turn promotes the development of the anxiety-like phenotype in males.

In particular, increase in the number of monocytes and their transmigration to the brain parenchyma in F1 and F2 males could be central to the development of anxiety.”


Due to my quick take on the study title – “Behavioural traits propagate across generations..” – I had expectations of this study that weren’t born out. My criticisms below relate to my expectations of what the researchers could have done versus what they did.

The researchers studied parental transmission of behavioral traits and epigenetic changes. Their study design removed prenatal and postnatal parental behavioral transmission of behavioral traits and epigenetic changes as each generation’s embryos were implanted into foster wild-type (WT) mothers.

The study design substituted the foster mothers’ prenatal and postnatal parental environments for the biological parents’ parental environments. So we didn’t find out, for example:

  • What effects the anxious F1 male children’s behaviors may have had on their offsprings’ behaviors and epigenetic changes
  • Whether the anxious, hypoactive, overly stress-reactive, hypothermic F2 male grandchildren’s behaviors affected their offsprings’ behaviors and epigenetic changes
  • To what extents the overly stress-reactive F1 female children’s prenatal environments and postnatal behaviors induced behaviors and/or epigenetic changes in their children, and whether the F2 grandchildren’s parental behaviors subsequently induced behaviors and/or epigenetic changes in the F3 great-grandchildren.

How did the study meet the overall goal of rodent studies: to help humans?

  1. Only a minority of humans experienced an early-life environment that included primary caregivers other than our biological parents.
  2. Very, very few of us experienced a prenatal environment other than our biological mothers.
  3. Maybe the researchers filled in some gaps in previous rodent studies, such as determining what is or isn’t a “true transgenerational mechanism.”

As an example of a rodent study that more closely approximated human conditions, the behavior of a mother whose DNA was epigenetically changed by stress induced the same epigenetic changes to her child’s DNA when her child was stressed per One way that mothers cause fear and emotional trauma in their infants:

“Our results provide clues to understanding transmission of specific fears across generations and its dependence upon maternal induction of pups’ stress response paired with the cue to induce amygdala-dependent learning plasticity.”

How did parental behavioral transmission of behavioral traits and epigenetic changes become a subject not worth investigating? These traits and effects can be seen everyday in real-life human interactions and physiology. But when investigating human correlates with behavioral epigenetic changes of rodents in the laboratory, parental behavioral transmission of behavioral traits is often treated the way this study treated it: as a confounder.

I doubt that people who have reached some degree of honesty about their early lives and concomitant empathy for others would agree with this prioritization. The papers of Transgenerational epigenetic inheritance week show the spectrum of opportunities to advance science that were intentionally missed.

http://www.nature.com/ncomms/2016/160513/ncomms11492/full/ncomms11492.html “Behavioural traits propagate across generations via segregated iterative-somatic and gametic epigenetic mechanisms”

A one-sided review of stress

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

“The stress response, involving the activation of the hypothalamic-pituitary-adrenocortical 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”

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

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 of 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 assumption of almost all of the cited references was that these distant causes can no longer be addressed. Aren’t such assumptions testable here in 2016?

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 the damage would also reverse the 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 human 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 misrepresents 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 seven references the review cited for telomere length that had “is associated with” or “is linked to” child abuse findings 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”