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)

A study of perinatal malnutrition where the paradigm excluded epigenetic inheritance

This 2017 New York/Swedish rodent study subject was the epigenetic effects on the F1 children of maternal low protein diet during pregnancy and lactation:

“Male, but not female, offspring of LPD [low protein diet] mothers consistently displayed anxiety- and depression-like behaviors under acute stress.

Our proposed pathway connecting early malnutrition, sex-independent regulatory changes in Egr1 [an Early growth response gene], and sex-specific epigenetic reprogramming of its effector gene, Npy1r [neuropeptide Y receptor Y1 gene], represents the first molecular evidence of how early life risk factors may generate sex-specific epigenetic effects relevant for mental disorders.”


The study was purposely incomplete regarding transgenerational epigenetic effects that may be transmitted from the F1 children to their F2 grandchildren and F3 great-grandchildren. Similar to How one person’s paradigms regarding stress and epigenetics impedes relevant research, the paradigm continued by one of this study’s coauthors restricted inquiry into epigenetic inheritance.

How can the other coauthors respond when a controller of funding publishes the paper referenced in What is epigenetic inheritance? and otherwise makes his narrow views regarding epigenetic inheritance well-known? If the controller’s restricted views won’t allow the funding scope to extend testing to study F2 grandchildren and F3 great-grandchildren, the experiments end, and our understanding of epigenetic inheritance isn’t advanced.

This purposely incomplete study showed that the coauthor only gave lip service to advancing science when he made statements like:

“Further work is needed to understand whether and to what extent true epigenetic inheritance of stress vulnerability adds to the well-established and powerful influence of genetics and environmental exposures.”

The papers of Transgenerational epigenetic inheritance week show the spectrum of opportunities to advance science that were intentionally missed.

https://www.nature.com/articles/s41598-017-10803-2 “Perinatal Malnutrition Leads to Sexually Dimorphic Behavioral Responses with Associated Epigenetic Changes in the Mouse Brain”

A gaping hole in a review of nutritional psychiatry

This December 2016 Australian review published in September 2017 concerned:

“..the nutritional psychiatry field..the neurobiological mechanisms likely modulated by diet, the use of dietary and nutraceutical interventions in mental disorders, and recommendations for further research.”


The reviewers inexplicably omitted acetyl-L-carnitine, which I first covered in A common dietary supplement that has rapid and lasting antidepressant effects. A PubMed search on “acetyl carnitine” showed over a dozen studies from the past twelve months that were relevant to the review’s subject areas. Here’s a sample, beginning with follow-on research published in June 2016 of the study I linked above:

Reply to Arduini et al.: Acetyl-l-carnitine and the brain: Epigenetics, energetics, and stress

Dietary supplementation with acetyl-l-carnitine counteracts age-related alterations of mitochondrial biogenesis, dynamics and antioxidant defenses in brain of old rats

Neuroprotective effects of acetyl-l-carnitine on lipopolysaccharide-induced neuroinflammation in mice: Involvement of brain-derived neurotrophic factor

ALCAR promote adult hippocampal neurogenesis by regulating cell-survival and cell death-related signals in rat model of Parkinson’s disease like-phenotypes

Analgesia induced by the epigenetic drug, L-acetylcarnitine, outlasts the end of treatment in mouse models of chronic inflammatory and neuropathic pain

The cited references in these recent studies were older, of course, and in the time scope of the review. There’s no excuse for this review’s omission of acetyl-L-carnitine.

https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/nutritional-psychiatry-the-present-state-of-the-evidence/88924C819D21E3139FBC48D4D9DF0C08 “Nutritional psychiatry: the present state of the evidence” (not freely available)

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”

Epigenetic effects of diet, and reversing DNA methylation

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?

Is it:

  • 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 is:

  • How can its information be used to help humans?

How does Pavlov conditioning answer:

  • What can a human do about the thoughts, feelings, behavior, epigenetic effects – the person – that they’ve been shaped into?

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

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


As an example, the review pointed out in a section about fear extinction that it 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 that 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?

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