Genetic imprinting, sleep, and parent-offspring conflict

This 2016 Italian review subject was the interplay of genetic imprinting and sleep regulation:

“Sleep results from the synergism between at least two major processes: a homeostatic regulatory mechanism that depends on the accumulation of the sleep drive during wakefulness, and a circadian self-sustained mechanism that sets the time for sleeping and waking throughout the 24-hour daily cycle.

REM sleep apparently contravenes the restorative aspects of sleep; however, the function of this ‘paradoxical’ state remains unknown. Although REM sleep may serve important functions, a lack of REM sleep has no major consequences for survival in humans; however, severe detrimental effects have been observed in rats.

Opposite imprinting defects at chromosome 15q11–13 are responsible for opposite sleep phenotypes as well as opposite neurodevelopmental abnormalities, namely the Prader-Willi syndrome (PWS) and the Angelman syndrome (AS). Whilst the PWS is due to loss of paternal expression of alleles, the AS is due to loss of maternal expression.

Maternal additions or paternal deletions of alleles at chromosome 15q11–13 are characterized by temperature control abnormalities, excessive sleepiness, and specific sleep architecture changes, particularly REM sleep deficits. Conversely, paternal additions or maternal deletions at chromosome 15q11–13 are characterized by reductions in sleep and frequent and prolonged night wakings.

The ‘genomic imprinting hypothesis of sleep’ remains in its infancy, and several aspects require attention and further investigation.”

http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006004 “Genomic Imprinting: A New Epigenetic Perspective of Sleep Regulation”


A commenter to the review referenced a 2014 study Troubled sleep: night waking, breastfeeding, and parent–offspring conflict that received several reactions, including one by the same commenter. Here are a few quotes from the study author’s consolidated response:

“‘Troubled sleep’ had two major purposes. The first was to draw attention to the oppositely perturbed sleep of infants with PWS and AS and explore its evolutionary implications. The involvement of imprinted genes suggests that infant sleep has been subject to antagonistic selection on genes of maternal and paternal origin with genes of maternal origin favoring less disrupted sleep.

My second major purpose was a critique of the idea that children would be happier, healthier and better-adjusted if we could only return to natural methods of child care. This way of thinking is often accompanied by a belief that modern practices put children at risk of irrevocable harm. The truth of such claims is ultimately an empirical question, but the claims are sometimes presented as if they had the imprimatur of evolutionary biology. This appeal to scientific authority often seems to misrepresent what 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.

Infant sleep may similarly lack the exquisite organization of systems without evolutionary conflict. Postnatal development, like prenatal development, is subject to difficulties of evolutionarily credible communication between mothers and offspring.”

The author addressed comments related to attachment theory:

“Infants are classified as having insecure-resistant attachment if they maintain close proximity to their mother after a brief separation while expressing negative emotions and exhibiting contradictory behaviors that seem to both encourage and resist interaction. By contrast, infants are classified as having insecure-avoidant attachment if they do not express negative emotion and avoid contact with their mother after reunion.

Insecure-avoidant and insecure-resistant behaviors might be considered antithetic accommodations of infants to less responsive mothers; the former associated with reduced demands on maternal attention, the latter with increased demands. A parallel pattern is seen in effects on maternal sleep. Insecure-avoidant infants wake their mothers less frequently, and insecure-resistant infants more frequently, than securely attached infants.

Parent–child interactions are transformed once children can speak. Infants with more fragmented sleep at 6 months had less language at 18 and 30 months. Infants with AS have unconsolidated sleep and never learn to speak. The absence of language in the absence of expression of one or more MEGs [maternally expressed imprinted genes] is compatible with a hypothesis in which earlier development of language reduces infant demands on mothers.”

Regarding cultural differences:

“China, Taiwan and Hong Kong have both high rates of bed-sharing and high rates of problematic sleep compared with western countries. Within this grouping, however, more children sleep in their own room but parents report fewer sleep problems in Hong Kong than in either China or Taiwan. Clearly, cultural differences are significant, and the causes of this variation should be investigated, but the differences cannot be summarized simply as ‘west is worst’.

The fitness [genetic rather than physical fitness] gain to mothers of an extra child and the benefits for infants of longer IBIs [interbirth intervals] are substantial. These selective forces are unlikely to be orders of magnitude weaker than the advantages of lactase persistence, yet the selective forces associated with dairying have been sufficient to result in adaptive genetic differentiation among populations. The possibility of gene–culture coevolution should not be discounted for behaviors associated with infant-care practices.”

Regarding a mismatch between modern and ancestral environments:

“I remain skeptical of a tendency to ascribe most modern woes to incongruence between our evolved nature and western cultural practices. We did not evolve to be happy or healthy but to leave genetic descendants, and an undue emphasis on mismatch risks conflating health and fitness.

McKenna [a commenter] writes ‘It isn’t really nice nor maybe even possible to fool mother nature.’ Here I disagree. Our genetic adaptations often try to fool us into doing things that enhance fitness at costs to our happiness.

Our genes do not care about us and we should have no compunction about fooling them to deliver benefits without serving their ends. Contraception, to take one obvious example, allows those who choose childlessness to enjoy the pleasures of sexual activity without the fitness-enhancing risk of conception.

Night waking evolved in environments in which there were strong fitness costs from short IBIs and in which parents lacked artificial means of birth-spacing. If night waking evolved because it prolonged IBIs, then it may no longer serve the ends for which it evolved.

Nevertheless, optimal infant development might continue to depend on frequent night feeds as part of our ingrained evolutionary heritage. It could also be argued that when night waking is not reinforced by feeding, and infants sleep through the night, then conflict within their genomes subsides. Infants would then gain the benefit of unfragmented sleep without the pleiotropic costs of intragenomic conflict. Plausible arguments could be presented for either hypothesis and a choice between them must await discriminating evidence.”


Commenters on the 2014 study also said:

[Crespi] The profound implications of Haig’s insights into the roles of evolutionary conflicts in fetal, infant and maternal health are matched only by the remarkable absence of understanding, appreciation or application of such evolutionary principles among the research and clinical medical communities, or the general public.

[Wilkins] A mutation may be selected for its effect on the trait that is the basis of the conflict, but that mutation also likely affects other traits. In general, we expect that these pleiotropic effects to be deleterious: conflict over one trait can actually drive other traits to be less adapted. Natural selection does not necessarily guarantee positive health outcomes.

[McNamara] Assuming that AS/REM is differentially influenced by genes of paternal origin then both REM properties and REM-associated awakenings can be better explained by mechanisms of genomic conflict than by traditional claims that REM functions as an anti-predator ‘sentinel’ for the sleeping organism.

[Hinde] Given this context of simultaneous coordination and conflict between mother and infant, distinguishing honest signals of infant need from self-interested, care-extracting signals poses a challenge.

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 [first generation] females and in which the proinflammatory state is acquired by F1 males from their H mothers, and then by F2 [second generation] 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 males’ behaviors may have had on their offsprings’ behaviors and epigenetic changes
  • Whether the anxious, hypoactive, overly stress-reactive, hypothermic F2 males’ behaviors affected their offsprings’ behaviors and epigenetic changes
  • To what extents the overly stress-reactive F1 mothers’ prenatal environments and postnatal behaviors induced behaviors and/or epigenetic changes in their children, and whether the F2 children’s parental behaviors subsequently induced behaviors and/or epigenetic changes in the F3 generation.

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 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.

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 human study of pain avoidance

This 2016 UK human study found:

“People differ in how they learn to avoid pain, with some individuals refraining from actions that resulted in painful outcomes, whereas others favor actions that helped prevent pain.

Learning in our task was best explained as driven by an outcome prediction error that reflects the difference between expected and actual outcomes. Consistent with the expression of such a teaching signal, blood-oxygen level-dependent (BOLD) responses to outcomes in the striatum were modulated by expectation.

Positive learners showed significant functional connectivity between the insula and striatal regions, whereas negative learners showed significant functional connectivity between the insula and amygdala regions.

The degree to which a participant tended to learn from success in avoiding than experiencing shocks was predicted by the structure of a participants’ striatum, specifically by higher gray matter density where the response to shocks was consistent with a prediction error signal. Higher gray matter density in the putamen (and lower gray matter density in the caudate) predicted better learning from shocks and poorer learning from success in avoiding shocks.”

The researchers termed the subjects’ pain responses “learning” instead of conditioning. The experiments presented no 100%-certain choices to avoid pain. The experiments were also rigged to force choices at similar rates among subjects because:

“Participants who learned more from painful outcomes developed a propensity to avoid gambling, whereas participants who learned more from success in preventing pain developed a propensity to gamble.”


Human responses to pain don’t arise out of nowhere. The subjects’ pain histories were clearly relevant, but weren’t investigated. The closest the study came to considering the subjects’ histories was:

“Before the experiment, participants completed an 80-item questionnaire composed of several measures of different mood and anxiety traits. Age, sex and mood and anxiety traits did not differ between participants later classified as positive and negative learners.”

Emotional content was neither included nor solicited. Emotions were inferred:

“Participants biased in favor of passive avoidance learning (i.e., learning what gambles should be avoided), striatal response to painful outcomes was consistent with an aversive prediction error, as seen in fear conditioning.”

As a result, there weren’t causal explanations for the subjects’ differing pain responses. How, when, and why did the behavioral, functional, and structural differences develop?


I didn’t see the level of detail needed to characterize striatal regions into the Empathy, value, pain, control: Psychological functions of the human striatum segments. I’d guess that the findings of “higher gray matter density in the putamen (and lower gray matter density in the caudate)” applied to the posterior putamen and the anterior caudate nucleus.

Two of the coauthors were also coauthors of If a study didn’t measure feelings, then its findings may not pertain to genuine empathy. The technique of Why do we cut short our decision-making process? was referenced.

http://www.pnas.org/content/early/2016/04/06/1519829113.full “Striatal structure and function predict individual biases in learning to avoid pain”

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”

A review that inadvertently showed how memory paradigms prevented relevant research

This 2016 Swiss review of enduring memories demonstrated what happens when scientists’ reputations and paychecks interfered with them recognizing new research and evidence in their area but outside their paradigm: “A framework containing the basic assumptions, ways of thinking, and methodology that are commonly accepted by members of a scientific community.”

1. Most of the cited references were from decades ago that established these paradigms of enduring memories. Fine, but the research these paradigms precluded was also significant.

2. All of the newer references were continuations of established paradigms. For example, a 2014 study led by one of the reviewers found:

“Successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones.

Recalling remote memories fails to induce histone acetylation-mediated plasticity.”

The researchers elected to pursue a workaround of the memory reconsolidation paradigm when the need for a new paradigm of enduring memories confronted them directly.

3. None of the reviewers’ calls for further investigations challenged existing paradigms. For example, when the reviewers suggested research into epigenetic regulation of enduring memories, they somehow found it best to return to 1984, a time when dedicated epigenetics research had barely begun:

“Whether memories might indeed be ‘coded in particular stretches of chromosomal DNA’ as originally proposed by Crick [in 1984] and if so what the enzymatic machinery behind such changes might be remain unclear. In this regard, cell population-specific studies are highly warranted.”


As an example of relevant research the review failed to consider, the 2015 Northwestern University study I curated in A study that provided evidence for basic principles of Primal Therapy went outside existing paradigms to research state-dependent memories:

“If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again.

It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories.”

What impressed me about the study was the obvious nature of its straightforward experimental methods. Why hadn’t other researchers used the same methods decades ago? Doing so could have resulted in dozens of informative follow-on study variations by now, which is my point in item 1 above.

The 2015 French What can cause memories that are accessible only when returning to the original brain state? was another relevant but ignored study that supported state-dependent memories:

“Posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval.”


The review also showed the extent to which historical memory paradigms depended on the subjects’ emotional memories. When it comes to human studies, though, designs almost always avoid studying emotional memories.

It’s clearly past time to Advance science by including emotion in research.

http://www.hindawi.com/journals/np/2016/3425908/ “Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories”

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”