The lifelong impact of maternal postpartum behavior

This 2018 French/Italian/Swiss rodent study was an extension of the work done by the group of researchers who performed Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies and Treating prenatal stress-related disorders with an oxytocin receptor agonist:

“Reduction of maternal behavior [nursing behavior, grooming, licking, carrying pups] was predictive of behavioral disturbances in PRS [prenatally restraint stressed] rats as well as of the impairment of the oxytocin and its receptor gene expression.

Postpartum carbetocin [an oxytocin receptor agonist unavailable in the US] corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior.

Moreover, postpartum carbetocin had an anti-stress effect on HPA [hypothalamic-pituitary-adrenal] axis activity in the adult PRS progeny and increased hippocampal mGlu5 [type 5 metabotropic glutamate] receptor expression in aging.

Early postpartum carbetocin administration to the dam enhances maternal behavior and prevents all the pathological outcomes of PRS throughout the entire lifespan of the progeny..proves that the defect in maternal care induced by gestational stress programs the development of the offspring.


This chart from Figure 4 summarized the behavioral performance of aged adult male progeny in relation to the experimental variables of:

  1. Stress administered to the mothers three times daily every day during the second half of pregnancy up until delivery; and
  2. The effects on the mothers’ behavior of daily carbetocin administration during postpartum days 1 through 7.

The symbols denote which of these relationships had statistically significant effects:

  • “* p [Pearson’s correlation coefficient] < 0.05 PRS-Saline vs. CONT-Saline;
  • # p < 0.05 PRS-Carbetocin vs. the PRS-Saline group.”

There are many interesting aspects to this study. Ask the corresponding coauthor Dr. Sara Morley-Fletcher at sara.morley-fletcher@univ-lille1.fr for a copy.

One place the paper referenced the researchers’ previous studies was in this context:

“Postpartum carbetocin administration reversed the same molecular and behavioral parameters in the hippocampus, as does adult chronic carbetocin treatment, i.e. it led to a correction of the HPA axis negative feedback mechanisms, stress and anti-stress gene expression, and synaptic glutamate release. The fact that postpartum carbetocin administration [to the stressed mothers in this study] had the same effect [on the PRS infants in this study] as adult carbetocin treatment [to the PRS offspring in the previous study] indicates a short-term effect of carbetocin when administered in adulthood and a reprogramming (long-term) effect lasting until an advanced age when administered in early development.”

This group’s research seems to be constrained to treatments of F0 and F1 generations. What intergenerational and transgenerational effects would they possibly find by extending research efforts to F2 and F3 generations?


As the study may apply to humans:

The study demonstrated that stresses during the second half of pregnancy had lifelong impacts on both the mothers’ and offsprings’ biology and behavior. Studies and reviews that attribute similar human biological and behavioral conditions to unknown causes, or shuffle them into the black box of individual differences, should be recognized as either disingenuous or insufficient etiological investigations.

The study showed that prevention of gestational stress was a viable strategy. The control group progeny’s biology and behavior wasn’t affected by carbetocin administration to their mothers because neither they nor their mothers had experience-dependent epigenetic deficiencies.

The study demonstrated a biological and behavioral cure for the PRS offspring by changing their stressed mothers’ behaviors during a critical period of their development. The above excerpt characterized improving the mothers’ behaviors as a long-term cure for the PRS descendants, as opposed to the short-term cure of administering carbetocin to the PRS children when they were adults.

What long-term therapies may be effective for humans who had their developmental trajectories altered by their mothers’ stresses during their gestation, or who didn’t get the parental care they needed when they needed it?

https://www.sciencedirect.com/science/article/pii/S0161813X18301062 “Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance” (not freely available)

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Prenatal stress produces offspring who as adults have cognitive, emotional, and memory deficiencies

This 2018 French/Italian/Swiss rodent study used the prenatally restraint stressed (PRS) model to create problems that could be resolved by various chemicals:

“S 47445 is a positive modulator of glutamate AMPA-type receptors, possessing neurotrophic and enhancing synaptic plasticity effects as well as pro-cognitive and anti-stress properties.

Most of studies examining the antidepressant effects of new molecules are carried out using behavioral tests performed in unstressed animals.

Corticosterone-treated mice and rats exposed to chronic stress are models that do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period. The PRS rat model is characterized by a prolonged corticosterone response to stress and by abnormal behavior.

All the behavioral alterations induced by PRS..were corrected by chronic S 47445 administration at both doses.”


The paper included a section comparing S 47445 to ketamine:

“Ketamine, however, causes severe cognitive impairment and psychotomimetic [mimics the symptoms of psychosis, reference not freely available] effects that are direct consequences of the prolonged inhibition of NMDA receptors in cortical and hippocampal interneurons, and seriously limit the chronic administration of the drug in the clinical setting. [reference not freely available]

S 47445 by inducing a direct activation of AMPARs displayed an antidepressant activity without the adverse effect of ketamine. Indeed, contrary to ketamine, S 47445 presented no psychotomimetic effects and induced no occurrence of spontaneous epileptic seizures. [reference freely available] Moreover, S 47445 also presented pro-cognitive properties.”

Compare the above with this April 2018 Chicago Tribune story that had opinions with no linked references:

“..ketamine, an anesthetic used to sedate both people and animals before surgery. It’s also a notorious street drug, abused by clubgoers seeking a trancelike, hallucinatory high. But in recent years, numerous studies have found that ketamine can be an effective and speedy treatment for people with depression.”

Which coverage better informed us?


Treating prenatal stress-related disorders with an oxytocin receptor agonist was performed by several of this paper’s coauthors. One of this paper’s references to it was:

“We have already reported that depolarization-evoked glutamate release in the ventral hippocampus is negatively correlated with risk-taking behavior of PRS rats, and that such correlation can be corrected by chronic treatment with monoaminergic/melatoninergic antidepressants or oxytocin receptor agonist. Thus, an impairment of glutamatergic transmission in the ventral hippocampus lies at the core of the pathological phenotype of PRS rats.”

Looking at the above graphic of the experimental design, I’m not sure why the term perinatal (occurring during or pertaining to the phase surrounding the time of birth) was used in the paper’s title and content to describe the stress period. The pregnant females were stressed three times daily every day during the second half of pregnancy up until delivery, so the prenatal (previous to birth) term was more applicable.


So, how does this study help humans?

One takeaway is to avoid stressing pregnant mothers-to-be if her children will be expected to become adults without cognitive, emotional, and behavioral problems.

The study demonstrated one way prenatal events cause lifelong effects. The PRS model provides another example of why it’s useless to ask adult humans to self-report the causes of epigenetic problems in their lives when these originated before birth, during infancy, or in early childhood well before humans develop the cognitive capability to recognize such situations. It’s incomprehensible that this unreliable paradigm is still given significant weight in stress experimental designs, especially when they:

“..do not recapitulate the early programming of stress-related disorders, which likely originates in the perinatal period.”

Also, the relevant difference between humans and PRS rats is that we can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments such as those mentioned above.

https://www.sciencedirect.com/science/article/pii/S0028390818301291 “The reduction in glutamate release is predictive of cognitive and emotional alterations that are corrected by the positive modulator of AMPA receptors S 47445 in perinatal stressed rats” (not freely available) Thanks to coauthors Stefania Maccari and Dr. Jerome Mairesse for providing a copy.

This dietary supplement is better for depression symptoms than placebo

This 2018 Italy/UK meta-analysis subject was the use of dietary supplement acetyl-L-carnitine to treat depression symptoms:

“Deficiency of acetyl-L-carnitine (ALC) appears to play a role in the risk of developing depression, indicating dysregulation of fatty acids transport across the inner membrane of mitochondria. However, the data regarding ALC supplementation in humans are limited. We thus conducted a systematic review and meta-analysis investigating the effect of ALC on depressive symptoms across randomized controlled trials (RCTs).

Pooled data across nine RCTs (231 treated with ALC versus 216 treated with placebo and 20 no intervention) showed that ALC significantly reduced depressive symptoms.


In three RCTs comparing ALC versus antidepressants (162 for each group), ALC demonstrated similar effectiveness compared with established antidepressants [fluoxetine (Prozac), duloxetine (Cymbalta), amisulpride (Solian) respectively below] in reducing depressive symptoms. In these latter RCTs, the incidence of adverse effects was significantly lower in the ALC group [79%] than in the antidepressant group.


Subgroup analyses suggested that ALC was most efficacious in older adults..Future large scale trials are required to confirm/refute these findings.”

From the Study selection subsection:

“Studies were excluded if:

  1. did not include humans;
  2. did not include a control group;
  3. did not use validated scales for assessing depression;
  4. did not report data at follow-up evaluation regarding tests assessing depression;
  5. included the use of ALC with another agent vs. placebo/no intervention.”

The Discussion section was informative regarding possible mechanisms of ALC affecting depression, pain, and linked symptoms. Several citations were of a review rather than of the original studies, however.


Research needs to proceed on to investigate therapies that address ultimate causes for depression and pain. Researchers and sponsors shouldn’t stop at just symptoms and symptom relief, notwithstanding the requirement from a statistical point of view for “future large scale trials.”

Here are other acetyl-L-carnitine topics I’ve curated:

https://journals.lww.com/psychosomaticmedicine/Citation/2018/02000/Acetyl_L_Carnitine_Supplementation_and_the.4.aspx “Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis” (not freely available)


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Non-CpG DNA methylation

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), 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 points 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. Maturing mouse hippocampal neurons in vitro also showed a gradual increase in CpH, but not CpG, methylation over time.”

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”

How to cure the ultimate causes of migraines?

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:

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

and abnormalities:

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

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 it will be necessary for scientists to do more than their funding sponsors expect?

BTW, comments are turned off for the above-mentioned post. Readers can comment on this post instead.

Differing approaches to a life wasted on beliefs

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 precious life’s time so far.

Such was my take on the embedded beliefs 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, although, when scrutinized, most human studies have demonstrated null effects of psychotherapeutic interventions on causes. Without sound evidence that treatments affect causes, this belief seemed driven by something else.

The author saw the 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 paper’s 300+ citations 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 the subject 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 the presenting problems’ motivating causes. Success in reaching this goal is realized when patients become better able to live their own lives.


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Transgenerational pathological traits induced by prenatal immune activation

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”