Epigenetic factors affecting female rat sexual behavior

This 2018 Baltimore/Montreal rodent study found:

“If sexually naïve females have their formative sexually rewarding experiences paired with the same male, they will recognize that male and display mate-guarding behavior towards him in the presence of a female competitor. Female rats that display mate-guarding behavior also show enhanced activation of oxytocin and vasopressin neurons in the supraoptic and paraventricular hypothalamic nucleus.

We examined the effect of a lysine-specific demethylase-1 inhibitor to block the action of demethylase enzymes and maintain the methylation state of corresponding genes. Female rats treated with the demethylase inhibitor failed to show any measure of mate guarding, whereas females treated with vehicle displayed mate guarding behavior. Demethylase inhibitor treatment also blocked the ability of familiar male cues to activate oxytocin and vasopressin neurons, whereas vehicle-treated females showed this enhanced activation.”

General principles and their study-specific illustrations were:

Histone modifications are a key element in gene regulation through chromatin remodeling. Histone methylation / demethylation does not have straightforward transcriptional outcomes as do other histone modifications, like acetylation, which is almost invariably associated with transcriptional activation.

What is of vital importance in regards to histone methylation / demethylation is the pattern of methylation that is established. Patterns of methylation incorporate both methylated and demethylated residues, and are what ultimately play a role in transcriptional outcomes.

In the present study, inhibiting LSD1 demethylase enzymes disrupted the ability of cells to properly establish histone methylation / demethylation patterns, thus creating a deficit in the cells’ ability to transcribe the gene products necessary for the enhanced induction of OT, AVP, and the subsequent mate-guarding behaviors we observed. This study is the first to demonstrate a definitive role of epigenetic histone modifications in a conditioned sexual response.”

https://www.sciencedirect.com/science/article/pii/S0031938418303421 “Inhibition of lysine-specific demethylase enzyme disrupts sexually conditioned mate guarding in the female rat” (not freely available)

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Wouldn’t it be nice?

Wouldn’t it be nice if we were older
Then we wouldn’t have to wait so long?
And wouldn’t it be nice to live together
In the kind of world where we belong?

You know it’s gonna make it that much better
When we can say goodnight and stay together

Wouldn’t it be nice if we could wake up
In the morning when the day is new?
And after having spent the day together
Hold each other close the whole night through?

Happy times together we’ve been spending
I wish that every kiss was neverending
Oh wouldn’t it be nice?

Maybe if we think and wish and hope and pray it might come true
Baby then there wouldn’t be a single thing we couldn’t do
We could be married (we could be married)
And then we’d be happy (and then we’d be happy)
Oh wouldn’t it be nice?

You know it seems the more we talk about it
It only makes it worse to live without it
But lets talk about it
Oh wouldn’t it be nice?

Good night my baby
Sleep tight my baby


From What was not, is not, and will never be:

We long for what was and is impossible.

The role of recall neurons in traumatic memories

This 2018 Swiss rodent study found:

“Our data show that:

  • A subset of memory recall–induced neurons in the DG [dentate gyrus] becomes reactivated after memory attenuation,
  • The degree of fear reduction positively correlates with this reactivation, and
  • The continued activity of memory recall–induced neurons is critical for remote fear memory attenuation.

Although other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated, these results suggest that fear attenuation at least partially occurs in memory recall–induced ensembles through updating or unlearning of the original memory trace of fear.

These data thereby provide the first evidence at an engram-specific level that fear attenuation may not be driven only by extinction learning, that is, by an inhibitory memory trace different from the original fear trace.

Rather, our findings indicate that during remote fear memory attenuation both mechanisms likely coexist, albeit with the importance of the continued activity of memory recall–induced neurons experimentally documented herein. Such activity may not only represent the capacity for a valence change in DG engram cells but also be a prerequisite for memory reconsolidation, namely, an opportunity for learning inside the original memory trace.

As such, this activity likely constitutes a physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans: the engagement, rather than the suppression, of the original trauma.”

The researchers also provided examples of human trauma:

“We dedicate this work to O.K.’s father, Mohamed Salah El-Dien, and J.G.’s mother, Wilma, who both sadly passed away during its completion.”


So, how can this study help humans? The study had disclosed and undisclosed limitations:

1. Humans aren’t lab rats. We can ourselves individually change our responses to experiential causes of ongoing adverse effects. Standard methodologies can only apply external treatments.

2. It’s a bridge too far to go from neural activity in transgenic mice to expressing unfounded opinions on:

“A physiological correlate sine qua non for effective exposure therapies against traumatic memories in humans.”

Human exposure therapies have many drawbacks, in addition to being applied externally to the patient on someone else’s schedule. A few others were discussed in The role of DNMT3a in fear memories:

  • “Inability to generalize its efficacy over time,
  • Potential return of adverse memory in the new/novel contexts,
  • Context-dependent nature of extinction which is widely viewed as the biological basis of exposure therapy.”

3. Rodent neural activity also doesn’t elevate recall to become an important goal of effective human therapies. Dr. Arthur Janov contrasted memory recall and reliving in his 2011 book Life Before Birth: The Hidden Script That Rules Our Lives p.33-34:

“I use memory here in an all-emcompassing physiologic and neurologic sense, not simply as a system of verbal recall. Recall is not curative, organic memory is.

Reliving means going back in time, reentering pains that were once too distressing to feel.”

Clearly, what the rodent subjects experienced translated into human reliving/re-experiencing, not recall. Terminology used in animal studies preferentially has the same meaning with humans, since the purpose of animal studies is to help humans.

4. The researchers acknowledged that:

“Other brain areas such as the prefrontal cortex and the amygdala are likely to be implicated in remote fear memories and remain to be investigated.”

A study that provided evidence for basic principles of Primal Therapy determined another brain area:

“The findings imply that 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.”

The study I curated yesterday, Organ epigenetic memory, demonstrated organ memory storage. It’s hard to completely rule out that other body areas may also store traumatic memories.

The wide range of epigenetic memory storage vehicles is one reason why effective human therapies need to address the whole person, the whole body, and each individual’s entire history.

http://science.sciencemag.org/content/360/6394/1239 “Reactivation of recall-induced neurons contributes to remote fear memory attenuation” (not freely available)

Here’s one of the researchers’ outline:

Organ epigenetic memory

This 2018 Japanese review subject was the relationships of organ memory and non-communicable diseases:

“Organ memory is the engraved phenotype of altered organ responsiveness acquired by a time-dependent accumulation of organ stress responses. This phenomenon is known as “metabolic memory” or “legacy effect,” which is similar to neuronal and immune memory.

Not only is the epigenetic change of key genes involved in the formation of organ memory but the alteration of multiple factors, including low molecular weight energy metabolites, immune mediators, and tissue structures, is involved as well. These factors intercommunicate during every stress response and carry out incessant remodeling in a certain direction in a spiral fashion through positive feedback mechanisms.

The systematic review revealed that each intervention type, that is:

  • Glucose lowering,
  • Blood pressure lowering, or
  • LDL-cholesterol lowering,

possessed unique characteristics of the memory phenomenon. Most of the observational periods of these studies lasted for > 10 years. Memory phenomenon was suggested to last for a long time and is thought to have a considerable effect on the clinical course of NCDs [non-communicable diseases].

Organs cannot possess consciousness, so it might not be appropriate to consider whether a recalling process exists in organs. However, the properties of organs are incessantly altered by external stimuli loaded on organs as if it is updating.

It is clinically important to investigate whether organ memory can be updated by our behaviors. Once organ memory is established in an organ, organ memory in each organ can influence one another and affect organ memory in a different organ.

Epigenome-modification enzymes, such as histone deacetylases and DNA methyltransferases, and transcription factors seem to be essential for the epigenetic regulation of gene expression, which is involved in the generation of organ memory. Cellular metabolism can epigenetically modulate the expression of genes that are related to the progression of diseases.”


The reviewers asserted:

“Organs cannot possess consciousness, so it might not be appropriate to consider whether a recalling process exists in organs.”

Memory studies don’t require this consciousness to investigate even the brain organ’s areas and functions. Researchers observe memory by measuring stimulus/response items like neuron activation and various levels of behavior. Consciousness is an emergent property.

Regarding recall: An organ’s “engraved phenotype of altered organ responsiveness” may not have recall itself, but it doesn’t have a separate existence apart from its body. An organ can’t be removed from its body for very long and still be part of its body.

When an organ is in its normal state as part of a body, it has access to recall-like functions via the “inter-organ communication of organ memory.” The review also mentioned:

“Organ memory in each organ can influence one another and affect organ memory in a different organ.

Evolution didn’t support unnecessary duplication for a kidney’s memory to include recall because it’s part of a body that includes a brain that has recall. Evolution didn’t duplicate functions of a kidney’s memory in a brain, either.

https://www.nature.com/articles/s41440-018-0081-x “Organ memory: a key principle for understanding the pathophysiology of hypertension and other non-communicable diseases” (not freely available)

Unindexed comment links?

It’s dawned on me that although links in blog posts are indexed by search engines, links in comments may not be. Here’s a post to elevate links in three comments that may have escaped notice.


From A review of biological variability:

“It is my view that all researchers have a narrow focus on what they want to research, without having an over-riding paradigm in which to fit the research and its results. Janovian Primal Therapy and theory, with its focus and understanding of the three different levels of consciousness would provide for a much needed over-arching paradigm, especially in the area of mental health.”

Congratulations on an excellent podcast, Gil!
59. Gilbert Bates in “Feel It Still” // Love, Primal Therapy & the Three Levels of Consciousness


From Remembering Dr. Arthur Janov:

“You are right on. The Norcross survey, in particular, is utter crap. More than half of those “experts” surveyed were CBT therapists who knew nothing about PT and yet deemed themselves confident to judge “primal scream therapy” as “discredited.” I feel the therapy will never be understood for what it is.”

Thanks for the detailed explanation, Bruce!
The Worst Comparative Psychotherapy Study Ever Published


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

“There is of course, reversibility. Michael Meaney’s baby rats had their epigenetic changes reversed with loving maternal care. There are several compounds in development which have been shown to reverse methylation. This former physician and researcher says, “Epigenetic changes affect the level of activity of our genes. Genetic activity levels affect our emotions, beliefs, and our bodies. Exploring epigenetics and chronic illness may help us understand causes that many of us suspect have played a role in the onset and evolution of our illnesses. Furthermore, these epigenetic changes have been found to be reversible, at least some of the time, even with a seemingly indirect treatment such as psychotherapy.” Epigenetics and Chronic Illness: Why Symptoms May Be Reversible

I looked up the psychotherapy references and found this: Serotonin tranporter methylation and response to cognitive behaviour therapy in children with anxiety disorders (reversible even with CBT, the weakest therapy of all!)

And this:
MAOA gene hypomethylation in panic disorder—reversibility of an epigenetic risk pattern by psychotherapy (also CBT)

So what gives? I suspect that your researcher is working with his/her head in the sand, hamstrung by their ideological biases. If CBT can effect epigenetic changes, imagine what primal therapy can do.”


And a seven-year anniversary repost of events that affect me every day:

Reflections on my four-year anniversary of spine surgery

Prenatal programming of human HPA axis development

This 2017 UC Irvine human review subject provided details of how fetal hypothalamic-pituitary-adrenal components and systems develop, and how they are epigenetically changed by the mother’s environment:

“The developmental origins of disease or fetal programming model predicts that intrauterine exposures have life-long consequences for physical and psychological health. Prenatal programming of the fetal hypothalamic-pituitary-adrenal (HPA) axis is proposed as a primary mechanism by which early experiences are linked to later disease risk.

Development of the fetal HPA axis is determined by an intricately timed cascade of endocrine events during gestation and is regulated by an integrated maternal-placental-fetal steroidogenic unit. Mechanisms by which stress-induced elevations in hormones of maternal, fetal, or placental origin influence the structure and function of the emerging fetal HPA axis are discussed.

Human gestational physiology and fetal HPA axis development differ even from that of closely related nonhuman primates, thereby limiting the generalizability of animal models. This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”


Every time I read a prenatal study I’m in awe of all that has to go right, and at the appropriate time, and in sequence, for a fetus to be undamaged. Add in what needs to happen at birth, during infancy, and throughout early childhood, and it seems impossible for a human to escape epigenetic damage.


1. The reviewers referenced human research performed with postnatal subjects, as well as animal studies, despite the disclaimer:

This review will focus solely on studies of prenatal stress and fetal HPA axis development in humans.”

This led to blurring of what had been studied or not with human fetuses regarding the subject.

2. The reviewers uncritically listed many dubious human studies that had both stated and undisclosed severe limitations on their findings. It’s more appropriate for reviewers to offer informed reviews of cited studies, as Sex-specific impacts of childhood trauma summarized with cortisol:

“Findings are dependent upon variance in extenuating factors, including but not limited to, different measurements of:

  • early adversity,
  • age of onset,
  • basal cortisol levels, as well as
  • trauma forms and subtypes, and
  • presence and severity of psychopathology symptomology.”

3. It would have been preferable had the researchers stayed with their stated intention and critically reviewed only a few dozen studies with solid evidence of the review title: “Developmental origins of the human hypothalamic-pituitary-adrenal axis.” Let other reviews cover older humans, animals, and questionable evidence.

I asked the reviewers to provide a searchable file so that their work could be better used as a reference.

https://www.researchgate.net/publication/318469661_Developmental_origins_of_the_human_hypothalamic-pituitary-adrenal_axis “Developmental origins of the human hypothalamic-pituitary-adrenal axis” (registration required)

Day after day

Gaze at the sky
And picture a memory of days in your life
You knew what it meant to be happy and free
With time on your side

Remember your daddy when no one was wiser
Your ma used to say
That you would go farther than he ever could
With time on your side

Think of a boy with the stars in his eyes
Longing to reach them
But frightened to try
Sadly,
You’d say
someday
someday

But day after day
The show must go on
And time slipped away
Before you could build any castles in Spain
The chance had gone by

With nothing to say
And no one to say it to
Nothing has changed
You still got it all to do
Surely you know
The chance has gone by

Think of a boy with the stars in his eyes
Longing to reach them
But frightened to try
Sadly,
You’d say
someday
someday

But day after day
The show must go on
And you gaze at the sky
And picture a memory of days in your life
With time on your side
With time on your side