Transgenerational pathological traits induced by prenatal immune activation

The third paper of Transgenerational epigenetic inheritance week is 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 and F2 generation 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 generation.

The next round of experiments done with the paternal lineage noted these epigenetic effects:

  • The F3 generation had impaired sociability, abnormal fear expression and behavioral despair; and
  • The F3 generation had normal sensorimotor gating.

Since the first round of tests didn’t show sex-dependent effects, the F3 generation was 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 and F3 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 generation, which resisted erasure and epigenetic reestablishment during germ cell development.
  2. Abnormal F1 generation sensorimotor gating followed by normal F2 and F3 sensorimotor gating demonstrated that prenatal immune activation may also modify somatic but not germ cells.
  3. Non-significant F1 generation behavioral despair followed by F2 and F3 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 first generation.
  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, a F3 generation from the maternal lineage was needed to confirm several of the study’s findings.

For example, effects that didn’t reach statistical significance in the F1 and F2 maternal lineage may have been different in a F3 generation. 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)

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Experience-induced transgenerational programming of neuronal structure and functions

The second paper of Transgenerational epigenetic inheritance week is 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)

Transgenerational effects of early environmental insults on aging and disease

The first paper of Transgenerational epigenetic inheritance week is a 2017 Canadian/Netherlands review that’s organized as follows:

“First, we address mechanisms of developmental and transgenerational programming of disease and inheritance. Second, we discuss experimental and clinical findings linking early environmental determinants to adverse aging trajectories in association with possible parental contributions and sex-specific effects. Third, we outline the main mechanisms of age-related functional decline and suggest potential interventions to reverse negative effects of transgenerational programming.”

A transgenerational phenotype was defined as an epigenetic modification that was maintained at least either to the F2 generation in the paternal lineage or to the F3 generation in the maternal lineage.

The reviewers noted that the mechanisms of transgenerational programming are complex and multivariate.  The severity, timing, and type of exposure, lineage of transmission, germ cell exposure, and gender of an organism were the main factors that may determine the consequences. The mechanisms reviewed were:

  1. Parental exposure to an adverse environment;
  2. Altered maternal behavior and care of the offspring; and
  3. Experience-dependent modifications of the epigenome.

There was a long list of diseases and impaired functionalities that were consequences of ancestral experiences and exposures. Most of the studies were animal, but a few were human, such as those done on effects of extended power outages during the Quebec ice storm of January 1998.


One intervention that was effective in reversing a transgenerational phenotype induced by deficient rodent maternal care was to place pups with a caring foster female soon after birth. It’s probably unacceptable in human societies to preemptively recognize all poor-care human mothers and remove the infant to caring foster mothers, but researchers could probably find enough instances to develop studies of the effectiveness of the placements in reversing a transgenerational phenotype.

The review didn’t have suggestions for reversing human transgenerational phenotypes, just  “..potential interventions to reverse negative effects of transgenerational programming.” The interventions suggested for humans – exercise, enriched lifestyle, cognitive training, dietary regimens, and expressive art and writing therapies – only reduced the impact of transgenerational epigenetic effects.

The tricky wording of “..reverse negative effects of transgenerational programming” showed that research paradigms weren’t aimed at resolving causes. The review is insufficient for the same reasons mentioned in How one person’s paradigms regarding stress and epigenetics impedes relevant research, prompting my same comment:

“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?”

When reversals of human transgenerational phenotypes aren’t researched, the problems compound as they’re transmitted to the next generations.

http://www.sciencedirect.com/science/article/pii/S014976341630714X “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)

It’s transgenerational epigenetic inheritance week!

Transgenerational epigenetic inheritance is a subject whose time has come. It’s the opposite of advancing science for those in the funding chain to give lip service to the subject, and then create an atmosphere where proposals to extend experiments to subsequent generations to study possible transgenerational epigenetic effects are neither encouraged nor funded.

This week I’ll sequentially curate the four 2016-2017 papers listed below, and update this post with the links:

Transgenerational effects of early environmental insults on aging and disease

http://www.sciencedirect.com/science/article/pii/S014976341630714X “Transgenerational effects of early environmental insults on aging and disease incidence” (not freely available)


Experience-induced transgenerational programming of neuronal structure and functions

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)


Transgenerational pathological traits induced by prenatal immune activation

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)


http://www.neurobiologyofaging.org/article/S0197-4580(16)30303-7/pdf “Transgenerational transmission of an anticholinergic endophenotype with memory dysfunction”

Does living near a forest keep your amygdala healthier?

A thought-provoking post from A Paper a Day Keeps the Scientist Okay entitled “Living Near a Forest Keeps Your Amygdala Healthier” referenced a 2017 German human study which found:

“..a relationship between place of residence and brain health: those city dwellers living close to a forest were more likely to show indications of a physiologically healthy amygdala structure and were therefore presumably better able to cope with stress.”

The researchers accomplished the imperative of meeting the study’s stated objective:

“We set out to identify and characterize the geographical elements of a city that are associated with these brain structures following a suggestion by Kennedy and Adolph that studies should begin to derive recommendations for urban planning and architecture.

The results of our study may suggest that forests in and around the cities are a valuable resource that should be promoted. However future longitudinal studies are needed to investigate the causal directionality of the effect in order to disentangle whether more forest in ones habitat facilitates brain structural integrity or potentially those people with better brain structural integrity choose to live closer to forests. Moreover we need to investigate whether living close to the forest is associated with an absence of risk factors such as noise, air pollution or stress and thereby has beneficial effects or whether the forest itself constitutes a salutary factor that promotes well-being.”


A major limitation of the study’s methodology that wasn’t noted by the researchers was the intentional non-use of an available data source. Referring to Do we need to study the brain to understand the mind? posted earlier this week:

“..self-report is still the gold standard for assessing emotional experience and the contents of thought..isn’t it easier just to ask?”

The researchers put the forest before the trees, and designed a study that didn’t ask the subjects important questions such as why they lived where they lived. The researchers inferred sketchy fMRI-geography associations because they didn’t solicit relevant primary information via individual self-reports.


I imagined myself as one of the study’s subjects. I don’t live in Berlin, and I’m not part of the selected cohort, but I otherwise generally meet the study’s subject parameters.

Something in my past causes me to actively select housing that isn’t in a noisy environment. If I were asked why I lived where I lived, my answer would have included:

  • A deciding factor in why I sold my second house was the traffic noise in wintertime;
  • A deciding factor in why I bought my fourth house was its location in the center of the housing development, away from street noise; and
  • A deciding factor in why I live where I now live is the house’s orientation away from both direct and reflective traffic noise sources.

Processing my hypothetical fMRI data with my self-reported historical housing choices may or may not have found:

“..geographical features in the proximal participants’ habitat are associated with brain integrity..”

Using the better-quality information of self-reports, though, it’s unlikely that an association this study would have found to be significant – the chance fact that I live within one kilometer of a forest – would have been deemed significant.

https://www.nature.com/articles/s41598-017-12046-7 “In search of features that constitute an “enriched environment” in humans: Associations between geographical properties and brain structure”

Review of The Honest Truth About Dishonesty: How We Lie to Everyone–Especially Ourselves

Here’s an Amazon book review I wrote five years ago when I regularly read 2-3 books a week while on the train to and from work. The book served as an example of how behavioral researchers couldn’t reach their stated goals by using standard scientific methods.

Review of The Honest Truth About Dishonesty: How We Lie to Everyone–Especially Ourselves by Dan Ariely

Everybody would benefit from reading this collection of experiments with human behavior.

I think it would be fair to compare the book’s accomplishments with its declared goals. The author states the book’s primary goal early on when he writes, “..We need to first figure out what forces really cause people to cheat and then apply this improved understanding to curb dishonesty. That’s exactly what this book is about.” He continues to state, “Once we more clearly understand the forces that really drive us, we discover that we are not helpless in the face of our human follies (dishonesty included), that we can restructure our environment, and that by doing so we can achieve better behaviors and outcomes.”

I appreciate the author’s research that describes and delineates what his experiments chose to observe. For example, in one series of experiments, people lied in order to get tokens that a few seconds later were exchanged into money. These subjects cheated to an extent that was almost twice the amount of people who lied in order to directly get money.

Another series of experiments showed that when people were tired or stressed, they were more likely to cheat. The amount that mentally exhausted subjects cheated was almost three times the amount of non-stressed subjects.

There was also a series of experiments that tested the “what the hell” effect. The researchers found that the amount of cheating was not linear. A point was frequently reached where the subjects apparently decided to abandon a little bit of cheating, and started to cheat at every opportunity.

The author proposes that a “fake it until you make it” approach doesn’t ultimately lead to honest behavior. He suggests that it would probably start a chain of events that proceed through the “what the hell” context, where a little bit of cheating becomes a lot, and ends up with suffering when the truth is eventually revealed.

But what these experiments examined, in my view, was not the origins of dishonest behavior, but rather the middle and ending parts of dishonest behaviors. As such, I don’t see how the book’s primary goal can be achieved.

Without exploring the precedents to dishonest behavior, we are also left with a patchwork approach to achieving the secondary goal of changing outcomes by influencing the salient aspects of behavior.

Understanding that I’m not an expert or a researcher, let me offer an approach that could be more conducive to achieving the primary and secondary goals of the book. In my opinion, the necessary but unexplored research area would be along the lines of, “What do I feel just before I act dishonestly?”

I feel that the subjects’ probable answers to this unasked question would indicate that the person’s unfulfilled needs were in play. These needs are for the most part unconscious, and are the sources of automatic behavior that seeks to fulfill these needs. The outward manifestations of this automatic behavior will lead the subjects to symbolic fulfillment of their old needs.

The subjects in the experiments may not be able to make the connection between their behaviors of say, cheating on a pledge to quit smoking, and their driving forces. This is probably because the subjects aren’t consciously aware of the feelings they had just before they acted.

The researchers may be able to bridge this gap with information obtained from measurements done by fMRIs and other instruments. They can integrate these measurements with the subjects’ reports of their feelings.

In my view, it is important that the researchers uncover the subjects’ underlying feelings to meet the goals of the book. This is necessary because their feelings are closer to the causes of behavior.

The subjects’ behaviors are symptoms of their problems, not the problems themselves. The researchers would be better served to study the entire situation as best they can.

All of us anticipate while we read a book that there will be prescriptions and answers to the circumstances and troubles presented. But because The (Honest) Truth About Dishonesty doesn’t identify “what forces really cause people to cheat,” the primary goal, to “clearly understand the forces that really drive us” isn’t attained.

Realization of the secondary goal is undecided. The author presented several examples of how environments affect people’s dishonesty, such as conflicts of interests. He showed how people’s rationalizations allow them to permit a level of dishonesty that doesn’t harm their ideas about their own morality.

But how can effective and enduring solutions arise “so we can achieve better behaviors and outcomes” when the roots of the behaviors aren’t examined?

Do we need to study the brain to understand the mind?

A coauthor of the studies referenced in:

offered an opinion piece in A Paper a Day Keeps the Scientist Okay entitled “Do We Need To Study The Brain To Understand The Mind?”:

“The emerging consensus appears to be that implementation is important. Interestingly, the inverse question is also being asked by neurobiologists—do we need consider the mind to understand the brain?—and answered largely and increasingly in the affirmative.

Is pain different from negative emotions such as sadness and anger, or are they variants on a common theme?..pain appears to be distinct from negative emotion, but commonalities suggest ways in which they may share underlying processes such as heightened attention.

One of the biggest pitfalls is the temptation to observe brain activity and make inferences about the psychological state—for example, to infer episodic memory retrieval from hippocampal activity, fear from amygdala activity, or visual processing from activity in the ‘visual cortex.’ These inferences ignore the scope of processes which may activate each of these areas and involve a fallacy in reasoning: “if memory then hippocampus” is not the same thing as “if hippocampus then memory.”

The fact that few brain areas, including the ‘visual cortex,’ are dedicated to one process means that self-report is still the gold standard for assessing emotional experience and the contents of thought. This is a serious challenge for those who would like, for example, to assess your brand preferences or your political affiliation from a brain scan. (And isn’t it easier just to ask?)”