Experiential feeling therapy addressing the pain of the lack of love.
“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?
- Only a minority of humans experienced an early-life environment that included primary caregivers other than our biological parents.
- Very few of us experienced a prenatal environment other than our biological mothers.
- 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”
This 2016 Oregon review’s concept was the inadequacy of drug-based therapies, explored with the specific subject of epilepsy:
“Currently used antiepileptic drugs:
- [aren’t] effective in over 30% of patients
- [don’t] affect the comorbidities of epilepsy
- [don’t] prevent the development and progression of epilepsy (epileptogenesis).
Prevention of epilepsy and its progression [requires] novel conceptual advances.”
The overall concept that current drug-based therapies poorly address evolutionary biological realities was illustrated by a pyramid, with the comment that:
“If the basis of the pyramid depicted in Figure 1 is overlooked, it becomes obvious that a traditional pharmacological top-down treatment approach has limitations.”
I would have liked the reviewer to further address the “therapeutic reconstruction of the epigenome” point he made in the Abstract:
“New findings based on biochemical manipulation of the DNA methylome suggest that:
- Epigenetic mechanisms play a functional role in epileptogenesis; and
- Therapeutic reconstruction of the epigenome is an effective antiepileptogenic therapy.”
As it was, the reviewer lapsed into the prevalent belief that the causes of and cures for human diseases will always be found on the molecular level – for example, the base of the above pyramid – and never in human experiences. This preconception leads to discounting human elements – notably absent in the above pyramid – that generate epigenetic changes.
A consequence of ignoring experiential causes of diseases is that the potential of experiential therapies to effect “therapeutic reconstruction of the epigenome” isn’t investigated.
http://journal.frontiersin.org/article/10.3389/fnmol.2016.00026/full “The Biochemistry and Epigenetics of Epilepsy: Focus on Adenosine and Glycine”
This 2015 French review focused on:
“The role of maternal health and nutrition in the initiation and progression of metabolic and other disorders.
The effects of various in utero exposures and maternal nutritional status may have different effects on the epigenome. However, critical windows of exposure that seem to exist during development need to be better defined.
The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course.”
The reviewer used the term “transgenerational” to refer to effects that were more appropriately termed parental or intergenerational. Per the definition in A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply there needed to be evidence in subsequent generations of:
“Altered epigenetic information between generations in the absence of continued environmental exposure.”
The review had separate sections for animal and human studies.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663595/ “Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood”
I arrived at the above review as a result of it citing the 2014 Harvard Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. I’ll quote a few items from that review’s informative “Role of DNA demethylation in neural development” section:
“Distinct parts of mammalian brains, including frontal cortex, hippocampus, and cerebellum, all exhibit age-dependent acquisition of 5hmC [an oxidized derivative of 5mC [methylation of the fifth position of cytosine]].
In fact, the genome of mature neurons in adult central nervous system contains the highest level of 5hmC of any mammalian cell-type (~40% as abundant as 5mC in Purkinje neurons in cerebellum). These observations indicate that 5mC oxidation and potentially DNA demethylation may be functionally important for neuronal differentiation and maturation processes.
A comprehensive base-resolution analyses of 5mC and 5hmC in mammalian frontal cortex in both fetal and adult stages indicate that non-CpG methylation (mCH) and CpG hydroxymethylation (hCG) drastically build up in cortical neurons after birth, coinciding with the peak of synaptogenesis and synaptic pruning in the cortex. This study demonstrated that mCH could become a dominant form of cytosine modifications in adult brains, accounting for 53% in adult human cortical neuronal genome.
In mature neurons, intragenic mCH is preferentially enriched at inactive non-neuronal lineage-specific genes, indicating a role in negative regulation of the associated transcripts. By contrast, genic hCG is positively correlated with gene expression levels.”
- How do our brains internally represent the external world?
- 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?
- 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?
- 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”
This 2015 German review was of aging and activity in the context of adult neurogenesis:
“Adult neurogenesis might be of profound functional significance because it occurs at a strategic bottleneck location in the hippocampus.
Age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis, because adult neurogenesis is neuronal development under the conditions of the adult brain.
The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes (e.g., in cell or synapse numbers), but emerge on a systems level and above when an organism ages. With respect to adult neurogenesis, only one multilevel experiment including morphology and behavior has been conducted, and, even in that study, only three time points were investigated.
In old age, adult neurogenesis occurs at only a small fraction of the level in early adulthood. The decline does not seem to be ‘regulated’ but rather the by-product of many age-related changes of other sorts.
From a behavioral level down to a synaptic level, activity increases adult neurogenesis. This regulation does not seem to occur in an all-or-nothing fashion but rather influences different stages of neuronal development differently. Both cell proliferation and survival are influenced by or even depend on activity.
The effects of exercise and environmental enrichment are additive, which indicates that increasing the potential for neurogenesis is sufficient to increase the actual use of the recruitable cells in the case of cognitive stimulation. Physical activity would not by itself provide specific hippocampus-relevant stimuli that induce net neurogenesis but be associated with a greater chance to encounter specific relevant stimuli.
Adult hippocampal neurogenesis might contribute to a structural or neural reserve that if appropriately trained early in life might provide a compensatory buffer of brain plasticity in the face of increasing neurodegeneration or nonpathological age-related functional losses. There is still only limited information on the activity-dependent parameters that help to prevent the age-dependent decrease in adult neurogenesis and maintain cellular plasticity.
The big question is what the functional contribution of so few new neurons over so long periods can be. Any comprehensive concept has to bring together the acute functional contributions of newly generated, highly plastic neurons and the more-or-less lasting changes they introduce to the network.”
I’ve quoted quite a lot, but there are more details that await your reading. A few items from the study referenced in the first paragraph above:
“The hippocampus represents a bottleneck in processing..adult hippocampal neurogenesis occurs at exactly the narrowest spot.
We have derived the theory that the function of adult hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty..a mechanism for preparing the hippocampus for processing greater levels of complexity.”
The role of the hippocampus in emotion was ignored as it so often is. It seems to me that the way to address many of the gaps mentioned by the author may be to Advance science by including emotion in research.
For example, from the author’s The mystery of humans’ evolved capability for adults to grow new brain cells:
“Adult neurogenesis is already effective early in life, actually very well before true adulthood, and is at very high levels when sexual maturity has been reached. Behavioral advantages associated with adult neurogenesis must be relevant during the reproductive period.”
When human studies are designed to research how “behavioral advantages associated with adult neurogenesis must be relevant” what purpose does it serve to exclude emotional content?
http://cshperspectives.cshlp.org/content/7/11/a018929.full “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”
This 2016 German review discussed the evolution of human adult neurogenesis:
“Mammalian adult hippocampal neurogenesis is a trait shaped by evolutionary forces that have contributed to the advantages in natural selection that are associated with the mammalian dentate gyrus. Adult hippocampal neurogenesis in mammals originates from an ectopic precursor cell population that resides in a defined stem-cell niche detached from the ventricular wall.
Neurogenesis in the adult olfactory bulb generates a diverse range of interneurons, and is involved in the processing of sensory input. In contrast, adult hippocampal neurogenesis produces only one type of excitatory principal neuron and plays a role in flexible memory formation.
A surplus of new neurons is generated first from which only a subset survives. And it is exactly these new neuronal nodes that, at least for a transient period, are the carriers of synaptic plasticity.
For a number of weeks after they were born, the new neurons have a lower threshold for long-term potentiation. This directs the action to the new cells and results in a bias toward the most plastic cells in the local circuitry.
It is a highly polygenic trait, and numerous genes have already been identified to ultimately have essentially identical effects on net neurogenesis.
Adult neurogenesis is also an individualizing trait. Even before an identical genetic background, subtle individual differences in starting conditions and differential behavioral trajectories result in an increase in phenotypic variation with time.”
The author continued the penultimate paragraph above to pose a question about adult neurogenesis that’s incompletely answered by evolutionary biology theory and evidence todate:
“How genetic variation in single genes (or many genes) would be able to exert a phenotypic change in neurogenesis that can provide a large enough advantage to be selected for.”
The development of new brain cells throughout our lives helps us continually adapt and learn. The “increase in phenotypic variation with time” helps us maintain the unique individual that each of us is.
The review emphasized to me how “individual differences” should neither be viewed as a mystery nor explained away nor treated as an etiological factor as researchers often do. Focusing on what caused the differences may provide clearer information.
http://cshperspectives.cshlp.org/content/8/2/a018986.full “Adult Neurogenesis: An Evolutionary Perspective”