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”

Does vasopressin increase mutually beneficial cooperation?

This 2016 German human study found:

“Intranasal administration of arginine vasopressin (AVP), a hormone that regulates mammalian social behaviors such as monogamy and aggression, increases humans’ tendency to engage in mutually beneficial cooperation.

AVP increases humans’ willingness to cooperate. That increase is not due to an increase in the general willingness to bear risks or to altruistically help others.”


One limitation of the study was that the subjects were all males, ages 19-32. The study’s title was “human risky cooperative behavior” while omitting subjects representing the majority of humanity.

Although the researchers claimed brain effects from vasopressin administration, they didn’t provide direct evidence for the internasally administered vasopressin in the subjects’ brains. A similar point was made about studies of vasopressin’s companion neuropeptide, oxytocin, in Testing the null hypothesis of oxytocin’s effects in humans.

A third limitation was that although the researchers correlated brain activity with social behaviors, they didn’t carry out all of the tests necessary to demonstrate the claimed “novel causal evidence for a biological factor underlying cooperation.” Per Confusion may be misinterpreted as altruism and prosocial behavior, the researchers additionally needed to:

“When attempting to measure social behaviors, it is not sufficient to merely record decisions with behavioral consequences and then infer social preferences. One also needs to manipulate these consequences to test whether this affects the behavior.”

http://www.pnas.org/content/113/8/2051.full “Vasopressin increases human risky cooperative behavior”

Epigenetic consequences of early-life trauma: What are we waiting for?

This 2015 UK human review discussed:

“The progress that has been made by studies that have investigated the relationship between depression, early trauma, the HPA axis and the NR3C1 [glucocorticoid receptor] (GR) gene.

Gene linkage studies for depression, as well as for other common complex disorders, have been perceived by some to be of only limited success; hence the focus on GWAS [genome-wide association studies]. However, even for simple traits, genetic variants identified by GWAS are rarely shown to account for more than 20% of the heritability.

Epigenetic changes are potentially reversible and therefore amenable to intervention, as has been seen in cancer, cardiovascular disease and neurological disorders.”


Five of the review’s references included FKBP5 (a gene that produces a protein that dampens glucocorticoid receptor sensitivity) in their titles, but it wasn’t mentioned in the review itself. A search on FKBP5 also showed human studies such as the 2014 Placental FKBP5 Genetic and Epigenetic Variation Is Associated with Infant Neurobehavioral Outcomes in the RICHS Cohort that found:

“Adverse maternal environments can lead to increased fetal exposure to maternal cortisol, which can cause infant neurobehavioral deficits. The placenta regulates fetal cortisol exposure and response, and placental DNA methylation can influence this function.

Placental FKBP5 methylation reduces expression in a genotype specific fashion, and genetic variation supersedes this effect. These genetic and epigenetic differences in expression may alter the placenta’s ability to modulate cortisol response and exposure, leading to altered neurobehavioral outcomes.”


The authors listed seven human studies conducted 2008-2015 “investigating interactions between methylation of NR3C1, depression and early adversity”:

“Newborn offspring exposed to maternal depression in utero had increased methylation at [a GR CpG site] as well as adverse neurobehavioural outcomes.

Unlike the majority of animal studies examining NR3C1 methylation, many types of potential stressors, sometimes at different developmental stages, have been used to represent early human adversity.

Substantial differences can be expected in the nature of stresses prenatally compared with postnatally, as well as their developmental consequences.”

Seven human studies over the past eight years was a very small number considering both the topic’s importance and the number of relevant animal studies during the period.

Is the topic too offensive for human studies? What makes people pretend that adverse prenatal and perinatal environments have no lasting consequences to the child?

“Many more studies will be needed before effects directly attributable to early life trauma can be separated from those relating to tissue type.

Although investigators have amassed a considerable amount of evidence for an association between differential methylation and HPA axis function in humans, a causal relationship still needs to be fully established.”

Factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.

Are the multitude of agendas that have resources thrown at them more important than ensuring the well-being of a human before and after they are born?

https://www.researchgate.net/publication/282048312_Early_life_trauma_depression_and_the_glucocorticoid_receptor_gene_-_an_epigenetic_perspective “Early life trauma, depression and the glucocorticoid receptor gene–an epigenetic perspective”

A missed opportunity to research the oxytocin receptor gene and autism

This 2013 study:

“Examined whether genetic variants of the OXTR [oxytocin receptor] affect face recognition memory in families with an autistic child.

We investigated whether common polymorphisms in the genes encoding the oxytocin and vasopressin 1a receptors influence social memory for faces.”

I feel that the researchers missed an opportunity to improve their assessment of the autism-related genetic contribution to the study’s findings by separating the degree of environmental influence on the oxytocin receptor gene expression, as did the How epigenetic DNA methylation of the oxytocin receptor gene affects the perception of anger and fear study.

An assessment of epigenetic DNA methylation of the oxytocin receptor gene may have been even more compelling because the researchers genetically sampled one non-autistic sibling in each of the autistic children’s families. I hope the study’s samples are still available, because they may offer the possibility of evaluating the contribution of the autistic children’s historical environment with potential confirmation from their siblings.

Both studies gave their subjects similar facial emotion recognition tests, with the current one deriving from findings about autism, and the second from findings about the amygdala. The studies also had common references, such as a 2010 study, A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function.

http://www.pnas.org/content/111/5/1987.full “Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills”

Oxytocin blocks alcohol intoxication symptoms

This joint 2015 Australian/German rodent study found that oxytocin bound to the brain receptors that cause loss of motor control with alcohol intoxication, and prevented rats from displaying these symptoms:

“While oxytocin might reduce your level of intoxication, it won’t actually change your blood alcohol level,” Dr Bowen said. “This is because the oxytocin is preventing the alcohol from accessing the sites in the brain that make you intoxicated, it is not causing the alcohol to leave your system any faster.”

Vasopressin didn’t have the same effect.

The level of alcohol used to produce this finding was roughly equivalent to a human drinking a bottle of wine over a few hours. Oxytocin didn’t prevent loss of motor control when the equivalent of a bottle of vodka was administered because the excess ethanol found its way into other brain receptors and put the rats to sleep.

The study showed oxytocin acting in its original functionalities such as water regulation rather than with its evolved social functions as described in How oxytocin and vasopressin were repurposed through evolution to serve social functions.

http://www.pnas.org/content/112/10/3104.full “Oxytocin prevents ethanol actions at δ subunit-containing GABA-A receptors and attenuates ethanol-induced motor impairment in rats”

Hypothalamic oxytocin and vasopressin have sex-specific effects on pair bonding, gregariousness, and aggression

This 2014 bird study showed the complementary effects of neurochemicals vasopressin and oxytocin in the hypothalamus.

Oxytocin neurons in the hypothalamus promote pair bonding and gregariousness in females.

Vasopressin neurons in the hypothalamus promote maternal care, social recognition, and gregariousness in both males and females, and aggression in males toward females.

Vasopressin and oxytocin released generally and in other parts of the brain have different effects. For example:

“Central administration of oxytocin also attenuates stress-induced effects on the brain and reverses stress-induced social avoidance.”

http://www.pnas.org/content/111/16/6069.full “Hypothalamic oxytocin and vasopressin neurons exert sex-specific effects on pair bonding, gregariousness, and aggression in finches”