Stress

The effects of imposing helplessness

gettingwell4 2-3 stars Required further work, Amygdala, Brainstem, Cerebrum, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Memory, Stress , , , , , , ,

This 2016 New York rodent study found:

“By using unbiased and whole-brain imaging techniques, we uncover a number of cortical and subcortical brain structures that have lower activity in the animals showing helplessness than in those showing resilience following the LH [learned helplessness] procedure. We also identified the LC [locus coeruleus] as the sole subcortical area that had enhanced activity in helpless animals compared with resilient ones.

Some of the brain areas identified in this study – such as areas in the mPFC [medial prefrontal cortex], hippocampus, and amygdala – have been previously implicated in clinical depression or depression-like behavior in animal models. We also identified novel brain regions previously not associated with helplessness. For example, the OT [olfactory tubercle], an area involved in odor processing as well as high cognitive functions including reward processing, and the Edinger–Westphal nucleus containing centrally projecting neurons implicated in stress adaptation.

The brains of helpless animals are locked in a highly stereotypic pathological state.”

Concerning the study’s young adult male subjects:

“To achieve a subsequent detection of neuronal activity related to distinct behavioral responses, we used the c-fosGFP transgenic mice expressing c-FosGFP under the control of a c-fos promoter. The expression of the c-fosGFP transgene has been previously validated to faithfully represent endogenous c-fos expression.

Similar to wild-type mice, approximately 22% (32 of 144) of the c-fosGFP mice showed helplessness.”

The final sentence of the Introduction section:

“Our study..supports the view that defining neuronal circuits underlying stress-induced depression-like behavior in animal models can help identify new targets for the treatment of depression.”

Helplessness is both a learned behavior and a cumulative set of experiences during every human’s early life. Therapeutic approaches to detrimental effects of helplessness can be different with humans than with rodents in that we can address causes.

The researchers categorized activity in brain circuits as causal in the Discussion section:

“Future studies aimed at manipulating these identified neural changes are required for determining whether they are causally related to the expression of helplessness or resilience.”

Studying whether or not activity in brain circuits induces helplessness in rodents may not inform us about causes of helplessness in humans. Our experiences are often the ultimate causes of helplessness effects. Many of our experiential “neural changes” are only effects, as demonstrated by this and other studies’ induced phenotypes such as “Learned Helplessness” and “Prenatally Restraint Stressed.”

Weren’t the researchers satisfied that the study confirmed what was known and made new findings? Why attempt to extend animal models that only treat effects to humans, as implied in the Introduction above and in the final sentence of the Discussion section:

“Future studies aimed at elucidating the specific roles of these regions in the pathophysiology of depression as well as serve as neural circuit-based targets for the development of novel therapeutics.”

http://journal.frontiersin.org/article/10.3389/fncir.2016.00003/full “Whole-Brain Mapping of Neuronal Activity in the Learned Helplessness Model of Depression” (Thanks to A Paper a Day Keeps the Scientist Okay)

Does shame keep you up at night?

gettingwell4 2-3 stars Required further work, Stress

This 2016 Netherlands human study found:

“Restless REM [rapid eye movement] sleep reflects a process that interferes with the overnight resolution of distress. Its accumulation may promote the development of chronic hyperarousal.

We use the term “restless REM sleep” here to refer to REM sleep with a high number of phasic events, including arousals and eye movements.

The present study focused on shame, because it may interfere the most with healthy psychological functioning and was shown to be predictive of developing depression and PTSD symptoms, including hyperarousal. By obstructing effective coping mechanisms, shame often hinders therapeutic progress, to the point that it may even lead to a negative therapeutic outcome.

A dedicated assessment of the subjective duration of distress after a shameful experience was complemented by assessments on nocturnal mentation, insomnia severity, hyperarousal, and major life events, as well as an Internet-implemented structured interview on health.”

From the Limitations section:

  1. “Restless REM sleep was not directly quantified but approximated by means of a validated questionnaire rating of thought-like nocturnal mentation.
  2. Non-REM sleep has also been implicated in the resolution of emotional distress.
  3. A third limitation regards the observational nature of the present study..a more definite conclusion will require studies using experimental manipulation of emotions and sleep.
  4. Whereas there was good reason to focus first on distress induced by shame in our innovative approach to the role of sleep in self-conscious emotions rather than the basic emotions usually studied, our findings should not be interpreted as supporting a unique role for shame or self-conscious emotions. Future studies could address whether the duration of distress elicited by other self-conscious and basic emotions has a similar two-factor structure.”

I applaud the inclusion of emotion in research. I’m not convinced that studying shame will lead to etiologic advances in science, though.

How does shame arise in our lives? Is it a biologic human need on the same level as nourishment, protection, and socialization?

Shame is a symptom along with “nocturnal mentation, insomnia severity, hyperarousal.” If a person’s thoughts, feelings, behavior, and sleep are adversely affected by shame, a resolution should be achieved by addressing the underlying causes, not by tamping down the symptoms.

http://www.pnas.org/content/113/9/2538.full “Slow dissolving of emotional distress contributes to hyperarousal”

Epigenetic memories of stress as therapeutic targets

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Memory, Stress

This 2015 Swedish rodent study found:

“Histone modifications induced by glucose are associated with activation of TXNIP gene [a proinflammatory gene involved in diabetic kidney disease] transcription.

Glucose-stimulated TXNIP gene expression can be

  • reversed by inhibition of histone acetyltransferase (HAT), or
  • enhanced by inhibition of histone deacetylase (HDAC).”

A 2016 Japanese commentary expounded on the study:

“Epigenetic changes accumulate as cell memory, and this epigenetic memory plays a crucial role in the long-term consequences of adult-onset diseases and aging.

The first stimulus, which might be high glucose levels or hypoxia, changes the condition of histone modification or chromosomal conformations. The changes are then memorized as epigenetic memory in the cells, which could help to maintain epigenetic status in response to the first stimulus.

Consequently, when a second stimulus occurs, cells with epigenetic memory respond to the stimulus promptly by the upregulation of downstream genes through binding transcriptional factors. The cells without epigenetic memory take longer to upregulate the expression of downstream target genes.

High glucose levels that are sustained for long periods appear to change histone modification, resulting in the prompt response of TXNIP gene upregulation. Considering that TXNIP is an important proinflammatory gene, this prompt response increases the likelihood of diabetic complications. TXNIP is reported to be augmented by high glucose levels and to promote oxidative stress.”

The study and commentary provided specific examples of the wide-ranging forms of physiological memory induced by stress.

http://www.sciencedirect.com/science/article/pii/S0085253815000927 “Epigenetic regulation of the thioredoxin-interacting protein (TXNIP) gene by hyperglycemia in kidney”

Lifelong effects of stress

gettingwell4 5+ stars Premium, Beliefs, Brain development, Cerebrum, Cortisol, Epigenetics, Immune system, Limbic system, Lower brain, Memory, Neurochemicals, Stress , , , ,

A 2016 commentary A trilogy of glucocorticoid receptor actions that included two 2015 French rodent studies started out:

“Glucocorticoids (GCs) belong to a class of endogenous, stress-stimulated steroid hormones. They have wide ranging physiologic effects capable of impacting metabolism, immunity, development, stress, cognition, and arousal.

GCs exert their cellular effects by binding to the GC receptor (GR), one of a 48-member (in humans) nuclear receptor superfamily of ligand-activated transcription factors.”

The French studies were exceedingly technical. The first GR SUMOylation and formation of an SUMO-SMRT/NCoR1-HDAC3 repressing complex is mandatory for GC-induced IR nGRE-mediated transrepression:

“GCs acting through binding to the GR are peripheral effectors of circadian and stress-related homeostatic functions fundamental for survival.

Unveils, at the molecular level, the mechanisms that underlie the GC-induced GR direct transrepression function mediated by the evolutionary conserved inverted repeated negative response element. This knowledge paves the way to the elucidation of the functions of the GR at the submolecular levels and to the future educated design and screening of drugs, which could be devoid of undesirable debilitating effects on prolonged GC therapy.”

The companion study Glucocorticoid-induced tethered transrepression requires SUMOylation of GR and formation of a SUMO-SMRT/NCoR1-HDAC3 repressing complex stated:

“GCs have been widely used to combat inflammatory and allergic disorders. However, multiple severe undesirable side effects associated with long-term GC treatments, as well as induction of glucocorticoid resistance associated with such treatments, limit their therapeutic usefulness.”

Even when researchers study causes, they often justify their efforts in terms of outcomes that address effects. Is an etiologic advancement in science somehow unsatisfactory in and of itself?

Once in a while I get a series of personal revelations while reading scientific publications. Paradoxically, understanding aspects of myself has seldom been sufficient to address historical problems.

Thoughts are only where some of the effects of problems show up, and clarifying my understanding can – at most – tamp down these effects. The causes are elsewhere, and addressing them at the source is what ultimately needs to happen.

A few glucocorticoid-related items to ponder:

  • How has stress impacted my life? When and where did it start?
  • Why do I feel wonderful after taking prednisone or other anti-inflammatories? What may be the originating causes of such effects?
  • Why have prolonged periods of my life been characterized by muted responses to stress? How did I get that way?
  • Have I really understood why I’ve reflexively put myself into stressful situations? What will break me out of that habit?
  • Why do the feelings I experience while under stressful situations feel familiar? Does my unconsciousness of their origins have something to do with “homeostatic functions fundamental for survival?”
  • Why haven’t I noticed that symptoms of stress keep showing up in my life? There are “physiologic effects capable of impacting metabolism, immunity,” etc. but I don’t do something about it?
  • How else may stress impact my biology? Brain functioning? Ideas and beliefs? Behavior?

Treating prenatal stress-related disorders with an oxytocin receptor agonist

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Oxytocin, Stress , , ,

This 2015 French/Italian rodent study found:

“Chronic systemic treatment with carbetocin [unavailable in the US] in PRS [prenatally restraint stressed] rats corrected:

  • the 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.

These findings disclose a novel function of oxytocin receptors in the hippocampus, and encourage the use of oxytocin receptor agonists in the treatment of stress-related psychiatric disorders in adult life.”

carbetocin

The adult male subjects were:

“PRS rats..the offspring of dams exposed to repeated episodes of restraint stress during pregnancy.

These rats display anxiety- and depressive-like behaviors and show an excessive glucocorticoid response to acute stress, which is indicative of a dysregulation of the hypothalamus-pituitary-adrenal (HPA) axis caused by an impaired hippocampal glucocorticoid negative feedback.

PRS rats show a selective reduction in glutamate release in the ventral hippocampus.”

The researchers cited several other studies they have performed with the PRS phenotype. In the current study:

“Carbetocin treatment had no effect on these behavioral and neuroendocrine parameters in prenatally unstressed (control) rats, with the exception of a reduced expression of the oxytocin receptor gene in the amygdala.

Carbetocin displayed a robust therapeutic activity in PRS rats, but had no effect in unstressed rats, therefore discriminating between physiological and pathological conditions.”

The PRS phenotype showed the ease with which a child can be epigenetically changed – even before they’re born – to be less capable over their entire life. Just stress the pregnant mother-to-be.

https://www.sciencedirect.com/science/article/abs/pii/S0306453015002395 “Activation of presynaptic oxytocin receptors enhances glutamate release in the ventral hippocampus of prenatally restraint stressed rats” (not freely available) Thanks to coauthor Dr. Eleonora Gatta for providing the full study.

Are hormone ratios useful in explaining health? Behavior? Neurobiology? Anything?

gettingwell4 2-3 stars Required further work, Cortisol, Neurochemicals, Stress, Testosterone

This 2015 Zurich human review addressed:

“A remarkable lack of discussion on the meaning and interpretation of frequently used hormone ratios.

The interpretation of hormone ratios is complicated and in many cases not sufficiently supported from a theoretical point of view.

Based on the assumption that the balance between two interdependent hormones determines their eventual effects on brain and other tissues, this index has been commonly interpreted as an indicator of the balance between two endocrine systems.

The ratio is typically calculated by simply dividing the raw value of one hormone by the raw value of a second hormone. However, endocrine parameters may fluctuate considerably within individuals across short periods of time on the basis of circadian rhythms or contextual factors. Nevertheless, the ratio method has so far only rarely been applied in the context of repeated endocrine assessments.”

The researchers made a non-exhaustive list of three dozen studies that used hormone ratios among cortisol, dehydroepiandrosterone sulfate (DHEA-S), estradiol, progesterone, testosterone, triiodothyronine (T3), thyroxine (T4), etc., to explain various outcome measures such as:

  • “Health status
  • Aggressive behavior
  • Psychopathy
  • Marital violence
  • fMRI response to angry and happy faces
  • Early life adversity
  • Depression
  • Chronic stress
  • Alexithymia”

Their 2015 study on “endocrine correlates of pro-environmental behavior” was used as an illustrative example. It had 229 male subjects between ages 19 and 77. Salivary cortisol (C) and testosterone (T) was sampled with these results:

“T/C and C/T ratios produce different means, standard deviations and distributional properties which significantly deviate from normality.

Height is not significantly associated with either T/C or C/T. In fact, looking at the original variables, C correlates positively with height while T shows no association.

When we include age as a covariate (assuming that it is associated with both height and hormone status) the partial correlation between T/C and height then is significant while the association between C/T and height is non-significant, even though both ratios are based on the exact same data.

Looking at the negative association between age and T/C the observed age-related ratio decline is mainly due to the fact that the T value in the numerator decreases with age while the C value in the denominator remains relatively constant. In this case, the analysis of the individual variables therefore offers more information and a more accurate picture of the underlying relationships.

A few previous studies have standardized the two underlying hormone distributions before calculating the ratio in order to account for the fact that two hormones often exhibit very different means and standard deviations. Standardization leads to values that express each subject’s hormone concentration relative to the sample mean.

A ratio calculated on the basis of such standardized hormones takes on a different meaning. In particular, the ratio no longer merely represents the proportion of the two hormones within the individual but also incorporates how high the two hormone concentrations are with respect to the sample distributions.”

Practices to improve the use and interpretation of hormone measurements included:

“Regression techniques employed on the original variables constitute a better suited alternative devoid of the problems associated with the ratio method. Moderation analysis, in particular, is a useful approach, which often provides more detailed insight into the relationships of interest.

Ratios should either be analyzed with non-parametric techniques, or be log-transformed before parametric statistical methods are applied.”

Set points and variations in an individual’s hormone balances are usually effects of underlying causes. Researchers will hopefully pay more attention to effectively dealing with ultimate causes as the preferred methods of managing an individual’s health, behavioral, and neurobiological effects.

https://www.sciencedirect.com/science/article/abs/pii/S0306453015009531 “How to use and interpret hormone ratios” (not freely available)

Stress consequences on gut bacteria, behavior, immune system, and neurologic function

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Hypothalamus, Immune system, Limbic system, Neurochemicals, Serotonin, Stress , ,

This 2015 Canadian rodent study found:

“Chronic social defeat induced behavioral changes that were associated with reduced richness and diversity of the gut microbial community.

The degree of deficits in social, but not exploratory behavior, was correlated with group differences between the microbial community profile.

Defeated mice also exhibited reduced abundance of pathways involved in biosynthesis and metabolism of tyrosine and tryptophan: molecules that serve as precursors for synthesis of dopamine, norepinephrine, serotonin, and melatonin, respectively.

This study indicates that stress-induced disruptions in neurologic function are associated with altered immunoregulatory responses.”

These researchers had an extensive Discussion section where they placed study findings in contexts with other rodent and human studies. For example:

“Our analyses also predicted reduced frequency of fatty acid biosynthesis and metabolism pathways, including that of propanoate and butanoate – byproducts of dietary carbohydrate fermentation by intestinal microorganisms.

Butyrate is a potent histone deacetylase (HDAC) inhibitor that exerts antidepressant-like effects by increasing histone acetylation in the frontal cortex and hippocampus, and consequentially, raising BDNF transcript levels.

Although it was previously unclear whether systemic levels of these metabolites achieved in vivo were sufficient to produce behavioral changes, progress has been made by discovering their presence in cerebrospinal fluid and the brain, and demonstrating that colon-derived SCFAs [short chain fatty acids] cross the blood–brain barrier and preferentially accumulate in the hypothalamus, where they can affect CNS activity.”

http://www.psyneuen-journal.com/article/S0306-4530%2815%2900934-8/fulltext “Structural & functional consequences of chronic psychosocial stress on the microbiome & host”

Epigenetic effects of cow’s milk

gettingwell4 2-3 stars Required further work, Brain development, Cerebrum, Epigenetics, Glutamate, Hypothalamus, Limbic system, Neurochemicals, Stress, Telomeres , , , , ,

This 2015 German paper with 342 references described:

“Increasing evidence that milk is not “just food” but represents a sophisticated signaling system of mammals.

This paper highlights the potential role of milk as an epigenetic modifier of the human genome paying special attention to cow milk-mediated overactivation of FTO [a gene associated with fat mass and obesity] and its impact on the transcriptome of the human milk consumer.”

The author declared “no competing interests” and “There are no sources of funding.” He presumably wasn’t pressured into writing this paper.

The paper wasn’t agenda-free, however. The main thesis was:

“Persistent milk-mediated epigenetic FTO signaling may explain the epidemic of age-related diseases of civilization.”

There were separate sections on how milk may promote:

  • Breast cancer
  • Prostate cancer
  • Obesity
  • Metabolic syndrome
  • Coronary heart disease
  • Early menarche
  • Type 2 diabetes
  • Neurodegenerative diseases

I don’t eat or drink dairy products because I’m lactose-intolerant. I coincidentally don’t have any of the diseases mentioned in the paper.

My life experiences haven’t led me to share the author’s sense of alarm, or to attribute other people’s problems to their consumption of milk products. However, more than a few problems I’ve had are things I’ve done to myself through actions or inaction that may have turned out differently if I had better information.

So I curated this article in case we’re insufficiently informed about the harmful epigenetic effects of milk. What do you think?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4687119/ “Milk: an epigenetic amplifier of FTO-mediated transcription? Implications for Western diseases”

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

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress, Vasopressin , , , , ,

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”

Assessing epigenetic origins of allergies and asthma

gettingwell4 2-3 stars Required further work, Epigenetics, Immune system, Memory, Primal Therapy, Stress , , , ,

This 2015 German paper described the study design of a birth cohort that’s being established to:

“Assess potential associations between early-life exposures and onset of childhood asthma and allergies taking into account epigenetics.

The study builds upon an existing cohort which has been recruited [1995] and in the meantime has been followed up twice [2002 and 2007].

This approach provides the unique opportunity to assess the effects of genetic predisposition, epigenetic factors, and environmental factors such as exposure to environmental tobacco smoke, living conditions, and parental occupation in a prospective and cross-generational study.”

The paper had informative references, one of which was the 2013 Epigenetic mechanisms and models in the origins of asthma:

“We need to determine whether epigenetics should be considered as a major integrator of multiple signals, or, alternatively, whether DNA methylation acts differently at various developmental stages conditional on genetic variants and exposures.

In addition, since there is a lack of critical knowledge on which genes are programmed or re-programmed at what time during gestation and in which developmental phase, birth cohort studies need to trace DNA methylation over time, and ideally over generations.

This will provide critical information about which phases in the course of life are most suitable to prevent deviant DNA methylation (preventive epigenomics) or intervene to normalize DNA methylation to prevent disease (pharmaco-epigenomics).”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670515/ “Establishing a birth cohort to investigate the course and aetiology of asthma and allergies across three generations – rationale, design, and methods of the ACROSSOLAR study”

I was encouraged by the referenced review’s emphasis that researchers start their investigations at the beginning of human life for causes that produce later-life effects. Subsequent emphasis on prevention was commendable.

The review also revealed a prevalent researcher bias, that causal and curative results of human disease will be found on the molecular level rather than in human experiences. This preconception leads to ignoring human elements that generate epigenetic changes that manifest themselves in symptoms such as asthma and allergies.

I don’t know how including human emotions in studies became viewed as unscientific, but here we are. I didn’t see any indication that its study design included investigating emotional states other than possibly work-related stress.

These researchers will have to pretend that proven etiologic factors such as emotional states of a pregnant woman have no affect on nervous and immune system development of her fetus. These human elements are unjustified exclusions from a study designed in 2015, but they’re easily ignored when they aren’t measured.

Here’s a search of what Dr. Arthur Janov had to say about allergies over the past eight years. A representative sample from earlier this month was:

“Every therapy we try will be temporary, something we need to do over and over again. It can be nothing else because the imprint has the force of survival, of a lifesaving memory and must endure until the life-endangering imprint is finally fully felt and resolved.

Clearly this applies to many problems, from high blood pressure to asthma and allergies. That is why it is urgent that we re-focus on the real problem.”

Fat made rats fat with dysfunctional brains

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Cerebrum, Cortisol, Epigenetics, Hippocampus, Limbic system, Neurochemicals, Stress, Testosterone , , ,

This 2015 New York rodent study found:

“Early stage [diet-induced] obesity, before the onset of diabetes or metabolic syndrome, produced deficits on cognitive tasks that require the prefrontal cortex.

These results strongly suggest that obesity must be considered as a contributing factor to brain dysfunction.”

The difference in the diets of the adult male subjects was that the control group ate 10% fat (20% protein, 70% carbohydrates) whereas the obese group ate 45% fat (20% protein, 35% carbohydrates). Significant changes in body weight were present after the first two weeks on the diets, but testing didn’t begin until after eight weeks.

I thought the study design prematurely terminated the experiments. The study didn’t justify the ultimate purpose of conducting rodent experiments, which is to find possible human applicability.

One study design possibility would have been to continue through old age to find how the conditions progressed. Another possibility would have been to reverse the high-fat diet to find whether the conditions reversed.

http://www.pnas.org/content/112/51/15731.full “Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function”

Beliefs about medical treatments affected perceived stress

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum, Neurochemicals, Oxytocin, Serotonin, Stress

This 2015 New Zealand human study found:

“Placebo effects can be translated to a real-life setting in the short-term reduction of stress, anxiety and symptoms of depression in a non-patient population.

In treating psychological distress, placebos may be useful addition to the treatment repertoire.“

The researchers provided a self-administered 3-day course of fake “anti-stress treatment spray” and told the participants the spray was either “oxytocin” or “serotonin” with these results:

“Both the ‘serotonin’ and ‘oxytocin’ treatment sprays were effective in reducing symptoms of depression; however, only those in the ‘oxytocin’ group reported less stress and anxiety as compared with controls. Overall, the ‘oxytocin’ was perceived as more effective.”

Will this study of non-patients be used to try to justify manipulating patients’ perceptions of their stress, anxiety, and depression?

http://anp.sagepub.com/content/early/2015/12/16/0004867415621390 “A take-home placebo treatment can reduce stress, anxiety and symptoms of depression in a non-patient population”

It is known: Are a study’s agendas more important than its evidence?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Brain hemispheres, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Stress , , , , ,

This 2015 Swiss human study’s Abstract began:

“It is known that increased circulating glucocorticoids in the wake of excessive, chronic, repetitive stress increases anxiety and impairs Brain-Derived Neurotrophic Factor (BDNF) signaling.”

The study had several statements that were unconvincingly supported by the study’s findings. One such statement in the Conclusions section was:

“This study supports the view that early-life adversity may induce long-lasting epigenetic changes in stress-related genes, thus offering clues as to how intergenerational transmission of anxiety and trauma could occur.”

However, the study’s evidence for “intergenerational transmission of anxiety and trauma” as summarized in the Limitations section was:

“This study did not directly associate child behavior or biology to maternal behavior and biology.”

In another example, the Discussion section began with:

“The severity of maternal anxiety was significantly correlated with mean overall methylation of 4 CpG sites located in exon IV of the BDNF promoter region as measured from DNA extracted from mothers’ saliva.

In addition, methylation at CpG3 was also significantly associated with maternal exposure to domestic violence during childhood, suggesting that BDNF gene methylation levels are modulated by early adverse experiences.”

The researchers assessed five DNA methylation values (four individual sites and the overall average). The CpG3 site was “significantly associated with maternal exposure to domestic violence during childhood” and the three other CpG sites’ methylation values were not.

IAW, the researchers found only one of four sites’ methylation values significantly associated to only one of many studied early adverse experiences. This finding didn’t provide sufficient evidence to support the overarching statement:

“BDNF gene methylation levels are modulated by early adverse experiences.”

To make such a generally applicable statement – more than one BDNF gene’s methylation levels could be directly altered by more than one early adverse experience – the researchers would, AT A MINIMUM, need to provide evidence that:

  1. The one category of significantly associated early adverse experience directly altered the one significantly associated CpG site’s DNA methylation level
  2. Other categories of early adverse experiences were fairly represented by the one significantly associated experience category
  3. Other categories of early adverse experiences could directly alter other BDNF genes’ DNA methylation levels
  4. The significantly associated DNA methylation level of only one out of four CpG sites was fairly represented by the overall average of the four sites
  5. Other BDNF gene’s methylation levels were fairly represented by the overall average of the four sites

If researchers and sponsors must have agendas, a worthwhile, evidence-supported one would be to investigate prenatal and perinatal epigenetic causes for later-life adverse effects.

As Grokking an Adverse Childhood Experiences (ACE) score pointed out, environmental factors that disrupt neurodevelopment may be the largest originators of epigenetic changes that are sustained throughout an individual’s entire lifespan.

What’s the downside of conducting studies that may “directly associate child behavior or biology to maternal behavior and biology” during time periods when a child’s environment has the greatest impact on their development?

When prenatal and perinatal periods aren’t addressed, researchers and sponsors neglect the times during which many harmful epigenetic consequences may be prevented. It is known.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0143427 “BDNF Methylation and Maternal Brain Activity in a Violence-Related Sample”

Emotional memories create long-term epigenetic changes

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Brain development, Epigenetics, Hippocampus, Limbic system, Memory, Stress , , , , , ,

This 2015 German rodent study found:

“Histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression.

Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning.”

Chromatin modifications in two limbic system brain areas were studied – the hippocampus (CA1 region) for short-term memories and the anterior cingulate cortex for short-and long-term memory formation and maintenance. The memories were induced by context (C) and context shock (CS) exposure:

“Overall, the data provides very strong and robust evidence for the establishment of long-term memory upon CS exposure, whereas C exposure alone did not induce the formation of long-term memory.”

So, without long-term shock/emotional memories, there would be no positive long-term findings for the researchers to report. There would be no lasting:

  • “Histone modifications
  • DNA methylation changes
  • Changes in gene expression”

The subjects were young adults at age 3 months. The CA1 and ACC studied brain areas are fully developed before this age.

It seemed feasible that if the study were performed with younger subjects, the results may have been different. For example:

“Context exposure alone did not induce the formation of long-term memory”

may not have been the finding for early learning situations.

The researchers qualified their results several times with the phrase “changes are limited to actively expressed genes.” A similar qualifier in A study of DNA methylation and age was a reminder that unexpressed genes may have also been important:

“The textbook case of DNA methylation regulating gene expression (the methylation of a promoter and silencing of a gene) remains undetected in many cases because in an array analysis, an unexpressed gene shows no signal that can be distinguished from background and is therefore typically omitted from the analysis.”

This general qualifier may not have necessarily applied to the current study, though, because the study’s design included an unexposed control group.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4194.html “DNA methylation changes in plasticity genes accompany the formation and maintenance of memory”

Brain-region-specific energy metabolism affected the social competitiveness of highly-anxious rats

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Cerebrum, Cortisol, Dopamine, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , ,

This 2015 Swiss rodent study found:

“Mitochondrial function in the nucleus accumbens, a brain region relevant for motivation and depression, is a critical mediating factor in the subordinate status displayed by high-anxious rats.

Treatment with nicotinamide, an amide form of vitamin B3 that boosts mitochondrial respiration, into the NAc [nucleus accumbens] of high-anxious rats at a time point before the social encounter and at a dose that increased accumbal mitochondrial respiration, abolished the disadvantage of high-anxious animals to become dominant against low-anxious animals.

Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.”

The researchers handled individual differences of the outbred subjects by separating them into high-, intermediate-, and low-anxiety categories according to their responses on two tests. The high- and low-anxiety subjects were matched by weight, age, and social experience.

Here are a few examples of the researchers thoroughly ruling out confounding factors:

“Differences in social competitiveness are not related to overall differences in social motivation or sociability.

Although social competition did significantly increase corticosterone compared with baseline levels, there were no significant differences between anxiety groups at either time point.

Microinfusion of either ROT, MA, or 3NP [mitochondrial respiration inhibitors] reduced the success of treated animals to win the social contest.

Importantly, these treatments did not induce side effects on social investigation or auto-grooming during social competition, or alter locomotor activity, anxiety, or sociability in additional experiments.

Furthermore, these inhibitor treatments did not produce neurotoxic effects, as the drugs were infused at low doses and we confirmed the absence of lesion and neuronal death.

The effects of complex I or complex II inhibition on social competition were specific for the NAc, as infusions of the same inhibitors into the BLA [basolateral amygdala] had no effect on social dominance and did not affect general locomotor activity.

We further showed that, unlike infusion of muscimol [a GABA receptor agonist] in the BLA that interferes with BLA-dependent auditory fear conditioning, 3NP did not affect conditioning in this task, discarding that neuronal inactivation could be a general mechanism whereby impairing mitochondrial function would affect putative functions from the affected brain region.

The impact of mitochondrial function in social competition described here is not mediated by oxidative stress.”

http://www.pnas.org/content/112/50/15486.full “Mitochondrial function in the brain links anxiety with social subordination”