Neurochemicals

Familiar stress opens up an epigenetic window of neural plasticity

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This 2015 Italian rodent study found:

“There is a window of plasticity that allows familiar and novel experiences to alter anxiety– and depressive-like behaviors, reflected also in electrophysiological changes in the dentate gyrus (DG).

A consistent biomarker of mood-related behaviors in DG is reduced type 2 metabotropic glutamate (mGlu2), which regulates the release of glutamate. Within this window, familiar stress rapidly and epigenetically up-regulates mGlu2..and improves mood behaviors.

These hippocampal responses reveal a window of epigenetic plasticity that may be useful for treatment of disorders in which glutamatergic transmission is dysregulated.”

The current study included two of the authors of A common dietary supplement that has rapid and lasting antidepressant effects.

The supplementary material showed the:

“Light–dark test as a screening method allowed identification of clusters of animals with a different baseline anxiety profile”

for the BDNF Val66Met subjects. This research methodology better handled the individual differences that often confound studies.

The study’s press release provided further details such as:

“Here again, in experiments relevant to humans, we saw the same window of plasticity, with the same up-then-down fluctuations in mGlu2 and P300 in the hippocampus, Nasca says. This result suggests we can take advantage of these windows of plasticity through treatments, including the next generation of drugs, such as acetyl-L-carnitine, that target mGlu2—not to ‘roll back the clock’ but rather to change the trajectory of such brain plasticity toward more positive directions.”

I disagree with the authoring researchers’ extrapolation of these rodent findings to humans, which seemed to favor chemical intervention. Causes of human stress should be removed or otherwise addressed.

I hope that the study’s “familiar stress” findings won’t be use to attempt to justify potentially harmful practices such as Critical Incident Stress Debriefing, which mandatorily guides people to process recent trauma. Instead, An interview with Dr. Rachel Yehuda on biological and conscious responses to stress made a point about “windows of plasticity” that’s relevant to who we are as feeling human beings:

“What I hear from trauma survivors — what I’m always struck with is how upsetting it is when other people don’t help, or don’t acknowledge, or respond very poorly to needs or distress.”

http://www.pnas.org/content/112/48/14960.full “Stress dynamically regulates behavior and glutamatergic gene expression in hippocampus by opening a window of epigenetic plasticity”

A review of genetic and epigenetic approaches to autism

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This 2015 Chicago review noted:

“Recent developments in the research of ASD [autistic spectrum disorder] with a focus on epigenetic pathways as a complement to current genetic screening.

Not all children with a predisposing genotype develop ASD. This suggests that additional environmental factors likely interact with the genome in producing ASD.

Increased risk of ASD is associated with mutations in genes that overlap with chromatin remodeling proteins, transcriptional regulators and synapse-associated proteins. Interestingly, these genes are also targets of environmentally induced changes in gene expression.”

Evidence was discussed for both broad and specific epigenetic ASD causes originating in the prenatal environment:

  • Maternal stress:

    “Prenatal stress exerts a profound epigenetic influence on GABAergic interneurons by altering the levels of proteins such as DNMT1 and Tet1 and decreasing the expression of various targets such as BDNF.

    Ultimately, this results in reducing the numbers of fully functional GABAergic neurons postnatally and a concomitant increased susceptibility toward hyperexcitability. The delayed migration of GABAergic interneuron progenitors results in reduced gene expression postnatally which is likely the consequence of increased amounts of DNA methylation.

    The net effect of stress during early development is to disrupt the balance of excitatory/inhibitory neuronal firing due to the loss of function associated with disrupted neuronal migration and maturation.”

  • Prenatal nutrition:

    “Exposure to a wide range of environmental toxins that impact neurodevelopment also result in global DNA hypomethylation. This model was extended to connect pathways between dietary nutrition and environmental exposures in the context of DNA hypomethylation. More recently, this hypothesis was expanded to show how dietary nutrients, environmental toxins, genome instability and neuroinflammation interact to produce changes to the DNA methylome.”

  • Maternal infections:

    “Inflammation, autoimmunity and maternal immune activation have long been suspected in the context of aberrant neurodevelopment and ASD risk.”

  • Exposure to pollutants, medications, alcohol

This was a current review with many 2015 and 2014 references. However, one word in the reviewers’ vernacular that’s leftover from previous centuries was “idiopathic,” as in:

“Idiopathic (nonsyndromic) ASD, for which an underlying cause has not been identified, represent the majority of cases.”

It wasn’t sufficiently explanatory to use categorization terminology from thousands of years ago.

Science has progressed enough with measured evidence from the referenced studies that the reviewers could have discarded the “idiopathic” category and expressed probabilistic understanding of causes. They could have generalized conditional origins of a disease, and not reverted to “an underlying cause has not been identified.”

Another word the reviewers used was “pharmacotherapeutic,” as in:

“The goal for the foreseeable future is to provide a better understanding of how specific genes function to disrupt specific biological pathways and whether these pathways are amenable to pharmacotherapeutic interventions.”

Taking “idiopathic” and “pharmacotherapeutic” together – causes for the disease weren’t specifically identified, but the goal of research should be to find specific drug treatments?

Of course reviewers from the Department of Psychiatry, The Psychiatric Institute, University of Illinois at Chicago are biased to believe that “the design of better pharmacotherapeutic treatments” will fulfill peoples’ needs.

Are their beliefs supported by evidence? Without using drugs, are humans largely incapable of therapeutic actions such as:

  • Preventing epigenetic diseases from beginning in the prenatal environment?
  • Treating epigenetic causes for and alleviating symptoms of their own disease?

http://www.futuremedicine.com/doi/full/10.2217/epi.15.92 “Merging data from genetic and epigenetic approaches to better understand autistic spectrum disorder”

An interview with Dr. Rachel Yehuda on biological and conscious responses to stress

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How Trauma and Resilience Cross Generations

“The purpose of epigenetic changes, I think, is simply to increase the repertoire of possible responses.

So let’s say, for some reason, your parents transmitted to you biologic changes that are very appropriate to starvation, but you don’t live in a culture where food is not plentiful.

You’re just not optimized, but I think that if we develop an awareness of what the biologic changes from stress and trauma are meant to do, then I think we can develop a better way of explaining to ourselves what our true capabilities and potentials are.

What I hear from trauma survivors — what I’m always struck with is how upsetting it is when other people don’t help, or don’t acknowledge, or respond very poorly to needs or distress.

Feel it instead of running to someone to give you a sleeping pill.”

Transcript: http://www.onbeing.org/program/rachel-yehuda-how-trauma-and-resilience-cross-generations/transcript/7791

Telomere dynamics, stress, and aging across generations

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This 2015 Pennsylvania/North Dakota animal and human review noted:

“The mechanisms linking stress exposure to disease progression and ageing either within individuals or across generations are still unclear, but recent work suggests that telomere dynamics (length and loss rate) may play an important role.

Parental stress may directly influence the parental germline telomeres pre-fertilization, affecting the telomere length inherited by offspring. Alternatively, parental stress may affect telomere dynamics indirectly either pre- or post-natally. The physiological mechanisms by which stress elicits changes in telomere length are also diverse.

We need more information about how these effects vary between developmental stages, among individuals, and within tissues of individuals..to mitigate the effects of early life adversity on human health.”

I was disappointed that the reviewers chose Problematic research with telomere length as a reference. Then again, maybe their statement:

“how these traits are related to one another clearly deserves more study”

is a polite way of saying that study’s methodology was flawed?

Regarding evolutionary biology:

“While most evidence suggests that the effect of parental stress exposure on offspring telomeres is negative, it is important to remember that this is just one trait that can contribute to parental and offspring fitness.

Investment in traits that increase fitness is expected to be favoured, even if they come at a cost to traits associated with longevity, such as telomere length.”

A similar point was made in a reference of A study of DNA methylation and age that:

“Aging has no purpose (neither for individuals nor for group), no intention. Nature does not select for quasi-programs. It selects for robust developmental growth.”

 

http://rsbl.royalsocietypublishing.org/content/11/11/20150396 “Telomere dynamics may link stress exposure and ageing across generations”

Psychological therapy and DNA methylation

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This 2015 worldwide human study was:

“The largest study to date investigating the role of HPA [hypothalamic–pituitary–adrenal] axis related genes in response to a psychological therapy. Furthermore, this is the first study to demonstrate that DNA methylation changes may be associated with response to psychological therapies in a genotype-dependent manner.

In this study, we tested the association between polymorphisms of FKBP5 [a gene that produces a protein that dampens glucocorticoid receptor sensitivity primarily in areas of the limbic system such as the hippocampus and amygdala] and GR [glucocorticoid receptor gene] and response to CBT [cognitive behavior therapy] in children with anxiety disorders (N = 1,152), and examined change in DNA methylation at specific regions of these genes during the course of CBT in a subset of the sample (n = 98).

No significant association was found between GR methylation and response. Allele-specific change in FKBP5 methylation was associated with treatment response.”

Regarding “treatment response:”

“Subjects aged 5–18 (mean: 9.8 years) met DSM-IV criteria for primary diagnosis of an anxiety disorder.

Clinical severity ratings (CSRs) were usually based on composite parent and child reports, and were assigned on a scale of 0–8. [36] [linked below]

Treatment response was defined as the change in primary anxiety disorder severity from pretreatment to follow-up. A diagnosis was made when the child met diagnostic criteria and received a CSR of 4 or more. Remission was regarded as the absence of the primary anxiety according to diagnostic criteria, as determined by the clinicians at the follow-up interview.”

Scenarios where nine-year-olds and their parents may have benefited from skewing their “composite parent and child reports” either way:

  1. Parents benefited from an anxious-child report (financial support provided, social services provided, avoided undesirable activities like going to work, continued psychological dependence, provided victim celebrity, enabled their own problems)
  2. Parents benefited from a well-child report (freed up time to pursue desirable activities, financial relief, relief from court-ordered or social-services-required activities, covered up their own contributions to the child’s problems)
  3. Nine-year-olds benefited from an anxious report (relief from undesirable activities like school attendance, continued psychological dependence, provided victim celebrity, activities structured around their condition, enabled the parents’ problems)
  4. Nine-year-olds benefited from a well report (symptom reduction, met parental expectations, freed up time to pursue desirable activities, covered up the parents’ contributions to the child’s problems).

I wonder what “treatment response” criteria were available other than self-serving reports and “diagnostic criteria, as determined by the clinicians.” Every day medical personnel hear patients self-report conditions where biological measurements may confirm or indicate something different. Did the “diagnostic criteria, as determined by the clinicians” include comparisons to relevant biological measurements?

The related study linked below points out:

“Although CBT has been established as an efficacious treatment, roughly 40% of children retain their disorder after treatment.”

Its focus was also on predictors (other than genetic) of CBT outcomes.

Neither study provided evidence of attempts to find originating causes for the children’s conditions. Were the international CBT approaches only interested in treating symptoms?

http://onlinelibrary.wiley.com/doi/10.1002/da.22430/full “HPA AXIS RELATED GENES AND RESPONSE TO PSYCHOLOGICAL THERAPIES: GENETICS AND EPIGENETICS”

Related 2015 study: http://www.jaacap.com/article/S0890-8567%2815%2900191-4/pdf “Clinical Predictors of Response to Cognitive-Behavioral Therapy in Pediatric Anxiety Disorders: The Genes for Treatment (GxT) Study”

Fetal exposure to sex hormones and female anxiety

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This 2015 Swedish rodent study found:

“Women with polycystic ovary syndrome (PCOS) display high circulating androgen levels that may affect the fetus and increase the risk of mood disorders in offspring.

Although clinical data are inconsistent, there are indications that androgens play a crucial role in behavior and mood regulation in females.

Studies on the link between testosterone and anxiety behavior in males have generated inconsistent results.

Higher circulating testosterone has previously been reported in female rat PNA [prenatal androgen] offspring. This discrepancy may be a result of the higher doses of maternal testosterone (5 mg) used in the previous study compared with the present study (0.5 mg).

Although the anxiety-like behavior observed in the female PNA offspring in the present study cannot be directly explained by high circulating androgens, the reduced AR [androgen receptor] expression in the amygdala suggests a compensatory response to the high prenatal testosterone exposure, a result implicating the amygdala as the CNS site underlying the changes in anxiety in the PNA offspring. This idea is further strengthened by our experiment showing that subchronic testosterone exposure into amygdala is sufficient to produce anxiety-like behavior in adult females.

Maternal testosterone exposure causes anxiety-like behavior in female, and to a lesser extent male offspring, an effect that seems to occur during fetal life and to be mediated via AR in the amygdala, together with changes in ER [estrogen receptor] and in the serotonergic and GABAergic pathways in the amygdala and hippocampus of female PNA rats.”

The news coverage – too much testosterone caused anxiety-like symptoms in females whether they are adults or fetuses – was NOT what the study found. The headlines disregarded its caveat:

“The anxiety-like behavior observed in the female PNA offspring in the present study cannot be directly explained by high circulating androgens.”

I look forward to research on floor levels of testosterone, below which there are also adverse effects on females. There is such evidence, but would it play well with popular memes?

See Sex hormone exposure to the developing female fetus causes infertility in adulthood for another study that used the PCOS phenotype.

http://www.pnas.org/content/112/46/14348.full “Maternal testosterone exposure increases anxiety-like behavior and impacts the limbic system in the offspring”

Transgenerational epigenetic programming with stress and microRNA

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This 2015 Pennsylvania rodent study found:

“Sperm miRs [microRNAs, a small non-coding RNA that has a role in gene expression] function to reduce maternal mRNA [messenger RNA, a large RNA that carries codes for protein production] stores in early zygotes, ultimately reprogramming gene expression in the offspring hypothalamus and recapitulating the offspring stress dysregulation phenotype.”

These researchers caused stress-induced changes at an early stage of embryonic development with microRNA injections. Resultant adverse effects weren’t observed until subjects were adults!

Most news coverage focused on it being a male’s stress, not a female’s, that affected a developing embryo. Either or both sexes can epigenetically disadvantage a fetus – okay.

Demonstrating how a damaging influence can begin immediately after conception, but symptoms didn’t present until adulthood made this study newsworthy.

Although the term “transgenerational” was used in the study’s title, abstract, and elsewhere, studied epigenetic effects were intergenerational rather than transgenerational. Per A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply, researchers need to provide evidence in at least the next 2 male or non-gestating female generations and/or 3 gestating female generations of:

“Altered epigenetic information between generations in the absence of continued environmental exposure.”

From a press release, a study coauthor who also coauthored How to make a child less capable even before they are born: stress the pregnant mother-to-be stated:

“Bale suspects that when a male experiences stress it may trigger the release of miRs contained in exosomes from epithelial cells that line the epididymis, the storage and maturation site for sperm between the testes and the vas deferens. These miRs may be incorporated into maturing sperm and influence development at fertilization.”

Not all stress-related gene expression in pituitary and adrenal glands differed.

http://www.pnas.org/content/112/44/13699.full “Transgenerational epigenetic programming via sperm microRNA recapitulates effects of paternal stress”

The roles of DNA methylation and demethylation in forming memories

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This 2015 Alabama combined animal and human review noted:

“Memories can last a lifetime, yet the proteins that enable synaptic plasticity, allowing for the establishment and maintenance of the memory trace, are subject to perpetual turnover.

DNA methylation may likely serve as the principle cellular information storage device capable of stably and perpetually regulating cellular phenotype.”

The authors developed a framework for understanding disparate findings of DNA methylation and demethylation concerning memory.

The dependencies expressed in the framework among the numerous factors – with their relative strengths, timings, and durations – reminded me of this video:

1) If such an error-prone framework accurately reflected the evolved architecture of our memory, we wouldn’t have the variety and number and intensity of memories that we have.

2) The framework neither accounted for prenatal memory processes nor differentiated emotional memories, although some of the referenced studies’ findings were applicable.

3) DNA methylation and demethylation aren’t the entirety of memory formation explanations. For example, they don’t explain state-dependent memories that can be instantiated, reactivated, and amnesia induced without involving “the proteins that enable synaptic plasticity” described in the authors’ framework. For completeness, the authors could have assessed the relative contributions of other memory processes, or at least enumerated them.

4) DNA methylation and demethylation explanations don’t cover all epigenetic biochemical processes. There are also placental interactions, histone/protein interactions, microRNA interactions, etc. For completeness, the authors could have placed the review’s topic within appropriate contexts of other epigenetic processes that influence memory.

This review of DNA methylation and demethylation roles in memory formation opened up a few slats in the blind covering one window. There’s more to be done to fully open that blind, and more window blinds to be opened before the workings of our memory are illuminated.

http://nro.sagepub.com/content/21/5/475.full “DNA Methylation in Memory Formation: Emerging Insights”

Inflexible behavior may be a byproduct of stress

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This 2015 German human study found:

“15-mo-old infants exposed to stress thereafter kept performing a previously effective action, even after the action suddenly became ineffective.

Infants in a no-stress control group flexibly adjusted their behavior by disengaging from the newly ineffective action in favor of exploring an alternative action.

This finding demonstrates that stress impairs infants’ ability to adjust their behavior to changing circumstances.”

The primary measurement of stress levels was cortisol. Stressful conditions were:

  • A stranger sat down next to them;
  • A dancing robot played loud music and moved around;
  • The infant’s caregivers left the room for up to four minutes.

News coverage stated that the study’s design was an adaptation of experiments that produced the same findings in adults. But would adult humans be stressed by being left alone for four minutes?

It’s likely that animal studies were the basis for some of this study’s experiments, as in the If research provides evidence for the causes of stress-related disorders, why only focus on treating the symptoms? study:

“Maternal separation in rodents is a useful model of early-life stress that results in enduring physiological and behavioral changes that persist into adulthood.”

A study limitation was that it involved just 26 infants.

http://www.pnas.org/content/112/41/12882.full “Stress impairs cognitive flexibility in infants”

A study that provided evidence for basic principles of Primal Therapy

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This 2015 Northwestern University rodent study found:

“Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar.

Memories formed in a particular mood, arousal or drug-induced state can best be retrieved when the brain is back in that state.

‘It’s difficult for therapists to help these patients,’ Radulovic said, ‘because the patients themselves can’t remember their traumatic experiences that are the root cause of their symptoms.’

The best way to access the memories in this system is to return the brain to the same state of consciousness as when the memory was encoded.”

The study demonstrated one method of activating neurobiological pathways with a drug to remove a hippocampal memory’s protection, which played a part in enabling subjects to relive their remembered experiences. This rodent study’s methods weren’t designed to therapeutically access similarly protected memories with humans.

From the Northwestern press release:

“There are two kinds of GABA [gamma-Aminobutyric acid] receptors. One kind, synaptic GABA receptors, works in tandem with glutamate receptors to balance the excitation of the brain in response to external events such as stress.

The other population, extra-synaptic GABA receptors, are independent agents.

If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again.

‘It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories,’ said lead study author Vladimir Jovasevic, who worked on the study when he was a postdoctoral fellow in Radulovic’s lab.

This different system is regulated by a small microRNA, miR-33, and may be the brain’s protective mechanism when an experience is overwhelmingly stressful.

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.”

I’d point out that “can’t remember” and “inaccessible traumatic memories” phrases used above were in reference to what’s usually called “memory” i.e., a recall initiated by the cerebrum.

The study’s findings should inform memory-study researchers if they care to understand how emotional memories can be formed and re-experienced.

The study provided evidence for fundamentals of Dr. Arthur Janov’s Primal Therapy, such as:

  • Experiences associated with pain can be remembered below our conscious awareness.
  • The retrieval and re-experiencing of emotional memories can engage our lower-level brain areas without our higher-level brain areas’ participation.

The obvious nature of this study’s straightforward experimental methods made me wonder why other researchers hadn’t used the same methods decades ago.

Use of this study’s methodology could have resulted in dozens of informative follow-on study variations by now, and subsequently found whether subjects’ physiological, behavioral, and epigenetic measurements differed from control group subjects, as in:

“miR-33 is downregulated in response to gaboxadol [the drug used to change subjects’ brain state] and modulates its effects on state-dependent fear.”

See Resiliency in stress responses for abstracts of three follow-on papers by these researchers.

http://www.nature.com/neuro/journal/v18/n9/full/nn.4084.html “GABAergic mechanisms regulated by miR-33 encode state-dependent fear”

MP3 with lead researcher Dr. Jelena Radulovic: http://www.thenakedscientists.com/HTML/specials/show/20150825/

Leaky gates, anxiety, and grocery store trips without buying list items

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An interview with Jeff Link, the editor of Dr. Arthur Janov’s 2011 book “Life Before Birth: The Hidden Script that Rules Our Lives” with Ken Rose:

“Even further confirmation for some of the views of Janov, that maybe weren’t widely accepted for a time, it’s new research now being done into memory and what a lot of scientist are seeing, a lot of different studies is that memory reactivates the same neuroimpulses that were initially firing off when the event happened.

So a traumatic event when you remember it, the act of remembering it is actually creating a neuromirror of what went on initially.

In a lot of ways that is what Primal Therapy is attempting to do; is to go back to that place and reconnect, or as it’s sometimes referred to, reconsolidate the brain state so that real healing can take place.”

Transcript (part 4 of 6): http://cigognenews.blogspot.com/2015/09/ken-rose-on-life-before-birth-part-46.html

MP3: http://www.pantedmonkey.org/podcastgen/download.php?filename=2011-12-15_1300_what_now_jeff_link.mp3

Adverse effects of inflammation and stress on hippocampal synapses

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This dense and highly-jargoned 2015 rodent study found:

“The suppression of BDNF [brain-derived neurotrophic factor] signaling, LTP [long-term potentiation], and memory may be driven by an increased sensitivity to IL-1β [the proinflammatory cytokine interleukin 1β] that occurs directly at synapses.”

The researchers reversed the adverse effects of IL-1β after they induced stress and inflammation. Blocking IL-1β when there wasn’t stress or inflammation, however, also caused adverse effects:

“Interestingly, administration of AS1 [the compound that blocked the proinflammatory responses] in the absence of LPS [the bacterial compound used to stress the subjects’ immune systems] treatment also impaired OLM [the object location memory test where control group rodents exhibited a preference for a novel location over a familiar location].

This finding is consistent with the notion that endogenous IL-1β at physiologically low levels may be essential for hippocampal memory function.”

The researchers asserted:

“Our data reveal a previously unidentified mechanism that explains the age-related vulnerability of hippocampal function to impairment by inflammation.”

Instead of couching their findings with a non-causal “age-related” term, could the researchers have specifically identified causes?

“IL-1β activates different pathways via AcP (proinflammatory) or AcPb (prosurvival) IL-1 receptor subunits.

This study demonstrates that the IL-1 receptor subunit system undergoes an age-dependent reconfiguration in hippocampal synapses.

This previously undescribed reconfiguration, characterized by an increase in the AcP/AcPb ratio, is responsible for potentiating impairments of synaptic plasticity and memory by IL-1β.”

What were the underlying causes for the relatively increased AcP activation over AcPb activation? The researchers didn’t say. Their explanations were left hanging at a correlated-but-not-causal “age-dependent” level rather than a “mechanism that explains.”

http://www.pnas.org/content/112/36/E5078.full “Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus”

A mechanistic study of neurotransmitters in the hippocampus

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This 2015 UK rodent study found:

“A mechanistic understanding of how alterations in dopamine and NMDAR [a type of glutamate receptor that participates in excitatory neurotransmission] function can lead to the disruption of hippocampal–PFC [prefrontal cortex] functional connectivity.

These results show how dopaminergic activation induces long-term hypofunction of NMDARs, which can contribute to disordered functional connectivity, a characteristic that is a hallmark of psychiatric disorders such as schizophrenia.”

One of the experiments applied theta-frequency (5 Hz) waves to the rats’ hippocampi and dampened the electrical activity of the NMDAR type of glutamate receptor.

However, this effect of theta waves was dependent on the activation of D2 dopamine receptors. The study’s findings should inform researchers who treat brain waves as base causes of behavior in studies such as What’s an appropriate control group for a schizophrenia study?

This study’s findings may also inform researchers of studies such as the What causes disconnection between the limbic system and the cerebrum? of a neurochemical basis for “the disruption of hippocampal–PFC functional connectivity.”

http://www.pnas.org/content/112/35/11096.full “Disruption of hippocampal–prefrontal cortex activity by dopamine D2R-dependent LTD of NMDAR transmission”

Who’s responsible for your physical and emotional health?

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This 2015 Houston human study measured 575 metabolites in 72 biochemical pathways. The researchers used “nontargeted metabolomics” with next-generation gene sequencing to:

“Take account of human individuality in genes, environment, and lifestyle for early disease diagnosis and individualized therapy.”

The 80 subjects were 45 men and 35 women, average age of 54, in “normal health with complete medical records and three-generation pedigrees.” The subjects all had college degrees, and were members or spouses of members of an upper-level socioeconomic organization.

The study’s range of 575 metabolites certainly cast a shadow over studies such as Running a marathon, cortisol, depression, causes, effects, and agendas that singled out 1 metabolite and tortured its data until it confessed a relationship that supported the preferred agenda.

Limitations of this study that weren’t mentioned by the researchers included:

  1. There were no specific target levels for each metabolite, which could lead to a misinterpretation that a “healthy” blood plasma level of a metabolite would always be the norm of the 80 subjects. This interpretation of each metabolite’s ideal level could be reinforced by the study calculating z-scores and P values of each individual’s measurement’s position within the cohort. The researchers stated:

    “The identification of abnormal metabolic signatures was restricted by the relatively small number of subjects in the cohort.”

    but that limitation wasn’t the flip side of omitted optimal levels.

  2. The metabolite measurements were mainly a one-time event although a series of measurements may have been more appropriate. Many of these metabolite levels vary with the time of day, what each individual had recently eaten, what each individual’s recent stress levels were, etc. This limitation may have been one of the sources for what the researchers noted:

    “Statistical analysis revealed a considerable range of variation and potential metabolic abnormalities across the individuals in this cohort.”

  3. There was no assessment of the relative contributions of epigenetic and genetic factors when discussing possible genetic impacts.

Regarding 1. above:

  • It may be interesting to compare an individual to their peers and to other sources of information. However, when it comes time for “individualized therapy” because of a metabolic measurement that’s an outlier compared to these other sources, an individual’s history also matters.
  • Each individual’s history could be used as a guide for optimal levels of some metabolites. For example, an optimal goal for “individualized therapy” for low testosterone levels of each of the 54-year old male subjects could be each individual’s previous higher levels of three decades earlier. It wouldn’t make sense for a 54-year old male to start testosterone therapy with a goal of raising his low levels to the non-therapeutic, low-level norm of other 54-year old males.

Regarding 2. above:

Regarding 3. above:

  • As an example of unconsidered epigenetic factors, there was a discussion of acetaminophen metabolites because:

    “The identification of at-risk populations could improve therapeutic options for individual patients and prevent adverse clinical outcomes.”

    The researchers specifically compared and contrasted two subjects with the highest levels of acetaminophen metabolites, and concluded:

    “These observations may suggest that volunteer 3976 was sensitive to acetaminophen-induced liver injury, whereas volunteer 3958 could tolerate acetaminophen well. This difference may relate to their cellular capability to maintain GSH [reduced glutathione] levels in response to acetaminophen. We searched for a genetic basis of this variation in acetaminophen degradation/toxic metabolism without success.”

  • The researchers shouldn’t have left the discussion hanging at this point. There’s no reason in 2015 for researchers to not investigate the contribution of epigenetic factors to:

    “Take account of human individuality in genes, environment, and lifestyle.”

I was put off by the researchers statement:

“The volunteer’s cardiologist was informed of this observation to monitor possible drug interaction or toxicity.”

It appeared that the researchers bypassed one subject and informed the subject’s doctor directly when the subject was doing something the researchers considered detrimental to the subject’s health. I don’t know if the subject gave prior consent to be bypassed, though, because I didn’t see either study’s consent terms in the below linked material.

A few concluding questions:

  • If it’s alright for personal health information to be transmitted without the consent of highly-educated, upper-level socioeconomic subjects, what can the rest of the population expect?
  • Is “individualized therapy” best done through individual choices, or by forcing an individual to conform to expert opinion?
  • Who is responsible for an individual’s physical and emotional health?

http://www.pnas.org/content/112/35/E4901.full “Plasma metabolomic profiles enhance precision medicine for volunteers of normal health”

http://www.pnas.org/content/110/42/16957.full “Personalized genomic disease risk of volunteers” (2013 original study with the same subjects)

Another factor in producing new brain neurons in the adult hippocampus

gettingwell4 4-5 stars Advanced knowledge, Glutamate, Hippocampus, Limbic system, Neurochemicals

This 2015 New York rodent study provided further details on the production of new neurons in the adult hippocampus. The researchers found that a protein that regulated a glutamate receptor also:

“Significantly influences hippocampal neurogenesis and that both the proliferation and survival of newborn neurons are impaired in the absence.”

The study showed:

“The effect of Norbin [the protein] on neurogenesis is likely caused by a nonautonomous niche effect.

These results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors.”

http://www.pnas.org/content/112/31/9745.full “Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice”