Brain neurons

State-dependent brain functions and adrenaline

gettingwell4 5+ stars Premium, Brainstem, Locus coeruleus, Lower brain, Memory, Neurochemicals

This 2015 German/Italian rodent study investigated:

“How a specific neuromodulatory input may influence the information content and the readout of cortical information representations of sensory stimuli.

The locus coeruleus (LC) is a brainstem neuromodulatory nucleus that likely plays a prominent role in shaping cortical states via a highly distributed noradrenaline release in the forebrain. In particular, the LC:

  • Contributes to regulation of arousal and sleep;
  • Is involved in cognitive functions such as vigilance, attention, and selective sensory processing; and
  • Modulates cortical sensory responses and cortical excitability.

An important addition of our work to previous models of state dependence was the inclusion of the contribution of an important neuromodulator – the noradrenergic system. Our results support the hypothesis that the temporal structure of LC firing causally influences cortical dynamics.

Our work highlights the importance of timing of LC burst: suitably timed LC burst (for example, triggered by an alerting stimulus) can very rapidly trigger transitions into excitable cortical states, which in turn decrease the threshold for cortical responses and thus dynamically facilitate the processing of salient or attended events.

State dependence may either:

  • Force neurons to transmit information only using codes that are robust to state fluctuations (e.g., relative firing rates), or may
  • Force downstream neurons to gain information about the state of the networks sending the sensory messages and then to use the knowledge of state to properly interpret neural responses.

Our results suggest that the latter information transmission scheme is feasible, because detecting state by either monitoring the dynamics of cortical ongoing activity alone or by also monitoring the dynamics of noradrenergic modulation substantially increased the amount of information about sensory stimuli in the late response components relevant for behavior.”

The study added to the evidence that state dependencies can’t be overlooked in explanations of brain function and resultant physical and mental activity. Locus coeruleus neural activity “can very rapidly trigger transitions into excitable cortical states..and thus dynamically facilitate the processing of salient or attended events.”

Adrenaline from the locus coeruleus produced a state of arousal in multiple brain and body areas tied into the subjects’ sympathetic nervous systems. Such internal state changes may be accompanied by state-dependent memories, following the findings of What can cause memories that are accessible only when returning to the original brain state?

The study highlighted the capability of a lower brain structure to influence other brain areas. Its findings should inform researchers in attention and behavior studies, especially when investigating causes of attention and behavior difficulties.

http://www.pnas.org/content/112/41/12834.full “Modeling the effect of locus coeruleus firing on cortical state dynamics and single-trial sensory processing”

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.

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”

A problematic study of beliefs and dopamine

gettingwell4 < 0 Detracted from science, Beliefs, Brainstem, Cerebrum, Dopamine, Limbic system, Lower brain, Neurochemicals, Thalamus , ,

This 2015 Virginia Tech human study found:

“Dopamine fluctuations encode an integration of RPEs [reward prediction errors, the difference between actual and expected outcomes] with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been.

How dopamine fluctuations combine the actual and counterfactual is unknown.”

From the study’s news coverage:

“The idea that “what could have been” is part of how people evaluate actual outcomes is not new. But no one expected that dopamine would be doing the job of combining this information in the human brain.”

Some caveats applied:

  • Measurements of dopamine were taken only from basal ganglia areas. These may not act the same as dopamine processes in other brain and nervous system areas.
  • The number of subjects was small (17), they all had Parkinson’s disease, and the experiment’s electrodes accompanied deep brain stimulation implantations.
  • Because there was no control group, findings of a study performed on a sample of people who all had dysfunctional brains and who were all being treated for neurodegenerative disease may not apply to a population of people who weren’t similarly afflicted.

The researchers didn’t provide evidence for the Significance section statement:

“The observed compositional encoding of “actual” and “possible” is consistent with how one should “feel” and may be one example of how the human brain translates computations over experience to embodied states of subjective feeling.”

The subjects weren’t asked for corroborating evidence about their feelings. Evidence for “embodied states of subjective feeling” wasn’t otherwise measured in studied brain areas. The primary argument for “embodied states of subjective feeling” was the second paragraph of the Discussion section where the researchers talked about their model and how they thought it incorporated what people should feel.

The study’s experimental evidence didn’t support the researchers’ assertion – allowed by the reviewer – that the study demonstrated something about “states of subjective feeling.” That the model inferred such “findings” along with the researchers’ statement that it “is consistent with how one should “feel” reminded me of a warning in The function of the dorsal ACC is to monitor pain in survival contexts:

“The more general message you should take away from this is that it’s probably a bad idea to infer any particular process on the basis of observed activity.”

The same researcher who hyped An agenda-driven study on beliefs, smoking and addiction that found nothing of substance was back again with statements such as:

“These precise, real-time measurements of dopamine-encoded events in the living human brain will help us understand the mechanisms of decision-making in health and disease.”

It’s likely that repeated hubris is one way researchers respond to their own history and feelings, such as their need to feel important as mentioned on my Welcome page.

The Parkinson’s patients were willing to become lab rats with extra electrodes that accompanied brain implantations to relieve their symptoms. Findings based on their playing a stock market game didn’t inform us about “mechanisms of decision-making in health and disease” in unafflicted humans. As one counter example, what evidence did the study provide that’s relevant to healthy humans’ decisions to remain healthy by taking actions to prevent disease?

The unwarranted extrapolations revealed a belief that the goal of research should be to explain human actions by explaining the actions of molecules. One problem caused by the preconceptions of this widespread belief is that it leads to study designs and models that omit relevant etiologic evidence embedded in each of the subjects’ historical experiences.

This belief may have factored into why the subjects weren’t asked about their feelings. Why didn’t the study’s design consider as relevant subject-provided evidence for feelings? Because the model already contrived explanations for feelings underlying the subjects’ actions.

http://www.pnas.org/content/113/1/200.full “Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward”

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”

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”

A study of stress factors and neuroplasticity during infancy/early childhood

gettingwell4 2-3 stars Required further work, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Stress , , , , ,

This 2015 French rodent study found:

“The coordinated actions of BDNF and glucocorticoids promote neuronal plasticity and that disruption in either pathway could set the stage for the development of stress-induced psychiatric diseases.

Genetic strategies that disrupted GR [glucocorticoid receptor] phosphorylation or TrkB [the BDNF receptor] signaling in vivo impaired the neuroplasticity to chronic stress and the effects of the antidepressant fluoxetine.

We demonstrate that fluoxetine prevented the neuroplasticity of chronic stress by priming GR phosphorylation at BDNF-sensitive sites.”

It wasn’t too difficult to see how many of the stressors had human equivalents during infancy/early childhood:

“To determine the plasticity of GR phosphorylation upon changes in the endogenous levels of BDNF and glucocorticoids, mice were exposed to a chronic unpredictable stress that included one daily random stressor for 10 consecutive days from P21 [immediately after weaning] to 1 mo of age.

Chronic unpredictable stress includes one of the following daily random stressors (wet bedding, no bedding, food deprivation, crowded cage, 2 h or 6 h restraining, forced swim, tail suspension).”

But who would give fluoxetine – Prozac – to a human infant or young child to prevent “the neuroplasticity of chronic stress” from having adverse effects?

http://www.pnas.org/content/112/51/15737.full “Neurotrophic-priming of glucocorticoid receptor signaling is essential for neuronal plasticity to stress and antidepressant treatment”

Improved methodology in studying epigenetic DNA methylation

gettingwell4 2-3 stars Required further work, Brain development, Cerebrum, Epigenetics, Glutamate, Neurochemicals , , , , ,

This 2015 New York human study was of:

“The two major populations of human prefrontal cortex neurons..the excitatory glutamatergic projection neurons and the inhibitory GABAergic interneurons which constitute about 80% and 20% of all cortical neurons, respectively.

Major differences between the neuronal subtypes were revealed in CpG, non-CpG and hydroxymethylation (hCpG).

A dramatically greater number of undermethylated CpG sites in GLU versus GABA neurons were identified. These differences did not directly translate into differences in gene expression and did not stem from the differences in hCpG methylation, as more hCpG methylation was detected in GLU versus GABA neurons.

Notably, a comparable number of undermethylated non-CpG sites were identified in GLU and GABA neurons, and non-CpG methylation was a better predictor of subtype-specific gene expression compared to CpG methylation.”

The researchers performed numerous cross checks to test the results of their methodologies. This was necessary because, for example, studies such as A human study of changes in gene expression point out that current technologies such as the 450K array:

“Queries only 1.6% of all CpGs in the genome and the CpG selection is biased towards CpG islands.”

From the Discussion section:

“The higher abundance of hmCpG sites in GLU versus GABA neurons appears indicative of a difference in transcriptional potential between the neuronal subtypes. The increased hydroxymethylation could enable certain genes (e.g. activity-dependent genes) to be more readily induced in GLU versus GABA neurons.

These findings emphasize the importance of even subtle differences in the promoter CpG methylation for neuron subtype-specific gene expression. They also suggest that differences in CpG methylation within gene bodies and distal regulatory elements are not always directly reflected in differences in gene expression between neuronal subtypes.

The functional relevance of the association between gene expression and distal non-CpG methylation remains to be characterized.

Our data suggest that, compared to GABA interneurons, GLU projection neurons are characterized by more permissive chromatin state that is less constrained by repressive DNA methylation marks and is instead controlled by more dynamic means of transcription inhibition, such as non-coding RNAs and/or histone modifications.”

This study was similar to A problematic study of DNA methylation in frontal cortex development and schizophrenia in examining:

“If common risk variants determined by the recent genome wide associated studies (GWAS) for several neuropsychiatric diseases including schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD), and Alzheimer’s disease (AD) significantly overlap.

These findings strongly suggest an association between the epigenetic specification of both GABA and GLU neurons and SCZ. Risk variants associates with ASD, MD, or AD were not enriched.

An alternative explanation of our negative results could be the involvement of different developmental stages and/or brain regions in different diseases.”

The current study performed more detailed analyses, but on fewer subjects. The emphasis was on demonstrating an improved methodology.

Both studies’ findings regarding disease were of effects, not causes. That both study designs were limited to the postmortem prefrontal cortex reminded me of the old joke about looking for lost keys under the street light because the light was better there. At least the current study acknowledged the existence of other areas to search.

http://nar.oxfordjournals.org/content/early/2015/11/25/nar.gkv1304.full “Substantial DNA methylation differences between two major neuronal subtypes in human brain”

Mitochondria interface genetic/epigenetic responses to psychological stress

gettingwell4 2-3 stars Required further work, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Neurochemicals, Serotonin, Stress , , ,

This 2015 Pennsylvania rodent study found:

“Mitochondria can regulate complex whole-body physiological responses, impacting stress perception at the cellular and organismal levels.

Mitochondrial dysfunctions altered the

  1. hypothalamic–pituitary–adrenal [HPA] axis, sympathetic adrenal–medullary activation and catecholamine levels,
  2. the inflammatory cytokine IL-6,
  3. circulating metabolites, and
  4. hippocampal gene expression

responses to stress.

Stress-induced

  1. neuroendocrine,
  2. inflammatory,
  3. metabolic, and
  4. transcriptional responses

coalesced into unique signatures that distinguish groups based on their mitochondrial genotype.”

The study’s design was comprehensive for the subject of mitochondrial function and stress response categories. It interrelated elements that had a common cause of stress, such as:

  • Hyperglycemia
  • Increased lipids
  • Corticosterone sensitivity
  • Epigenetic changes within the brain

The study’s Figure 6E was a hierarchical “heat map” of the correlations among the 77 stress-induced changes that were measured. Figure 6G presented these variables per the five mitochondrial genotypes (a control wild-type and four genetic dysfunctions). Many of the lines forming the hierarchy needed careful reading of the study’s interpretations.

I downgraded the study’s rating because the authors inappropriately forced the “allostatic load” buzzword into the Significance statement and otherwise informative Discussion section. The term refers to a hypothetical long-term situation, but the study’s experiments lasted 2 hours at most before the subjects were killed.

www.pnas.org/content/112/48/E6614.full “Mitochondrial functions modulate neuroendocrine, metabolic, inflammatory, and transcriptional responses to acute psychological stress”

Neural pathways for forgetting bad smells

gettingwell4 4-5 stars Advanced knowledge, Dopamine, Glutamate, Memory, Neurochemicals, Stress ,

This 2015 New York fruit fly study found:

“Forgetting is regulated by multiple neural pathways that impinge upon a memory center.

Forgetting over time and the acute forgetting of conflicting memory during reversal learning rely on separable neural circuits.

Inactivating these neurons inhibits memory decay without altering learning, whereas activating them promotes forgetting. These neurons [include] a cluster of dopaminergic neurons and a pair of glutamatergic neurons.

Although activity of these neurons is required for memory decay over time, they are not required for acute forgetting during reversal learning. Our results thus not only establish the presence of multiple neural pathways for forgetting in Drosophila but also suggest the existence of diverse circuit mechanisms of forgetting in different contexts.”

Here’s a 3D view of the glutamatergic neurons:

http://movie-usa.glencoesoftware.com/video/10.1073/pnas.1512792112/video-2

http://www.pnas.org/content/112/48/E6663.full “Dissecting neural pathways for forgetting in Drosophila olfactory aversive memory”

Familiar stress opens up an epigenetic window of neural plasticity

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

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

gettingwell4 0-1 star Wasted resources, Beliefs, Brain development, Cerebrum, Cortisol, Epigenetics, Glutamate, Hippocampus, Immune system, Limbic system, Neurochemicals, Serotonin, Stress, Telomeres, Thalamus , , , , , , , ,

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”

A molecular study of the epigenetic regulation of memory

gettingwell4 4-5 stars Advanced knowledge, Epigenetics, Hippocampus, Limbic system, Memory, Stress ,

This 2015 Norwegian rodent study provided:

“New insights into the molecular underpinnings of synaptic plasticity.

We report the first global transcriptome [all RNA found in specific cells] analysis of in vivo synaptic plasticity, using the well-established model of LTP [long-term potentiation, an increase in synaptic strength that underlies memory] in the rat dentate gyrus [a region of the hippocampus where neurogenesis occurs].

We have identified a number of novel lncRNAs [long (more than 200 nucleotides) noncoding (non-protein coding) RNA] that are dynamically regulated in response to LTP. In addition, we also observed an altered expression of multiple classes of repeat elements [mobile DNA sequences often involved in mutations] including retrotransposons [a repeat element type formed by copy-and-paste mechanisms].

The results presented here reveal a vast extension of mRNAs [messenger RNA, a large RNA that carries codes for protein production] previously not associated with neuronal plasticity; the discovery of extensive, dynamic regulation of lncRNAs, repeat elements, and tRNA [transfer RNA that links mRNA and amino acids during protein production] following LTP induction in the adult rat brain.

These findings provide a broader foundation for elucidating the transcriptional and epigenetic regulation of synaptic plasticity.”

Regarding lncRNA:

“We annotate a total of 10,256 novel lncRNAs in the rat transcriptome.

To infer possible functions of lncRNAs, we correlated [71] differentially expressed lncRNAs with regulated protein coding genes.

There are no established rules for predicting the function of lncRNAs.”

Regarding repeat elements:

“It is intriguing to consider that expression of repeat elements during LTP is the first step toward retrotransposition and reshaping of the neuronal genome. A hypothetical mechanism for how these repeat elements could be linked to memory, would be that a certain stimuli, whether it is stress or a learning task (here LTP), deregulate the repression of repeat elements which are then rapidly and transiently transcribed. These elements reinsert themselves back into the genome of stimulated neurons where they influence the expression of neighboring genes.

The present work supports the intriguing hypothesis that dynamic retrotransposition may act as a molecular means to reprogram the neuronal genome as part of long-term synaptic plasticity and memory formation.”

See RNA as a proxy signal for context-specific biological activity for more about lncRNA.

http://journal.frontiersin.org/article/10.3389/fnins.2015.00351/full “Dynamic expression of long noncoding RNAs and repeat elements in synaptic plasticity”