Neurotransmitters, some of which are synthesized by microbes;
Immune via cytokines; and
Metabolic via microbially generated short-chain fatty acids.
How does nature maintain the gut-microbiome-brain axis? Mechanisms to maintain homeostasis of intestinal epithelial cells and their underlying cells are a key consideration.
The symbiotic relationship that exists between microbiota and the human host is evident when considering nutrient requirements of each. The host provides food for microbes, which consume that food to produce metabolites necessary for health of the host.
Consider function of the human nervous system, not in isolation but in integration with the gastrointestinal ecosystem of the host, in expectation of a favorable impact on human health and behavior.”
This 2020 food chemistry review provided phenolic-compound reasons to eat oats:
“Phenolamides result from the conjugation of hydroxycinnamic acids with amines. These products contain a variety of metabolic, chemical, and functional capabilities due to the large number of possible combinations among the parent compounds.
Of the currently known phenolamides, the most common are avenanthramides (AVAs), which are unique in oats. AVAs possess anti-inflammatory, anti-itch, anti-atherosclerosis, antioxidant, anti-cancer, anti-obesity, anti-fungal, anti-microbial, and neuroprotective properties.
Twenty-nine C-type AVAs have been identified in oats, and twenty-six A-type AVAs.
C-type AVAs in commercially available oat products range from 36.49-61.77 mg/kg (fresh weight).
A-type AVAs represent approximately 22.5% of total AVA levels in regular oats and 24.7-33.0% in commercial sprouted oats.
Steeping raw groats increased AVA concentrations.”
“Since publication of these two reviews, a few new studies reported AVAs’ beneficial health effects, mainly related to their anti-inflammatory and anti-cancer activities. AVAs can:
Significantly decrease IL-6, IL-8, and MCP-1 in endothelial cells;
Inhibit IL-1β- and TNF-α-induced NF-κB activation; as well as
Expression of adhesion molecules; and
Adhesion of monocytes to endothelial cell monolayer.
In 2020, the first evaluation of anti-inflammation effects of A-type AVAs was published from our own group. Fifteen A-type AVAs from commercial sprouted oat products interacted with lipopolysaccharide-induced nitric oxide production and iNOS expression.
Colloidal oatmeal’s natural components, AVAs, help to restore and maintain skin barrier function. AVAs are safe, well tolerated, and can be effective as adjuvant treatment in atopic dermatitis.
In one mouse model, a C-type AVA was able to mitigate many adverse effects of Alzheimer’s Disease. It restored hippocampal long-term potentiation and synaptic function, enhanced memory function, suppressed pro-inflammatory cytokines TNF-α and IL-6 levels, reduced caspase-3 levels, and increased pS9GSK-3β and IL-10 levels.
AVAs downregulated expression of hTERT and MDR1, pro-survival genes for cancer cells, and COX-2 mRNA and PGE2 levels, known pro-inflammatory markers. AVAs induced apoptosis by activating caspases 8, 3, and 2.”
Two papers illustrated how actions of food compounds are affected by their contexts. The first was a 2020 UCLA rodent study:
“Long-chain polyunsaturated fatty acids (PUFAs), particularly omega-3 (n-3) PUFAs, have been indicated to play important roles in various aspects of human health. Controversies are observed in epidemiological and experimental studies regarding the benefits or lack of benefits of n-3 PUFAs.
Dietary docosahexaenoic acid (DHA; 22:6 n-3) supplementation improved select metabolic traits and brain function, and induced transcriptomic and epigenetic alterations in hypothalamic and hippocampal tissues in both context-independent and context-specific manners:
In terms of serum triglyceride, glycemic phenotypes, insulin resistance index, and memory retention, DHA did not affect these phenotypes significantly when examined on the chow diet background, but significantly improved these phenotypes in fructose-treated animals.
Genes and pathways related with tissue structure were affected by DHA regardless of the dietary context, although the direction of changes are not necessarily the same between contexts. These pathways may represent the core functions of DHA in maintaining cell membrane function and cell signaling.
DHA affected the mTOR signaling pathway in hippocampus. In the hypothalamus, altered pathways were more related to innate immunity, such as cytokine-cytokine receptors, NF-κB signaling pathway, and Toll-like receptor signaling pathway.
DHA exhibits differential influence on epigenetic loci, genes, pathways, and metabolic and cognitive phenotypes under different dietary contexts.”
“The biological activities of food phytochemicals depend upon their bioaccessibility and bioavailability which can be affected by the presence of other food components including other bioactive constituents. For instance, α-tocopherol mixed with a flavonol (kaempferol or myricetin) is more effective in inhibiting lipid oxidation induced by free radicals than each component alone.
Interactions of phytochemicals may enhance or reduce the bioavailability of a given compound, depending on the facilitation/competition for cellular uptake and transportation. For example, β-carotene increases the bioavailability of lycopene in human plasma, and quercetin-3-glucoside reduces the absorption of anthocyanins.
Combinations of food extracts containing hydrophilic antioxidants and lipophilic antioxidants showed very high synergistic effects on free radical scavenging activities. A number of phytochemical mixtures and food combinations provide synergistic effects on inhibiting inflammation.
More research should be conducted to understand mechanisms of bioavailability interference considering physiological concentrations, food matrices, and food processing.”
Each of us can set appropriate contexts for our food consumption. Broccoli sprout synergies covered how I take supplements and broccoli sprouts together an hour or two before meals to keep meal contents from lowering sulforaphane bioavailability.
Combinations of my 19 supplements and broccoli sprouts are too many (616,645) for complete analyses. Just pairwise comparisons like the second paper’s example below would be 190 combinations.
Contexts for each combination’s synergistic, antagonistic, or additive activities may also be influenced by other combinations’ results.
My consumption of flax oil (alpha linolenic acid C18:3) probably has effects similar to DHA since it’s an omega-3 PUFA and I take it with food. The first study’s human equivalent DHA dose was 100mg/kg, with its citation for clinical trials stating “1–9 g/day (0.45–4% of calories) n-3 PUFA.”
This 2020 Swiss review subject was potential glutathione therapies for stress:
“We examine available data supporting a role for GSH levels and antioxidant function in the brain in relation to anxiety and stress-related psychopathologies. Several promising compounds could raise GSH levels in the brain by either increasing availability of its precursors or expression of GSH-regulating enzymes through activation of Nrf2.
GSH is the main cellular antioxidant found in all mammalian tissues. In the brain, GSH homeostasis has an additional level of complexity in that expression of GSH and GSH-related enzymes are not evenly distributed across all cell types, requiring coordination between neurons and astrocytes to neutralize oxidative insults.
Increased energy demand in situations of chronic stress leads to mitochondrial ROS overproduction, oxidative damage and exhaustion of GSH pools in the brain.
Several compounds can function as precursors of GSH by acting as cysteine (Cys) donors such as taurine or glutamate (Glu) donors such as glutamine (Gln). Other compounds stimulate synthesis and recycling of GSH through activation of the Nrf2 pathway including sulforaphane and melatonin. Compounds such as acetyl-L-carnitine can increase GSH levels.”
Many animal studies of “stress-related psychopathologies” were cited without noting applicability to humans. These reviewers instead had curious none-of-this-means-anything disclaimers like:
“Comparisons between studies investigating brain disorders of such different nature such as psychiatric disorders or neurodegenerative diseases, or even between brain or non-brain related disorders should be made with caution.”
Regardless, this paper had informative sections for my 27th week of eating broccoli sprouts every day.
1. I forgot to mention in Broccoli sprout synergies that I’ve taken 500 mg of trimethyl glycine (aka betaine) twice a day for over 15 years. Section 3.1.2 highlighted amino acid glycine:
“Endogenous synthesis is insufficient to meet metabolic demands for most mammals (including humans) and additional glycine must be obtained from diet. While most research has focused on increasing cysteine levels in the brain in order to drive GSH synthesis, glycine supplementation alone or in combination with cysteine-enhancing compounds are gaining attention for their ability to enhance GSH.”
2. Amino acid taurine dropped off my supplement regimen last year after taking 500 mg twice a day for years. It’s back on now after reading Section 3.1.3:
“Most studies that reported enhanced GSH in the brain following taurine treatment were performed under a chronic regimen and used in age-related disease models.
Such positive effects of taurine on GSH levels may be explained by the fact that cysteine is the essential precursor to both metabolites, whereby taurine supplementation may drive metabolism of cysteine towards GSH synthesis.”
“Thalamic GSH values significantly correlated with blood GSH levels, suggesting that peripheral GSH levels may be a marker of brain GSH content. Studies point to the capacity of sulforaphane to function both as a prophylactic against stress-induced behavioral changes and as a positive modulator in healthy animals.”
This 2020 review attempted to consolidate thousands of research papers on oxytocin:
“Chemical properties of oxytocin make this molecule difficult to work with and to measure. Effects of oxytocin are context-dependent, sexually dimorphic, and altered by experience. Its relationship to a related hormone, vasopressin, have created challenges for its use as a therapeutic drug.
Widely used medical interventions i.e.:
Exogenous oxytocin, such as Pitocin given to facilitate labor;
Opioid medications that block the oxytocin system; or
Cesarean sections that alter exposure to endogenous oxytocin
have lasting consequences for the offspring and/or mother.
Such exposures hold the potential to have epigenetic effects on the oxytocin systems, including changes in DNA methylation. These changes in turn would have lasting effects on the expression of receptors for oxytocin, leaving individuals differentially able to respond to oxytocin and also possibly to the effects of vasopressin.
Regions with especially high levels of OXTR [oxytocin receptor gene] are:
Decreasing a chromatin protein that is released during inflammation
which can activate microglia through the receptor for advanced glycation end products (RAGE). RAGE acts as an oxytocin-binding protein facilitating the transport of oxytocin across the blood-brain barrier and through other tissues.
Directionality of this transport is 5–10 times higher from the blood to the brain, in comparison with brain to blood transport. Individual differences in RAGE could help to predict cellular access to oxytocin and might also facilitate access to oxytocin under conditions of stress or illness.
Oxytocin and vasopressin and their receptors are genetically variable, epigenetically regulated, and sensitive to stressors and diet across the lifespan. As one example, salt releases vasopressin and also oxytocin.
Nicotine is a potent regulator of vasopressin. Smoking, including prenatal exposure of a fetus, holds the potential to adjust this system with effects that likely differ between males and females and that may be transgenerational.
Relative concentrations of endogenous oxytocin and vasopressin in plasma were associated with:
Frank interpretations of one’s own study findings to acknowledge limitations is one way researchers can address items upfront that will be questioned anyway. Such analyses also indicate a goal to advance science.
Although these reviewers didn’t provide concrete answers to many questions, they highlighted promising research areas, such as:
Improved approaches to oxytocin measurements;
Prenatal epigenetic experience associations with oxytocin and OXTR; and
Possible transgenerational transmission of these prenatal epigenetic experiences.
A trio of papers, with the first being a 2017 review exploring broccoli sprout compounds’ effects on head hair:
“Skin appendages, notably hair follicles (HFs), can be exposed to high levels of reactive oxygen species (ROS), which are generated through metabolic reactions occurring mostly in the mitochondria, peroxisomes and the endoplasmic reticulum as well as in the plasma membrane. Despite their involvement in redox stress and cellular damage, ROS also have key roles in physiological signalling processes, including but not limited to, control of stem cell quiescence / differentiation, regulation of innate and adaptive immune responses and importantly, normal HF development.
HFs are composed of a series of concentric keratinocyte layers with a central hair shaft, all of which are encapsulated by a mesenchymal connective tissue sheath. Within this structure is an area known as the ‘bulge’, housing a population of epithelial and melanocyte stem cells. The hair bulb, the lowermost portion of the HF, contains transient amplifying cells that produce the rapidly proliferating matrix keratinocytes that give rise to the various cell types of the inner root sheath and hair shaft itself.
Putative impact of NRF2 activation on protection against hair disorders:
Accumulation of excess ROS within crucial HF compartments (i.e. bulb and bulge) can be induced by endogenous and exogenous stressors associated with androgenetic alopecia (AGA), alopecia areata (excessive mast cell degranulation), chemotherapy, UV exposure and even physiological processes such as melanogenesis.
In the HFSCs [hair follicle stem cells] of the bulge, this can lead to reduced FOXP1 signaling, increased senescence and P21-mediated telogen retention, contributing the hair ageing.
In the hair bulb, negative consequences of excessive ROS can include reduced matrix keratinocyte proliferation and Bcl-2 expression, coupled to increased p53 activity and apoptosis. This redox imbalance may also stimulate the dermal papilla-derived TGF-b1 release associated with AGA.
NRF2 activation via SFN [sulforaphane] can induce the expression of numerous downstream targets, hence suggesting the potential to counteract excessive ROS and associated pathologies, for example via enhanced clearance of reactive species, detoxification, NADPH generation and GSH maintenance.
In addition, NRF2 may down-regulate genes that would negatively impact on proliferation and stimulate apoptosis.
Ultimately, the activation of NRF2 has the potential to protect against HF miniaturization, chemotherapy-induced apoptosis, HFSC aging and hair greying, through maintenance of normal redox homeostasis.
Whereas eumelanin (black) is involved in natural UV protection by reducing generation of free radicals, pheomelanin (red) can trigger generation of ROS. It would certainly be interesting to determine whether NRF2 activity is therefore higher in individuals with red as opposed to black hair, in order to mitigate any negative impact from higher ROS generation.
Modulation of NRF2 activity is an attractive approach for further study in the prevention of hair greying and HFSC ageing. The remarkable prospect for NRF2 activators in modulating other oxidative stress-linked disease states, strongly advocates for the development of NRF2 targeting as a novel strategy in modulating redox-associated disorders of the HF.”
“This study aimed to assess the potential of genetic data to predict hair greying in a population of nearly 1000 individuals from Poland. Most of the prediction information was brought by age alone. Genetic variants explained < 10% of hair greying variation and the impact of particular SNPs on prediction accuracy was found to be small.
Study population included 673 males (67.4%) and 325 (32.6%) females. The mean age of the participants was 30.5 ± 8.8.
Hair greying was recorded in 14.3% of individuals aged 18–30 and the prevalence of grey hair was noted to be significantly higher in young males when comparing to young females (17.8 and 9.2%, respectively). The incidence of grey hair increased to 29.5% in the group of people aged 18–40 years and was 84.2% when people aged ≥40 years were considered.
Because pleiotropy is so common, it would be impossible to predict natural phenotypes avoiding genes involved in determination of pathological phenotypes. The penetrance of individual SNP variants is usually low and they altogether can only explain a small fraction of the predisposition to the disease.
Prediction of hair greying status solely based on genetic information is currently impossible.”
A 2020 review had a pertinent evaluation scheme:
“Geroprotectors are pharmacological agents that decrease the rate of aging and extend lifespan. We proposed a set of primary and secondary selection criteria for potential geroprotectors. Primary criteria:
The life extension in experiments with wild type animal models. The geroprotector should prolong the life of the model beyond the intact maximum lifespan, protecting it from one or more mechanisms of aging.
Improvement of molecular, cellular, and physiological biomarkers to a younger state or slow down the progression of age-related changes in humans.
Most potential geroprotectors are preventive only when applied at relatively high concentrations. The lifespan-extending dose should be several orders of magnitude less than the toxic dose.
Minimal side effects at the therapeutic dosage at chronic application.
The potential benefit of taking a geroprotector may come after a long period. Potential geroprotectors should initially improve some parameters of health-related quality of life: physical, mental, emotional, or social functioning of the person.”
“Vitamin D administration decreased tumor incidence and size, and the co-administration with SFN [sulforaphane] magnified the effects. The addition of SFN decreased the activity of histone deacetylase and increased autophagy.”
Protecting mitochondrial enzymes and/or stimulating mitochondrial enzyme activities, for example, enzyme cofactors, such as B vitamins and coenzyme Q10 .
In addition to using mitochondrial nutrients individually, the combined use of mitochondrial nutrients may provide a better strategy for mitochondrial protection.”
The review provided a boatload of mitochondrial multifactorial analyses for Alzheimer’s. But these analyses didn’t include effective mitochondrial treatments of ultimate aging causes. I didn’t see evidence of why, after fifteen years of treating mitochondrial effects with supplements, treating one more effect could account for my Week 9 vastly different experiences.
“It is clear that the increasing number of senescent cells depends on the post-adult developmental stage rather than chronological age. The coincidence that these processes result in particular forms of impairment in old age does not seem to be random as it is present in all mammals, and may be causative of many aspects of aging.”
A derived hypothesis: After sufficient strength and duration, broccoli sprout compounds changed my signaling environment, with appreciable effects beginning in Week 9.
I offered weak supporting evidence in Upgrade your brain’s switchboard with broccoli sprouts where a study’s insufficient one week duration of an insufficient daily 17.3 mg sulforaphane dosage still managed to change a blood antioxidant that may have changed four thalamus-brain-area metabolites. For duration and weight comparisons, I doubled my daily amount of broccoli seeds from one to two tablespoons just before Week 6 (Day 35), and from that point onward consumed a estimated 52 mg sulforaphane with microwaving 3-day-old broccoli sprouts every day.
Maybe a promised “In a submitted study, we will report that peripheral GSH levels may be correlated with cognitive functions” will provide stronger evidence? I’m not holding my breath for relevant studies because:
There wouldn’t be potential payoffs for companies to study any broccoli sprout compound connections with research areas such as aging, migraines, etc. Daily clinically-relevant broccoli sprout dosages can be grown for < $500 a year.
Sponsors would have to change paradigms, a very-low-probability event. They’d have to explain why enormous resources dedicated to current frameworks haven’t produced effective long-term treatments.
What long-term benefits could be expected if I continue eating broccoli sprouts every day?
“Biomarkers of effect need more time than biomarkers of exposure to be influenced by dietary treatment.”
A contrary argument: Perhaps people don’t require long durations to effectively change their signaling environments?
I apparently didn’t start eating an effective-for-me daily broccoli sprouts dosage until Day 35, when I changed from one to two tablespoons of broccoli seeds a day. If so, Weeks 6 through 8 may account for my substantial responses during Week 9.
Could eating broccoli sprouts every day for four weeks dramatically change a person’s signaling environment?
Do you have four weeks and $38 to find out? Two tablespoons of broccoli seeds = 21.4 g x 30 days = .642 kg or 1.42 lbs.
This is what twice-a-day one-tablespoon starting amounts of broccoli seeds look like through three days:
Maintaining the sprouting process hasn’t been a big effort compared with the benefits.
In the absence of determinative evidence, I’ll continue eating broccoli sprouts every day. Several areas of my annual physical have room for improvements. Extending my four lifestyle “interventions” a few more months may also provide hints toward inadequately researched connections.
* Results may not be extrapolatable to other people, to any specific condition, etc.
“The risk of bias was high in both trials of different ALC doses and low in the other two trials.
No included trial measured the proportion of participants with at least moderate (30%) or substantial (50%) pain relief.
At doses greater than 1500 mg/day, ALC reduced pain more than placebo. This subgroup analysis should be viewed with caution as the evidence was even less certain than the overall analysis, which was already of very low certainty.
The placebo-controlled studies did not measure functional impairment and disability scores.
No study used validated symptom scales.
Two studies were funded by the manufacturer of ALC and the other two studies had at least one co-author who was a consultant for an ALC manufacturer.
We are very uncertain whether ALC causes a reduction in pain after 6 to 12 months treatment in people with DPN, when compared with placebo, as the evidence is sparse and of low certainty.
Data on functional and sensory impairment and symptoms are lacking, or of very low certainty.
The evidence on adverse events is too uncertain to make any judgements on safety.”
“A long history of diabetes mellitus and increasing age are associated with the onset of diabetic neuropathy, a painful and highly disabling complication with a prevalence peaking at 50% among elderly diabetic patients. The management of diabetic neuropathy is extremely difficult: in addition to the standard analgesics used for pain control, common treatments include opioids, anticonvulsants, antidepressants, and local anesthetics, alone or in combination. Such therapies still show a variable, often limited efficacy, however.
Many patients do not spontaneously report their symptoms to physicians, but, if asked, they often describe having experienced a persistent and non-abating pain for many years. The prevalence of painful symptoms is just as high in patients with mild neuropathy as in those with more advanced DPN.
Through the donation of acetyl groups, ALC exerts a positive action on mitochondrial energy metabolism. ALC has cytoprotective, antioxidant, and antiapoptotic effects in the nervous system.
ALC has also been proposed for the treatment of other neurological and psychiatric diseases, such as mood disorders and depression, dementia, Alzheimer’s disease, and Parkinson’s disease, given that synaptic energy states and mitochondrial dysfunctions are core factors in their pathogenesis. Compared to other treatments, ALC is safe and extremely well tolerated.”
“In nerve injury, the mGlu2 receptor overexpressed by ALC binds the glutamate, reducing its concentration in the synapses with an analgesic effect. ALC may improve nerve regeneration and damage repair after primary nerve trauma.”
Where will the money come from to realize what the 2017 review promised, as well as provide what the 2019 meta-analysis required?
Do we prefer the current “limited efficacy” treatments of “opioids, anticonvulsants, antidepressants, and local anesthetics?”
Who will initiate clinical trials of a multiple of the normal dietary supplement dose (500 mg at $.25 a day, retail)? How profitable is a product whose hypothetical effective dosage for diabetic neuropathy (3000 mg) sells for only $1.50 a day?
This 2019 US rodent study concerned transmitting poor maternal care to the next generation:
“The quality of parental care received during development profoundly influences an individual’s phenotype, including that of maternal behavior. Infant experiences with a caregiver have lifelong behavioral consequences.
Maternal behavior is a complex behavior requiring the recruitment of multiple brain regions including the nucleus accumbens, bed nucleus of the stria terminalis, ventral tegmental area, prefrontal cortex, amygdala, and medial preoptic area. Dysregulation within this circuitry can lead to altered or impaired maternal responsiveness.
We administered zebularine, a drug known to alter DNA methylation, to dams exposed during infancy to the scarcity-adversity model of low nesting resources, and then characterized the quality of their care towards their offspring.
We replicate that dams with a history of maltreatment mistreat their own offspring.
We show that maltreated-dams treated with zebularine exhibit lower levels of adverse care toward their offspring.
We show that administration of zebularine in control dams (history of nurturing care) enhances levels of adverse care.
We show altered methylation and gene expression in maltreated dams normalized by zebularine.
These findings lend support to the hypothesis that epigenetic alterations resulting from maltreatment causally relate to behavioral outcomes.”
“Maternal behavior is an intergenerational behavior. It is important to establish the neurobiological underpinnings of aberrant maternal behavior and explore treatments that can improve maternal behavior to prevent the perpetuation of poor maternal care across generations.”
The study authors demonstrated intergenerational epigenetic effects, and missed an opportunity to also investigate transgenerational epigenetically inherited effects. They cited reference 60 for the first part of the above quotation, but the cited reviewer misused the transgenerational term by applying it to grand-offspring instead of the great-grand-offspring.
There were resources available to replicate the study authors’ previous findings, which didn’t show anything new. Why not use such resources to uncover evidence even more applicable to humans by extending experiments to great-grand-offspring that would have no potential germline exposure to the initial damaging cause?
This 2018 US government rodent study used extreme dosages to achieve its directed goals of demonizing nicotine and extolling the biomarker paradigm:
“This study examined whether adolescent nicotine exposure alters adult hippocampus-dependent learning, involving persistent changes in hippocampal DNA methylation and if choline, a dietary methyl donor, would reverse and mitigate these alterations.
Mice were chronically treated with nicotine (12.6mg/kg/day) starting at post-natal day 23 (pre-adolescent), p38 (late adolescent), or p54 (adult) for 12 days followed by a 30-day period during which they consumed either standard chow or chow supplemented with choline (9g/kg).
Our gene expression analyses support this model and point to two particular genes involved in chromatin remodeling, Smarca2 and Bahcc1. Both Smarca2 and Bahcc1 showed a similar inverse correlation pattern between promoter methylation and gene expression.
Our findings support a role for epigenetic modification of hippocampal chromatin remodeling genes in long-term learning deficits induced by adolescent nicotine and their amelioration by dietary choline supplementation.”
Let’s use the average weight of a US adult male – published by the US Centers for Disease Control as 88.8 kg – to compare the study’s dosages with human equivalents:
Neither of these dosages are even remotely connected to human realities:
The human-equivalent dosage of nicotine used in this study would probably kill an adult human before the end of 12 days.
What effects would an adult human suffer from exceeding the choline “Tolerable Upper Intake Level” BY 228 TIMES for 30 days?
Isn’t the main purpose of animal studies to help humans? What’s the justification for performing animal studies simply to promote an agenda?
A funding source of this study was National Institute on Drug Abuse (NIDA) Identification of Biomarkers for Nicotine Addiction award (T-DA-1002 MG). Has the biomarker paradigm been institutionalized to the point where research proposals that don’t have biomarkers as goals aren’t funded?
This 2018 Chinese study electronically modeled the brain’s circuits to evaluate memory transfer mechanisms:
“During non-rapid-eye-movement (NREM) sleep, thalamo-cortical spindles and hippocampal sharp wave-ripples have been implicated in declarative memory consolidation. Evidence suggests that long-term memory consolidation is coordinated by the generation of:
enabling memory transfer from the hippocampus to the cortex.
Consolidation has also been demonstrated in other brain tasks, such as:
In the acquisition of motor skills, where there is a shift from activity in prefrontal cortex to premotor, posterior parietal, and cerebellar structures; and
In the transfer of conscious to unconscious tasks, where activity in initial unskilled tasks and activity in skilled performance are located in different regions, the so-called ‘scaffolding-storage’ framework.
By separating a neural circuit into a feedforward chain of gating populations and a second chain coupled to the gating chain (graded chain), graded information (i.e. information encoded in firing rate amplitudes) may be faithfully propagated and processed as it flows through the circuit. The neural populations in the gating chain generate pulses, which push populations in the graded chain above threshold, thus allowing information to flow in the graded chain.
In this paper, we will describe how a set of previously learned synapses may in turn be copied to another module with a pulse-gated transmission paradigm that operates internally to the circuit and is independent of the learning process.”
The study had neither been peer-reviewed, nor were the mechanisms tested in living beings.
This 2018 Loma Linda review subject was gestational hypoxia:
“Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic-pituitary-adrenal axis and adipose tissue.
An understanding of the specific hypoxia-induced environmental and epigenetic adaptations linked to specific organ systems will enhance the development of target-specific inhibition of DNA methylation, histone modifications, and noncoding RNAs that underlie hypoxia-induced phenotypicprogramming of disease vulnerability later in life.
A potential stumbling block to these efforts, however, relates to timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.
With future developments, it may even become possible to intervene before conception, before the genetic determinants of the risk of developing programmed disease are established.”
Table 3 “Antenatal hypoxia and developmental plasticity” column titles were Species | Offspring Phenotypes of Disorders and Diseases | Reference Nos.
This review was really an ebook, with 94 pages and 1,172 citations in the pdf file. As I did with Faith-tainted epigenetics, I read it with caution toward recognizing 1) the influence of the sponsor’s biases, 2) any directed narrative that ignored evidence contradicting the narrative, and 3) any storytelling.
One review topic that was misconstrued was transgenerational epigenetic inheritance of hypoxic effects. The “transgenerational” term was used inappropriately by several of the citations, and no cited study provided evidence for gestational hypoxic effects through the F3 great-grandchild generation.
“One substance that fetuses are frequently exposed to is caffeine, which is a non-selective adenosine receptor antagonist. We discovered that in utero alteration in adenosine action leads to adverse effects on embryonic and adult murine hearts. We find that cardiac A1ARs [a type of adenosine receptor] protect the embryo from in utero hypoxic stress, a condition that causes an increase in adenosine levels.
After birth in mice, we observed that in utero caffeine exposure leads to abnormal cardiac function and morphology in adults, including an impaired response to β-adrenergic stimulation. Recently, we observed that in utero caffeine exposure induces transgenerational effects on cardiac morphology, function, and gene expression.”
Why was this review and its studies omitted? It was on target for both gestational hypoxia and transgenerational epigenetic inheritance of hypoxic effects!
It was alright to review smoking, cocaine, methamphetamine, etc., but the most prevalent drug addiction – caffeine – couldn’t be a review topic?
The Loma Linda review covered a lot, but I had a quick trigger due to the sponsor’s bias. I started to lose “faith” in the reviewers after reading the citation for the review’s last sentence that didn’t support the statement.
My “faith” disappeared after not understanding why a few topics were misconstrued and omitted. Why do researchers and sponsors ignore, misrepresent, and not continue experiments through the F3 generation to produce evidence for and against transgenerational epigenetic inheritance? Where was the will to follow evidence trails regardless of socially acceptable beverage norms?
The review acquired the taint of storytelling with the reviewers’ assertion:
“..timing of the intervention. The greatest potential effect would be accomplished at the critical period in development for which the genomic plasticity is at its peak, thus ameliorating the influence of hypoxia or other stressors.”
Contradictory evidence was in the omitted caffeine study’s graphic above which described two gestational critical periods where an “intervention” had opposite effects, all of which were harmful to the current fetus’ development and/or to following generations. Widening the PubMed link’s search parameters to “caffeine hypoxia” and “caffeine pregnancy” returned links to human early life studies that used caffeine in interventions, ignoring possible adverse effects on future generations.
This is my final curation of any paper sponsored by this institution.