4-5 stars Advanced knowledge

Advanced knowledge

A mechanistic study of neurotransmitters in the hippocampus

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

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”

Words are neither the problem nor the solution

gettingwell4 4-5 stars Advanced knowledge, Cerebrum, Limbic system, Lower brain, Primal Therapy , , , , , ,

“Words are neither the problem nor the solution. They are the last evolutionary step in processing the feeling or sensation. They are the companions of feelings.

We cannot make progress on the third-line cognitive level alone. We can become aware of why we act the way we do but nothing changes biologically; it is like being aware of a virus and expecting the awareness alone to kill it. Our biology has been left out of the therapeutic equation.”

Janov’s Reflections on the Human Condition: On the Difference Between Abreaction and Feeling (Part 6/9).

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”

Further limits on using monkeys to understand human brains

gettingwell4 4-5 stars Advanced knowledge, Brain hemispheres, Cerebrum

This 2015 Columbia human/macaque study found:

“Fundamental differences in the attention-related brain areas in the two species, including the complete absence, in monkeys, of a ventral-attention network present in humans.

We did not find functional evidence of a temporoparietal junction in macaques.

The two species last shared a common ancestor 25 million years ago, and in the intervening time the brain areas underlying cognition have likely evolved along different paths.

The results of this study indicate that macaque data should be applied to human models of cognition cautiously, and demonstrate how evolution may shape cortical networks.”

The main point of this study was the same as noted in Limits of dMRI brain studies, which advised – instead of performing studies on monkeys to understand humans:

“Assess human anatomical connections directly and comprehensively.”

We can look forward to times when using macaques in studies such as:

is no longer acceptable.

http://www.pnas.org/content/112/30/9454.full “Functional evolution of new and expanded attention networks in humans”

Genetic statistics don’t necessarily predict the effects of an individual’s genes

gettingwell4 4-5 stars Advanced knowledge, Epigenetics

I curated this 2015 Howard Hughes Medical Institute rodent study of DNA methylation because of the reason driving the researchers’ efforts:

“Epigenomic analyses are limited by averaging of population-wide dynamics and do not inform behavior of single cells. We observe dynamics at the single-cell level not predicted by epigenomic analysis.”

This rationale was also the driving force behind the Is what’s true for a population what’s true for an individual? study and its companion Changing an individual’s future behavior even before they’re born. The methodology of genome-wide association studies (GWAS) usually:

“Focuses on the average effect of alternative alleles averaged in a population.”

What this methodology often missed was:

“When phenotypic variation results from alleles that modify phenotypic variance rather than the mean, this link between genotype and phenotype will not be detected.”

Population-wide epigenetic statistics don’t necessarily inform us about the epigenetic activities and attributes of an individual’s genes, even down at the single-cell level.

http://www.pnas.org/content/112/31/E4216.full “The Xist RNA-PRC2 complex at 20-nm resolution reveals a low Xist stoichiometry and suggests a hit-and-run mechanism in mouse cells”

How brain neurons remain stable when constantly stimulated

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

This 2015 UK rodent study provided details of how neurons in the hippocampus respond to stimuli. The researchers found that hippocampal neurons:

“Remain electrically stable when confronted with chronic increases in neuronal activity.”

Changes in electrical potential changed the initial segment of the neuron’s axon.

Synapses formed along the segment, and stayed in place while this highly-plastic segment moved along the axon. The location mismatch:

“Allows the GABAergic [producing gamma-Aminobutyric acid, an inhibitory neurochemical] synapses to strongly oppose action potential generation, and thus downregulate pyramidal cell excitability.”

The researchers also used the two antioxidants endogenous to humans, superoxide dismutase and glutathione, to supplement the culture medium.

http://www.pnas.org/content/112/31/9757.full “Activity-dependent mismatch between axo-axonic synapses and the axon initial segment controls neuronal output”

A walk in the park increases poor research practices and decreases reviewer critical thinking

gettingwell4 4-5 stars Advanced knowledge

“That’s right folks – the key behavioral interaction of the paper – is non-significant. Measly. Minuscule.

Forget about p-values for a second and consider the gall it takes to not only completely skim over this fact (nowhere in the paper is it mentioned) and head right to the delicious t-tests, but to egregiously promote this ‘finding’ in the title, abstract, and discussion as showing evidence for an effect of nature on rumination!

No correlations with the (non-significant) behavior. Just pure and simple reverse inference piled on top of fallacious interpretation of a non-significant interaction.”

http://www.pnas.org/content/112/28/8567.full “Nature experience reduces rumination and subgenual prefrontal cortex activation”

One way our bodies remember our histories

gettingwell4 4-5 stars Advanced knowledge, Immune system, Memory

This 2015 California rodent study found:

“Potentially pathogenic memory cells in lymph nodes and redistribution throughout normal and inflamed skin may help explain the generalized worsening of psoriasis reported in patients undergoing localized skin treatment with imiquimod.”

The opening sentence was:

“An attribute of adaptive immunity is the generation of memory cells that mount enhanced responses after rechallenge.”

Of course an immune system remembers – that’s part of its function.

When the subject is memory, let’s not disregard the multiple ways that our bodies remember our histories.

http://www.pnas.org/content/112/26/8046.full “Inflammation induces dermal Vγ4+ γδT17 memory-like cells that travel to distant skin and accelerate secondary IL-17–driven responses”

The effects of inescapable, uncontrollable, repeated stress on the hippocampus

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

This 2015 MIT rodent study found:

“Behavioral stress impairs cognitive function via activation of a specific direct neural circuit from the basolateral amygdala to the dorsal hippocampus. Moreover, we delineate a molecular mechanism by which behavioral stress is translated to hippocampal dysfunction via a p25/Cdk5 (cyclin-dependent kinase 5)-dependent pathway and epigenetic alterations of neuroplasticity-related gene expression.”

The researchers made several intermediate findings to develop their main finding:

1. “Repeated stress is accompanied by

  • generation of p25,
  • up-regulation and phosphorylation of glucocorticoid receptors,
  • increased HDAC2 [the gene encoding the histone deacetylase 2 enzyme] expression, and
  • reduced expression of memory-related genes [most, but not all that were tested] in the hippocampus.”

2. “BLA [basolateral amygdala] activation is both necessary and sufficient for stress-associated molecular changes and memory impairments.”

3. “This effect [2. above] relies on direct glutamatergic projections from the BLA to the dorsal hippocampus.”

4. “p25 generation is necessary for the stress-induced memory dysfunction.”

From the Results section:

“Control mice showed a significant preference for the novel over the familiar object or location, whereas RFS [repetitive foot shock]-treated mice performed no better than chance.”

The subject adult mice underwent:

“Inescapable, uncontrollable repeated stress.”

Do humans also experience impaired “cognitive function” and “hippocampal dysfunction” and “epigenetic alterations of neuroplasticity-related gene expression” caused by “inescapable, uncontrollable repeated stress”?

And what are the real histories of people who aren’t curious, who don’t show “a significant preference for the novel over the familiar object or location”?

http://www.pnas.org/content/112/23/7291.full “Basolateral amygdala bidirectionally modulates stress-induced hippocampal learning and memory deficits through a p25/Cdk5-dependent pathway”

Epigenetic changes in the developing brain change behavior

gettingwell4 4-5 stars Advanced knowledge, Brain development, Epigenetics, Hippocampus, Limbic system, Neurochemicals, Serotonin, Stress , , , , ,

This 2015 review cited 143 studies to tie together findings in epigenetic chemistry and behavioral neuroscience.

In addition to studies I’ve previously curated, other research included:

  • a 2012 study which completely abolished mouse maternal behavior by silencing a gene encoding an estrogen receptor;
  • a 2012 study which found that stress-induced changes in the rat hippocampus were heritable;
  • a 2014 study that distinguished between transgenerational and intergenerational epigenetic effects such as:

    “in utero exposure to nutritional status, stress, or toxic environmental factors that act on the developing embryo and its germ line”

  • a 2013 study that showed how genomic imprinting coordinated:

    “Genetic coadaptation where beneficially interacting alleles evolve to become coinherited.”

The current status of research incorporating both epigenetic chemistry and behavioral neuroscience was summed up as:

“A large number of behavioral epigenetic studies attempt to correlate epigenetic marker changes at global levels and in mixed populations of cells with phenotypic changes.

Specific changes at specific gene levels and at single cell levels correlating with behavioral changes remain largely unknown.”

http://www.pnas.org/content/112/22/6789.full “Epigenetic changes in the developing brain: Effects on behavior”

Stress in early life can alter physiology and behavior across the entire lifespan

gettingwell4 4-5 stars Advanced knowledge, Amygdala, Brain development, Cerebrum, Cortisol, Epigenetics, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress, Testosterone , , , , , , , ,

I’ll quote a few sections of this 2014 summary of 111 studies concerning stress, including the authors’ research:

“The brain is the central organ of stress and adaptation to stressors because:

  • It not only perceives what is threatening or potentially threatening and initiates behavioral and physiological responses to those challenges,
  • But also is a target of the stressful experiences and the hormones and other mediators of the stress response.

The stress history of parents is a significant factor in the resilience of their offspring.

Environmental stress transduces its effects into lasting changes on physiology and behavior, which can vary even among genetically identical individuals.

Stress in early life can alter physiology and behavior across the entire lifespan.

Structural stress memory is even more apparent with regard to gene expression in stress-sensitive brain regions like the hippocampus.

Individual history is important and that there is a memory of stress history retained by neurons at the cellular level in regions like the hippocampus.

Stress has a number of known effects on epigenetic marks in the brain, producing alterations in DNA methylation and histone modifications in most of the stress-sensitive brain regions examined, including the hippocampus, amygdala, and prefrontal cortex.”

It seemed to be taboo to note that most of – and the largest of – detrimental effects of stress occurred during womb-life in the mother’s environment. The authors instead opted for a politically correct “the stress history of parents” phrase.

Referenced studies had findings relevant to the earliest periods of life, including Figure 1:

interactions

“Those organs that show the highest levels of retrotransposon [a repeat element (mobile DNA sequences often involved in mutations) type formed by copy-and-paste mechanisms] activity, such as the brain and placenta, also seem to be both steroidogenic and steroid-sensitive.”

However, Figure 1 was given a beneficial context, and other studies’ findings weren’t mentioned in their contexts of detrimental effects on fetuses of mothers who were stressed while pregnant.

http://www.pnas.org/content/112/22/6828.full “Stress and the dynamic genome: Steroids, epigenetics, and the transposome”

One way beliefs produce pleasure and reward in the cerebrum

gettingwell4 4-5 stars Advanced knowledge, Beliefs, Cerebrum, Dopamine, Neurochemicals ,

This 2014 Singapore human study found:

“Differences in belief learning – the degree to which players were able to anticipate and respond to the actions of others, or to imagine what their competitor is thinking and respond strategically – was associated with variation in three genes which primarily affect dopamine functioning in the medial prefrontal cortex.

In contrast, differences in trial-and-error reinforcement learning – how quickly they forget past experiences and how quickly they change strategy – was associated with variation in two genes that primarily affect striatal dopamine.”

One of the researchers said:

“The findings correlate well with previous brain studies showing that the prefrontal cortex is involved in belief learning, while the striatum is involved in reinforcement learning.”

The study didn’t demonstrate cause and effect, however, and the researchers cautioned:

“It would be mistaken to interpret our results as suggesting that dopamine genes function as “belief learning genes.”

The study added to the science of how beliefs act on the pleasure and reward parts of the cerebrum.

http://www.pnas.org/content/111/26/9615.full.pdf “Dissociable contribution of prefrontal and striatal dopaminergic genes to learning in economic games” (the pdf file is linked because the html had errors)

The critical period for some aspects of human sight can be extended past childhood

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum

This 2013 human study provided further details of critical periods in human development. The study subjects were:

“11 children enrolled in a humanitarian and scientific effort in India that provides corrective surgery to children with treatable cataracts and subsequently studies their visual abilities.”

The researchers found:

“The human visual system can retain plasticity beyond critical periods, even after early and extended blindness.

We define “early-onset” blindness as occurring before 1 y of age. We define “extended” blindness as lasting at least until early childhood, when many visual abilities in normally developing children reach adult levels. Contrast sensitivity in particular develops until approximately age 7 in normally sighted humans.

Of the 11 children, five had no discernible improvement, whereas one child’s vision grew worse, probably because of post-surgical complications. Five of the patients showed remarkable enhancement, however, and of these, an 11-year-old and a 15-year-old showed 30-fold improvement in contrast sensitivity.

“The visual brain can be plastic for longer than we originally thought,” concludes Kalia. “Many of the kids dramatically improve their quality of life.”

http://www.pnas.org/content/111/5/2035.full “Development of pattern vision following early and extended blindness”

The prefrontal cortex develops more repressive function at puberty

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cerebrum, Primal Therapy , ,

This 2014 primate study found:

“The average magnitude of functional connections measured between neurons was lower overall in the prefrontal cortex of peripubertal [age when puberty starts] monkeys compared with adults. The difference resulted because negative functional connections (indicative of inhibitory interactions) were stronger and more prevalent in peripubertal compared with adult monkeys.”

The researchers found more inhibitory functional connections at the onset of puberty than during adulthood. This repressive functionality presumably develops at puberty because that’s when it’s relatively more needed:

“The bias toward increased inhibitory connectivity we report here for young monkeys might also be an intrinsic feature of human prefrontal cortex at a comparable stage of development.”

One hypothesis of Dr. Arthur Janov’s Primal Therapy is that repression is an important function that the prefrontal cortex evolved.

http://www.pnas.org/content/111/10/3853.full “Age-dependent changes in prefrontal intrinsic connectivity”

A possible link between stress responses and human cancers?

gettingwell4 4-5 stars Advanced knowledge, Brain development, Cortisol, Epigenetics, Neurochemicals, Primal Therapy, Stress ,

This 2015 UK rodent study found:

“An unexpected role for the GR [glucocorticoid receptor] in promoting accurate chromosome segregation during mitosis.

We also identify reduced GR expression in several common human cancers, thereby implicating GR as a novel tumor suppressor gene.”

One of the researchers said:

“Cancer is caused by cell division going wrong, but no one has previously looked at the role GR has to play in this process. It’s now clear that it is vital.”

From the study:

“Our findings now show that GR function regulates accurate mitotic progression, with clear implications for human health.

Add a previously unidentified perspective to GR action in cell division, affecting mitotic spindle function.

It may be that this action can be targeted by specific ligands, potentially opening up new therapeutic approaches to treat common cancers.”

The Translating PTSD research findings from animals to humans study also found reduced expression of glucocorticoid receptor genes, which appeared in some rodents after stress. Unfortunately, those researchers’ priorities weren’t to research the causes of this reduced expression.

One relevant hypothesis of Primal Therapy is that trauma in the earliest parts of human life epigenetically impairs the proper functioning of human development processes. A follow-on hypothesis is that the arrival of diseases in later life may be traceable back to the damage done during early-life development processes.

An example of this would be that a developing fetus adapts to being constantly stressed by an anxious and stressed mother. When the changes persist after birth, they may present as maladaptations of the infant to a non-stressful environment. These enduring changes may be among the causes of symptoms decades later such as over- and/or under-reactions to stress.

It seems possible that further research in these areas may find links among human stress responses and human cancers. The current study suggested that the glucocorticoid receptor may play a part in these links.

http://www.pnas.org/content/112/17/5479.full “Glucocorticoid receptor regulates accurate chromosome segregation and is associated with malignancy”