Hippocampus

The current paradigm of child abuse limits pre-childhood causal research

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Brain development, Brainstem, Cerebrum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Locus coeruleus, Lower brain, Neurochemicals, Oxytocin, Serotonin, Stress, Telomeres, Testosterone, Thalamus, Vasopressin , , , , ,

As an adult, what would be your primary concern if you suspected that your early life had something to do with current problems? Would you be interested in effective treatments for causes of your symptoms?

Such information wasn’t available in this 2016 Miami review of the effects of child abuse. The review laid out the current paradigm mentioned in Grokking an Adverse Childhood Experiences (ACE) score, one that limits research into pre-childhood causes for later-life symptoms.

The review’s goal was to describe:

“How numerous clinical and basic studies have contributed to establish the now widely accepted idea that adverse early life experiences can elicit profound effects on the development and function of the nervous system.”

The hidden assumptions of almost all of the cited references were that these distant causes could no longer be addressed. Aren’t such assumptions testable today?

As an example, the Discussion section posed the top nine “most pressing unanswered questions related to the neurobiological effects of early life trauma.” In line with the current paradigm, the reviewer assigned “Are the biological consequences of ELS [early life stress] reversible?” into the sixth position.

If the current paradigm encouraged research into treatment of causes, there would probably already be plenty of evidence to demonstrate that directly reducing the source of damage would also reverse damaging effects. There would have been enough studies done so that the generalized question of reversibility wouldn’t be asked.

Aren’t people interested in treatments of originating causes so that their various symptoms don’t keep bubbling up? Why wouldn’t research paradigms be aligned accordingly?

The review also demonstrated how the current paradigm of child abuse misrepresented items like telomere length and oxytocin. Researchers on the bandwagon tend to forget about the principle Einstein expressed as:

“No amount of experimentation can ever prove me right; a single experiment can prove me wrong.”

That single experiment for telomere length arrived in 2016 with Using an epigenetic clock to distinguish cellular aging from senescence. The review’s seven citations for telomere length that all had findings “associated with” or “linked to” child abuse should now be viewed in a different light.

The same light shone on oxytocin with Testing the null hypothesis of oxytocin’s effects in humans and Oxytocin research null findings come out of the file drawer. See their references, and decide for yourself whether or not:

“Claimed research findings may often be simply accurate measures of the prevailing bias.”

http://www.cell.com/neuron/fulltext/S0896-6273%2816%2900020-9 “Paradise Lost: The Neurobiological and Clinical Consequences of Child Abuse and Neglect”

This post has somehow become a target for spammers, and I’ve disabled comments. Readers can comment on other posts and indicate that they want their comment to apply here, and I’ll re-enable comments.

Beneficial epigenetic effects of mild stress with social support during puberty

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

This 2016 Pennsylvania rodent study found:

“Stress in the context of social support experienced over the pubertal window can promote epigenetic reprogramming in the brain to increase resilience to age-related cognitive decline in females.

These findings are actually consistent with previous studies showing that some amount of adversity, or adversity under more favorable circumstances such as social support or a protective gene polymorphism, provides a measure of ‘grit’ in coping with later life challenges.

Our findings provide a unique perspective on this relationship, as they highlight the important link between experience during the pubertal window and cognitive health during aging.”

These researchers made efforts to further investigate causes of unexpected results, such as:

“Peripubertal stress alone did not significantly alter Barnes maze performance in aging compared to aged Controls. Mice that had experienced stress with concurrent social support (CVS + SI) actually performed better than Control aged mice, specifically in learning the reversal task faster.

Peripubertal stress had no effect on corticosterone levels in response to an acute restraint stress or in sensorimotor gating and baseline startle reactivity.”

Their investigations led to epigenetic findings:

“Consistent with our behavioral findings, stress in the context of social interaction resulted in long-term reprogramming of gene expression in the PFC [prefrontal cortex]. While there were no differentially expressed genes between Control and CVS females, there were 88 genes that were significantly different between Control and CVS + SI groups. Of genes that were downregulated, a large portion (23 genes; 35%) were microRNAs.

We found that the PFC transcriptome of CVS + SI aged females was significantly enriched for predicted targets of the 23 microRNAs that were downregulated in the PFC in these mice. This suggests that microRNAs represent a mode of regulation capable of enacting far-reaching programmatic effects, and are a critical epigenetic gene expression regulatory mechanism.”

Applicability to humans was suggested by associations such as:

“A single microRNA can target more than a hundred different mRNA targets, and more than 45,000 conserved microRNA binding sites have been annotated in the 3′ UTR of 60% of human genes.”

A few limitations were noted:

“Given that mice at this age (1 year) are commonly compared to ‘late middle aged’ humans, later aging time points may yield differences in this group. Alternatively, it is possible that there was an effect of peripubertal stress that was not long-lasting due to the mild nature of our chronic stress model.

To include early neglect as a part of the stressor experience, CVS females were weaned one week earlier (PN21) than Control and CVS + SI mice. Addition of stress of this earlier weaning likely poses a significant contribution to programming of the PFC.”

One of the study coauthors was also a coauthor of:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4870871/ “Peripubertal stress with social support promotes resilience in the face of aging”

A review that inadvertently showed how memory paradigms prevented relevant research

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

This 2016 Swiss review of enduring memories demonstrated what happens when scientists’ reputations and paychecks interfered with them recognizing new research and evidence in their area but outside their paradigm: “A framework containing the basic assumptions, ways of thinking, and methodology that are commonly accepted by members of a scientific community.”

A. Most of the cited references were from decades ago that established these paradigms of enduring memories. Fine, but the research these paradigms excluded was also significant.

B. All of the newer references were continuations of established paradigms. For example, a 2014 study led by one of the reviewers found:

“Successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones.

Recalling remote memories fails to induce histone acetylation-mediated plasticity.”

The researchers elected to pursue a workaround of the memory reconsolidation paradigm when the need for a new paradigm of enduring memories directly confronted them!

C. None of the reviewers’ calls for further investigations challenged existing paradigms. For example, when the reviewers suggested research into epigenetic regulation of enduring memories, they somehow found it best to return to 1984, a time when dedicated epigenetics research had barely begun:

“Whether memories might indeed be ‘coded in particular stretches of chromosomal DNA’ as originally proposed by Crick [in 1984] and if so what the enzymatic machinery behind such changes might be remain unclear. In this regard, cell population-specific studies are highly warranted.”

Two examples of relevant research the review failed to consider:

1. A study that provided evidence for basic principles of Primal Therapy went outside existing paradigms to research state-dependent memories:

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

It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories.”

What impressed me about that study was the obvious nature of its straightforward experimental methods. Why hadn’t other researchers used the same methods decades ago? Doing so could have resulted in dozens of informative follow-on study variations by now, which is my point in Item A. above.

2. A relevant but ignored 2015 French study What can cause memories that are accessible only when returning to the original brain state? which supported state-dependent memories:

“Posttraining/postreactivation treatments induce an internal state, which becomes encoded with the memory, and should be present at the time of testing to ensure a successful retrieval.”

The review also showed the extent to which historical memory paradigms depend on the subjects’ emotional memories. When it comes to human studies, though, designs almost always avoid studying emotional memories.

It’s clearly past time to Advance science by including emotion in research.

http://www.hindawi.com/journals/np/2016/3425908/ “Structural, Synaptic, and Epigenetic Dynamics of Enduring Memories”

Epigenetic effects of diet, and reversing DNA methylation

gettingwell4 2-3 stars Required further work, Acetylcholine, Brain development, Cerebellum, Cerebrum, Cortisol, Dopamine, Epigenetics, Hippocampus, Limbic system, Lower brain, Neurochemicals, Stress , , , , , ,

This 2015 French review focused on:

“The role of maternal health and nutrition in the initiation and progression of metabolic and other disorders.

The effects of various in utero exposures and maternal nutritional status may have different effects on the epigenome. However, critical windows of exposure that seem to exist during development need to be better defined.

The epigenome can be considered as an interface between the genome and the environment that is central to the generation of phenotypes and their stability throughout the life course.”

The reviewer used the term “transgenerational” to refer to effects that were more appropriately termed parental or intergenerational. Per the definition in A review of epigenetic transgenerational inheritance of reproductive disease, for the term to apply there needed to be evidence in at least the next 2 male and/or 3 female generations of:

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

The review had separate sections for animal and human studies.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663595/ “Impact of Maternal Diet on the Epigenome during In Utero Life and the Developmental Programming of Diseases in Childhood and Adulthood”

I arrived at the above review as a result of it citing the 2014 Harvard Reversing DNA Methylation: Mechanisms, Genomics, and Biological Functions. I’ll quote a few items from that review’s informative “Role of DNA demethylation in neural development” section:

“Distinct parts of mammalian brains, including frontal cortex, hippocampus, and cerebellum, all exhibit age-dependent acquisition of 5hmC [an oxidized derivative of 5mC [methylation of the fifth position of cytosine]].

In fact, the genome of mature neurons in adult central nervous system contains the highest level of 5hmC of any mammalian cell-type (~40% as abundant as 5mC in Purkinje neurons in cerebellum). These observations indicate that 5mC oxidation and potentially DNA demethylation may be functionally important for neuronal differentiation and maturation processes.

A comprehensive base-resolution analyses of 5mC and 5hmC in mammalian frontal cortex in both fetal and adult stages indicate that non-CpG methylation (mCH) and CpG hydroxymethylation (hCG) drastically build up in cortical neurons after birth, coinciding with the peak of synaptogenesis and synaptic pruning in the cortex. This study demonstrated that mCH could become a dominant form of cytosine modifications in adult brains, accounting for 53% in adult human cortical neuronal genome.

In mature neurons, intragenic mCH is preferentially enriched at inactive non-neuronal lineage-specific genes, indicating a role in negative regulation of the associated transcripts. By contrast, genic hCG is positively correlated with gene expression levels.”

What’s the underlying question for every brain study to answer?

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Beliefs, Cerebrum, Cortisol, Dopamine, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Primal Therapy, Serotonin, Stress, Testosterone, Thalamus , , , , , ,

Is the underlying question for every brain study to answer:

  • How do our brains internally represent the external world?

Is it:

  • How did we learn what we know?
  • How do we forget or disregard what we’ve learned?
  • What keeps us from acquiring and learning newer or better information?

How about:

  • What affects how we pay attention to our environments?
  • How do our various biochemical states affect our perceptions, learning, experiences, and behavior?
  • How do these factors in turn affect our biology?

Or maybe:

  • Why do we do what we do?
  • How is our behavior affected by our experiences?
  • How did we become attracted and motivated toward what we like?
  • How do we develop expectations?
  • Why do we avoid certain situations?

Not to lose sight of:

  • How do the contexts affect all of the above?
  • What happens over time to affect all of the above?

This 2015 UCLA paper reviewed the above questions from the perspective of Pavlovian conditioning:

“The common definition of Pavlovian conditioning, that via repeated pairings of a neutral stimulus with a stimulus that elicits a reflex the neutral stimulus acquires the ability to elicit that the reflex, is neither accurate nor reflective of the richness of Pavlovian conditioning. Rather, Pavlovian conditioning is the way we learn about dependent relationships between stimuli.

Pavlovian conditioning is one of the few areas in biology in which there is direct experimental evidence of biological fitness.”

The most important question unanswered by the review was:

  • How can its information be used to help humans?

How can Pavlovian conditioning answer: What can a human do about the thoughts, feelings, behavior, epigenetic effects – the person – the phenotype – that they’ve been shaped into?

One example of the unanswered question: the review pointed out in a section about fear extinction that this process doesn’t involve unlearning. Fear extinction instead inhibits the symptoms of fear response. The fear memory is still intact, awaiting some other context to be reactivated and expressed.

How can this information be used to help humans?

  • Is inhibiting the symptoms and leaving the fear memory in place costless with humans?
  • Or does this practice have both potential and realized adverse effects?
  • Where’s the human research on methods that may directly address a painful emotional memory?

One relevant hypothesis of Dr. Arthur Janov’s Primal Therapy is that a person continues to be their conditioned self until they address the sources of their pain. A corollary is that efforts to relieve symptoms seldom address causes.

How could it be otherwise? A problem isn’t cured by ameliorating its effects.

http://cshperspectives.cshlp.org/content/8/1/a021717.full “The Origins and Organization of Vertebrate Pavlovian Conditioning”

Use it or lose it: the interplay of new brain cells, age, and activity

gettingwell4 2-3 stars Required further work, Brain development, Cortisol, Epigenetics, Glutamate, Hippocampus, Hypothalamus, Limbic system, Memory, Neurochemicals, Serotonin, Stress, Telomeres, Testosterone , , , ,

This 2015 German review was of aging and activity in the context of adult neurogenesis:

“Adult neurogenesis might be of profound functional significance because it occurs at a strategic bottleneck location in the hippocampus.

Age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis, because adult neurogenesis is neuronal development under the conditions of the adult brain.

The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes (e.g., in cell or synapse numbers), but emerge on a systems level and above when an organism ages. With respect to adult neurogenesis, only one multilevel experiment including morphology and behavior has been conducted, and, even in that study, only three time points were investigated.

In old age, adult neurogenesis occurs at only a small fraction of the level in early adulthood. The decline does not seem to be ‘regulated’ but rather the by-product of many age-related changes of other sorts.

From a behavioral level down to a synaptic level, activity increases adult neurogenesis. This regulation does not seem to occur in an all-or-nothing fashion but rather influences different stages of neuronal development differently. Both cell proliferation and survival are influenced by or even depend on activity.

The effects of exercise and environmental enrichment are additive, which indicates that increasing the potential for neurogenesis is sufficient to increase the actual use of the recruitable cells in the case of cognitive stimulation. Physical activity would not by itself provide specific hippocampus-relevant stimuli that induce net neurogenesis but be associated with a greater chance to encounter specific relevant stimuli.

Adult hippocampal neurogenesis might contribute to a structural or neural reserve that if appropriately trained early in life might provide a compensatory buffer of brain plasticity in the face of increasing neurodegeneration or nonpathological age-related functional losses. There is still only limited information on the activity-dependent parameters that help to prevent the age-dependent decrease in adult neurogenesis and maintain cellular plasticity.

The big question is what the functional contribution of so few new neurons over so long periods can be. Any comprehensive concept has to bring together the acute functional contributions of newly generated, highly plastic neurons and the more-or-less lasting changes they introduce to the network.”

I’ve quoted quite a lot, but there are more details that await your reading. A few items from the study referenced in the first paragraph above:

“The hippocampus represents a bottleneck in processing..adult hippocampal neurogenesis occurs at exactly the narrowest spot.

We have derived the theory that the function of adult hippocampal neurogenesis is to enable the brain to accommodate continued bouts of novelty..a mechanism for preparing the hippocampus for processing greater levels of complexity.”

The role of the hippocampus in emotion was ignored as it so often is. The way to address many of the gaps mentioned by the author may be to Advance science by including emotion in research.

For example, from the author’s The mystery of humans’ evolved capability for adults to grow new brain cells:

“Adult neurogenesis is already effective early in life, actually very well before true adulthood, and is at very high levels when sexual maturity has been reached. Behavioral advantages associated with adult neurogenesis must be relevant during the reproductive period.”

When human studies are designed to research how “behavioral advantages associated with adult neurogenesis must be relevant” what purpose does it serve to exclude emotional content?

http://cshperspectives.cshlp.org/content/7/11/a018929.full “Activity Dependency and Aging in the Regulation of Adult Neurogenesis”

The mystery of humans’ evolved capability for adults to grow new brain cells

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

This 2016 German review discussed the evolution of human adult neurogenesis:

“Mammalian adult hippocampal neurogenesis is a trait shaped by evolutionary forces that have contributed to the advantages in natural selection that are associated with the mammalian dentate gyrus. Adult hippocampal neurogenesis in mammals originates from an ectopic precursor cell population that resides in a defined stem-cell niche detached from the ventricular wall.

Neurogenesis in the adult olfactory bulb generates a diverse range of interneurons, and is involved in the processing of sensory input. In contrast, adult hippocampal neurogenesis produces only one type of excitatory principal neuron and plays a role in flexible memory formation.

A surplus of new neurons is generated first from which only a subset survives. And it is exactly these new neuronal nodes that, at least for a transient period, are the carriers of synaptic plasticity.

For a number of weeks after they were born, the new neurons have a lower threshold for long-term potentiation. This directs the action to the new cells and results in a bias toward the most plastic cells in the local circuitry.

It is a highly polygenic trait, and numerous genes have already been identified to ultimately have essentially identical effects on net neurogenesis.

Adult neurogenesis is also an individualizing trait. Even before an identical genetic background, subtle individual differences in starting conditions and differential behavioral trajectories result in an increase in phenotypic variation with time.”

The author continued the penultimate paragraph above to pose a question about adult neurogenesis that’s incompletely answered by evolutionary biology theory and evidence todate:

“How genetic variation in single genes (or many genes) would be able to exert a phenotypic change in neurogenesis that can provide a large enough advantage to be selected for.”

The development of new brain cells throughout our lives helps us continually adapt and learn. The “increase in phenotypic variation with time” helps us maintain the unique individual that each of us is.

The review emphasized to me how “individual differences” should neither be viewed as a mystery, nor explained away, nor treated as an etiological factor as researchers often do. Focusing on what caused the differences may provide clearer information.

http://cshperspectives.cshlp.org/content/8/2/a018986.full “Adult Neurogenesis: An Evolutionary Perspective”

Early-life epigenetic regulation of the oxytocin receptor gene

gettingwell4 5+ stars Premium, Amygdala, Brain development, Cerebellum, Cortisol, Epigenetics, Hippocampus, Hypothalamus, Limbic system, Lower brain, Neurochemicals, Oxytocin, Stress , ,

This 2015 US/Canadian rodent study investigated the effects of natural variation in maternal care:

“The effects of early life rearing experience via natural variation in maternal licking and grooming during the first week of life on behavior, physiology, gene expression, and epigenetic regulation of Oxtr [oxytocin receptor gene] across blood and brain tissues (mononucleocytes, hippocampus, striatum, and hypothalamus).

Rats reared by high licking-grooming (HL) and low licking-grooming (LL) rat dams exhibited differences across study outcomes:

  • LL offspring were more active in behavioral arenas,
  • Exhibited lower body mass in adulthood, and
  • Showed reduced corticosterone responsivity to a stressor.

Oxtr DNA methylation was significantly lower at multiple CpGs in the blood of LL versus HL males, but no differences were found in the brain. Across groups, Oxtr transcript levels in the hypothalamus were associated with reduced corticosterone secretion in response to stress, congruent with the role of oxytocin signaling in this region.

Methylation of specific CpGs at a high or low level was consistent across tissues, especially within the brain. However, individual variation in DNA methylation relative to these global patterns was not consistent across tissues.

These results suggest that:

  • Blood Oxtr DNA methylation may reflect early experience of maternal care, and
  • Oxtr methylation across tissues is highly concordant for specific CpGs, but
  • Inferences across tissues are not supported for individual variation in Oxtr methylation.

nonsignificance

Individual DNA methylation values were not correlated across brain tissues, despite tissue concordance at the group level.

For each CpG, we computed the Pearson correlation coefficient r between methylation values for matched samples in pairs of brain regions (bars). Dark and light shaded regions represent 95% and 99% thresholds, respectively, of distributions of possible correlation coefficients determined from 10,000 permutations of the measured values among the individuals. These distributions represent the null hypothesis that an individual DNA methylation value in one brain region does not help to predict the value in another region in the same animal.

(A) Correlations based on pyrosequencing data for matched samples passing validation in both hippocampus (HC) and hypothalamus (Hypo). Correlations for individuals at each CpG were either weak (.2 < r < .3) or absent (r < .2), and none were significant, even prior to correction for multiple comparisons.

(B) Correlations for matched samples passing validation in both hippocampus and striatum (Str). Two correlations (CpG 1 and 11) were individually significant prior to but not following correction, and this result could be expected by chance.

Correlations between hippocampus and blood (described in the text) yielded similar results, and no particular CpG yielded consistently high correlation across multiple tissues.”

The study focused on whether or not an individual’s experience-dependent oxytocin receptor gene DNA methylation in one of the four studied tissues could be used to infer a significant effect in the three other tissues. The main finding was NO, it couldn’t!

The researchers’ other findings may have been strengthened had they also examined causes for the observed effects. The “natural variation in maternal licking and grooming” developed from somewhere, didn’t it?

The subjects’ mothers were presumably available for the same tests as the subjects, but nothing was done with them. Investigating at least one earlier generation may have enabled etiologic associations of “the effects of early life rearing experience” and “individual variation in DNA methylation.”

https://www.sciencedirect.com/science/article/abs/pii/S0018506X1500118X “Natural variation in maternal care and cross-tissue patterns of oxytocin receptor gene methylation in rats” (not freely available)

Does vasopressin increase mutually beneficial cooperation?

gettingwell4 < 0 Detracted from science, Amygdala, Anterior cingulate cortex, Beliefs, Brain hemispheres, Cerebrum, Hippocampus, Limbic system, Neurochemicals, Oxytocin, Vasopressin

This 2016 German human study found:

“Intranasal administration of arginine vasopressin (AVP), a hormone that regulates mammalian social behaviors such as monogamy and aggression, increases humans’ tendency to engage in mutually beneficial cooperation.

AVP increases humans’ willingness to cooperate. That increase is not due to an increase in the general willingness to bear risks or to altruistically help others.”

One limitation of the study was that the subjects were all males, ages 19-32. The study’s title was “human risky cooperative behavior” while omitting subjects representing the majority of humanity.

Although the researchers claimed brain effects from vasopressin administration, they didn’t provide direct evidence for the internasally administered vasopressin in the subjects’ brains. A similar point was made about studies of vasopressin’s companion neuropeptide, oxytocin, in Testing the null hypothesis of oxytocin’s effects in humans.

A third limitation was that although the researchers correlated brain activity with social behaviors, they didn’t carry out all of the tests necessary to demonstrate the claimed “novel causal evidence for a biological factor underlying cooperation.” Per Confusion may be misinterpreted as altruism and prosocial behavior, the researchers additionally needed to:

“When attempting to measure social behaviors, it is not sufficient to merely record decisions with behavioral consequences and then infer social preferences. One also needs to manipulate these consequences to test whether this affects the behavior.”

http://www.pnas.org/content/113/8/2051.full “Vasopressin increases human risky cooperative behavior”

The effects of imposing helplessness

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

This 2016 New York rodent study found:

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

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

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

Concerning the study’s young adult male subjects:

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

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

The final sentence of the Introduction section:

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

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

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

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

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

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

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

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

Advance science by including emotion in research

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This 2015 analysis of emotion studies found:

“Emotion categories [fear, anger, disgust, sadness, and happiness] are not contained within any one region or system, but are represented as configurations across multiple brain networks.

For example, among other systems, information diagnostic of emotion category was found in both large, multi-functional cortical networks and in the thalamus, a small region composed of functionally dedicated sub-nuclei.

The dataset consists of activation foci from 397 fMRI and PET [positron emission tomography] studies of emotion published between 1990 and 2011.”

From the fascinating Limitations section:

“Our analyses reflect the composition of the studies available in the literature, and are subject to testing and reporting biases on the part of authors. This is particularly true for the amygdala (e.g., the activation intensity for negative emotions may be over-represented in the amygdala given the theoretical focus on fear and related negative states). Other interesting distinctions were encoded in the thalamus and cerebellum, which have not received the theoretical attention that the amygdala has and are likely to be bias-free.

Some regions—particularly the brainstem—are likely to be much more important for understanding and diagnosing emotion than is apparent in our findings, because neuroimaging methods are only now beginning to focus on the brainstem with sufficient spatial resolution and artifact-suppression techniques.

We should not be too quick to dismiss findings in ‘sensory processing’ areas, etc., as methodological artifacts. Emotional responses may be inherently linked to changes in sensory and motor cortical processes that contribute to the emotional response.

The results we present here provide a co-activation based view of emotion representation. Much of the information processing in the brain that creates co-activation may not relate to direct neural connectivity at all, but rather to diffuse modulatory actions (e.g., dopamine and neuropeptide release, much of which is extrasynaptic and results in volume transmission). Thus, the present results do not imply direct neural connectivity, and may be related to diffuse neuromodulatory actions as well as direct neural communication.”

Why did the researchers use only 397 fMRI and PET studies? Why weren’t there tens or hundreds of times more candidate studies from which to select?

The relative paucity of candidate emotion studies demonstrated the prevalence of other researchers’ biases for cortical brain areas. The lead researcher of the current study was a coauthor of the 2016 Empathy, value, pain, control: Psychological functions of the human striatum, whose researchers mentioned that even their analyses of 5,809 human imaging studies was hampered by other imaging-studies researchers’ cortical biases.

Functional MRI signals depend on the changes in blood flow that follow changes in brain activity. Study designers intentionally limit their findings when they scan brain areas and circuits that are possibly activated by human emotions, yet exclude emotional content that may activate these areas and circuits.

Here are a few examples of limited designs that led to limited findings when there was the potential for so much more:

It’s well past time to change these practices now in the current year.

This study provided many methodological tests that should be helpful for research that includes emotion. It showed that there aren’t impenetrable barriers – other than popular memes, beliefs, and ingrained dogmas – to including emotional content in studies.

Including emotional content may often be appropriate and informative, with the resultant findings advancing science. Here are a few recent studies that did so:

http://journals.plos.org/ploscompbiol/article?id=10.1371%2Fjournal.pcbi.1004066 “A Bayesian Model of Category-Specific Emotional Brain Responses”

Publicly-funded researchers need to provide unqualified free access to their studies

gettingwell4 0-1 star Wasted resources, Hippocampus, Limbic system, Memory

Starting the second year of this blog with a magazine article New Clues to How the Brain Maps Time reviewed the findings of a 2015 Boston rodent study During Running in Place, Grid Cells Integrate Elapsed Time and Distance Run. The article’s information was mixed such that when the reader arrived at this phrase:

“Moreover, time cells rely on context; they only mark time when the animal is put into a situation in which time is what matters most.”

it wasn’t clear whether the “time cells” referred to grid cells located in the entorhinal cortex (per the referenced study) or some other cells located in the hippocampus.

The hippocampus also has “time cells.” One of the first studies I curated when I started this blog one year ago today was Our memories are formed within a specific context. That 2014 study’s Significance section included:

“A number of recent studies have shown that the hippocampus, a structure known to be essential to form episodic memories, possesses neurons that explicitly mark moments in time.

We add a previously unidentified finding to this work by showing that individual primate hippocampal neurons not only track time, but do so only when specific contextual information (e.g., object identity/location) is cued.”

I attempted to disambiguate the “time cells” location by reading the 2015 study, only to find it was behind a paywall for which the public doesn’t have unqualified free access.

I assert that the study was performed using public funds, and that the researchers’ infrastructure and facilities were paid in part by the US taxpayers. Only US government funding sources were disclosed on the organization Mission Statement page of the study’s lead researcher, whose position is Lab Chief.

I assume that whether or not the study had unqualified free access was the researchers’ decision. Here’s a typical US NIH statement:

“The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”

There are multiple problems with placing publicly-funded studies behind paywalls. One pertinent to this study and article was the accurate presentation of the study’s findings in news coverage.

The article’s author gave her interpretation of the study and the lead researcher’s remarks. She solicited five other researchers’ opinions, and one researcher provided an appraisal in the Comments section.

Was this treatment of the study’s findings sufficient for the public to understand what the US taxpayers paid for?

It was nice to have interpretations and remarks and opinions and appraisals, but these may have diverged from what the study actually found. Without unqualified free access to the study, there was no base on which to compare and contrast the article’s POVs.

Other news coverage of the study provided further examples of why publicly funded research needs to be freely available without qualification:

  • NPR’s coverage also confused the cells’ location: “If grid cells in the hippocampus and entorhinal cortex..”
  • An article carried by multiple sites headlined the cells as “Odometer neurons.” Did the study find that grid cells operated cumulatively like an odometer that began at some stage of the subjects’ development? Or did it find that the grid cells operated more like a trip meter?
  • In the Discover Magazine coverage the lead researcher stated: “..could point to ways to treat memory loss, whether from old age or illness, like Alzheimer’s disease.” Did the study actually find anything about “memory loss?” Was there anything in it about “old age or illness, like Alzheimer’s disease?”

As the study’s news coverage discrepancies and ambiguities demonstrated, there’s every reason for researchers to provide all the details of their work. We’re well past the days when “wise old men” selectively gate information flows.

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.

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

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

This 2015 Canadian rodent study found:

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

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

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

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

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

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

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

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

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

The cerebellum’s role in human behavior and emotions

gettingwell4 2-3 stars Required further work, Amygdala, Anterior cingulate cortex, Cerebellum, Cerebrum, Hippocampus, Limbic system, Lower brain

This 2016 Italian human review considered the lower brain’s contributions to an individual’s behavior and temperament:

“In evidencing associations between personality factors and neurobiological measures, it seems evident that the cerebellum has not been up to now thought as having a key role in personality.

Cerebellar volumes correlate positively with novelty seeking scores and negatively with harm avoidance scores. Subjects who search for new situations as a novelty seeker does (and a harm avoiding does not do) show a different engagement of their cerebellar circuitries in order to rapidly adapt to changing environments.

Cerebellar abilities in planning, controlling, and putting into action the behavior are associated to normal or abnormal personality constructs. In this framework, it is worth reporting that increased cerebellar volumes are even associated with high scores in alexithymia, construct of personality characterized by impairment in cognitive, emotional, and affective processing.”

The full paper wasn’t freely available, but a list of the 173 references was. 17 references were of alexithymia, also mentioned in the title.

One freely available reference was The embodied emotion in cerebellum: a neuroimaging study of alexithymia, a 2014 study performed by these same authors, which found:

“Alexithymia scores were linked directly with cerebellar areas and inversely with limbic and para-limbic system, proposing a possible functional modality for the cerebellar involvement in emotional processing.

The increased volumes in Crus 1 of subjects with high alexithymic traits may be related to an altered embodiment process leading to not-cognitively interpreted emotions.”

“Alexithymia scores” referred to one of the methods used to characterize alexithymia symptoms, self-reported answers to questionnaires such as this one. Sample questions from the questionnaire used by the referenced study are:

  • “I am often confused about what emotion I am feeling
  • It is difficult for me to reveal my innermost feelings, even to close friends”

The questionnaire mainly engages a person’s cerebrum. The person may recall emotions, and form ideas as framed by each question. Then they’ll describe these ideas in terms of a scaled answer.

Cerebral answers may provide historical contexts for feelings. However, the person’s cerebellum and other brain areas aren’t necessarily engaged by the diagnostic questionnaire.

Without this engagement, the person may not experience feelings when providing answers about feelings. The answers may be more along the lines of “This is what I think I should be feeling” or “This is what I think I should tell the researchers about what I think I should feel.”

  • Can a questionnaire accurately determine associations among engaged and unengaged brain areas?
  • What can be done regarding “impairment in cognitive, emotional, and affective processing?”
  • What’s the lower brain’s “involvement in emotional processing?”
  • How does the lower brain shape a person’s behavior and traits?
  • When and where in an individual’s lifespan does their cerebellum develop?

http://link.springer.com/article/10.1007/s12311-015-0754-9 “Viewing the Personality Traits Through a Cerebellar Lens: a Focus on the Constructs of Novelty Seeking, Harm Avoidance, and Alexithymia”