Control group

Testing the null hypothesis of psychological therapy

gettingwell4 2-3 stars Required further work, Primal Therapy , , ,

What forms of medicine don’t require an etiological approach, other than psychology and psychiatry?

This 2015 UK human study found:

“Supported cCBT [computerised cognitive behaviour therapy] does not substantially improve depression outcomes compared with usual GP [general practitioner] care alone.

In this study, neither a commercially available nor free to use computerised CBT intervention was superior to usual GP care.”

Subjects had concurrent access to most of the relevant UK health system:

“We imposed no constraints on usual GP care in the control or intervention groups, and participants were therefore free during the trial to access any treatment usually available in primary care, including the use of antidepressants, counselling, psychological services (including Improving Access to Psychological Therapy services, which were present in most sites during the course of the trial), or secondary care mental health services.”

The study’s null hypothesis was developed as follows:

“We based our sample size calculation on the usual care arm of primary care depression trials, where the proportion of patients responding to usual care was in the region of 0.6. This proportion is similar to that found in a UK Health Technology Assessment trial of antidepressants in primary care.

We regarded a figure of not more than 0.15 below this proportion as being acceptable, given the additional care options that are available to patients who do not initially respond to cCBT within a stepped care framework. In our original calculation, to detect non-inferiority with the percentage success in both groups as 60% and a non-inferiority margin of 15% with over 80% power and assuming 25% attrition, we required 200 participants in each of the three arms.”

The study’s null hypothesis was: the two cCBT methods wouldn’t improve on the “60%” “success” of both “the usual care arm” and “antidepressants in primary care.”

What outcome does a person desire when they seek out psychological care? I’d guess that their first need would be to stop their current suffering.

From a patient’s short-term perspective, the null hypothesis – any form of psychological therapy in the UK healthcare system wouldn’t improve their short-term condition – is likely to be initially disproved.

So, what accounts for the 40% failure rate? Or, as phrased in Psychological therapy and DNA methylation:

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

The treatments’ methods aren’t capable of anything more than temporarily suppressing symptoms. But the symptoms return, and require further interventions in order to stay suppressed.

From a patient’s long-term perspective, what would it take to disprove the null hypothesis – any form of psychological therapy in the UK healthcare system wouldn’t improve their long-term condition?

To effectively treat patients in the long term, and to prevent future suffering, the originating causes need to be addressed. IAW, hold psychological therapy to the same standard of care expected in other medical treatments.

http://www.bmj.com/content/351/bmj.h5627 “Computerised cognitive behaviour therapy (cCBT) as treatment for depression in primary care (REEACT trial): large scale pragmatic randomised controlled trial”

Beliefs about medical treatments affected perceived stress

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum, Neurochemicals, Oxytocin, Serotonin, Stress

This 2015 New Zealand human study found:

“Placebo effects can be translated to a real-life setting in the short-term reduction of stress, anxiety and symptoms of depression in a non-patient population.

In treating psychological distress, placebos may be useful addition to the treatment repertoire.“

The researchers provided a self-administered 3-day course of fake “anti-stress treatment spray” and told the participants the spray was either “oxytocin” or “serotonin” with these results:

“Both the ‘serotonin’ and ‘oxytocin’ treatment sprays were effective in reducing symptoms of depression; however, only those in the ‘oxytocin’ group reported less stress and anxiety as compared with controls. Overall, the ‘oxytocin’ was perceived as more effective.”

Will this study of non-patients be used to try to justify manipulating patients’ perceptions of their stress, anxiety, and depression?

http://anp.sagepub.com/content/early/2015/12/16/0004867415621390 “A take-home placebo treatment can reduce stress, anxiety and symptoms of depression in a non-patient population”

Emotional memories create long-term epigenetic changes

gettingwell4 2-3 stars Required further work, Anterior cingulate cortex, Brain development, Epigenetics, Hippocampus, Limbic system, Memory, Stress , , , , , ,

This 2015 German rodent study found:

“Histone modifications predominantly changed during memory acquisition and correlated surprisingly little with changes in gene expression.

Although long-lasting changes were almost exclusive to neurons, learning-related histone modification and DNA methylation changes also occurred in non-neuronal cell types, suggesting a functional role for non-neuronal cells in epigenetic learning.”

Chromatin modifications in two limbic system brain areas were studied – the hippocampus (CA1 region) for short-term memories and the anterior cingulate cortex for short-and long-term memory formation and maintenance. The memories were induced by context (C) and context shock (CS) exposure:

“Overall, the data provides very strong and robust evidence for the establishment of long-term memory upon CS exposure, whereas C exposure alone did not induce the formation of long-term memory.”

So, without long-term shock/emotional memories, there would be no positive long-term findings for the researchers to report. There would be no lasting:

  • “Histone modifications
  • DNA methylation changes
  • Changes in gene expression”

The subjects were young adults at age 3 months. The CA1 and ACC studied brain areas are fully developed before this age.

It seemed feasible that if the study were performed with younger subjects, the results may have been different. For example:

“Context exposure alone did not induce the formation of long-term memory”

may not have been the finding for early learning situations.

The researchers qualified their results several times with the phrase “changes are limited to actively expressed genes.” A similar qualifier in A study of DNA methylation and age was a reminder that unexpressed genes may have also been important:

“The textbook case of DNA methylation regulating gene expression (the methylation of a promoter and silencing of a gene) remains undetected in many cases because in an array analysis, an unexpressed gene shows no signal that can be distinguished from background and is therefore typically omitted from the analysis.”

This general qualifier may not have necessarily applied to the current study, though, because the study’s design included an unexposed control group.

http://www.nature.com/neuro/journal/vaop/ncurrent/full/nn.4194.html “DNA methylation changes in plasticity genes accompany the formation and maintenance of memory”

Brain-region-specific energy metabolism affected the social competitiveness of highly-anxious rats

gettingwell4 4-5 stars Advanced knowledge, Acetylcholine, Amygdala, Cerebrum, Cortisol, Dopamine, Epigenetics, Limbic system, Memory, Neurochemicals, Stress , ,

This 2015 Swiss rodent study found:

“Mitochondrial function in the nucleus accumbens, a brain region relevant for motivation and depression, is a critical mediating factor in the subordinate status displayed by high-anxious rats.

Treatment with nicotinamide, an amide form of vitamin B3 that boosts mitochondrial respiration, into the NAc [nucleus accumbens] of high-anxious rats at a time point before the social encounter and at a dose that increased accumbal mitochondrial respiration, abolished the disadvantage of high-anxious animals to become dominant against low-anxious animals.

Our findings highlight a key role for brain energy metabolism in social behavior and point to mitochondrial function in the nucleus accumbens as a potential marker and avenue of treatment for anxiety-related social disorders.”

The researchers handled individual differences of the outbred subjects by separating them into high-, intermediate-, and low-anxiety categories according to their responses on two tests. The high- and low-anxiety subjects were matched by weight, age, and social experience.

Here are a few examples of the researchers thoroughly ruling out confounding factors:

“Differences in social competitiveness are not related to overall differences in social motivation or sociability.

Although social competition did significantly increase corticosterone compared with baseline levels, there were no significant differences between anxiety groups at either time point.

Microinfusion of either ROT, MA, or 3NP [mitochondrial respiration inhibitors] reduced the success of treated animals to win the social contest.

Importantly, these treatments did not induce side effects on social investigation or auto-grooming during social competition, or alter locomotor activity, anxiety, or sociability in additional experiments.

Furthermore, these inhibitor treatments did not produce neurotoxic effects, as the drugs were infused at low doses and we confirmed the absence of lesion and neuronal death.

The effects of complex I or complex II inhibition on social competition were specific for the NAc, as infusions of the same inhibitors into the BLA [basolateral amygdala] had no effect on social dominance and did not affect general locomotor activity.

We further showed that, unlike infusion of muscimol [a GABA receptor agonist] in the BLA that interferes with BLA-dependent auditory fear conditioning, 3NP did not affect conditioning in this task, discarding that neuronal inactivation could be a general mechanism whereby impairing mitochondrial function would affect putative functions from the affected brain region.

The impact of mitochondrial function in social competition described here is not mediated by oxidative stress.”

http://www.pnas.org/content/112/50/15486.full “Mitochondrial function in the brain links anxiety with social subordination”

Mitochondria interface genetic/epigenetic responses to psychological stress

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

This 2015 Pennsylvania rodent study found:

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

Mitochondrial dysfunctions altered the

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

responses to stress.

Stress-induced

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

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

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

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

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

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

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

Identifying epigenetic DNA changes with blood tests

gettingwell4 2-3 stars Required further work, Epigenetics , ,

This 2015 Chinese human study found:

“With reference to methylation profiles of different tissues, we developed a general approach for studying the major tissue contributors to the circulating DNA pool. This development has opened up numerous research avenues and diagnostic applications.

Our study takes advantage of the recent availability of reference methylomes of a number of tissues. It is likely that such reference databases would be continually updated to include more sample types and from more individuals.”

Up to 41% of plasma DNA in pregnant women was from the placenta. However, I didn’t understand why the non-pregnant women in the control group had measurable placental DNA of up to 2.9%. Maybe it was leftover from a prior pregnancy?

http://www.pnas.org/content/112/40/E5503.full “Plasma DNA tissue mapping by genome-wide methylation sequencing for noninvasive prenatal, cancer, and transplantation assessments”

What can cause memories that are accessible only when returning to the original brain state?

gettingwell4 5+ stars Premium, Hippocampus, Limbic system, Memory, Primal Therapy , , , , ,

This 2015 French rodent study found:

“Memories can be established and maintained without de novo protein synthesis and that experimental amnesia may not result from a disruption of memory consolidation/reconsolidation.

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.

This integration concept includes most of the previous explanations of memory recovery after retrograde amnesia and critically challenges the traditional memory consolidation/reconsolidation hypothesis, providing a more dynamic and flexible view of memory.”

From Neuroskeptic’s analysis of the study:

“A different drug, lithium chloride, produces the same pattern of effects – it blocks ‘reconsolidation’, but this can be reversed by a second dose at the time of recall. However, lithium chloride is not an amnestic [a drug that blocks memory formation] – it doesn’t block protein synthesis. Rather, it causes nausea.

The implication of the lithium experiment is that any drug that causes an ‘internal state change’, even if it’s just nausea, can trigger state-dependent memory and behave just like an ‘amnestic’.”

As this study may apply to humans, a drug wouldn’t necessarily be required to “induce an internal state.” If the findings of studies such as Are 50 Shades of Grey behaviors learned in infancy? extend to humans, an emotional or physical experience may be sufficient to produce a state-dependent memory. For example, A study that provided evidence for basic principles of Primal Therapy found, albeit with rodents and use of a drug:

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

Memories triggered while in a brain state reentered through an emotion or a physical reaction are experienced by Primal Therapy patients and observed by therapists every day. However, as mentioned in What scientific evidence can be offered for Primal Therapy’s capability to benefit people’s lives? there’s a difficulty in developing human evidence for such state-dependent emotional memories.

Standard procedures would use human subjects and control groups in a way that retrieved memories according to the researchers’ schedule and experimental parameters. In order for the retrieval of an emotional memory to be therapeutic, though, the methods of an experiential therapy such as Dr. Arthur Janov’s Primal Therapy leave the timing of entering a triggering brain state up to the patient.

When a brain state protects a human emotional memory from being accessed, it probably wouldn’t be therapeutic to:

  • Force a return to that brain state, and thereby
  • Remove the memory’s protection, then
  • Retrieve and re-experience the memory

just for the sake of research.

The evidence for retrieving and re-experiencing a state-dependent memory lies mainly within the individual’s experiences.

A challenge is to find innovative ways to document human evidence for state-dependent emotional memories while ensuring a therapeutic process.

http://www.jneurosci.org/content/35/33/11623 “Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?”

Inflexible behavior may be a byproduct of stress

gettingwell4 2-3 stars Required further work, Cortisol, Neurochemicals, Stress ,

This 2015 German human study found:

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

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

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

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

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

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

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

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

A study limitation was that it involved just 26 infants.

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

A study that provided evidence for basic principles of Primal Therapy

gettingwell4 5+ stars Premium, Cerebrum, Epigenetics, Glutamate, Hippocampus, Limbic system, Memory, Neurochemicals, Primal Therapy, Stress , , , , , ,

This 2015 Northwestern University rodent study found:

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

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

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

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

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

From the Northwestern press release:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Adverse effects of inflammation and stress on hippocampal synapses

gettingwell4 2-3 stars Required further work, Hippocampus, Immune system, Limbic system, Memory, Neurochemicals, Stress , , ,

This dense and highly-jargoned 2015 rodent study found:

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

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

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

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

The researchers asserted:

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

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

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

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

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

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

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

DNA damage to fat cells may cause obesity and insulin resistance

gettingwell4 2-3 stars Required further work, Epigenetics, Stress ,

This 2015 Indiana rodent study found:

“DNA damage is a root cause of adipocyte senescence [fat cells that can no longer replicate], which plays a determining role in the development of obesity and insulin resistance.”

The researchers removed the capability for the subject mice to produce a protein that “plays an essential role in preventing cutaneous cancer caused by UV radiation-induced DNA damage.” They showed that this genetic deficiency:

“Causes obesity with visceral fat accumulation, hepatic steatosis, hyperleptinemia, hyperinsulinemia, and glucose intolerance.”

These researchers – in contrast with the Pulling on the chain of causes and effects with insulin resistance study – investigated causes for the various effects that included insulin resistance. However, the study’s applicability to humans wasn’t clear, since we most often develop symptoms such as insulin resistance due to causes other than genetics.

The study also demonstrated that treatment with a common dietary supplement – N-acetyl cysteine (NAC) – or metformin (Met):

“Reduce[d] adipose DNA damage.

Ameliorated cellular senescence and metabolic abnormalities.”

Body fat

High-fat and high-fructose diets caused the opposite effects in the subject genetic-deficient mice.

http://www.pnas.org/content/112/33/E4556.full “Ablation of XP-V gene causes adipose tissue senescence and metabolic abnormalities”

What’s an appropriate control group for a schizophrenia study?

gettingwell4 < 0 Detracted from science, Cerebrum ,

The researchers who did Our long-term memory usually selects what we pay closer visual attention to study were back zapping subjects’ brains again in this 2015 human study.

Prior to zapping subjects’ brains:

“In healthy individuals, these theta waves were steady and synchronized, but in people with schizophrenia, the waves were weak and disorganized, suggesting that they were having a harder time processing the mistake. And the subjects’ behavior bore that out—the healthy subjects slowed down by a few milliseconds when they made mistakes and did better in the next round, while the subjects with schizophrenia did not.”

Processing of an appropriate control group wasn’t clear to me from reading supplementary material. Subject patients were diagnosed with schizophrenia and took psychoactive medication which these researchers equated to chlorpromazine (Thorazine) dosages. Control group subjects had neither the condition nor were prescribed medications.

  • How did these researchers differentiate influences of psychoactive medications on experimental results from other influences on subjects’ conditions?
  • Were there numerical calculations not shown in supplementary material that somehow nullified effects of psychoactive medications?
  • To be sure that zapping was effective for subjects’ conditions, wouldn’t control group subjects need to take the same medications so that experimental data reflected only differences attributable to schizophrenia?

These researchers also asserted:

“Causal changes in the low-frequency oscillations improved behavioral responses to errors and long-range connectivity at the single-trial level.”

However, brain waves can’t be termed as base causes of human behavior. Studies such as:

clearly established that brain waves are effects of base causes.

http://www.pnas.org/content/112/30/9448.full “Synchronizing theta oscillations with direct-current stimulation strengthens adaptive control in the human brain”

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.

How brains mature during critical periods

gettingwell4 5+ stars Premium, Brain development, Epigenetics, Hippocampus, Limbic system , , , ,

This 2015 German rodent study found:

“Once silent synapses are consolidated in any neural circuit, initial experience-dependent functional optimization and critical periods end.

Silent synapses are thought to be immature, still-developing excitatory synapses.”

The number of silent synapses related to visual processing was measured at ~50% at eye opening. Visual experience reduced this to 5% or less by adulthood in the study’s control group. Removing a protein in the subjects’ hippocampus silenced the synapses back up to ~50%, even in adults.

Critical periods are:

“Characterized by the absolute requirement for experience in a restricted time window for neural network optimization.

Although some functions can be substantially ameliorated after the CP [critical period], they are rarely optimally restored.”

Two human studies were cited on critical periods in second-language and musical skills development, Sensitive periods in human development: Evidence from musical training (not freely available).

The researchers generalized their findings as:

“Experience-dependent unsilencing of silent synapses constitutes an important general maturational process during CPs of cortical development of different functional domains and suggest an interplay with inhibitory circuits in regulating plasticity.”

http://www.pnas.org/content/112/24/E3131.full “Progressive maturation of silent synapses governs the duration of a critical period”

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”

An inhibitory gene that affects alcohol binge behavior

gettingwell4 2-3 stars Required further work, Beliefs, Cerebrum, Dopamine, Limbic system, Lower brain, Neurochemicals, Thalamus , , ,

This 2015 La Jolla rodent study found that an inhibitory gene affected alcohol binging behavior:

“Our study reveals the behavioral impact of this cellular effect, whereby the level of GIRK3 [the gene] expression in the VTA [ventral tegmental area] tunes ethanol intake under binge-type conditions: the more GIRK3, the less ethanol drinking.”

GIRK3-silenced mice still binged, though, and got alcohol’s rewarding effects through dopamine’s other neural pathways.

High concentrations of the gene were found in the thalamus part of the limbic system of wild-type mice, the control group. Per the study’s title, this gene presumably contributes to the thalamus’ overall function of gating information from limbic system and lower brain areas to reach the cerebrum and vice versa.

And the potential causes for reduced GIRK3 expression are..?? Hopefully – someday – researchers will be focused on finding causes for abnormal gene expression rather than being content to just study effects of abnormal gene expression. Until then, the usual practice of considering only the effects led these researchers to:

“Believe that a compound selectively targeting GIRK3-containing channels may hold promise for reducing alcohol consumption in heavy binge drinkers.”

http://www.pnas.org/content/112/22/7091.full “GIRK3 gates activation of the mesolimbic dopaminergic pathway by ethanol”