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Flashcards in Chapter 11, 12, and 13 review Deck (72):
1

What do Robert Sapolksy’s studies with stress in baboons tell us about the role of social status in stress and health/sickness associated with stress?

What about the role of culture in social stress?

How does the baboon work coincide with what was observed in the Whitehall study of British civil servants of different seniority rankings?

Baboon Study Shows Why High Social Status Boosts Health
Ranking

Being at the bottom of the social ladder is generally a predictor of bad health: research shows that poor people die sooner and have more disease than rich people, even when you account for factors like lack of access to health care.

But the data on social hierarchy and health — including studies in primates other than humans — contains a paradox for males: high status is linked with high levels of testosterone, and high testosterone can in turn lower immunity and increase disease risk. So, why is high rank consistently associated with good health?

Scientists examined wild baboons living Kenya. The researchers looked specifically at the relationship between illness & injury and rank — that is, whether higher- or lower-ranking males fell ill or were hurt more frequently. Scientists also measured how fast the males recovered. (Females were not studied due to complexities related to their reproductive cycles and childbirth.)

There were significant differences, all favoring the higher-ranked animals. In fact, at any particular time, the odds of recovery from sickness/injury for a high-status animal were 3x's greater than for a male at the bottom. The alpha males at the very top healed faster than all other males. And this outcome occurred even when the high-ranking males had high levels of glucocorticoids (stress hormones), as well as high levels of testosterone, both of which can suppress immunity.

Based on their stress & hormone levels, one would expect the males at the top to get sicker and recover from wounds more slowly than their low-on-the-totem-pole peers. In part, the findings can be explained by age: top-ranked males tend to be younger and healthier than lower-ranking animals. But age didn’t account for the differences completely. High status was a better predictor of healing than age was.

Alpha and low-ranking males seem to experience elevated glucocorticoids as a result of different stressors and over different periods of time. Such differences may alter the immunosuppressive effects of stress. Specifically, high glucocorticoids in alpha males probably are caused primarily by energetic stress, whereas high glucocorticoids in low-ranking males probably are caused largely by social stressors, such as high rates of received aggression, a lack of a sense of control, and few coping mechanisms.
In other words, the short-term stress experienced by alpha males tends to be “good” stress, the kind that comes from exercise or sex. It doesn’t last long, it doesn’t include feelings of loss of control, and it doesn’t involve a persistent threat to important social relationships. When you consistently win battles for dominance, you don’t worry much about how the losers will treat you.

In contrast, lower-ranked males experience ongoing, uncontrollable stress, which does affect their relationships, particularly the amount of bullying they face from higher-ranked males. Among baboons, “displacement” aggression is common, wherein the top guy kicks the guy below him when he’s pissed off and that guy kicks a lower-ranking dude, all the way down the chain. This leads to chronically elevated stress hormones in low-ranking members of the pack, which can be harmful.

The top animals also tend to get more social support. In baboons, this involves being groomed by others, which not only removes parasites, but more importantly, also calms the stress system and lowers the animal’s levels of glucocorticoids.

In the short term, then, elevated levels of testosterone and glucocorticoids seem to improve immunity; if they remain consistently high, however, they lower immunity and harm health. Social contact seems to be an important way to “turn down” the stress system.

The researchers note that the study cannot determine whether an animal’s high or low rank is caused by its health status in the first place, or vice versa — and these explanations aren’t mutually exclusive. Strong, resilient animals may rise through the ranks, and then their alpha position may reinforce their good health. Similarly, poor health may drive rank downward by impairing an animal’s performance. The authors write: “It is likely that both forces interact to shape differences in health and immune function.”

(MORE: How Bullying and Abuse May Age Children Prematurely)

In humans, decades worth of data suggest it is higher social status itself that improves health, and the chronic stress of low social status that harms it, particularly when this stress starts early in life.

As stress researcher Robert Sapolsky who has studied baboons in Amboseli, said: “When humans invented inequality and socioeconomic status, they came up with a dominance hierarchy that subordinates like nothing the primate world has ever seen before.”

There is a remedy for status stress that works even in the face of social inequality. While humans don’t typically groom each other like baboons, research finds that high levels of social support, esp. physical contact like hugs & massages, can mitigate the effects of stress for humans.

2

According to the video viewed in class, how does stress alter teleomeres on the chromosomes?

How does this impact health?

Chronic Stress is harming our DNA

Personality, stress processes, and environment affect our DNA

Money problems, a heavy work load, caregiving.... increasingly common pressures have helped make stress a part of modern life.

According to APA's Stress survey, 42% of adults in the U.S. say their stress level has increased over the past 5 years.

Even teens reported stress rivaling adult levels.

Chronic stress damage starts before we're even conceived and cuts into our very cells.

Studies link stress with shorter telomeres, a chromosomal component that's associated with cellular aging and risk for heart disease, diabetes, and cancer.

Telomeres are a protective casing at the end of a strand of DNA.
Each time a cell divides, it loses a bit of its telomeres.
Telomerase enzyme can replenish it, but chronic stress and cortisol exposure decrease your supply.
When the telomere is too diminished, the cell often dies or becomes pro-inflammatory.
This sets the aging process in motion, along with associated health risks.

How does stress rank in terms of factors that affect telomere length?
The 2 biggest factors are chronological aging and genetics, but stress is now on the map as one of the most consistent predictors of shorter telomere length.

The type of stress determines how big its effect is.
Exposures to multiple early life adversities, such as child neglect, have the largest effects, since they track through to late adulthood, or they set in place persistent mechanisms that maintain short telomeres throughout life, such as exaggerated stress reactivity and poor health behaviors.

Stressors such as caregiving in late life also have an effect. This relationship between stress and cell aging spans a lifespan, and it's fundamental to how we're built.
When we expose our bodies to years of chronic stress arousal, we see effects that override normal aging, making our telomeres look like they are from a significantly older person.
People with psychiatric disorders related to dysregulated emotional responses (esp. depression) consistently have shorter telomeres than controls who have never experienced these disorders.

3

According to the video viewed in class, how does stress in non-human primates alter blood vessels, cardiovascular health, risk for stroke and heart attacks, as well as feelings of pleasure and dopamine sensitivity in the brain?

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4

How do the studies of the Dutch famine winter suggest that stress experienced by mothers can influence the development and health of the fetus?

Famine is never a good thing, particularly if you’re a developing fetus.
While the role of maternal diet in fetal programming is not new to the world of DNA methylation, there’s still a lot to be learned about the subtle variations.
When it comes to growth & metabolism, timing of the environmental exposure appears is important, whether it be the seasonal diet differences at conception affecting methyl donor avalibility or, as in today’s case, which trimester the mother experienced famine.
DNA methylation signatures link prenatal famine exposure to later abnormalities in growth & metabolism.
By using RRBS (Reduced representation bisulfite sequencing) on blood from 24 sibling pairs discordant for prenatal famine exposure (from the Dutch Hunger Winter Cohort), the team made interesting observations in the children:
There are a number prenatal famine exposure-related DMRs that occur in regulatory regions of intermediate levels of DNA methylation.
There is differential DNA methylation in growth & metabolic pathways from 1st trimester famine exposure.
But, surprisingly, these individuals were born with a normal birthweight, in stark contrast to those exposed to famine in the later trimesters, who are born with a signficantly lower birthweight.
The team was able to “pin point” the sensitive developmental period to right after conception, and think it is occurring just after implantation, since that is when major methylation remodelling goes down.
Adding function to finding, their experiments showed that DNA methylation in INSR was associated with birthweight, while CPT1A has a criminal association with cholesterol with both DMRs showing strong enhancer activity in vitro.
Ultimately, prenatal exposure to famine sets up a long-lasting metabolic and growth-related program, with variation coming from the timing of exposure.
“Individuals conceived in the Dutch Hunger Winter may have survived this horrendous period of WW2 thanks to many small epigenetic differences in growth & developmental pathways a few weeks after fertilization.
These changes may be somewhat unfavourable for them as adults, as they seem slightly more at risk to obesity & diabetes.
But overall they are a genomic testament for human resilience.
It is no mean feat for a tiny foetus to grow, when mum gets less than 25% of the minimum caloric.
The Dutch Hunger Winter children, now in their seventies, offer a rare window on how the early environment may leave a lasting imprint on our epigenetic make-up.”

5

What is the definition of stress?

Stressor?

Stress response?

Stress is a state of threatened homeostasis or disruption in homeostatic balance.

The thing responsible for the imbalance is the stressor.

The body’s response to the imbalance is the stress-response

6

What are the 2 main hormonal systems that comprise the stress response?

SYMPATHETIC NERVOUS SYSTEM
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

7

What hormones does the sympathetic nervous system stimulate the release of?

Where from?

What portion of the stress response does this induce?

The Sympathetic NS stimulates the release of norepinephrine & epinephrine from the adrenal medulla

“Fight or flight”

8

What are the hormones and endocrine organs that are part of the HPA axis?

Know how the HPA axis is turned on during a stressor, and turned off once the stressor ends.

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9

What other hormones are released in response to stress?

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10

What is the difference between an acute and a chronic stress?

Which is adaptive and which is maladaptive and why?

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11

What is the metabolic response to acute stress?

What is the pathological consequence of this stress response under chronic conditions?

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12

What is the cardiovascular response to acute stress?

What is the pathological consequence of this stress response under chronic conditions?

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13

What is the gastrointestinal response to acute stress?

What is the pathological consequence of this stress response under chronic conditions?

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14

What is the gut microbiome?

How might stress influence the microbiome to influence stress-related outcomes in the brain and behavior?

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15

What is the effect of acute stress on the reproductive system?

What is the pathological consequence of this stress response under chronic conditions?

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16

What is the effect of acute stress on growth?

What is the pathological consequence of this stress response under chronic conditions?

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17

What is the effect of acute stress on analgesia?

What is the pathological consequence of this stress response under chronic conditions?

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18

What is the effect of acute stress on the immune system and inflammatory response?

What is the pathological consequence of this stress response under chronic conditions?

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19

How does the hippocampus regulate the stress response, mechanistically?

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20

How does acute versus chronic stress impact memory/LTP, dendritic structure and neurogenesis on the hippocampus?

Which hormones are responsible?

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21

How does chronic stress influence the anatomy of the amygdala?

What are the pathological consequences of this?

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22

How does stress during pregnancy in rodents influence the development of the HPA axis in offspring?

How does this happen mechanistically?

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23

What are some outcomes of prenatal stress on human offspring?

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24

What are the different effects of mild versus severe stressors in young animals/humans on programming later responses to stress?

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25

What is the ACE study?

What does a higher ACE score predict for adult health/illness?

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26

What is the role of epigenetics in programming early life stress effects on offspring stress response?

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27

Which genes does low maternal care or early life stress change epigenetically?

How are these changes in gene methylation lead to changes in the hormonal stress response?

(Know both effects on glucocorticoid receptor and vasopressin)

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28

What epigenetic changes are seen in brains of individuals who committed suicide that either did or did not experience childhood abuse?

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29

How is social status in monkeys (vervet monkeys and baboons), and African dogs related to CORT levels?

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30

How does social support influence effects of chronic stress in humans and animals?

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31

Does repeated exposure to stress sensitize or desensitize the subsequent stress response? Which factors contribute to this?

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32

How does age influence the HPA axis?

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33

Are there sex difference in the stress response in rodents & humans?

What are they?

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34

How does controllability & predictability influence the magnitude of the stress response?

(Know the yoked control experiments)

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35

How do outlets for frustration influence the stress response?

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36

How common is anabolic steroid use?

What receptors do steroids act on?

What are the behavioral & physiological side effects of use?

Estimated over a million high school students use per year
8% of high school students.

Most steriods act on androgen receptors.

Side Effects:
Substantial risk for heart attack, suicide, cancer due to immunosuppression.
Euphoria, irritability, mood instability, anger
“Roids rage”

37

What are the main symptoms of premenstrual syndrome and premenstrual dysphoric disorder?

Which symptoms must you have to be diagnosed?

How is the disorder similar to and different from depression/anxiety?

Main symptoms:
Depressed mood, anxiety, emotional lability, anhedonia, mania...
Bloating, pain, changes in feeding, fatigue, muscle soreness, sleep disturbances.

To be diagnosed with Premenstrual Dysphoric Disorder, one must have at least 1 physical and 1 psychological symptom.
Otherwise, it’s just premenstrual syndrome.

38

Which hormones might be involved in PMS/PMDD?

What evidence supports this?

Decrease of Progesterone, low Estrogen

PMS = ‘withdrawal’ symptoms once P levels decrease at menstruation

Progesterone can act on GABA receptors to increase their action (at benzodiazepine receptor), so loss of P can induce anxiety


GnRH agonist can help PMS/PMDD by preventing reproductive cycling

GnRH is Highly effective at reducing depressive symptoms
GnRH leads to reduced progesterone

39

What is the hypothesis that links numbers of periods experienced in the lifetime with PMS symptoms?

What treatments might prevent PMS if this theory is true?

PMS is associated with long term consequences of having ‘too many’ periods versus our ancestors

Seasonique (constant birth control) or SSRIs as treatment

40

Which hormones/treatments help with PMS/PMDD?

Seasonique (constant birth control) or SSRIs

GnRH

41

How common is postpartum depression?

15-20% of women

42

Which hormones that change before and during parturition may be associated with postpartum depression?

Which show no association?

Beta-Endorphin concentrations rise during pregnancy, peak at parturition, and then plummet.

Women with most PPD issues had biggest change (decrease) in B-endorphin after child birth.

Women that end up having PPD have higher CRH (stress hormone releaser) levels at mid-gestation


43

How common is major depressive disorder?

MDD affects 1 in 5 Americans at some point in their lives

44

What is the difference in incidence in males and females prior to and after puberty?

How does depression change in men and women as they enter old age?

How might sex hormones play a role and how might cultural expectations of males and females?

Prior to adolescence:
Boys & Girls are equally likely to experience depression

Adulthood:
Women are about 2x's as likely as men to be diagnosed with MDD

The risk for MDD increases with age in men.
Women experience their peak risk between the ages of 35 and 45.

45

What genetic risk factors contribute to depression?

Which environmental factors?

Concordance rate between identical twins is 40% versus 11% for fraternal twins
Genes: polymorphisms, epigenetics.

Environmental: STRESS, trauma, illness

Many single nucleotide polymorphisms associated with increased risk if environmental risk is present.
Several relate to serotonin, hormones, or stress response.

46

How is the HPA axis dysregulated in depressed people?

At rest?

Following stressors?

Structural abnormalities in several brain areas:
Decreased volume of hippocampus and orbitofrontal cortex
Increased amygdala volume

Functional changes:
Decreased ACC activation leads to blunted emotions (anhedonia).
Increased blood flow in PFC & amygdala --->
Increased anxiety, fear response
Incresased stress response



At rest: Much higher baseline cortisol levels

Impaired negative feedback following stressors —probably at level of hippocampus

47

How is negative feedback of HPA axis altered in depressed individuals?

Know the basics of the dexamethasone test.

Impaired negative feedback—probably at level of hippocampus

The dexamethasone suppression test (DST) is used to assess adrenal gland function by measuring how cortisol levels change in response to an injection of dexamethasone.

It is typically used to diagnose Cushing's syndrome.
May also be used in diagnosing depression.

Dexamethasone is an exogenous steroid that provides negative feedback to the pituitary gland to suppress the secretion of adrenocorticotropic hormone (ACTH).
Specifically, dexamethasone binds to glucocorticoid receptors in the anterior pituitary gland, which lie outside the blood brain barrier, resulting in regulatory modulation.

48

What do the common incidence of depression in people with either Cushing’s disease or Addison’s disease tell us about the optimal level of cortisol?

Bell-curve graph of optimal hormonal amount.

Cushing’s Disease:
TOO MUCH CORTISOL

Addison’s Disease:
TOO LITTLE CORTISOL

49

How are thyroid hormones involved in depression?

How about estrogens?

Depressed people often have low thyroid function

Treatment with TRH can alleviate depressive mood in some.
Thyroid hormones can also help with PMDD/PMS.

Not always high or low in PMDD, but much more variable than in control group.

Autoimmune thyroidosis most associated with depression


Estrogens:
Depressed women have sig. decreased E2

Women hospitalized with depression show dramatic improvement following E2 treatment (very high doses)

Mood improvements seen most dramatically in post-menopausal women

50

What is the relationship between monoamines, like serotonin & melatonin, circadian rhythms, and depression?

Monamines play essential role in regulation of sleep & wake cycles

The adrenal glands release Cortisol in response to both circadian rhythms and stress-related activity (HPA axis)

Depressed people have disrupted circadian rhythms:
Too much REM, phase delays, high melatonin, low serotonin

Links stress, circadian disruption, and development of depression

Chicken and egg…

51

What is seasonal affective disorder (SAD)?

Type of depression that's related to changes in seasons

SAD begins and ends at about the same times every year.

Most people with SAD experience symptoms starting in the fall and continueing into the winter months.

Sapping energy and moodiness.

Less often, SAD causes depression in the spring or early summer.

Treatment for SAD may include light therapy (phototherapy), psychotherapy and medications.

52

How is melatonin implicated in SAD .... both the pattern of melatonin onset and its regulation by light.

Overproduction of melatonin in winter due to less light or dimmer light

SAD patients have dysregulated melatonin onset

53

How is the serotonin system influenced by time of year?

Seasonal variation of serotonin turnover in human cerebrospinal fluid relates to depressive symptoms

Serotonin transporter binding potential is greatest in summer

Monoaminergic Seasonality is involved in neurobiological mechanisms underlying season-associated physiological & pathophysiological behavior.

Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results.

To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period.
Circannual variation in 5-HIAA fitted a spring-peak model that was significantly associated with sampling month (P=0.0074).

Season of sampling explained 5.4% (P=1.57 × 10−7) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345).

In conclusion, there's a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality, and a positive correlation between 5-HIAA seasonality and depressive symptomatology.

This data sets the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.

54

How does light treatment help with SAD?

When should light be administered and what kind of light is best?

Prevent phase delays with melatonin and light

Avoid exposure to light at bedtime

55

How is the stress response dysregulated in PTSD?

Which brain regions are important?

There is Poor negative feedback tone of HPA axis

Hyperactive stress response (both HPA and Sympathetic Nervous System)

PTSD sufferers have bigger amygdala, responds with more activity to ‘fearful’ stimuli

Also have decreased inhibition of AMYGDALA by prefrontal cortex
-Prefrontal cortex is important for extinction of conditioned fear

-Estrogens slow extinction of conditioned fear, and lead to persistent negative associations

56

What is the role for other hormones in PTSD (ghrelin, neuropeptide Y, and PACAP) and how might they be used to help treat or prevent the disorder?

Reduced Neuropeptide Y may be a predictor for PTSD risk.
Neuropeptide Y is associated with stress, emotion, and feeding.

Stress or fearful stimuli increase levels of ghrelin, which might increase response to fear in amygdala
Anti-ghrelin drugs that are developed as anti-obesity drugs may be useful as therapeutics.
PTSD is highly associated with increased obesity.

Blood levels of PACAP are increased in women with PTSD.

Unbiased screens showed a polymorphism in PACAP increases PTSD risk in women

The polymorphism is in an estrogen response element…so it is regulated by female-hormone action

Risk allele (CC) associated with higher amygdala activation to fearful stimuli

57

What is learning, what is memory?

What are the different phases?

Why are they important to distinguish between when testing the role of hormones on learning & memory?

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58

How does acute stress influence memory, versus chronic stress?

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59

What is the Yerkes-Dodson law and how does it propose that the amount of stress experienced relates to learning & memory performance?

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60

How does epinephrine influence memory?

When does epinephrine have its effects and what does this tell us about the phase of memory influenced by the hormone?

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61

What are the 2 theories of how epinephrine affects learning & memory mechanistically?

What evidence supports each theory?

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62

How do glucocorticoids influence memory at different ‘doses’?

Does it matter if the stress is acute or chronic?

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63

How does acute stress influence Morris water maze performance?

Which phase of learning is affected?

What about the role of chronic stress on spatial learning in radial arm maze?

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64

Are effects of stress on learning and memory different in males and females?

What about the effects of stress on hippocampal dendritic morphology and spines?

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65

How does cortisol influence memory in humans?

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66

What are baseline sex differences in learning and memory?

How are learning strategies different in males and females?

Are these sex differences organized by hormones?

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67

What is the role of androgens in memory?

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68

What is the role of estrogens in memory?

How does estrogen influence the hippocampus?

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69

What is the relationship between estrogens, aging/menopause and memory?

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70

How do oxytocin & vasopressin influence learning & memory?

What evidence supports this conclusion?

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71

How does insulin influence learning and memory?

What evidence supports this conclusion?

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72

Corticotropin-releasing hormone (CRH)

A peptide hormone and neurotransmitter involved in the stress response.

It is a releasing hormone that belongs to corticotropin-releasing factor family.

In humans, it is encoded by the CRH gene.

Its main function is the stimulation of the pituitary synthesis of ACTH, as part of the HPA Axis.