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Animal models > Lecture Roozendaal > Flashcards

Lecture Roozendaal Flashcards

1
Q

What does Emotional arousal induce in humans and rodents? Which hormones are involved?

A

Emotional arousal induces activation of stress
hormone systems. Epinephrine from adrenal medulla and glucocorticoids from adrenal cortex. Cortisol is released in humans, corticosterone in rodents.

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2
Q

How would you do a model in animals for PTSD?

A

Doing something very stressful to the animals? No, it is not really a good model for PTSD, because not everyone who has a traumatic experiences develops PTSD.

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3
Q

Are drug treatments based on animal models of anxiety disorder working in patients?

A

No, most do not work

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4
Q

What happens as response to stress in the Amygdala in terms of hormone levels?

A

A rise in noradrenaline (norepinephrine) and then a slower rise in corticosterone

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5
Q

Can Epinephrine from the adrenal gland directly enter the brain?

A

No, it can bind to ascending fibres on the vagus nerve and that will be translated into norepinephrine

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6
Q

Can corticosterone directly enter the brain?

A

Yes

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7
Q

Are noradrenaline and corticosteroids present at the same time?

A

Yes, corticosteroids see a dely in rise, but they persist

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8
Q

Experimenting with mouse

A

Mouse is placed in light compartment with access to dark compartment (mice prefer darker spaces). In the transition from the light to the dark area they are given a little shock. If shock is given the animals takes longer to move from one place to the other the next time (10 sec vs 50 sec ca.). But, if the rat is given dexamethasone (0.3 mg/kg) - synthetic glucocorticoid. (binds to the glucocorticoidreceptors The rat stays even longer (increased stress response.

If beta-blockers are also given in the amygdala, the effect of dexamenthasone is blocked.

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9
Q

If emotional training releases norepinephrine. If glucocorticoids need norepinephrine and norepinephrine is only released during arousing conditions, does that mean that glucocorticoid only have an effect for emotional information and not enhance memory for not emotional events?

A

object recognition test (necessary because it did not cause stress). 2 conditions:
1. habituated - Animal in the box for 7 days so that box is completely familiar (to avoid norepinephrine release due to arousal)

  • corticosterone does not enhance memory (glucocorticoids need an emotional arousal in order to have an effect
  1. not habituated, i.e. training induced norepinephrine Animal in the new box
  • corticosterone enhanced memory (object is explored more)
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10
Q

How does glucocorticoid level change throughout the day?

A

In the morning glucocorticoid levels are very high, compared with later in the day.

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11
Q

Did the beta blocker for rats in the object recognition task without habituation who received corticosterone decrease or increase the discrimination index (time spent on new object vs old one)?

A

When given Propranol (beta blocker) the effect of corticosterone was deleted. So, the effect of the glucocorticoids was not there anymore.

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12
Q

Did norepinephrine for rats in the object recognition task with habituation who received corticosterone decrease or increase the discrimination index (time spent on new object vs old one)?

A

Rats that where given Yohlmbine (0.3 mg/kg), (pharmachologically) and corticosterone who previously only received corticosterone, they increased their memory a lot. So in the morning, when glucocorticoids levels are higher, one still needs norepinephrine to be able to recall things well.

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13
Q

Where in the brain does it work?

A

Hormones can activate the amygdala, and the amygdala can facilitate the storage of the information in other brain regions.

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14
Q

Does emotional arousal and stress hormones also influence the accuracy or specificity of memory. What i

A
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15
Q

What is the inhibitory discrimination task?

A

Rat is positioned in lighter area, tends to go to darker one as rats prefer the dark, but if e.g. shock is given that might alter the rats response.

2 boxes to test accuracy:

2 boxes, one with shock, one without box and one new box.

1 min in one box, then in another (1-min interval)

Yohimbine –> high specificity

Corticosterone –> low specificity

2 min in one box and then in another (2-min interval

they treat the boxes differently.

corticosterone decreased specificity

shock/non/shock/novel

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16
Q

is specificity related to hippocampus? What happens if the hippocampus is blocked?

A

if muscimol infusion is done on hippocampus, the effect of norepinephrine is not effective anymore. This can be seen by comparing 2/day retention and 28/days retention tests.

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17
Q

Muscimol infusion in the hippocampus, how does it work

A

Muscimol binds to GABAA receptors, increasing chloride ion influx into neurons. Neurons are hyperpolarized, silencing or inhibiting their activity

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18
Q

How does NE and corticosterone influence the connection between amygdala and hippocampus/neocortex?

A

NE improves amygdala hippocampus connection, while corticosterone might reduce that and rather strengthen amygdala-neocortex connection
both strengthen the memory, but in different ways.

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19
Q

How do the two hormones affect remembering? Is the effect different?

A

In the long-run the memory storage of the two hormones is different

20
Q

consolidation, specificity and retrieval. What happens if stress levels are very high during retrieval of memories?

A

watermaze. Are rats swimming where the platform was or where it it is not. COntrol animals spend much more time in the place where the platform was. But if animals are very stressed they spend the same amount of time searching in both places (almost). most effect 30 min after stress (more than 2 min after or 4 hours after)

higher dosis, they swim all over.

glucocorticoid-induced impairment of spatial memory retrieval

21
Q

Is impaired memory also seen in normal levels of glucocorticoids?

A

Normal level/lower level of glucocorticoids does not have an effect, effect is only seen when high dose

When you wake up in the morning, you can remember just fine, even though corticosterone levels are higher, but if you are also very very stressed, it might be more difficult to retrieve memories.

22
Q

What does tht mean?

A

Plan lecture in the morning and exam in the evening ;)

23
Q

Do glucocorticoi effects on memory retrieval need noradrenergic activation?

A

Yes, beta-blockers made time rats searched for platform in each quadrants about the same

24
Q

summary memory retrieval

A

glucocorticoids impair memory retrieval of previously acquired information, and the effect depends on concurrent arousal-induced noradrenergic activation

25
Q

What is the translation to human subjects?

A

Learning words as many as they could remember. Either cortisol or placebo.
Placebo condition (17 words)
Cortisone (25 mg) condition (11 words)

in memory retrieval. 30% fewer in study setting with high cortisone

MRI shows reduced activity of hippocampus under cortisone condition.

Glucocorticoids injected directly in hippocampus showed same effect ( impaired retrieval)

Retrieval needs norepinephrine

high arousing words/low arousal words.

cortisone - and low arousal showed higher number of words recalled compared to placebo.

When beta blockers where introduced (propanol) , the effect of the cortisone was reversed, and both high and low arousal words had same effect

GLUCOCORTICOIDS NEED NOREPINEPHRINE TO IMPAIR RETRIEVAL

it only impairs retrieval of high arousal words under norepinephrine and

Propanol by itself did not cause

26
Q

Summary comparison Placebo/Cortisone;
Placebo/ Corstisone + Propranol; Placebo/Propranol

A

Placebo/Cortisone:

impaired retrieved memory with high arousal words

Placebo/ Cortisone + Propranol:

Effect of cortisone is reversed, i.e. cortisone has no effect

Placebo/Propranol:
no significant decrease in in memory retrieval

27
Q

PTSD

A

Intrusive and persistent traumatic memories which can manifest as daytime recollections, traumatic nightmares or flashbacks in which components of the event are relived

28
Q

Research in intensive care unit

A
  • People with open heart surgery
  • People with pulmonary failure (ARDS) –> high survival rates but also high number of traumatic memories from ICU treatment (30% develop PTSD), results in significant impairments in health-related quality of life outcomes (intertwined with psychological issues)
  • a lot of people get epinephrine or norepinephrine for blood pressure and glucocorticoids to suppress immune system (especially with organ transplants)
29
Q

What do people with ARDS remember in percentages?

A

Nightmares: (over 60%)
Anxiety/Panic: (around 40%)
Pain: (almost 40 %)
Respiratory distress: (almost 40%)

30
Q

What are the cortisol levels in PTSD

A

Those who develop PTSD have lower cortisol levels compared to people who did not develop PTSD.

31
Q

What is the positive feedback model of PTSD?

A

Traumatic memories –> retrieval –> re-experiencing/flashbacks with the releaseof stress hormones –> consolidation –> traumatic memories.

32
Q

If you administer people with cortisone, can you suppress the development of PTSD?

A

Hydrocortisone (syntetic cortisone) decreased PTSD

33
Q

Glucocorticoid effect on retrieval of traumatic memory (3 patients)

A

Patient 1 (50-year old man who survived 4.5 years before) - intrusions written in diary

cortisol was given for 1 month, and it significantly reduced the intrusive memories

34
Q

What did patients with a Glucocorticoid Receptor polymorphism show in term of PTSD memories?
Bc/l allele

A

Less sensitive glucocorticoid receptors, those are the ones that develop PTSD.

Heterozygous or non-carriers of the Bc/l*G allele

less traumatic memories and less PTSD

Homozygous carriers of BC/l* G allele

more traumatic memories and more PTSD

35
Q

Increased DNA methylation at the NGFI-A binding site of the NR3C1 promotor was associated with less intrusive memories of traumatic events and reduced PTSD risk in male, but not female, survivors of the Rwandan genocide

A
36
Q

Does epigenetic modification of the glucocorticoid receptor Gene increase glucocorticoid levels?

A

yes

37
Q

Pharmacological interventions for preventing post-traumatic stress disorder (PTSD) with 5 pharmacological tratments results

A

hydrocortisone, propranol,
escitalopram,
temazepam,
gabapentin

HYDROCORTISONE is the most effective pharmacotherapy for the prevention of PTSD

38
Q

Do glucocorticoid effect phobias?

A

People with social phobia.

In the group where participants where given cortisone the fear rised less compared to those
The more cortisone increased, the less fearful they were.

39
Q

How is it explainable that fear is reduced with higher cortisone levels?

A

Cortisone decreases memory retrieval, decreasing

40
Q

fear exposure with spider in phobias

A

People given cortisone significantly reduced the fear response

41
Q

Glucocorticoids improve consolidation and impair retrieval

A
  • Re-experiencing
  • Phobic fear

–> glucocorticoids

–> extinction memory

42
Q

How can phobias be cured?

A

Exposure therapy in combination with glucocorticoids.

People with fear of heights

  • exposure therapy is effective
  • with glucocorticoids, the therapy effect is enhanced compared to placebo

Effect is there even 30 days later

43
Q

Animal model with with altered glucocorticoid receptors/levels

A
44
Q

Behavioral therapy morning vs afternoon

A

Treatment worked much better when done in the morning (high cortisol) rather than in the afternoon (lower cortisol)

45
Q

What are adverse consequences of glucocorticoid medication? (psychological, cognitive and behavioral effects

A

High doses

suicide/suicide attempt
delirium, confusion, disorientation
mania
depression
panic disorder
>5 neuropsychiatric outcomes

46
Q

Differential targeting of brain stress circuits with a selective glucocorticoid receptor modulator

A

Animal models (10 decks)

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