Lecture 16 (Luckman)

Question 1

what is the Sympatho-adreno-medullary axis?

Answer 1

(autonomic nervous system)
Immediate responses but short-lived (e.g. increase heart rate and blood pressure)

fight/flight

Question 2

what is the Hypothalamic-pituitary-adrenocortical (HPA) axis?

Answer 2

Slower responses but longer duration (e.g. increase circulating glucocorticoids)

prolonged response to stress.

Question 3

HPA axis response?

Answer 3

1) Paraventricular nucleus of the hypothalamus:
CRH: corticotropin-releasing hormone
AVP: arginine vasopressin

they act on
2) Pituitary gland:
ACTH: adrenocorticotropic hormone produced

acts on
3) Adrenal gland:
Glucocorticoids produced (corticosterone [rodents] /cortisol [humans])
Catecholamines (adrenaline, noradrenaline)

glucocorticoids feedback on central nervous system via
4) Negative feedback to the brain:
GR: glucocorticoid receptor
MR: mineralocorticoid receptor

switch off hpa axis at pineal/hypothalamus.
also GR receptors in frontal and hippocampus.

Question 4

Glucocorticoid effects on the HPA axis?

Answer 4

Glucocorticoid receptors (GR) in CNS are key to negative feedback to CRH.

High levels of GR serve to suppress CRH more effectively (potentiates feedback).

This leads to lowered stress response.

Excess glucocorticoids have detrimental effects on CNS function.

Question 5

glucocorticoid effects of prolonged stress on the brain?

Answer 5

hippocampus:

prolonged low levels of stress:
changes in glucocort, norad, adr, catecholamines, leading to learning/memory problems.

spynaptic plasticity, morphological changes, necrosis, ageing and neurogenesis with worse stress.

all effect learning and memory.

????

Question 6

typical rat maternal behaviour?

Answer 6

first 2-3 weeks after birth.

1- Mother approaches the litter and gathers the pups under her.

2- Mother nurses her offspring, intermittently licking and grooming (LG) the pups.

3- Mothers also show arched-back nursing (ABN).

BUT
There are individual differences in pup nursing level between dams.

High LG-ABN or
Low LG-ABN
(Meaney’s group)

Question 7

High/low LG-ABN pups stress response?

Answer 7

As adults, the offspring of high-LG-ABN mothers showed reduced plasma ACTH and corticosterone responses to restraint stress (basal levels were similar)

only when stressed/restrained in a tube. normal stress/ACTH/corticosterone same.

CRH mRNA expression in the PVN was decreased and GR mRNA expression was increased in the offspring of high-LG-ABN mothers.

Question 8

effect of good mothers on HPA axis?

Answer 8

increases GR in hippocampus.

reduces CRH in hypothalamus.

reduces ACTH in pituitary

reduced Glucocorticoid secretion

leads to strong negative feedback on CRH

Question 9

intelligence of High LG-ABN offspring

Answer 9

Adults reared by high-LG-ABN mothers performed better in the Morris water maze test.

Synaptic marker protein (synaptophysin and NCAM) results showed higher amounts of these, this suggests increased levels of hippocampal synaptogenesis or increased synaptic survival in the offspring of high-LG-ABN mothers.

Question 10

Non genomic behavioural transmission across generations?

Answer 10

if removed and handled, mothers lick/groom more as a reward for pup coming back.

1- Females lick pups that have been handled. High groomers do not further groom pups if handled, low groomers do.

2- Pups of low groomers get more attention if handled.

3- Female offspring of low groomers that were handled are also better groomers.

4. F3 offspring still show differences in stress depending if handled or not.

carried through generations.

Variations in maternal care can serve as the basis for non genomic behavioural transmission of individual differences in stress reactivity across generations.

Question 11

Cross-fostering studies?

Answer 11

give Low pups to High mother, grow up as High/low anxiety.

if give high pups to low mother, still have low anxiety.

some genetic influence, also maternal care.

Question 12

lil summary

Answer 12

In the rat, variations in maternal behaviour can directly influence the pup’s hippocampal development

Variations in maternal care influence the development of behavioural and endocrine responses to stress in the offspring

The mechanisms underlying the differences in pup’s sensitivity to maternal care are unclear

Variations in maternal care can serve as the basis for non genomic behavioural transmission of individual differences in stress reactivity across generations

Question 13

Mechanisms underlying the long-term effects of maternal care?

Answer 13

Epigenetic mechanisms (changes in gene expression not due to changes in DNA sequence)
ie not mutation:

changes occur in chromatin:
1) DNA methylation

2) Histone modification (e.g. acetylation, methylation)

3) Synthesis of small
non-coding RNAs

Question 14

two forms of chromatin?

Answer 14

Repressive chromatin:
occurs when High levels of DNA methylation or Repressive histone marks.

condensed so transcription factors can’t access DNA, leads to suppression of gene expression.
OFF

Permissive chromatin:
occurs when Low levels of DNA methylation or Active histone marks.
looser, transcription factors (ie polymerase II) can access DNA sequence and transcribe gene.
ON

maybe look dis up

Question 15

Epigenetic mechanisms & long-term effects of maternal care

Answer 15

GR is a key player, as it regulates the stress feedback response.

High-LG-ABN mothers have thyroid-dependent increases in hippocampal serotonin.

this activates a cascade of secondary messengers, activates a transcription factor - NGFiA .

this activates expression of GR gene.

glucocorticoid receptors then expressed?

Question 16

what is NGFiA?

Answer 16

Nerve Growth Factor-inducible A
Nr3c1 gene encodes the GR

activates expression of GR gene.

Question 17

Role of DNA methylation in Low/High mums?

Answer 17

Low levels NGFI-A in hippocampus permit increased methylation and repression of GR gene.

High levels NGFI-A in hippocampus result in demethylation of GR gene.

Question 18

Role of histone modifications

Answer 18

Histone H3K9 acetylation and H3K4 methylation marks are both present at actively transcribed regions of the genome.

There is a decrease in the levels of H3K9ac and H3K4me in the exon 17 of the GR promoter in the hippocampus of adult offspring of low-LG mothers.

leads to reduced GR

Question 19

High/Low mothers in terms of epigenetics, also effects on pups

Answer 19

MOTHERS:
Low:
High DNA methylation.
Low histone modification.

High:
Low DNA methylation.
High histone modification.

PUPS:
Low:
low GR expression in hippocampus.
high corticosterone levels.
high anxiety.
low licking/grooming.

High:
high GR expressio in hippocampus.
low corticosterone levels.
low anxiety.
high licking/grooming.

Question 20

effect of childhood trauma or abuse on humans

Answer 20

Altered HPA stress responses.

Decreased GR expression in hippocampus.

Increased risk of antisocial/aggressive behaviour.

Increased risk of mental health problems (e.g. schizophrenia, mood disorders).

Increased risk of suicide.

Question 21

suicide victim study

Answer 21

McGowan et al., Nat. Neurosci., 2009

Hippocampal GR expression is decreased in suicide victims with a history of childhood abuse (but not in non-abused suicide victims or controls).

The Nr3c1 (GR) promoter has increased methylation levels in suicide abuse victims, compared to suicide non abused and controls. in line with rat studies.

Question 22

holocaust survivor studies

Answer 22

Low urinary cortisol levels

Increased risk of
anxiety and depression disorders

Increased risk of PTSD development, linked to maternal (not paternal) PTSD

Maternal age at Holocaust exposure and presence of maternal PTSD are associated with increased PTSD-related symptoms and increased stress sensitivity in their children.
older mother was at camp, higher chance of offspring to develop PTSD.

Question 23

Impact of maternal PTSD and depression following exposure to the September 11 attacks

Answer 23

Increase in death of males with foetal defects in womb and reduced male live births across the US following the attacks.

Increased behavioural problems in preschool children (e.g. increased emotional reactivity and aggressive behaviour) of mothers who suffered PTSD from 9/11.

Question 24

cumulative stress hypothesis?

Answer 24

requires high early life stress and high adult stress to be vulnerable to disease.

Question 25

what is the mismatch hypothesis?

Answer 25

high early stress means high adult stress is prepared for. if low adult stress can’t cope.

low early life stress don’t develop coping strategies so if high adult stress can’t cope.

Question 26

what is the three dimensional model?

Answer 26

early life/adult stress/programming sensitivity

Programming sensitivity depends on:
1- Environment (e.g. type and intensity level of stress stimulus)
2- Genetic background
3- Individual factors (e.g. age, gender, hormonal status)

all determine risk of psychiatric disease later in life.

check graph

Question 27

Why not all victims of maltreatment grow up to victimise others?

Answer 27

MAOA - Monoamine oxidase A breaks down serotonin, dopamine, noradrenaline.

MAOA KO mice prone to aggression.

in humans MAOA promoter polymorphisms leads to high/low MAOA activity.

boys experiencing severe, probable or no abuse as child.
severe abuse had low MAOA and showed high antisocial behaviour later in life.
High MAOA, childhood had little effect.

Boys with low MAOA activity had increased risk for adolescent and adult antisocial behaviour,

however

Maltreatment did not increase the risk of antisocial behaviour on boys with the high-activity MAOA allele.

Question 28

Why does PTSD only develop in 15% of individuals that experience severe trauma?

Answer 28

Posttraumatic stress disorder (PTSD) also show decreased hippocampal size.

thought that:
stress –> increased glucocorticoids –> hippocampal damage.

look at twins, one at war one not.
If normal hippcampus, war made no difference for PTSD risk.

If small, high risk with stress.

Therefore:
Low hippocampal volume is a predisposing factor for PTSD rather than a consequence of the disease