Stress and Pregnancy Flashcards
1
Q
What happens during pregnancy to stress hormones and precursors? Where is it produced?
A
CRH increases thousand fold from 8-10 weeks. The CRH produced is not from the hypothalamus, but from the placenta, decidua and fetus. The rise in maternal plasma CRH leads to increased maternal cortisol.
2
Q
What happens to the accompanying CRH binding protein?
A
• CRH binding globulin is also raised until the 2nd or 3rd semester which limits the free CRH. Binding protein sequesters the hormone as it stops it from binding to its receptor. Corticosteroid binding globulin (CBG) is stimulated by estrogen, so levels are raised during pregnancy
3
Q
What happens towards the end of pregnancy?
A
• Towards the end of pregnancy the ratio of CBG to free cortisol changes – probably due to displacement by progesterone and 17-OH-progesterone
4
Q
What happens literally just before birth?
A
• A transient peak is seen in free cortisol just prior to birth – may signal the onset of parturition
5
Q
What is the effect of cortisol on progesterone and other effects?
A
Cortisol is an endogenous inhibitor of the activating effect of progesterone upon prostaglandin-degrading enzymes.
Prostaglandins interfere with the maternal uterus and can be used to initiate abortions.
The peak in cortisol may allow the activation of prostaglandin signalling for the onset of parturition.
6
Q
What evidence is there for the effect of cortisol on parturition?
A
Evidence: Intravenous infusion of antalarmin (a CRH receptor antagonist) to fetal sheep significantly delayed parturition
7
Q
What does the peak in cortisol just before birth allow? Why is this clinically important
A
• 36/37 weeks foetal lungs not mature, glucocorticoids play a key role in developing them
• In the lungs, surfactant decreases surface tension in the alveoli and allows efficient gas exchange
• The peak in GCs seen during late gestation is essential for lung maturation, as they promote surfactant production
• The primary cause of death for premature infants is respiratory distress (RD) due to insufficient surfactant
• Antenatal GCs, given 2-7 days before preterm delivery, significantly decrease the incidence of infant RDS and death
• Synthetic GC treatment is now routine - 10% of all births
Glucocorticoids are needed for differentiation
8
Q
In rats, what happens just after birth? Evidence?
A
- Just after birth until post natal day 14, rats have very low basal corticosterone
- Stressfull stimuli that would cause a full response in adults have a blunted effect in neonates, e.g. injecting LPS versus saline
- Serum ACTH concentrations in immature and adult rats determined 20 min after laparatomy stress or in untreated controls, n = 6-8
- The SHRP is not a stress non-responsive period - an increase in circulating corticosterone can still be induced by a sufficiently powerful stimulus
- Rats are precocious, i.e. significant brain development occurs after birth
- The SHRP is a protective phase which ensures that the developing individual is not s hazardous and may have important long-term consequences to health
9
Q
Why is the stress hyporesponsive period important in rats?
A
- Rats are precocious, i.e. significant brain development occurs after birth
- The SHRP is a protective phase which ensures that the developing individual is not s hazardous and may have important long-term consequences to health
10
Q
What are three potential mechanisms of the SHRP in rats?
A
Pituitary ACTH Release
Hypothalamic lesion
Enhanced glucocorticoid feedback
11
Q
What happens in the rat model of pituitary ACTH release for SHRP?
A
Pituitary ACTH release increases linearly with age. Pituitary CRH binding sites – actually seems to decrease with age and neonates seem to have more than more developed. The ability of Pituitary to bind CRH is maintained throughout puberty and adulthood. Have ACTH and the pituitary is responsive to it.
12
Q
What about in the hypothalamic lesion theory of SHRP in rats?
A
The hypothalamic PVN CRH mRNA content in rats decreases at birth then increases the first week afterwards. Hypothalamic CRH content remains low during the SHRP and then increases with age. During this period, stress in the form of a saline injection can still stimulate a CRH response in the hypothalamus in the absence of any increase in plasma of ACTH or corticosterone.
13
Q
Generally what happens in the early stages of pregnancy versus the late stage?
A
Early is growth, late is maturation/ differentiation
14
Q
What three ways is the foetus protected?
A
a) Cortisol binding globulin (Maternal)
b) Placental 11β-hydroxysteroid
dehydrogenase (Maternal/Foetus interface)
c) GR levels (Foetus)
15
Q
What is prematurity in terms of the UK
A
<37 weeks, 13% pregnancy. Increasing perhaps due to increasing maternal age/ number of pregnancies
16
Q
How does enhanced glucocorticoid feedback in the SHRP work?
A
Injection of a subcutaneous GR antagonist during the SHRP causes a dramatic increase in ACTH and corticosterone release (no negative feedback) implying there is increased sensitivity of the axis. Administration of a GR antagonist during the mouse SHRP:
Decreased GR expression in the PVN
Decreased GR expression in the hippocampus
Increased POMC expression in the anterior pituitary
Suggests a high, tonic level of negative feedback inhibition by GCs during the SHRP
Low corticosterone + low corticosteroid binding globulin
= high free corticosterone
Young rats have much more sensitive pituitary glands:
- IC 50 – the amount of dexamethasone required to reduce ACTH secretion by 50% through negative feedback.
17
Q
How can the mother affect the SHRP?
A
• 24 hours of maternal deprivation led to a significantly increased corticosterone response to ACTH injection compared with non-deprived pups during the SHRP
• Increasing periods of maternal deprivation on P7 led to steadily rising basal corticosterone, and a proportionately greater stress response to saline injection
• Separation has been shown to have significant effects in the brain at P9
- Decreased GR and MR expression in the hippocampus and hypothalamus
- Increased basal ACTH and corticosterone
• Stroking pups reversed the effects of maternal separation on ACTH and MR mRNA, but had no effect on GR – suggesting a role for maternal contact
18
Q
Do humans have a SHRP?
A
- Most of the experiments done have been in rats that are precocious animals meaning a large part of their development occurs after birth
- Unclear whether that humans have an SHRP
- Vast majority of human organ development occurs during pregnancy. SHRP could potentially occur in utero
19
Q
Why can steroids readily cross the placenta? Protected by? Positive and negative regulators
A
Because they are lipophilic. placental trophoblasts of the enzyme 11β-hydroxysteroid dehydrogenase type 2. • The barrier to maternal GCs provided by 11β-HSD II is not complete – some maternal GCs can get across
• If the mother is stressed, 11β-HSD II can become saturated, and the fetus can be exposed to high levels of GCs since the barrier becomes saturated
• The efficiency of human and rat placental 11β-HSD II varies considerably, and seems to correlate with birth weight, although whether this is cause or effect is unclear
Some of the most important negative regulators are: Estrogen, Inflammatory cytokines, Hypoxia. Positive regulators include maternal stress and GCs
20
Q
How do maternal and foetal blood come into contact with each other?
A
Intervilla space: Have maternal spiral arteries interweaving with intervilla space, as well as terminal villa of the placenta. Allows the transfer between maternal and foetal blood. Cortisol very lipid soluble meaning cortisol can easily diffuse across.
21
Q
What are the problems with synthetic glucocorticoids?
A
Synthetic GCs;
- Do not bind to CBG
- Poor substrates for 11b-HSD II
Therefore foetus may be exposed to high levels of
glucocorticoid
22
Q
What evidence is there for long term effects of glucocorticoids crossing the placenta?
A
Looking at PEPCK levels (important in gluconeogenesis), much higher in foetus exposed to dexamethasone controls
23
Q
What happens with glucocorticoid receptors in the foetus during pregnancy?
A
High numbers of GR means very high negative feedback, meaning very small amounts of cortisol
GR only in brain
As you approach term, amount of glucocorticoid increases for differentiaion so GR in brain numbers decrease later in term.
At term in guinea big, decrease in GR dramatic
This is for Foetal HPA activation, ↑ foetal adrenal GC production
24
Q
How does glucocorticoids in utero affect blood pressure?
A
Males are far more responsive and increase BP, and recover far more slowly.females, also take longer to recover. INJECTED AMPHETAMINE TO INDUCE A SNS RESPONSE/ RESTRAINING RATS THEN POST RESTRAINT
- ↑ renal Na/K-ATPase (so more sodium reabsorbed, water follows osmotic gradient)
- ↑ AT1 and AT2 receptor expression
- Altered coronary responsiveness
25
What effect does GC in utero have on 11bHSD?
Increases 11bHSD relative mRNA expression in subcutaneous fat that is linked to visceral adiposity
26
What are the effects of GC in utero on behaviour?
Higher GC during pregnancy are linked to increased anxiety in adulthood, seen by less time/ grid crossings spent in the open field.
Additionally, more CRHmRNA (anxiolytic hormone) in the fear centre of the brain, the AMYGDALA.
27
What happens in pituitary ACTH content with age?
Increases linearly from throughout pregnancy.
28
What is the risk for the foetus in terms of centiles and birth weight?
Baby at increased risk if it moves up centiles as grows. This implies that baby was genetically programmed to be larger, but was born in a stressful/ low nutrition period and thus fetal programming would have occurred. Also increased risk are babies who are born very long but not very wide, implying that their growth in utero was compromised. But it is a U-shaped curve with increased risk for very large babies as well.
29
Other than endogenous glucocorticoids, how might a mother in pregnancy be affected?
Women have more symptoms of depression and anxiety during pregnancy than post natally, not much media attention compared to post natal depression. 10-15% of mothers affected.
30
How common are neurodevelopmental disorders?
More than 1 million children in UK suffer from neurodevelopmental disorders, 8% of females and 11% of males.
31
How might some of the changes be happening in utero?
More than 1 million children in UK suffer from neurodevelopmental disorders, 8% of females and 11% of males.
32
What behavioural outcomes are associated with maternal stress?
If mother stressed, child more likely to be bullied at school – victimization. Many behavioural issues, but also mixed handedness (involved in many neurodevelopmental disorders), altered finger print pattern, decreased telomere length (leading to reduced longevity), ASTHMA, ALTERED IMMUNE FUNCTION, reduced birthweight and gestational age.
33
What was a key study for glucocorticoids in utero and pregnancy?
ALSPAC – large prospective birth cohort about 14000 pregnant women recruited around Bristol 1990-1991 and then detailed information on the children up to 13. Maternal anxiety and 18 and 32 weeks of pregnancy, compared children of 15% most anxious or depressed mothers with the rest. Good because has data for all the confounders eg maternal postnatal anxiety and depression as well as paternal, parenting, maternal age, birth weight, gestational age, smoking, alcohol and psychosocial factors such as crowding.
A clinical doubling of the risk after all the confounders have been taken into account . For top 15% of most anxious/depressed women in pregnancy, rate of probable mental disorder
• doubled from about 6 to 12% at age 13 years (after multivariate analysis allowing for a wide range of possible confounders).
34
What is one estimate of attributable load of probable mental disorder in whole population due to prenatal anxiety/stress?
10-15%
35
What is a way of assessing cognitive function in early life?
Bayley score
36
What evidence of the role of genes in stress?
COMT breaks down the catecholamines (such as dopamine, noradrenalin) – looking at genetic variants of this gene with ADHD. A single nucleotide (GG) polymorphism linked to maternal stress in pregnancy – WORSENED WORKING MEMORY AGE 8. Gene environment interaction.
37
What is a study for diabetes and Barker hypothesis?
Relative risk of type 2
diabetes
US Nurses’ Study (n=69,526)
38
What studies are there for the mechanisms of high stress transmitting to foetus?
Recruited day before elective caesarian and did anxiety questionnaire. Later collected the placenta and was found that the more stressed, the less 11bHSD2 present in placenta, allowing more cortisol to pass through (was proposed).
Queen Charlotte, measured amniotic fluid for cortisol then at 18 months did Bayley test. The more cortisol there was in the amniotic fluid, the worse the child did in the Bayley test.
39
What is the evolutionary value of prenatal stress?Potential benefits
Protective value of prenatal stress?
Eg in ADHD help survival, notice a danger and readily shifted attention
Anxious – more vigilant
Impulsive - more willing to explore new environments
Females – more anxious and vigilant, males more aggressive, ADHD.
40
In males, what are LH and FSH required for? What is like throughout males life?
• FSH→ sertoli cells and spermatogenesis
• LH→ Leydig→ Androgens (testosterone, DHEA and androstenedione)→ Secondary sexual characteristics
It is reasonably consistent throughout life.
41
What is gonadotrophin secretion like?
• Pulses every 30 mins, many tissues do not like a continuous exposure. If was released more steadily then there would be a down regulation of the receptors. Hence GnRH agonists being used for prostate and breast cancer
42
Mini summary of the menstrual cycle?
* E2 gradual rise that becomes exponential, positive feedback. The rising levels of oestrogen triggers LH surge. before is a negative feedback.
* Ovulation – one graffian follicle becomes dominant. Second half of the cycle rising levels of progesterone. If implantation occurs, the hcg produced will have a similar action to lh and fsh and cause progesterone to be elevated so that uterus lining does not decline
When oestrogen becomes positive regulator, increases frequency and amplitude of GnRH pulses.
FSH+LH→ graffian follicles
LH→ corpus luteum
43
What happens when oestrogen becomes the positive regulator?
When oestrogen becomes positive regulator, increases frequency and amplitude of GnRH pulses.
FSH+LH→ graffian follicles
LH→ corpus luteum
44
What is the difference between sex and gender?
Sex: Distinguishes male or female subjects according to the reproductive organs and functions that derive from the chromosomal complement (male XY or female XX sex chromosomes)
Gender: A [human] subject’s self-representation as male or female
45
What is the early embryo like?
Female/ neutral
46
How and when does masculinization occur?
Masculinization of the mammalian gonads is genetically determined by the Sry gene (Sex determining Region of the Y chromosome), about 6 weeks after conception to form testes
47
After testes are formed, what is the next step?
From testes
Mullerian inhibitory factor - stops female internal genitalia
Testosterone> Aromatase leading to masculination of brain through oestrogen
Testosterone> 5 alpha reductase to DHT leading to external and internal genitalia through Wolffian ducts
48
How do female gonads form?
Absence of mullerian inhibitory factor, internal genitalia and absence of testosterone, external genitalia
49
What is the period where testes produce testosterone like?
Testes are transiently activated during development to secrete testosterone. This co-incides with a critical window when the hypothalamic circuitry is susceptible to masculinization or defeminization that persists throughout life.
50
In relation to birth, what are testosterone levels like?
Peak in testosterone in males before and after birth.No peak in mother or in female offstpring.
51
What is male steroidogenisis like compared to female? What does this establish?
Steroidogensis in the developing testes is activated earlier in development than ovarian steroidogenesis. This establishes irreversible sex dimorphisms in specific neural circuits = sexual differentiation of the brain
52
Which effects are reversible and irreversible in the differentiation of the brain?
* At critical developmental stages hormones induce specific neural substrates or circuits to develop differently in males and females such that they react differently at a later stage when they are exposed to the same hormonal environment.
* These effects are irreversible.
* In adulthood, the response of a given neural element will differ depending on the hormonal environment e.g. even low dose androgens will make women more assertive and increase libido.
* These effects are reversible.
53
Key evidence for sexual differentiation in early development?
Ovarian tissue transplanted:
adult male rats (normal-produce test or castrated)- grafts show normal follicular growth, but no ovulation (ovarian tissue survives as males produce LH and FSH, which stimulates the ovaries to grow and survive. But no trigger for ovulation in these males)
adult male rats castrated at birth- cyclical ovulation occurs
Conclusion- there must be something in the testes at the time of birth that is having this effect, because if you take it away, you get an LH surge and stimulate ovulation. This is testosterone
Only presence of hormones at birth required for functioning of ovary
Testicular extracts given to neonatal female rats, prevented generation of the LH surge in adulthood and permanently blocked ovulation (‘masculinised’ the HPG axis)
Conclusion: a hormone dependent sex difference could exist at the level of the pituitary gland
54
What evidence is there that sexual differentiation is not happening at the level of the pituitary?
A male pituitary gland was transplanted beneath the hypothalamus in
hypophysectomised female rats.
Ovulation still occurred
Conclusion: Sex differences must lie in the brain and not pituitary gland
55
What three bits of evidence are there for testosterone being the major driving force?
LH surge generation, neuro anatomical evidence and behaviours such as lordosis
56
What near-anatomical evidence is there? Females
the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the hypothalamus (influences copulatory behaviour in adult rats).
• Males’ SDN is bigger than females, unless the females are treated with testosterone
* Control adult female- female adult nucleus is much smaller than male
* Gave ester of testosterone- then tested in adulthood- increase size of SDN 3 fold
* However, did not reach male size, so gave for longer- Injected between E16-P10 In adulthood SDN reached the size of males. Very potent effect early life
* If give estradiol benzoate single injection. When grew to adulthood, increased size of SDN→ oestrogen must be masculinizing brain (aromatization)
* Diethylstillboestrol- given for same extended period between E16-P10- could completely masculine nucleus
57
What neuroanatomical evidence is there for males?
Males: control- high volume of SDN
Gonadectomised on day of birth- when grow to adulthood size of SDN halves. But no testes in adulthood, so cant say this effect is due to taking away hormones at birth – no testosterone at birth or at adulthood
So gonadectomised at birth and given injection of testosterone,measured in adulthood. Size of SDN is almost completely restored.
Suggests perinatal environment programmes sex differences in brain size
Animals treated with tamoxifen- blocks estrogen receptors- given to mothers between E16 and P10- time period where oestrogen and testosterone could fully masculinise female SDN. If block estrogen receptors, also block increase in size of SDN
Testicular feminised male- androgen receptors not working due to mutation- normal XY chromosome so develop testes normally. But androgen receptors not effective- don’t produce adult genitalia. Enough testosterone produced early on- don’t have normal androgen receptor and but have normal estrogen receptor. So SDN normal size.
58
What happens in tesitular feminised males?
Testicular feminised male- androgen receptors not working due to mutation- normal XY chromosome so develop testes normally. But androgen receptors not effective- don’t produce adult genitalia. Enough testosterone produced early on- don’t have normal androgen receptor and but have normal estrogen receptor. So SDN normal size.
59
Experimental evidence for the LH surge being sexually diamorphic?
- ovariectomise (Ovx) adult female rats
- administer oestradiol (E2) followed 48h later by progesterone (P) to mimic the natural stimulus for an LH surge and ovulation. If give females testosterone from birth then no surge
- measure circulating LH
- Follow similar paradigm in castrated (Cx) male rats, which will have the same basal sex hormone status as Ovx female rats. The LH surge could be established if the rats were gonadectomised at birth but not in adulthood. Also from birth give aromatase inhibition so cannot produce testosterone then they have LH surge→ changes to the hypothalamus occurring
60
What evidence is there for lordosis being sexually dimorphic?
Castrated females then replaced E&P to stimulate lh and fsh surge→lordosis
Male in adulthood doesn’t not exhibit this behaviour, when giving E&P so there is a masculinisation as not responsive
Female neonatal testosterone has inhibited ability for lordosis →Masculinised the behaviour
Anti-sense:Block production of ER so neo natal testosterone cannot masculinise brain so still exhibit lordosis when have oestrogen and progesterone replaced.
Instead of giving proper antisense, scrambled oligonucleotide is when same bases put together in random order- won’t bind to ER mRNA- another control
61
Why does maternal/foetal oestrogen masculinise the female brain?
Castrated females then replaced E&P to stimulate lh and fsh surge→lordosis
Male in adulthood doesn’t not exhibit this behaviour, when giving E&P so there is a masculinisation as not responsive
Female neonatal testosterone has inhibited ability for lordosis →Masculinised the behaviour
Anti-sense:Block production of ER so neo natal testosterone cannot masculinise brain so still exhibit lordosis when have oestrogen and progesterone replaced.
Instead of giving proper antisense, scrambled oligonucleotide is when same bases put together in random order- won’t bind to ER mRNA- another control
62
Where is the SDN found and differences between males and females?
In the medial pre-optic nucleus. ➢ major site for regulating male sexual behaviours in all vertebrate species studies
➢ 2-3 times as many dendritic spine synapses (excitatory input from glutamate) in males compared with females
Adult males have a two to threefold greater density of spine synapses than females which is associated with male sexual behaviour in adulthood.
Oestradiol aromatized from testosterone in the neonatal male hypothalamus stimulates glutamate release which induces a long-term increase in the density of spine synapses
63
What is one reason for the SDN being bigger in males?
Testosterone exposure in early life on apoptosis ( a natural process as the brain produces too many cells and synapses). Testosterone could be preventing apoptosis in SDN, hence males bigger 6-10 key developmental time peroid.
Lateral preoptic area in adulthood shows no gender difference and thus the removal of testosterone made no difference. Not all neurons respond in the same way to testosterone.
Castrate males at birth, and give vehicle or testosterone and compare SDN levels and lateral hypothalamus total cells undergoing apoptosis.
64
Which nucleus is important for female sexual behaviour?
• Ventrolateral division is important for female sexual behaviour (lordosis)
➢ In females (not males) gonadectomised as adults, high physiological levels of E2 induce PR expression, increase spine and synaptic density and induce lordosis in presence of receptive male
➢ Estradiol promotes glutamate release from synaptic terminals, activating NMDA receptors and the MAP kinase pathway.
➢ In males, exposure to estradiol early (as a result of aromatisation) causes defeminisation. Loss of responsiveness of dendrites and spines to E2 in adulthood, rendering males unable to display female sexual behavior.
• Sex differences are due to testosterone (aromatised to estradiol) in the perinatal period
65
Which nucleus for mediating the LH surge? Evidence AND MECHANISM
ARCUATE NUCLEUS. In male rats: Oestradiol synthesized from testosterone increased the complexity of astrocyte structure, leading to permanent elimination of synapses in newborn males.
GFAP identifies astrocytes: The more complex astrocytes dendrite becomes, the less likely that neurons can form synapses and reduce synaptic contacts
In males conversion to oestrogen, increases GABA neurons and that increase in GABA seems key in stellation (star shape) of astroctes and thus reduces excitatory input into these regions.
Summary: T after aromatisation to E2 acts via multiple mechanisms on neonatal hypothalamic neurones and glial cells to induce permanent structural changes and confer resistance to oestrogenic influences in adulthood.
66
Which other nucleus is key in females? Think kisspeptin
AVPV (a region of the POA)
• hypothalamic anteroventral periventricular nucleus is involved in regulating ovulatory cycles.
• Larger (more neurones) in females than males
• Oestrogenic metabolites of testosterone induce apoptosis during development
67
Which nucleus is important for male penis function?
Spinal nucleus of the bulbocavernosus
• motor neurones in the lumbar spinal cord innervating striated muscles at the base of the penis
• larger in males than females.
• neurone survival is AR-dependent, but secondary to testosterone effects to prevent death of target muscle cells.
68
What are sexual hormone differentiation like between males and females
Here you can see that in both rats and humans there are similar patterns of exposure to testosterone
So, in both cases we see a transient rises in testosterone in early life,that then lies dormant until puberty. In rats the critical period occurs just before and after birth whereas in humans it is likely to occur around or just before mid gestation.
The patterns of E2 exposure are also similar across species, with cyclicity emerging at puberty to trigger the LH surge and ovulation.
69
What is the human SDN like?
➢ The 3rd interstitial nucleus of the anterior hypothalamus (INAH-3) is the human homologue of the rodent SDN-POA
70
What other brain areas are relatively bigger in men and women?
* Amygdala volume is greater in men than women.
| * Hippocampal volume, regional cortical thickness and gyrificationis greater in women than men
71
For males, larger nucleus?
SDN in medial preoptic nucleus not lateral
72
For females, larger nucleus?
Ventro lateral and AVPV
73
Which nucleus for LH surge?
Arcuate
74
What human evidence is there?
Congenital Adrenal Hyperplasia
o Girls exhibit an increase in male-typical play and a decrease in female-typical play
o This correlates with a reduction in heterosexual orientation as adults and a 600 fold increase in the likelihood to experience severe gender dysphoria as adults
75
What human evidence is there 2?
2 Androgen Insensitivity Syndrome
o XY individuals have normal SRY; early development of testes and testosterone synthesis occurs
o autosomal gene mutations (i.e. not on the X or Y sex chromosomes) give rise to lack of functional ARs, so external genitalia appear feminine - raised as girls; as adults self-identify as women
o Mullerian Inhibitory factor acts normally to suppress development of internal female genitalia
o the resultant XY ‘women’ have an underdeveloped vagina and no oviduct, uterus or cervix
o display feminine spatial learning behaviour and verbal skills – lack of AR = deficient masculinization
o unclear whether prenatal steroids or social influences determine sex difference in human behavior
76
Human evidence 3 and 4?
Diethylstilboestrol during pregnancy
o Girls showed greater evidence of cognitive lateralisation (listening task and visual search task) ie. a more male-type pattern than their non-DES -exposed sisters
o Girls exhibit an increase in male-typical play and a decrease in female-typical play compared with their non-DES -exposed sisters
o This correlates with a reduction in heterosexual orientation as adults and a 600 fold increase in the likelihood to experience severe gender dysphoria as adults
o This was given to women who had repeated premature births. But then stopped as female offspring developed cancer of repro tract at young age
4. Amniotic fluid
o Levels of testosterone in amniotic fluid or maternal circulation during pregnancy correlate with the degree of male-typical behaviour and brain structure, suggesting that gonadal hormones contribute to intra- as well as inter-sex differences.
77
How can you know a stressed mother has higher cortisol?
Did a self reported questionnaire, the mothers had raised evening salivary cortisol if stressed
78
What are the four dopaminergic midbrain pathways?
- Nigrostriatal pathway: transmits dopamine from the substantia nigra to the dorsal striatum- important for sensorimotor control. Parkinsons disease is related disorder
- Mesolimbic pathway- transmits dopamine from the VTA in the midbrain to the nucleus accumbens in the ventral striatum – involved in reward and memory. Activated in response to drugs such as amphetamines
- AVP impinges on reward centres.
- Mesocortical pathway- transmits dopamine from the VTA to the prefrontal cortex- executive behaviour- involved in remembering stresses and how you cope with it
- TIDA (tubero-infundibular system)- transmits dopamine from the hypothalamus to the median eminence
79
Describe nigrostriatal pathways
transmits dopamine from the substantia nigra to the dorsal striatum- important for sensorimotor control.
80
Describe the mesolimbic pathway
transmits dopamine from the VTA in the midbrain to the nucleus accumbens in the ventral striatum – involved in reward and memory.
81
Describe the mesocortical pathway
transmits dopamine from the VTA to the prefrontal cortex- executive behaviour- involved in remembering stresses and how you cope with it
82
Describe the TIDA pathway
transmits dopamine from the hypothalamus to the median eminence
83
Describe the general effects of dopamine on the brain
Marked effects on neuroplasticity (spine and dendrite morphology, adult neurogenesis), regional volume and neural activity (fMRI) in brain regions such as the hippocampus, amygdala and PFC are associated with behavioural changes and an increased risk of developing conditions such anxiety and depression and PTSD (mostly linked with altered HPA reactivity).
84
What are the midbrain dopaminergic pathways involved in?
* respond to stress in adulthood: pivotal regulators of adaptive behaviours and stress-coping strategies
* impairment of MLDA system responses to stress leads to development of anhedonia (depression-like psychopathology)
* impairment of mDA responses are also implicated in schizophrenia, drug abuse/addictive behaviours, ADHD, autism
85
What do animal models tell us about midbrain dopaminergic pathways?
maternal exposure to restraint stress (psychogenic stress), hypoxia (perinatal birth complications), immune challenge (intra-uterine infections) and malnutrition (famine/natural disasters. Animal models suggest that perinatal stress and birth complications lead to hyper-activity of the adult midbrain dopaminergic systems. Stress:
-In utero stressors (maternal restraint, infection)
-C-section +/- hypoxia
Caused:
-Increased locomotor & exploratory behaviour- (put animals in new cage)
-Propensity to self-administer amphetamine associated with exaggerated DA release in NAc
-Impaired cognition(maze)
86
What is one problem with modelling dopaminergic pathways in animals?
Most investigations of mDAs have been performed in male animals
87
What are the tests like for assessing dopaminergic pathways?
Used studies to provide neurobiological indicators of DA transmission+ behavioural tests known to depend on midbrain DA circuitry
tests of psychomotor activation and reinforcement, assessed through systemic administration of amphetamine, and the acquisition and maintenance of cocaine self-administration, which depend on the mesolimbic DA system.
Assessed spontaneous locomotor activity in a novel environment, known to depend on mesolimbic and nigrostriatal DA systems. Prepulse inhibition (PPI) of the startle reflex and Pavlovian
learning as behavioral assays of DA function in the nucleus accumbens (NAc).
Used dexamethasone administered in the mother’s drinking water towards the end of gestation, then stopped for a normal delivery
88
What did glucocorticoid treatment in the VTA do?
Females have more DA neurons in their VTA than males controls
Greater number of DA neurons (increased total TH-IR
cell count) in AGT group 50-60% increase in both sexes
If divide nucleus into 3 regions- levels 1-3. Controls: males, similar distribution of %TH-IR cells in all 3 levels. In females, much more neurons accumulated in level 2
After AGT, in males, more neurons distributed in level 2- given female pattern.
More neurons in level 3 in female- so squeezing in rostral caudal direction
Overall Prenatal dexamethasone treatment induces a 60% increase in total number of TH-IR cells, plus a rostro-caudal shift in their distribution in the adult VTA.
Nb. Cell size is unaffected by prenatal dexamethasone treatment
89
How were dopamine levels assessed>
brains processed for immunohistochemical identification of
| tyrosine hydroxylase immunoreactivity (TH-IR) as a marker of DA cell bodies in the VTA).
90
What happened in the striatal regions AGT?
An increase in striatal fiber density accompanies expansion of SNc and VTA populations in adult AGT offspring
AGT increased DA cell counts in SNc and VTA compared with controls
AGT also increased fibre density in the striatum: males> females
91
What happened in the paraventricular nucleus in terms of dopamine numbers? What is the control like
In control, arcuate nucleus F>M. In females AGT
- Reduced numbers of TIDA neurones, lactotroph cell size (not number) & pituitary prolactin content
- Increased circulating prolactin levels
- Males unaffected
92
What happens in dexamethasone exposure in the paraventricular nucleus?
In control, paraventricular nucleus, F=M
- Unaffected by AGT (M, F).
- Normal somatotrophs
93
What can be said of the midbrain dopaminergic neutrons after dexamethasone exposure?
Midbrain DA neurones display normal basal electrophysiological characteristics in in adult offspring of dams exposed to AGT.
94
Does the increase in dopamine levels mean an increase in dopamine?
DA released and bind to and post-synaptic D1 and D2 receptors
DA also binds to D2 presynaptic autoinhibitory receptors, which prevents more DA release and limits amount of DA in synapse
DA transporter (DAT) pumps DA out of synapse and back into cytosol- reuptake mechanism
Although more DA neurones, no increase in DA release
95
What is and is not sexually dimorphic in terms of dopamine release?
In vivo microdialysis coupled with electrochemical detection reveals similar baseline DA release in control and AGT male and female groups, but inherent sexual dimorphisms in amphetamine-stimulated accumbal dopamine efflux and a sexually dimorphic effect of AGT
96
What does dopamine do to amphetamine release?
In controls, amphetamine response was 3.5 times greater in females than males, determined by summation of DA levels above baseline over the 2-hr period following amphetamine injection
After exposure to AGT, the amphetamine response increased 3-fold in males, but decreased in female
97
How was behaviour effected1?
Spontaneous locomotor response to a novel environment is suppressed in female progeny of dams exposed to AGT, but unaffected in male progeny
Locomotor behaviour in a novel, open-field environment decreased with time for all groups and was significantly higher in control females.
AGT suppressed activity in females whereas males were unaffected
Photobeam breaks measured- higher the breaks, higher the movement- objective and accurate measure
98
How was behaviour affected 2?
Sensorimotor gating (prepulse inhibition of the startle response, PPI) is significantly modified after exposure to AGT in adult male, not female, progeny
In both sexes, presentation of a prepulse stimulus inhibited the response to the 120-dB startle stimulus (loud noise)
AGT enhanced PPI in males, but females were unaffected
99
What about dexamethasone on ampethamine induced behaviour?
There was no change
100
What happened to cocaine self administration after dexamethasone?
Significantly higher rates of cocaine self-administration achieved by females, but there was no main effect of AGT
101
What about Pavlovian learning and dexamethasone?
differences between the sexes, or between controls and AGT groups
102
What is a summary for the effects of dopamine on mesolimbic pathways?
• Marked neurobiological changes induced by AGT in mDAs were often not accompanied by predicted changes in behavioural functions dependent on mDA transmission.
103
What does AGT cause to mDA pathways?
Increased allostatic load
104
When can the most marked effects of AGT be seen in adulthood?
• If behavioural tests are performed under stressful conditions in adulthood more marked effects of AGT are seen (depressive-like behaviour, drug-seeking behaviour
105
What factors influence neural development in a child?
Genes
Oxygen and blood supply
Nutrition- micronutrients – iron, vit D, zinc
Physical environment – air, water and food toxins
Socio-emotional environment
Adverse childhood experiences such as divorce, neglect
106
What other link is there for behaviour and children
Smoking in utero linked to hyperactivity and behavioural outcomes in children
107
What nutrition is very important in utero?
Iron, reduced IQ children, adolescents inattentive
108
What are the healthy child programme aims?
strong attachment
positive parenting.
improved social/emotional well-being
care which promotes health and safety
increased breastfeeding.
healthy nutrition and increased physical activity
prevention of communicable diseases.
readiness for school and improved learning.
early recognition of growth disorders and risk factors for obesity.
early detection of deviations from normal physical and neurodevelopmental pathways
109
How does the healthy child programme achieve this?
Screening eg hearing, parental support, immunisation, health and development reviews at certain milestone. Eg the family nurse partnership programme.
110
What are the 4 steps for parents? which age group is particularly important
1) parental preparation, 2) joint agenda setting with parent. 3) 3. Child Development- parental discussion and child observation 4. Guidance, health promotion and goal setting
2-2.5 years Nutrition, active play and obesity prevention
Immunisation
Personal, social and emotional development
Speech, language and communication
Injury prevention
