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Impact of Sex Hormones and Motherhood on Extinction - Coggle Diagram
Impact of Sex Hormones and Motherhood
on Extinction
Sex Hormones
Impact of the estrous cycle on fear extinction in female rats: Graham BM, Scott E (2018)
what they did:
fear conditioning done when half the rats were in metestrus (low hormones) and half were in proestrus (high hormones)
extinction training > beforehand, metestrus rats were either given veh or estradiol, and same with proestrus rats.
extinction retention tested the day after.
what they found:
Tend not to be any effect of estrous phase in extinction TRAINING, but those in proestrus (peak in hormones) show good extinction retention.
Metestrus shows fear relapse.
Possibly due to the fluctuations in estradiol.
Giving metestrus rats an injection of estradiol results in more similar fear behaviours to vehicle proestrus rats.
Estrogen is a class of hormones, of which estradiol is the most common.
Never have elevated progesterone without elevated estradiol.
Seems to enhance extinction but also reverse the effects of estradiol in the long run > too much is not good, as well as too little.
Menstrual effects on fear extinction in humans: Milad et al (2010)
Just like the rats, periods of heightened estradiol seem to be beneficial for fear extinction in women.
Sex hormone receptors are seen all over the brain > important for executive functioning, working memory, learning, etc.
vmPFC is important for extinction > thicker or better-activated vmPFCs show better extinction, those with PTSD show worse vmPFC and worse extinction retention.
Zeidan et al 2011 functional changes in naturally cycling women
Women with heightened estradiol levels showed an increase in activity in vmPFC during extinction, those with low estradiol levels showed the opposite.
Dendritic spines are protrusions on the dendrites (receive information from neuron- axons send info) that are plastic > can grow, recede, etc.
The density of dendritic spines refers to the number of spines per micrometre of dendrite.
Specialised sites of synaptic plasiticity in the brain > the more spines the more capacity the cell has to become activated from the input from another cell.
Structural changes: impact of the estrous cycle on hippocampal dendritic spines (Woolley and McEwen 1993) > female rats
what they did:
Sacrificed rats during different points in the estrous cycle to check their dendritic spine density (specifically in the hippocampus)
what they found:
much higher dendritic spine density during proestrus than metestrus (spines may die and develop over the cycle? i think thats what this implies)
Stress badly affects dendritic spine density > chronically stressed male rats have similar density to females with low estradiol
Unclear if these structural changes are similar in humans (have to kill them to check)
in humans
How well connected two brain regions are = functional connectivity.
Changes in functional connectivity in regions of the brain during it menstrual cycle
Not sure what the implications are for behaviour, but it could be a mechanism that explains the change in extinction retention.
Nodes = clusters of brain regions known to communicate with each other.
Hormonal contraceptives: Graham and Milad (2013)
Inhibit ovarian production of estradiol and progesterone
Cycle works through negative feedback > hypothalamus signals the production of gonadotropin-releasing a hormone which triggers luteal hormones. Once the body has enough of these hormones, the hormones stop releasing as much.
Low levels of endogenous hormones, high levels of synthetic hormones.
Fear extinction NEEDS estradiol.
what they did:
took women naturally cycling > half high in est, other half low in est. also took women on hormonal contraceptives.
fear conditioned them, extinctioned them
tested retention the day after
what they found:
No difference during extinction learning
hormonal contraceptives cause LOW retention. followed by L-EST and then H-EST
Translation to the clinic: Graham et al (2018)
what they did:
took women with spider phobia. some were early follicular, some were late follicular, some luteal, some HC
Can be treated within a single day > easier to isolate certain menstrual cycle times
treated them for spider phobia in the lab over the course of a few hours > extinction
what they found
pre treatment all had similar anxiety scores w spiders
follow-up had late follicular being more comfortable
treatment efficiency was higher with more estradiol
self reported symptoms lower with more estradiol
Symptom expression is not changed by hormone level.
Males: Graham and Milad (2014)
Testosterone is produced, travels to the brain, and can be converted into oestradiol.
Block aromatase with fadrozole > blocking the conversion of testosterone to oestradiol.
what they did:
fear conditioning
next day extinction training, giving FAD or VEH pre, post, or 4 hr post training
next day retention testing
what they found:
No diff during conditioning and extinction training, but FAD-PRE and FAD-POST people show a lower extinction retention.
Post-4 hours is after consolidation so FAD has no effect on it (vehicle shows the same results)
can be reversed with injections of estradiol: injection of FAD and then EST has same results as vehicle
Motherhood/Pregnancy
80% of human females by age 44 will be mothers
Massive consequences for hormones (exposed to higher levels of estradiol and progesterone in 9 months than cumulative exposure over the lifetime of a nonpregnant person)
Motherhood-induced memory improvement persists across the lifespan in rats but is abolished by gestational stress (Lemaire et al 2006)
what they did:
Took female rats and allowed them to mate with males
Some were nulliparous > never been pregnant or mated before
Some were exposed to stress during the gestation period (restraint stress)
tested rats on a MWM to see their distance to find the platform 2 weeks and 16 months after weaning
2 weeks after weaning, rats are fertile and ready to have babies again, and they go back to their regular estrous cycle.
what they found:
motherhood consistently shown to take the smallest distance to find the platform for both time periods
motherhood + stress has the same memory as nulliparous rats (more distance to find platform)
Motherhood and dendritic spines: Kinsley et al (2006)
what they did
Sacrified animals that were virgins (sacrificed during diestrous, estrous or proestrus), and sacrificed during late pregnancy and sacrificed during lactation to check dendritic spine density.
what they found:
Virgin rats in proestrus show high dendritic spine levels (compared to diestrous and estrous) > due to higher hormone levels.
Dendritic spine density in late pregnant and lactating rats was even higher.
Increase in dendritic spine density as a consequence of pregnancy.
what they did:
follow up study: Took female virgin rats and removed their ovaries (and then left them) or took their ovaries and replaced their hormone levels with high levels (consistent with pregnancy).
what they found
Exposure to those hormones increases dendritic spine density.
Pregnancy leads to long-lasting changes in human brain structure (Hoeekzema et al)
Looking at changes in grey matter volume (where the neurons are)
scanned women brains
what they found:
A consistent pattern of reduction in grey matter volume in women who had been pregnant and had children.
% reduction during pregnancy is identical to what you see with synaptic pruning in adolescence.
possible change in the brain to prepare the mother to learn to manage her offspring.
Did not scan the mothers during pregnancy > are the brain changes happening in pregnancy, or very quickly post-partem, and are then due to offspring exposure?
Subsequent study scanned brains during pregnancy and shows that it is a pregnancy phenomenon unique to the female brain
Scanned the same women again 2 years later, and all changes in grey matter were stille evident except in the hippocampus (partial recovery of grey matter volume).
Structural changes are also associated with functional changes.
Motherhood and fear extinction- rats
Hormonal phenomena: Tang and Graham (2020)
what they did
took NP proestrus and metestrus, PP (primiparous- 1 prior litter) proestrus and metestrus rats
2 weeks after weaning; conditioning, extinction training, extinction retention
what they found:
all groups condition and extinguish pretty much the same.
NP PRO rats show good retention, and PP rats show good retention regardless of estrous phase.
effect of hormones on extinction retention is still true (met rats worse than pro rats) but for VIRGINS (NP) rather than previous mothers.
Behavioural phenomena
primiparous rats, irrespective of estrous phase during extinction, show no fear when put through renewal or reinstatement training post extinction