Thread by @JaredWYoung

Here we go with:
"And the hits just keep on coming: Sex-specific effects of multiple stressor exposures on cognition"
Starting with @SEcksDifference setting us up well on the importance of early life stressor, working on limited bedding and nesting altering maternal care #Sfn2019

https://twitter.com/jordanmarrocco/status/1186983056277725184

@SEcksDifference Limited bedding and nesting negly impacted maternal care, including affecting body weight throughout life, and gonadal hormones (elevating testosterone in males, estradiol in females. Interestingly an enriched environment there is also less time spent in nest building! #sfn2019

@SEcksDifference .@SEcksDifference showing the LBN model didn't affect vaginal opening or estrus cycle duration though, so unclear where effects on sex arise! Interestingly, prelim data shows that LBN enhanced male sex behavior, e.g., mounts less intromissions, and shorter latencies #sfn2019

@SEcksDifference Brilliant work as it makes evolutionary sense - where times are lean, less time copulating with higher outcomes indicate resiliency to the environmental stressor, also seen in tadpoles (Gomez-Mestre et al, 2013), impaired growth also seen!

@SEcksDifference Then added 2nd stress hit after LBN-does the 2-hit have a greater effect than LBN alone? Sex differences seen here, where 2-hit affected novel object recognition (was it memory or novelty preference?).
Supports Seery 2011 work showing the neg of cumulative life stress! #sfn2019

@SEcksDifference .@jordanmarrocco asks an important question whether acute stressors were affected, but no changes in cort after acute seen. @GeorgiaHodes asks the important question about novelty seeking behavior, apparently they were just as active explorers! #sfn2019

@SEcksDifference Claire Manning then describing chronic stressor effects in adults on mice. vHPC-NAc excitability drove susceptibility in male mice. From Williams, Manning et al, 2019, showing ephys of this region a sex diff in spiking of this circuit #sfn2019

@SEcksDifference Investigate whether gonadal hormones drove such changes, but saw no differences. In castrated males however, there was then a change in excitability. Also true of testos given to females. So androgen/testo (male/female) driven diff in vHPC-NAc circuit #sfn2019

@SEcksDifference The alterations in this circuit drove changes in sucrose preferences in both male and female mice - does that recreate anhedonia seen in depression?! #sfn2019
Using DREADD for that circuit they recreate this change, sensitive to stress!

@SEcksDifference Next up will be Nikolaos Krokras to discuss their work on sex and age differences in hippocampal metabolism after aromatase inhibition and forced swim test #sfn2019
Aromatase inhibition used in medicine- background you can see Jenkins et al 2008 Henry et al 2011 Blaustein 2017

@SEcksDifference Such cancer treatments (aromatase inhibitoin) can have negative effects on cognition and mood! Can even induce mania episodes in bipolar patients. Effects may dissapate with adult chronic treatment (Kokras et al 2014)
#sfn2019
Acute letrozole reduced immobility n inc head shakes

@SEcksDifference Such changes in immobility actually correlated with testosterone levels. Then worked on gonadectomized rodents, seeing higher aromatase in males, negatively affected by G-under control but not stress cond, as stress reduce all round #sfn2019

@SEcksDifference Interestingly, aromatase inhibition reduced dopamine transmission in male and female rats, intact and castrated rats.
So such cancer treatments may impact cognition by lowering dopamine levels #sfn2019
#cancertreatment

@SEcksDifference Metabolomoic analysis on letrozole treatment consistently showed a sex difference when hippocampus assessed, in young animals, where females but not males were affected. Sex diff may disappear in older animals. #sfn2019

@SEcksDifference Next up, the Chair @jordanmarrocco who will describe his work on transcriptional profiling of the stressed hippocampus, does sex make a difference #SexMatters #sfn2019
McEwen 1998 describe how the brain is a primary organ of stress driving allostasis and adaption

@SEcksDifference @jordanmarrocco Basically, balance is massively important to maintain adaptation, not get into maladaption (see Gray et al, 2017).
For example of genes that respond transcriptionally differently, see BDNF mice (Marocco et al 2017 Nat Comm)
#LifeBalance
#SexMatters
#sfn2019

@SEcksDifference @jordanmarrocco This work will determine whether corticosterone as the mediator of dealing with stress and adaptation.
Low-dose of oral CORT affected circadian rhythm.
Here, 8wks of oral cort given to mice (BDNF n WT littermates).
Oral cot increased "emotionality" score in males dec in females

@SEcksDifference @jordanmarrocco .@jordanmarrocco now showing some really interesting data on gene pathway analysis, would love to share but it's data in prep so keeping this one out, sorry - you'll have to wait to see his publication coming out, I have no doubt soon!
#GoodUseOfSymbols
#Respect
#sfn2019

@SEcksDifference @jordanmarrocco Next, going to see some nice data on importance of stress during adolescence from Molly Hyer describing "Chronic adolescent stress has sex-specific consequences on adult cognitive function"
#sfn2019
#TeenStress
#Adolescence

@SEcksDifference @jordanmarrocco Describing how stress is a risk factor for disease, how the stress response system is tightly regulated via the immune response system given their energy demands, linking to neuroinflammation!
Today's talk will focus on altered neuronal function
#Sfn2019

@SEcksDifference @jordanmarrocco McCarthy et al 2017 showed nicely how gonadal hormone levels spike greatly in males and females during adolesence, differently in males n females. Add chronic stress, and combination is problematic.
Social isolation used here, very interesting for thoughts of high school
#Sfn2019

@SEcksDifference @jordanmarrocco Adolescent wistar rats from PND35-54 they are stressed, defeated, and isolated (CAS), from PND 54-80, they aren't touched though, only those that derived from adolescence!
Used Barnes Maze to assess spatial learn/memory, males unaffected, females better!
#adolescence
#SexMatters

@SEcksDifference @jordanmarrocco So adolescent social isolation (among others), drove females to perform as well as males, driven by reduced errors in the Barne's Maze!
Trouble is, flip the location and females are impaired, males unaffected
#CognitiveFlexibility
#Sfn2019

@SEcksDifference @jordanmarrocco Better way to assess such reversal learning though is the Attentional Set Shifting Task from Verity Brown.
Males again unaffected by reversal. Females no longer better at initial learning, and are still impaired in reversals.
So CAS can affect reversal learning in fems
#Sfn2019

@SEcksDifference @jordanmarrocco Question of course is what brain regions are affected?!
Examined synaptophysin labeling, no effect in DG, CA3, CA1, or PFC, or NMDA function, affected AMPA receptors in CA3 in females only.
What of OFC since it's reversal learning?!
#Sfn2019

@SEcksDifference @jordanmarrocco Next up is Holly Hunsberger to talk about prior life stress impacting late adulthood anxiety-like behavior in a sex-specific manner.
Great to have an aging researcher looking at long-term consequences with interactions of anxiety.
#sfn2019
Talk will follow Benjamin Button ;-)

@SEcksDifference @jordanmarrocco Alzheimer's pathology is widespread with a myriad of symptoms, including anxiety.
Imp, anxiety is a strong predictor of moving to dementia, more than depression. Females more susceptible to anxiety and have 2x representation in Alzh
#sfn2019

@SEcksDifference @jordanmarrocco Mouse model of AD exhibit higher anxiety-like behavior as they age (accelerated aging?). Only seen in females, not males! Also examined marble burying, saw sex differences.
Examined aged female mice in fear conditioning/extinction
Males extinguished early, females still not 10d

@SEcksDifference @jordanmarrocco Overall, females exhibit higher cfos in dorsal hippocampus vs. males. Females also worse on pattern separation (context of freezing). #sfn2019

@SEcksDifference @jordanmarrocco Quick change of direction, looking at the imapct of stress at 2 m old, given 2 shocks. Males exhibit elevated anxiety-like behavior, females did not!
Going to use future calcium imaging to determine whether mice change in transients during behavior, it's all kicking off
#sfn2019

@SEcksDifference @jordanmarrocco Great work from @hhunsber
Got questions about circadian rhythm and sleep disturbances etc, important to check those out!
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber Now up is Jennifer Rainville Of mice and wo/men: Translating the relationship between cytokines and depression associated behavior.
Back translating from depressed humans back to mice given the heterogeneity in the former!
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber Innate & Adaptive immune systems important for depression. E.g., depression sees increase white blood cells in males and females, but being driven by innate in men, but by adaptive in females! Maes et al 1992
#SexMatters
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber Looked at healthy humans, plus treatment sensitive & resistant depressed people. Elevated cytokines seen from treatment resistant folks, but more in females than men!
Q is, can similar patterns be seen in rodent models, eg repeated social defeat or variable stress
#Sfn2019

@SEcksDifference @jordanmarrocco @hhunsber Social defeat done in males, chemogenetically in females. Then assessed for social interaction. Some mice were susceptible to models, some insensitive. Stressor increased innate immune cells in males and females irrespective of sensitivity/resiliency
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber Social defeat drove some similarities in females to depressed patients, but only 1 or 2 markers vs. ~30 in patients. None in males, again unlike patients. Def ! veracity of outcome. Also, mice weren't given drugs..., important results!!
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber Importantly wanted to use RDoC approach to understand susceptibility etc. But then showed a Zscore from many behaviors, not sure what was important! Also, not the same profile in cytokines either, but 1 or 2.
#sfn2019 #depression
#SexMatters
#BehaviorMatters

@SEcksDifference @jordanmarrocco @hhunsber .@Bangasser_Lab & @jordanmarrocco keeping people on time and moving along, great chairing!
There's still a lot to go, stick with us!

#sfn2019
#SexMatters

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab Kylie Huckleberry now talking of her work on endocannabinoid (ECB) signalling for generalization in vHipp-BLA circuitry relevant to PTSD, working with @ShanskyLab
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab CB1R antagonist given prior to fear conditioning generalization testing. Did not affect males in learning or generalization, and remembered tone.
Females had increased freezing though, and more generalization, and tone!
(love that males = green, females blue n grey!)
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab So sex-specific effect of systemic CB1R blockade, in females not males
What of intra-vent hipp injections? In females, CB1R antag had no effect! or on generalization or tone!
Are the cannulae damaging the hipp, impairing context proc? Males to follow
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab Maria Tickerhoof no going to investigate sex differences in stress and social behavior in prairie voles. All novel data, so afraid there'll be limited tweets on data.
We all know social stress is problematic though (30k people at SFN!!) but how?!
@sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab Important to look at females as well given higher sensitivity to social stress - looking at defeat stress is difficult in females but there are some naturally aggressive mouse strains. Prairie voles are darn cute though, and they bond! But non-bonded lead to attack behav
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab Showed a variety of similar behaviors of males and females Tickerhoof et al 2019 in BioRvix
While normal voles approach, defeated voles run away in both males and females.
What drives this behavior though to ID treatment targets?Serotonin? Oxytocin?
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab Showed social defeat causes long-term changes in behavior, increasing avoidance. Then use some nice targeted brain region analyses to see hints of changes that have occurred, you'll have to await the publication to hear more about it though :D
#WatchThisSpace
#sfn2019
#Respect

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab Major takeaway from @mariatickerhoof is that prairie voles are fantastic model to use for social defeat, check out their first characterization of the vole defeat model ob Bioarchives!
#sfn2019
#PrairieVoles

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof Now up is Andre Deutschmann working with @lisa_briand looking at adolescent isolation stress on brain development, particularly in glu signaling in the Nuc Acc!
Such isolation confers long-term changes, e.g., increase breakpoint for cocaine etc Fosnocht et al 2018
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand Adolescent stress decreased paired pulse ratios in males and females in nucleus accumbens. Interestingly, reduced readily releasable pool size in males and females, but diff effect sizes with sex effects already seen! #sfn2019
#sexMatters

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand Andre then looked at NucAcc connections to other brain regions. Eg, from vHipp paired pulse effect same in males and females. From BLAmy however, elevation seen in males, but no effect in females. Vice versa from mPFC however!
So topdown/bottomup sex diff?!
#SexMatters
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand Using opto, showed that vHipp-NAcc inhib recovers the paired pulse ratio in males and females, that was affected by adolescent stress! Nice data from Andre and @lisa_briand
showing the importance of presynaptic plasticity from adolescent stress, even in adulthood
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand Now up, Rand Eid working with @LiisaGalea going beyond sex differences and focusing on ovarian hormones and depression and resiliency!
Ovarian hormones can increase depression risk in women (Salk et al 2017), but may also be resiliency Duarte-(Guterman et al, 2019)
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea They did chronic unpredictable stress (CUS) after sham or ovariectimized mice, gave SSRIs, then looked at immobility.
estradiol seemed to track with fluox effects, though few precise effects were seen.
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Next looked at OVX or sham treated mice and then did a short stress. OVX reduced latency to immobility and reduced sensitivity to sucrose. Saw elevated IL-6:IL-10 ratio, and IL-1B, so may be involved in these changes in behavior.
All data in resubmission will see soon
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea This work nicely ties together where ovarian hormones can be useful in some circumstances, but likely detrimental while undergoing chronic stress conditions. #Stress
#SexMatters
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Now up is Molly Kwiatkowski, working with yours truly describing how altered photoperiod exposure during gestation can affect behavior long-term!
People born in late winter and early spring exhibt increased psychiatric conditions
#sfn2019
#photoperiod

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Shortened active period drives depression-relevant behavior and stress-related changes in male rats and mice (Dulcis et al 2013; Young et al 2018)
But what of females? Molly exposed female mice to short active photoperiods and measured CORT, saw same increase in CORT
3sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Then to test if offspring of females in such a stress photoperiod would be affected?! While gestated and born in shortened light cycle, they were tested as adults after long-term exposure to normal active period.
Tested a variety of behaviors relevant to psyciatry
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Mice born in a short-active photoperiod drove deficits in:
1) prepusle inhibition in males only
2) elevated plus maze in females only
3) decreased immobility in force swim in all mice, like Green 2015
4) poor reinforcement learning in females only!
#sfn2019
#behavior
#SexMatters

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Amazingly, these mice also had impaired motivation as measured by progressive ratio breakpoint, deficits overall but seen in predominantly in males only.
Reduced breakpoint and PPI seen in schizophrenia patients
Altered anxiety and reinforcement learning in females!
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea Importantly, work is ongoing to determine the effect of short active photoperiod on placental gene expression changes, timepoints consistent with important RNAseq from @TheBaleLab work! Exciting times
#sfn2019
#WinterBirth

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea @TheBaleLab Q - is it the dams that are affecting the offspring differentially? That will be checked out of course with ongoing studies. Ultimately likely to be prenatal effect!
Will definitely need to see if the depression-like behavior of females drive any of the changes too though.

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea @TheBaleLab Final talk from Yasmine Cisse on racial disparities on maternal stress outcomes from @TheBaleLab
How do people like Dr. Irving, as an African American dual PhD, end up dying leaving her child behind because of lack of maternal health for all races
@sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea @TheBaleLab We know that racism is stressful!
Chronic stress-induced accelerated 'wear and tear' on the body means it will happen in the African-American community more!
#sfn2019
#RaceAndHealth

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea @TheBaleLab Perfect example of such 'weathering' has been on the recent passing of Rep Elijah Cummings, a stalwart of American Democracy that passed far too early at 68!
#Racism
#Weathering
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea @TheBaleLab Of course, noone is suggesting that to understand mechanisms racism will be investigated in mice. No. Exposing mice to 6-week multiodal stress gives some insight into the effects of chronic stress itself, with construct validity of same circulating hormones in humans
#sfn2019

@SEcksDifference @jordanmarrocco @hhunsber @Bangasser_Lab @ShanskyLab @mariatickerhoof @lisa_briand @LiisaGalea @TheBaleLab Additional hits for people is not only the addition of stress, but also pregnancy. Mice got stressed, then 2weeks rest, then breeding, and offspring tested for growth and HPA (P60), and transcriptional profiling (E12.5).
Massive changes are seen with many sex differences
#sfn2019