Game of Hormones: Why Sex Matters for Brain Health and Lessons from Studying the Heterogeneity of Perinatal Depression

October 18, 2022

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YCSC Grand Rounds October 18, 2022
Liisa Galea, PhD
Professor, Distinguished University Scholar, Health Research Advisor to VP Research, Lead Women's Health Research Cluster, Scientific Advisor, Women’s Health Research Institute, EIC FIN, Djavad Mowafaghian Centre for Brain Health, The University of British Columbia

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00:00Good afternoon. Once again,
00:01it's a pleasure to welcome you here
00:03to Grand Rounds in the Cohen.
00:05No, oh, there we go.
00:09Is that a little bit better?
00:13Where is IT support when you need it?
00:17And good afternoon, everyone.
00:18I see some new faces in the audience
00:21and some new faces joining us on zoom.
00:23And for those of you who don't know me,
00:24I'm Kieran O'Donnell and it's my
00:26pleasure to Co-chair the Grand Rounds
00:29committee here in the Child Study Center.
00:31And now just a little note about next
00:34week we'll be continuing our in person
00:36Grand Round series with Doctor Pasco
00:38Fearon will be joining us from
00:40the University College London and
00:42with sharing his perspective on
00:44attachment theory with the rest
00:46Perspective analysis and then a
00:48forward-looking perspective on attachment.
00:49And so moving to our distinguished
00:52international scholar that's
00:53joining us today,
00:54it's my pleasure to introduce
00:55and to welcome Doctor Liisa Galea
00:57to the Child Study Center.
00:59We have tried to make this talk happen
01:00for over a year now through various
01:02different phases of the pandemic and
01:04it really is wonderful that you've
01:06been able to join us in person.
01:08And today now when I was tasked
01:10with introducing Dr Galea,
01:12I was planning to print out her bio,
01:13but then I was worried about
01:15the environmental impact.
01:16Printing such a large document.
01:18And so I thought I would share just
01:20a few of the highlights and from
01:22Doctor Galea's illustrious career.
01:24She is a professor of psychology
01:26and University of British Columbia,
01:27where she also serves as a health
01:29adviser to the vice President
01:30for Research and Innovation and
01:32the scientific advisor for the
01:33Women's Health Research Institute.
01:35And also currently leads the
01:36Women's Health Research cluster,
01:37which has 280 members worldwide.
01:40And I think maybe you'll share some
01:41information about how others perhaps
01:43join this initiative in the future.
01:45And she is a fellow with the Cavalli.
01:46Foundation and with the International
01:49Behavioral Neuroscience Society and
01:51is the chief Editor of Frontiers in
01:54your endocrinology and the incoming
01:57president-elect of the organization
01:58for the Study of sex differences,
02:01which I think we'll hear a little
02:03bit more about later on today.
02:05But just to mention that Doctor
02:08Galea as of the end of October,
02:11I believe will be the incoming inaugural
02:14chair in women's mental health.
02:16This interfere addiction and mental
02:18health and also known as Cam H in Toronto,
02:21which is one of the world's leading
02:23mental health research centres and
02:24indeed Canada's largest teaching
02:26hospital for mental health research.
02:28And I think these leadership positions,
02:30these honors are just a testament
02:32to the tremendous contribution that
02:34doctor Gillian her lab has made to
02:36sex and gender based health research,
02:38which we're very excited to learn
02:40more about today.
02:41So please join me in thanking Dr Galea
02:44for joining us today for Grand Rounds.
02:53Well, thank you so much for
02:55that kind introduction.
02:56My bio is not that big.
02:57It's 250 words, so it's not that bad.
03:00But, but thank you nonetheless.
03:01So I also thank you for the opportunity
03:03to talk about what I'm really,
03:05really passionate about saying,
03:06to talk for the first half about
03:08sex and mostly sex differences
03:10and major depressive disorder.
03:12And then I'm going to pivot to talk
03:14about Women's Health and how that
03:15should play a role in forming.
03:17About perinatal depression,
03:20I want to begin by just
03:21acknowledging that I live,
03:22work and play in Vancouver,
03:23which is part of the unseated traditional
03:26and ancestral territories of the
03:27Coast Salish peoples and Musqueam,
03:29Squamish and Suela 2 the First Nations.
03:32I always start my talk by giving
03:34a definition of sex versus gender.
03:36So when I'm talking about sex differences,
03:38I'm referring to the biological and
03:41physiological mechanisms that define males,
03:43females, and intersex individuals.
03:46Gender.
03:47Some people think of as sexual orientation,
03:49as gender identity,
03:50and it's much more than that.
03:52It's how a society has expectations
03:56and attribute has attributes for
03:58you based on your gender identity
04:00and that society at every level.
04:02Home life, education, work life.
04:06And here is my spouse who identifies
04:08as a man showing what's appropriate in
04:11terms of the household and expected
04:14of him based on his gender identity.
04:16Neither of these terms are binary,
04:18as you can well imagine,
04:20and I'll be talking about more the sex
04:22differences and biomedical differences
04:24that we see in major depressive disorder.
04:27But I want to make it really clear
04:29that all the disparities that I'm
04:31talking about between females and
04:32males and women and men are many fold
04:35greater in people of color, indigenous,
04:37trans and non binary individuals.
04:40And all of that work deserves
04:43attention and acknowledgement.
04:44And I put some people mostly Canadian.
04:47Researchers there that I do
04:48quite a bit of that work so,
04:50but I'm happy to maybe answer
04:52questions about some of that later.
04:54So using my own family as an example,
04:57I think it's really obvious
04:59that there are a number of sex
05:01differences across the lifespan,
05:02and probably many of you are very
05:04well aware that females are more
05:05likely to live longer than males are.
05:08But what you might not be aware of is
05:10that females are also more likely to
05:12deal with chronic illness than males are.
05:14And this is my mom who suffered
05:15from a very severe form.
05:17Parkinson's disease towards the end of life,
05:19and this paper came out a few years ago now,
05:22showing that on average for
05:24a variety of diseases,
05:26females were diagnosed 2 years later
05:28than males were for the very for
05:31obviously the very same disease.
05:33And this is true for diseases even in
05:35which females show a greater prevalence.
05:38Now there are many reasons for
05:40this disparity,
05:41both on the sex and on the gender side,
05:44but I would argue her,
05:46I'd hesitate to say not hesitate.
05:47I'm not hesitating at all.
05:48I would imagine that a lot of this
05:50has to do with the fact that a
05:52much of our medical knowledge and
05:54scientific knowledge has come from
05:56male Physiology studying the male.
05:58And our playbook seems to be more in
06:01terms of the male Physiology, in fact,
06:04so much so that even in diseases where
06:06you see a greater prevalence in females.
06:09Females are said to have atypical symptoms.
06:12Like, let's just think about
06:14that just for a second.
06:15If there's more females that present
06:17with the disorder and yet they're
06:19classified as having atypical symptoms,
06:21that suggests we are using
06:23the wrong playbook.
06:25And so this might take a message.
06:26If none of you want to pay any
06:28more attention after the slide,
06:29this is totally fine because basically
06:31my message is that males cannot serve
06:34as a default for females that much
06:37of our knowledge has been based on.
06:40Out the male playbook, which is fine,
06:42but it's like if you're trying
06:44to fix a refrigerator.
06:46It's like using an oven manual.
06:49So as a neuroscientist,
06:51I'm interested in sex differences
06:53in the brain of course,
06:54and there are a number of them,
06:56and it's not one sex that's
06:57predominating the other.
06:58This is in terms of Gray matter.
06:59You can see a lot of different
07:02variation there,
07:03and also you see differences in white matter.
07:06So females are more likely to
07:08have interhemispheric connections
07:09and males are more likely to have
07:12intra hemispheric connections.
07:13And this may or may not lead to sex
07:16differences in the prevalence of brain
07:18disease that put some common ones up there.
07:20What I think is even more fascinating
07:22is that we see sex differences
07:24in the manifestation of disease.
07:25And that's true even in diseases
07:27where you don't see a sex difference
07:29in the prevalence of the disorder,
07:30like schizophrenia.
07:31And in my lab and in my work,
07:33I've been looking more at diseases that
07:36show a greater lifetime risk for it,
07:39for females,
07:40so Alzheimer's disease and depression.
07:42And today I'll be talking more
07:44about the depression work.
07:45So hopefully I've started to
07:47convince you that it's important to
07:49study sex differences in disease.
07:51Because it can give us clues
07:53on how a disease develops,
07:55the manifestation of that disease and
07:57also the treatment aspect and that
07:59treatment part is very rarely studied,
08:02but it also allows us to build
08:04better models of disease and that's
08:05true from both a preclinical
08:07and a clinical perspective.
08:09And of course better models with just
08:11give us better precision therapeutics
08:13and obviously if that doesn't
08:16convincing you are federal funding
08:18agencies are mandating incorporation.
08:21So anytime you see a sex difference
08:23in the work that you're doing,
08:25that should automatically queue you to
08:26think that one of two things are involved,
08:28or a combination of the two of them.
08:30One, sex chromosomes,
08:31the second sex hormones.
08:33And I'll be talking mostly
08:35about hormones today.
08:36And just because this gives
08:38me another excuse to put
08:39my adorable adult children
08:40back up on the screen.
08:41And so they were all on the same page.
08:43I'm talking about ovarian hormones like
08:45estrogens and females and testicular
08:47hormones like testosterone and males.
08:49And of course we.
08:50Have each other's hormones,
08:52or just at different concentrations,
08:54and these act on hormone receptors
08:56that are located across the body,
08:58not just in the reproductive
09:00tract across the brain,
09:01across the body.
09:03It gets more complicated than that,
09:04because testosterone itself can get converted
09:07to a very powerful estrogen called estradiol,
09:10or a very potent androgen called
09:14dihydrotestosterone.
09:15And sex hormones themselves can affect risk,
09:17symptomology and treatment.
09:18I'll give you an example from the
09:21schizophrenia literature showing
09:22across the menstrual cycle,
09:24as estradiol levels decline,
09:27psychotic symptoms increase.
09:29I thought I'd spent a couple of minutes just
09:32talking about what sex differences is not.
09:34It's not sexist, it's not more
09:37complicated in one sex versus the other.
09:40It's not believing that males and females are
09:43polar opposite and it's not the final step.
09:45So what do I mean by all of that?
09:47One is that I see this idea that when
09:51you see a Gray matter volume difference,
09:53that that somehow means that one
09:55sex is inferior to the other.
09:57I'm not sure really where that comes from.
09:59That's an empirical question,
10:00right?
10:01It just means that the two brains
10:02are different.
10:03It doesn't mean that one sex is inferior.
10:05And in fact I'll give you some examples.
10:07I might forget to give you one of them,
10:09but I'll give you some examples.
10:10You can ask me at the end of where
10:12you might see a Gray matter volume
10:14difference actually has beneficial
10:16effects to one sex versus the other.
10:18So that's a notion.
10:19So we should dispel ourselves
10:21of these notions.
10:22Another notions is is that
10:24females are more complicated to
10:25study because of their hormones.
10:27And Rebecca Shansky did a great editorial,
10:30not editorial, but a commentary,
10:32on this in science a couple of years ago.
10:35And these papers have come
10:37out and rats versus mice,
10:38and there's another one coming
10:40out in humans showing that the
10:42variability for a variety of traits,
10:44physiological and behavioral,
10:46there's no sex difference.
10:48So there's not one sex that's more
10:51inherently variable than the other sex.
10:53Now,
10:53what this doesn't mean is that the
10:56variability within each sex might not
10:58be driven at least in part by hormones.
11:00I thought I'd give you this example.
11:03These are testosterone levels and
11:04human males and this should indicate
11:07to you that you see a dramatic decline
11:09in testosterone levels on diurnal on
11:12a daily fashion by as much as 50%.
11:15So given that males have a diurnal
11:17fluctuation in hormones and females
11:20have a monthly fluctuation in their
11:24astral and progesterone levels,
11:26I have one question for you which
11:29is who's more hormonal? Now.
11:34The other point I want to make is that
11:36there are many types of sex differences,
11:39and I see this a lot.
11:40Sexual dimorphism.
11:41Sexual dimorphism just refers to one thing,
11:44which is very different,
11:45polar opposites, if you will,
11:47different morphs of the same trait.
11:50But there are many kinds of sex differences,
11:52and the 1:00 today that I'll talk about
11:54first at least, is mechanistic differences.
11:56And this is what I really want people
11:58to think about in their own data.
12:00And that might be where you don't
12:02see a sex difference in the
12:03trait that you're interested in.
12:04As a matter what trade it is,
12:06but that doesn't mean that the neural or
12:09molecular mechanisms underlying that trait
12:11are completely different between the sexes.
12:13Another might be that you don't
12:15see a sex difference in a trait
12:16that you're interested in,
12:17but that doesn't mean with stress,
12:20disease, age,
12:20hormones, genotype,
12:21that that doesn't elicit a sex difference
12:24either in the trait or in the molecular
12:26and neural mechanisms guiding that trait.
12:29So keep looking sounds weird,
12:32but keep looking.
12:34And I'll come back to that
12:35point at the very end.
12:36The last point I want to make
12:39about this is that studying sex
12:41differences isn't the final step.
12:43There are a number of female unique
12:45experiences that we already know drive
12:48health outcomes and disease risk.
12:50And I'll be talking about pregnancy
12:52and the postpartum at the at
12:54the latter half of this talk.
12:55I really do think we can improve
12:57our knowledge of pretty much any
12:59disease if we give full consideration
13:01to sex and gender differences.
13:03And so I'd like to use the term like we
13:05can harness that power of sex differences.
13:07So today I'll talk to you a little bit
13:09about some sex differences and major
13:11depressive disorder that we see clinically.
13:14I'll talk about a new preclinical model
13:15that we have that's not fully formed,
13:17but I'm going to tell you about it
13:19anyway on the negative cognitive bias.
13:21And then I'm going to pivot to talk about
13:23the heterogeneity of perinatal depression.
13:26So I think it's always useful to
13:28look at whatever disease that you're
13:30interested in across a lifespan.
13:32And here's the female to male ratio
13:34have a major depressive disorder.
13:36And I think what pops out immediately
13:38is that where you see that twice more
13:41likely is during those reproductive years.
13:44So suggesting that females have a
13:46unique Physiology that results in these
13:49specific periods of susceptibility
13:51to depression across the lifespan.
13:53It also lends itself to two
13:56alternative biological explanations
13:57for sex differences and depression.
13:59One being that females are more
14:01susceptible and I'm and are an ecologist,
14:04so I'm always going to think it
14:05has something to do with hormones.
14:06But the other is that males are more
14:08resistant, again due to their hormones.
14:11And we've created a number of
14:12animal models to look at this.
14:14Another question that we've been
14:16interested in is does antidepressant
14:19efficacy is it varied based on hormonal
14:21status in either males or females
14:23under an animal model of depression?
14:26Now, I always get asked this question,
14:27so it's better to put it up front
14:29and that is, do males and females
14:31just show depressant differently?
14:33So to be diagnosed with
14:35major depressive disorder,
14:36you have to one of the two blue symptoms
14:38and five out of the other seven symptoms.
14:41And I think somebody that's studying
14:43this with the best last name ever,
14:45I don't know if you can see that,
14:47but and you can't really argue with that.
14:50And it's a very large end and these
14:52are in person interviews and this is
14:55door to door 5 different countries
14:57in Europe and it wasn't until
14:59there were five or more symptoms.
15:02Maybe I have to use this, right.
15:03Yeah, it wasn't until there were five or
15:04more symptoms that you saw that shift.
15:06And the ratio,
15:07the DSM five also recognizes
15:09a number of other symptoms.
15:11You can have with major depressive disorder,
15:14but some of the common ones there and
15:16they recognize that there's actually 250
15:18unique symptom control combinations.
15:21So it's a very heterogeneous disorder.
15:23It makes it difficult to model.
15:25Like I know I'm going to try to sell
15:26you a story because I'm modeling
15:28this in in animals.
15:29I actually think it's really hard
15:30to model in humans as well, right,
15:32because you can have weight gain or
15:34weight loss, you can have insomnia,
15:36you can oversleep,
15:37and you can have second order
15:39agitation or retardation.
15:40So there's a lot of.
15:42Heterogeneity even within the
15:45clinical presentation.
15:47Not a ton of studies and I'm gonna
15:49end off with this particular now,
15:51but not a ton of studies.
15:51Look at sex differences even now even
15:54though it's been mandated for a while.
15:56But there are some studies that show
15:58some sex differences in symptoms
16:00for of major depressive disorder.
16:01So females are more likely to present
16:04with hypersomnia, hyperphagia,
16:06those a atypical symptoms,
16:09which I really don't like that term and
16:13possibly cognitive symptoms as well.
16:16What about biomarkers of depression?
16:18Well,
16:18the Olympics systems very much
16:20involved in terms of integrity.
16:22I tend to fixate on the hippocampus,
16:25so I have to get this up there.
16:26But you can just use a limbic system.
16:28There are a number of meta analysis show
16:31that it's related to duration of illness.
16:33In terms of volume?
16:35The stress system is obviously perturbed
16:37also in major depressive disorder.
16:39Meta analysis show increased levels
16:42of cortisol impairments in negative
16:45feedback of the HP or hypothalamic
16:48pituitary adrenal system and we see Pro
16:51inflammatory immune system is also perturbed.
16:54You see more pro inflammatory
16:57markers and metabolomics,
16:58so we see higher levels
17:00of tryptophan metabolism.
17:02And again few studies out there,
17:04but there are some,
17:05there's some evidence of sex differences
17:07in some of these biomarkers.
17:09But because they're so few and far between,
17:11it's hard to make a,
17:12you know,
17:12definitive knowledge about
17:14all of this or definitive
17:15statement of all of this.
17:17So I want to say we really need to start
17:19using sex as a variable because if we're not,
17:22it's hampering our understanding, right.
17:24So a lot of these, sometimes you'll
17:25see one study will show one thing,
17:27sometimes we'll say another thing
17:28in terms of sex differences that
17:30few studies that are out there but.
17:32They don't always pay attention
17:33to age or treatment remission,
17:34or whether they're treatment naive.
17:36And all of these things
17:38obviously will matter.
17:39I would be remiss if I didn't
17:41show these two studies,
17:42both fantastic studies looking at the
17:45transcriptomic signatures of major
17:47depressive disorder in males versus females.
17:49Obviously humans,
17:50and you can see in their Venn diagrams
17:53across a variety of brain regions,
17:55not a lot of overlap.
17:56So the genes that are differentially
17:59upregulated, downregulated,
18:00do not overlap.
18:03However,
18:04in the small little sliver,
18:05this comes from Marianne Stanley's
18:07work and the small little sliver
18:08here that does overlap.
18:09You can see that the gene
18:11expression patterns are opposite,
18:13so genes that are down regulated and
18:15females are updated in males and vice versa.
18:17So this suggests that the representation
18:20of this disorder is quite different
18:22in males versus females and likely
18:25has implications for treatment.
18:27So what are the common risk factors
18:29for major depressive disorder?
18:30Female sex being one.
18:32I've talked about that.
18:33Another is chronic illness.
18:35Family history and chronic stress,
18:38and I would argue as mostly an
18:40animal research that we can lump
18:42a lot of this into chronic stress
18:44or chronic stress category.
18:45So we've been looking at that
18:47intersection between female sex and
18:49chronic stress and our work and we do
18:51use a lot of animal models of depression.
18:54And I know that's a tall order
18:56because you can't ask them about
18:58their thoughts of suicide,
18:59what you can,
19:00but they don't tell you anything but most
19:03of the animal models that are out there.
19:05Will perturbed either stress
19:07hormones or sex hormones.
19:09Now you can't ask them about their
19:11symptoms that you can look at some
19:13endophenotypes of depression,
19:14including those biomarkers, very easily,
19:17obviously in animal models.
19:19And in our studies,
19:21I know there's a busy slide,
19:22but I put this up there to say,
19:24look, it's a heterogeneous disorder.
19:25It's difficult to model in humans.
19:27It's difficult to model in animals as well.
19:29But I do think it's really important
19:31to look at a variety of endophenotypes
19:34of depression in any kind of study
19:36that you're doing.
19:37So we try to look at a number
19:39of different kinds of behavior,
19:40maternal behavior for looking
19:41at postpartum depression,
19:43look at endocrine factors as well
19:45as some neural factors as well.
19:47I am a bit fixated on the hippocampus.
19:50Why am I so interested in it?
19:52We know it's important for memory
19:54and emotion.
19:55We see integrity loss with
19:57major depressive disorder.
19:58This the early work came from Shailene
20:00who showed with untreated depression,
20:01small hippocampus that negative correlation.
20:05I'm interested in sex differences,
20:07so of course they have to have it has
20:08a lot of these estrogen receptors and
20:11androgen receptors within the campus itself.
20:13And the late great Bruce McEwen
20:15showed that that the hippocampus.
20:17Had very high levels of these
20:19glucocorticoids in the hippocampus.
20:21So if stress is playing a role,
20:22it's kind of an important to show
20:24that those receptors are there.
20:25And it's attractive to study to me because
20:28it's very plastic in adulthood and
20:30there are many forms of plasticity that
20:32show both the sex and stress difference.
20:35And here's the late great Bruce McEwen there.
20:37This is a coronal section of a rodent
20:40hippocampus in every single area.
20:42I can give you examples.
20:43I'm going to give you one because in his lab,
20:46his.
20:47They showed that chronic restraint
20:49stress caused atrophy in the April good
20:51dendrites in the CA 3 pyramidal cells.
20:54And when I did a postdoc with him,
20:56he said what about females?
20:57And he allowed me to do that study.
20:59Is a great postdoc supervisor
21:01allows you to do.
21:02And I did it and we saw
21:04that the atrophy happened,
21:05but it happened in the basal dendrites.
21:07And I'm sure many of you are
21:09thinking this is the most boring
21:11study you could possibly show us,
21:13but I'm putting it up there because
21:15this is one of those examples.
21:17Where you can see at a different
21:20out functional outcome.
21:22So even though you have atrophy
21:23and that should say to you,
21:25oh,
21:25they're going to be worse at
21:26something and this is absolutely true.
21:28Vicki Lowe's group has shown that in
21:30males this causes a functional impairment
21:32for spatial learning and memory.
21:34In females it does the opposite.
21:37So it actually improves learning and
21:39memory and females this paradigm.
21:42So watch those notions.
21:45The dental gyrus is my very favorite area,
21:47the hippocampus,
21:47because it retains the ability to
21:49produce new neurons throughout adulthood,
21:52and that's shown in all mammalian species,
21:54which I'm happy to talk about afterwards.
21:57There are many different ways
21:59you can measure neurogenesis.
22:00I'm not going to go through all of them,
22:02but you can look at self proliferation,
22:05which is the production of new neurons,
22:07and you can use an endogenous
22:09marker like case 57.
22:11You'll also see some data looking another
22:13endogenous marker called DOUBLECORTIN,
22:15which is expressed in
22:17all amateur new neurons.
22:19Or if you're looking at a longer time point,
22:21you'd use a DNA synthesis marker
22:23like from a deoxyuridine,
22:25and then determine whether that new
22:27cell is Co labeled with a mature
22:29neuronal protein like new one.
22:31And it might not even be the number
22:33of these new cells or new neurons
22:35that are produced,
22:36but how are they active and are
22:38they active in an appropriate way?
22:40And one of the ways that people do
22:42this is by using immediate early
22:44genes which are expressed after
22:45an action potential,
22:47and some common ones are ZIF 268.
22:49Cfas.
22:49Now,
22:50the I don't neurogenesis in the campus
22:52was sort of rediscovered in the
22:53early 90s and and since then there
22:55have been a lot of studies trying to
22:58figure out what these new neurons do.
23:00And I would say there's no real
23:02argument that they're involved.
23:04A little bit of stress resilience,
23:06antidepressant efficacy,
23:06efficacy for some behaviors as well as
23:09something called pattern separation,
23:11which I'm going to talk about in a bit.
23:13And of course we see sex differences.
23:17The other thing that people found is,
23:20and this is from Boldrini's work,
23:22that major depressive disorder
23:24is associated with reduction in,
23:26in this case self proliferation.
23:28So that's that endogenous marker
23:31of K67 of self liberation.
23:33And with major depressive disorder you
23:35see reduction in supply operation with a
23:38selective serotonin reuptake inhibitors,
23:40you see a normalization and in this data
23:42a tricyclic antidepressants overshot.
23:44But she didn't see that every
23:45time she's done this study.
23:46So this just happened to be one of those.
23:48Prosperous things.
23:49We were really interested when this
23:51first came out because loan of course,
23:54postmortem tissue.
23:54That's what happens.
23:55What we were what about sex?
23:57Are there sex differences?
23:59So John EPP,
24:00who's now an assistant professor
24:01at University of Calgary,
24:02he was doing PhD with me at the time
24:04and I got her hands and some tissue from
24:07the Stanley Medical Research Foundation.
24:09So there are three groups,
24:10non depressed individuals,
24:12depressed individuals that were
24:13prescribed antidepressants and
24:15depressed individuals that had psychotic
24:17symptoms as well and were prescribed
24:19both antidepressants and antipsychotics.
24:21And he looked at these immature new neurons,
24:24these double court and expressing
24:25cells that are right down there,
24:27and we didn't see any large
24:29differences in males.
24:30Actually a little decrease
24:32with antipsychotics,
24:33but we did see that up regulation
24:36in females that were prescribed
24:38antidepressants and this actually kind of,
24:40even though they're not that
24:41many studies out there,
24:42but matches what people found
24:45in terms of hippocampal volume.
24:47There's an increase in female responders,
24:49not so much male responders
24:52to antidepressants.
24:53And the neurogenesis effect that we saw
24:55here was only in the younger populations.
24:58We didn't have enough power to
24:59look at age by sex interactions.
25:01But we saw that this aggregation
25:03was only in people that were
25:05younger than 50 or younger,
25:07not in the older population,
25:08which is the same thing that
25:10Paul Lucas and had found.
25:12So hopefully what I've told you
25:13for this part of the talk is that
25:16sex differences in major depressive
25:18disorder go beyond prevalence of the
25:20disease to symptomology and biomarkers,
25:22and that it really needs to be
25:25considered and along with age,
25:27treatment response, but also whether
25:30or not there are treatment naive.
25:32I want to pivot to talk about a new
25:35model that we're thinking about.
25:37And this is negative kind of bias.
25:39It's a kind of symptom of major
25:42depressive disorder.
25:43And what is it?
25:44It's an interpretation of ambiguous
25:46stimuli as being negative.
25:47So Doctor Travis Hodges,
25:49who did a postdoc in my
25:51lab and is now an assistant professor
25:53at Mount Holyoke University,
25:55he always uses this example.
25:57So somebody could say to him that's an
26:00interesting shirt you have on and if you.
26:02That you can interpret that in a negative
26:04way or if you're very a positive person,
26:06like you can see Travis's, you'd be like,
26:08well, thank you very much.
26:09It is a very interesting shirt, isn't it?
26:11So people with major depressive
26:13disorder will have a negative
26:15bias to these ambiguous stimuli.
26:17It's resistant to treatment,
26:19it predicts future depressive episodes,
26:21and it requires pattern separation,
26:24which I'm going to tell you
26:25about what that means now.
26:26So pattern separation or
26:28pattern discrimination is the
26:30ability to form distinct.
26:32Representations of similar inputs
26:35during memory encoding and storage.
26:38So it's like trying to find the jar of peanut
26:42butter in a sea of similar looking jars.
26:45And this is a scene that plays
26:47out in my household all the time,
26:50which is why we now have two peanut butters,
26:52I think, he said the other day.
26:53We don't have any prunes.
26:55And we had to.
26:56We actually had two and I bought
26:57another one because I believed him.
26:59I should know better.
27:01It turns out that females and males
27:03pay attention to different cues.
27:04And so sometimes you'll see
27:05females perform better,
27:06sometimes you'll see males or perform better.
27:07And I'm happy to talk about that,
27:10that particular work.
27:11But right now,
27:11I'm going to talk to you about the
27:13kind of biased task we developed.
27:15So with similar ish inputs,
27:17one,
27:18they had a context where they got shocked in,
27:20another they didn't have a shock,
27:21got shocked in and this was across 16 days.
27:25And then on the 18th day Travis gave them
27:27what we're calling an ambiguous context.
27:30So it had half the features of
27:32the shot context and half the
27:34features of the non shot context.
27:35And rats and mice will tell you
27:38if they remember fear the fearful
27:40context by freezing or that's
27:41one thing they can show you.
27:43And so we are interpreting.
27:45High freezing as a negative
27:47bias to this ambiguous context.
27:50If they didn't have this,
27:51higher freezing levels would say they
27:52have a neutral or maybe even a positive bias.
27:55And then Travis went on to look
27:56at a variety of biomarkers,
27:58including activity using the
28:00immediate early Gene C Fox.
28:02And so first he looked across the lifespan,
28:06adolescence and adulthood at middle
28:08age and we actually, to our surprise,
28:11didn't see any sex or age difference
28:13in that pattern.
28:14Discrimination in terms of their ability
28:16to discriminate between those two contexts.
28:19Where we started to see some
28:21differences was with negative bias.
28:23So this is the freezing basically
28:26to the ambiguous context.
28:28And in males we saw as lifetime
28:31as life progressed.
28:33Age.
28:33As they aged,
28:34I showed more negative bias,
28:36and I really wanted to subtitle
28:38this as grumpy old men,
28:40but the reviewers and Travis
28:42wouldn't let me do it.
28:44Females you see this upregulation
28:45when it starts to come down again,
28:48and the only time you see significant
28:50sex differences in middle age.
28:52But that's in under normal basal situations.
28:55What happens in an animal model of stress?
28:59So using chronic unpredictable stress
29:01paradigm in both males and females,
29:03we found an increase in negative bias
29:05which maybe you'd expect to see.
29:07Now a lot of labs I know would stop.
29:09It's there's no sex difference.
29:10I'm just going to use males from now on,
29:11but we're not that lap.
29:14And and look at what you can see when
29:17you don't assume that it's the same.
29:20So this is what we're calling
29:22functional connectivity.
29:22There's like CFOs.
29:23I know this is really confusing, but I
29:25think you'll see some patterns right away.
29:27There are 15 different brain regions.
29:29This activity in each brain region
29:31and then correlated with each other.
29:32These are only correlations of .5 or above.
29:36Absolute value of .5 or five.
29:38Red lines,
29:39positive correlations,
29:40blue lines negative correlations.
29:42And hopefully what you can see
29:44right away is sometimes you'll
29:45see a negative correlation.
29:47Females very strong as so the
29:49thickness will say how large they are
29:51and a positive in males or a very -,
29:541 in males and non existent one in females.
29:57So what this suggests to us is.
29:59The neural representation of
30:01negative cognitive biases is very
30:03different in males versus females,
30:04so if you're trying to treat this,
30:06you can imagine you're going to
30:09get some different responses.
30:10He also looked at inflammatory signaling,
30:13and in the basolateral amygdala,
30:15he found that for a variety of
30:17prone flammatory cytokines,
30:18females had an upregulation, males didn't.
30:22At all.
30:23So again,
30:25completely different representation.
30:27Of course, we looked at neurogenesis,
30:28our bread and butter,
30:29and what we found for both males
30:31and females is with chronic,
30:32unpredictable stress,
30:33there was a decrease in neurogenesis.
30:36But when we did correlations with
30:38freezing to the ambiguous context,
30:40we actually only saw a correlation
30:43in the males,
30:44a significant correlation in males,
30:45but not in females.
30:47So what this suggests to us is that
30:50using this negative kind of bias.
30:52Has different representation
30:54and females versus males.
30:55We see more of a tie to
30:58neuroinflammation and females,
30:58perhaps neuroplasticity in males
31:00and for sure different neuronal
31:02networks that are activated.
31:04And actually in the human data,
31:08and this is Marianne Stanley's
31:10working at Chen Sibil,
31:11they've shown some of the same kinds
31:12of things in their transcriptomic
31:14signatures as well,
31:15that there seems to be maybe not like
31:19completely separate neuroinflammation,
31:21neuroplasticity,
31:21but that goes in opposite directions
31:23between males and females.
31:25So that's why I think it's so
31:28important to continue to study this.
31:30Now,
31:30I want to totally not totally switch
31:33gears like so we know that depression
31:36is seen in females compared to males,
31:39more females and males.
31:40That should really give us to think that,
31:43sorry,
31:43that we should look at some female
31:46specific factors.
31:47And I put some common ones up there and
31:49we know there's good evidence to show
31:51that all of these factors can influence
31:54the risk for major depressive disorder.
31:56But I'm going to talk about pregnancy
31:58and postpartum and before I do.
32:00Let's talk about estrogens again,
32:02one of my favorite hormones.
32:05So I showed you the first graph already,
32:07right this I said ohh reproductive hormones.
32:09So that suggests the estrogens and
32:11ovarian hormones are associated with
32:13a risk to develop depression, right?
32:14You look at that graph and that's
32:16what you think.
32:16But actually when you think about once a
32:19greatest time of rest to develop denovo
32:22depression and a female's lifetime
32:24and that's during postmenopausal
32:27period and during perimenopause.
32:29And in fact these periods are
32:31actually associated with a fluctuation
32:33or a decrease in these.
32:35Variant hormones,
32:36so I'm going to use postpartum.
32:38I'm going to talk about a style because,
32:39again, it's my favorite.
32:40I know I'm not supposed to have favorites,
32:41but it's not my children, so it's fine.
32:44At Week 20,
32:46Australia levels are 200 times normal levels.
32:50At week 30,
32:51they're 300 times normal levels and they
32:53climb even more dramatically after that.
32:56And then what happens with
32:57the expulsion of the placenta?
32:59People are hypogonadal during
33:00this time period,
33:02so that's been thought of as a
33:05possible risk factor for depression.
33:08I'm sure many of you are thinking on
33:10that's weird because I see all these
33:12images in the media of pregnancy
33:14and how glamorous and amazing.
33:16It is, and it's just wonderful, amazing time.
33:18And I'm going to blame Demi Moore because
33:21most of you were not born in 1991.
33:23But she posed on the cover of
33:25Vanity Fair magazine.
33:26And I don't know if the older
33:27people in the audience remember,
33:28but this was like a huge, big deal.
33:30This was like, so like, Oh my God,
33:32she said it's outrageous.
33:33She's pregnant and naked.
33:35But now look, like at the Grammys,
33:37you see the amazing Beyoncé,
33:39pregnant and naked.
33:40But I thought I'd share with you the
33:43worst picture of me ever taken in my life.
33:45And this is to prove a point that it is,
33:49yeah,
33:50it's a point,
33:51all right,
33:52that it takes a tremendous toll
33:55on a person's body to just state
33:58that parasite penny fetus.
34:00Pulmonary output decreases by 50%.
34:03Cardiac output increases by
34:0550% for extra fluid.
34:07Liters of fluid are pumped through a
34:09person's body when they're pregnant,
34:11and so it's not super surprising
34:14that there might be some health
34:17repercussions for pregnancy.
34:19And in fact we boycotters coined
34:21this as a perfect storm for
34:24depression because a number of the
34:27so-called biological outcomes or
34:29biomarkers with pregnancy and the
34:31postpartum mirror that of what you
34:34see in major depressive disorder.
34:35So volume decreases in the hippocampus and
34:38this is some work by the not by maxima.
34:43The stress system is also perturbed,
34:46increased levels of cortisol impairments
34:48and negative feedback as pro
34:50inflammatory towards the end of
34:52pregnancy and you see up regulations
34:54and tryptophan metabolism,
34:55all of these same kind of biological
34:58outcomes you see with depression.
35:02The DSM 5 does not recognize perinatal
35:05depression as something different.
35:08It's a specifier,
35:09but it describes it as depression during
35:12gestation or up to four weeks postpartum.
35:14But if you look a little bit carefully
35:16at what who's getting depression during
35:19pregnancy versus in the postpartum,
35:21it's actually could be quite different.
35:23So Munk, Olsen.
35:25Showed that for first time admission
35:27to hospital with any mental disorder,
35:30not just major depressive disorder,
35:32it's actually a lower risk during pregnancy.
35:35First time admission, OK.
35:37But in the postpartum you see much
35:39higher levels or much greater risk.
35:41And it turns out that depression
35:43onset during pregnancy is associated
35:45with a history of depression.
35:47Depression onset postpartum is
35:49associated with the Novo Depression.
35:51So we were really interested in
35:53modeling that de Novo depression.
35:55And we have two different models,
35:57one of them that we work on more now.
35:59But I'll tell you a little
36:01bit about both of them.
36:03So hormonal withdrawal after pregnancy.
36:05So we just wanted to model
36:06pregnant a rodent pregnancy,
36:07in this case,
36:08very high levels of estrogens
36:10and progesterone.
36:11And then we withdrew them very quickly
36:12from these hormones and what happened?
36:14And we published this a long time ago,
36:16although Laura Bean,
36:16this group's been showing some,
36:18I think she's got actually two papers out
36:20now showing some very similar findings.
36:22What we found is that this this increased the
36:25expression of depressive like endophenotypes,
36:28so increased passive coping and
36:30the forced swim test decreases.
36:32Sucrose preference is akin to anodontia
36:36and decreased neuroplasticity.
36:38This is very similar to what's
36:40seen in humans.
36:41So Rubino's Group has looked at a
36:44hormone simulated pregnancy and
36:46people with a history of postpartum
36:48depression or not and seeing an up
36:50regulation in these depressive symptoms.
36:52And the individuals that had postpartum
36:54depression and VBA for Garger didn't
36:56give a hormone stimulated pregnancy or
36:58withdraw from home simulate pregnancy.
37:00She just withdrew them from ovarian
37:02hormones using a GNRH agonist and you can
37:05see a slight statistically significant.
37:07Increase in Hamilton depression scores.
37:11Viper's gone on to show that this
37:13increase in Hamilton Depression scores
37:15was related to the amount of decrease
37:17in estradiol and related to an increase
37:20in functional connectivity to the
37:22amygdala and a decrease in functional
37:24connectivity to the hippocampus.
37:27So hopefully what this clearly
37:28shows you from this work is that
37:31withdrawal from a variant hormones
37:32can increase depressive symptoms in
37:34both younger women and in rodents,
37:36which suggests that ovarian
37:37hormones are providing some.
37:39Resilience.
37:41Now Rand Eade,
37:42who did her PhD in my lab and is
37:44now doing a postdoc with Kieran
37:46O'Donnell and Rose Baggott,
37:48really was interested in this
37:50sort of perimenopausal period.
37:51And So what she did here was overact,
37:54demonized or did not recognize
37:57sham surgery to these sort of
38:00quasi perimenopausal females.
38:03And then she gave six weeks of chronic,
38:05unpredictable stress.
38:06Now she did that because three
38:08weeks will increase these
38:10depressive like endophenotypes.
38:11We wanted to mirror what
38:13might happen in humans.
38:15You present with depressive
38:17like endophenotypes.
38:18You're given an antidepressant like an SSRI.
38:21Fluoxetine is the one that we chose,
38:24better known as Prozac.
38:25And then she looked at a variety
38:27of behaviors and neural outcomes.
38:29And I'm going to show you a graph
38:31that's going to look really busy,
38:32but it's like the clearest data,
38:34I think, that we've ever had.
38:36The pale green bars are
38:37their overactive mized,
38:38so removal of ovarian hormones
38:41and it didn't matter.
38:42That behavior we looked at passive
38:44coping and the four swim test sucrose,
38:47anhedonia,
38:47sucrose preference over atomized
38:49group showed this greater
38:51depressive like endophenotype,
38:53so more anxiety.
38:54And we also looked at negative feedback HP,
38:58a negative feedback.
38:59And the way we did this is by using
39:02a dexamethasone suppression test you
39:03have a synthetic glucocorticoid that
39:05should shut down release of corticosterone,
39:08the main glucocorticoid and
39:10rodents and it's sort of.
39:12That was in the Shams you can see,
39:13but in the over recognized
39:14group that overshoots.
39:15So we see an impairment
39:17and negative feedback.
39:18Now we have this idea that fluoxetine
39:21would have different outcomes depending on.
39:23I have a really nice coat,
39:24but I took it out because it takes too long.
39:26But anyway I didn't work.
39:27So we didn't see any difference
39:31in the efficacy of fluoxetine
39:33based on the based on the hormonal
39:37background of the females.
39:38But we actually didn't see efficacy at all,
39:41at least in terms of the behavior.
39:43The only time we saw efficacy was in
39:45this endocrine and neurochemistry,
39:47not just show you that.
39:48Looking out here,
39:49you see that flat response here
39:51in the sham individuals?
39:52In the obex individuals,
39:53it does come down a bit,
39:54but it's still overshooting.
39:56So even with the longer term
39:58withdrawal from a variant,
40:00home owners in combination with
40:02stress increases the expression
40:03of depressive like anathema types.
40:06And we found that the efficacy of
40:08fluoxetine was limited to neural and
40:09endocrine outcomes very different
40:11than what we see in terms of male
40:13outcome even in our own lab.
40:14But I would say that this also
40:17suggested a variant hormones
40:19provide some resilience.
40:21So I want to talk in the last few
40:23minutes about the second model we have.
40:26So hormone withdrawal after birth
40:27is to mimic that de Novo depression
40:30right after pregnancy, right,
40:31because we're withdrawing right away looking.
40:33But we were also interested in later,
40:35like maybe three months later,
40:37that kind of time period.
40:39And also this is really the
40:41brainchild of Suzanne Vermette.
40:43I would keep forgetting which mouse to use.
40:45Remote,
40:45who's an associate professor
40:46at Wayne State University,
40:48she came to the lab.
40:48She's like, I don't like your model because.
40:51They're not actually giving birth,
40:52and that's Fairpoint.
40:53So we came up with this model,
40:57which I'll tell you in a second
40:58because I forgot this was coming up.
41:00But I'm glad we came up with the model
41:02because 15 years later somebody showed us,
41:04hey, this is a good model.
41:06So this is looking at cortisol
41:09levels on postpartum week 6IN humans.
41:12And this is people that had
41:16depressive symptoms postpartum
41:18versus depressive symptoms that
41:19occurred before or during pregnancy.
41:21Versus healthy controls.
41:23And it's only those individuals that
41:25showed postpartum depression postpartum,
41:28sort of postpartum depression postpartum,
41:30yeah, you,
41:30I think you understand what I'm saying.
41:31Only those with postpartum symptoms
41:34that started onset postpartum that
41:36show these higher levels of cortisol.
41:39That's good because our model
41:41involves having a normal pregnancy,
41:43normal birth,
41:44and getting really high
41:45levels of corticosterone,
41:46which again is the main
41:49glucocorticoid for rodents.
41:51And we looked at eternal care and the
41:54force from test and N plasticity and we
41:57see these depressive like endophenotypes.
41:59So we see a reduction in maternal care.
42:01And I'm going to show you the
42:03rest of the data.
42:03So you'll see it in just a second and
42:06then we will give concurrent fluoxetine
42:09and it restores maternal care.
42:11But what does it do to the
42:13rest of the endophenotypes?
42:15So you can see the answer right there.
42:18It doesn't rescue it,
42:19so here's a postpartum court.
42:21These are really high levels of
42:23corticosterone and increases passive
42:25coping in the four swim test.
42:27The Hatch bars here are given fluoxetine.
42:30It doesn't help.
42:32In fact, it makes things worse.
42:34It was a significant effect to
42:36worsen symptoms with fluoxetine
42:38in the postpartum period.
42:40In terms of neurogenesis,
42:41again the dark Gray bars here
42:43are the corticosterone group,
42:45reduction in neurogenesis and both
42:48dorsal and ventral hippocampus,
42:49and these hash bars are the
42:52fluoxetine treated group.
42:53And you can see it's not restoring it.
42:54It should increase neuroplasticity.
42:56It does outside of the postpartum,
42:58does in males,
42:59it does outside of the postpartum in females,
43:01but during the postpartum
43:02period it doesn't do its job.
43:05So we've tried citrulline as well.
43:08Neither one of them are efficacious
43:09in the long term, so we wondered,
43:11why might this be?
43:12And I want to chew who's who
43:14did a PhD in my lab,
43:16looked at a variety of things,
43:17and I just want you to pay attention
43:18to the information because that's
43:20what I'm going to talk about.
43:21But we can talk about the other part.
43:23Just looked at some serotonin markers.
43:25Those seem to be perturbed as well.
43:26That might be another Ave to go.
43:29In terms of hippocampal inflammation,
43:32the pink bars or the court treated animals,
43:34hatched bars are also those
43:36fluoxetine treated animals.
43:37It didn't matter when we gave
43:39them fluoxetine that upregulated
43:41IL 1 beta and the hippocampus.
43:43So that that.
43:46To this route,
43:47because Siad at all in 2018
43:50had shown that for a variety
43:53of inflammatory markers,
43:54there was an increase in non
43:57responders and so and also in IL 1 beta.
43:59So we thought if we could
44:01block the actions of IL 1 beta,
44:03could we improve antidepressant
44:05efficacy in the postpartum.
44:07And we did this using Anakinra and Romina.
44:11Garcia de Leon is doing a PhD in my lab
44:13and she's looking at perineuronal Nets.
44:16Now playing around on Nets are an
44:19extracellular structure that are
44:20associated with neuroplasticity.
44:22More of these perineuronal Nets
44:25reductions in neuroplasticity,
44:26and this is early days,
44:29you're going to see a low end.
44:30There's actually more than two
44:31in that pink group.
44:32It just looks like there's two.
44:34But the Anna,
44:35we're going to have more data very soon.
44:37So I'm not going to say
44:38anything about Corpus,
44:39who knows which way it's going to go.
44:41But with fluoxetine again and
44:43those hash bars only under court,
44:45you see an increase.
44:46Increase in prayer in our own on
44:48that's decrease the plasticity that's
44:49what we see in terms of neurogenesis.
44:51So it kind of makes sense and with
44:54anakinra we actually see a decrease.
44:57So we don't,
44:57I don't know about behavior yet those
44:59animal that's all getting crunched
45:01right now in terms of the data.
45:03But we're we're kind of excited
45:06that this might show what we
45:09thought I think it might show so.
45:12Just to to finish off the
45:14postpartum depression,
45:14I want to say that our data mirrors
45:18what's seen in the literature.
45:19There is limited evidence for
45:22efficacy in the postpartum.
45:24Specifically those dashed lines
45:26are to say there's not any data.
45:28This came out just last year.
45:30The eye is to show insufficient data.
45:33And so you can see low efficacy for
45:35citrulline and moderate efficacy,
45:37efficacy for because I'm alone.
45:39So I have to talk about brexanolone for two.
45:42Reasons one is fantastic
45:44translation from animal to human.
45:47I think partially because
45:49a Jimmy Grier is amazing,
45:50but be because she,
45:52you know,
45:53we're paying attention to sex and
45:55gender and female specific factors.
45:57So she has another model
45:58of postpartum depression,
45:59showing that allopregnanolone and
46:01that it's very high during pregnancy
46:03decreases in the postpartum.
46:05And when you give an analog allopregnanolone,
46:07this can reverse some of the
46:09depressive like behaviors that
46:11she saw in her animals and this.
46:12That led to some clinical trials.
46:14And for the first time ever,
46:16the FDA approved a drug specifically
46:18for postpartum depression.
46:20So it's a good news story.
46:21That's brexanolone,
46:23analog of allopregnanolone
46:25that shows some efficacy.
46:27So I do.
46:28I mean,
46:29I I started I think by saying that
46:31depression is very heterogeneous,
46:33so perinatal depression.
46:34So I think we do ourselves a
46:36disservice when we don't look at that
46:38heterogeneity and embrace it, right.
46:40It'll give us some maybe some clarity,
46:42maybe not,
46:43but maybe it'll give us some clarity and
46:46I won't belabor the point, but it isn't.
46:49It isn't.
46:50It doesn't.
46:51I know that this is the child center group,
46:54and I haven't shown you
46:55anything on offspring,
46:56so I just,
46:56I give you a couple of slides
46:58on offspring just because,
46:59of course, like Susie said,
47:00you know, there's no offspring.
47:02So now we have some offspring.
47:03I should show you what happens.
47:05I'm not going to show it.
47:06Don't worry.
47:07I'm going to show you too much data.
47:08This paper came out just
47:09a couple of weeks ago.
47:10I forgot to put the exact
47:12volume and everything,
47:12but it was just like a couple
47:13of weeks ago showing that
47:15antidepressant use during gestation.
47:16Remember,
47:16we're not giving it during gestation,
47:18we're giving it in the postpartum.
47:20It is quite different in our lab
47:22but we can talk about that but it it
47:24wasn't associated after adjustments
47:25wasn't associated with any higher risk
47:27for nerve developmental disorders.
47:29But what about in our own data.
47:31So we've seen this part of the graph already.
47:32This is a moms this is hippocampus,
47:34Iowa beta SSRI,
47:36fluoxetine increase inflammatory markers
47:39and the offspring male and female.
47:41No sex difference here but I don't
47:43want I'll tend I13 and interferon
47:45gamma and always all were reduced.
47:47This is an adult offspring
47:49the offspring don't get.
47:50Accessorize, it's all through the mom.
47:52It's not during gestation,
47:53it's all through either a change in
47:55behavior or through breast milk that
47:57we see these this outcome is there.
48:00That's our thought.
48:00I put this one up here because
48:03it's kind of cute.
48:04We've also given non pharmacological
48:06treatments like exercise,
48:07so course increase in their genesis,
48:08that's what it should do and it does.
48:10And females thank thank you,
48:11thank you, thank you.
48:12And in the adult offspring they don't,
48:15they weren't exposed to a running wheel,
48:17they didn't run.
48:18But in the adult offspring that increased.
48:20Regenesis.
48:20So I think that's kind of cute if your mom,
48:22my mom was on an exerciser.
48:23So I know what that means.
48:25And I'm not a rat though, so I think I'm OK.
48:28And last little bit of the state
48:32is Tim Oberlander is a pediatrician
48:34at BC Children's Hospital and he
48:37has a group of individuals that
48:39were exposed to SSRI's in utero.
48:41And Susie looked at the neuroplastic
48:44protein reelin and found that
48:46an SSRI exposed individuals.
48:48It was a girls that showed
48:50a reduction in Wheeling.
48:51And in our rat and our rat model,
48:53we also see an early time point
48:55only that the walk maternal
48:57fluoxetine reduced neurogenesis.
48:59So if you're thinking
49:00about neoplastic proteins,
49:01it's kind of a mirroring of the two.
49:04So my last point,
49:06which you already know what the point is.
49:09So at the beginning of the pandemic,
49:10I had some undergrads and they're like, ohh,
49:12can't work in your lab because you can't go.
49:14And yeah, you know,
49:15play with the rats.
49:16And I said no,
49:17but you can do this study that
49:18I've been thinking about.
49:20And so I made them look at 3191
49:23articles published in 2009 and 2019.
49:27And they just look to see are
49:29they set in the article,
49:31do they say it's across 6
49:33journals in neuroscience,
49:343IN neuroscience, 3IN psychiatry, do they
49:36say did they use males and females or not?
49:40So many more of these studies are using
49:42males and females and many fewer are
49:44omitting whether they what sex they used,
49:46which is that's the good news story.
49:49But then very few of these papers are
49:52using what we call an optimal design.
49:55And So what I mean by that is just
49:57did they disclose sample size?
49:58That was one of our criteria.
50:00Sample size. It's a pretty low bar.
50:03And then did they use it in the analysis?
50:065% if you aren't looking,
50:08you're never going to see a sex difference,
50:11right, if you don't look.
50:12And then to my other horror,
50:149 times more male only studies and female
50:17studies and we know those female specific.
50:20Experiences matter half the population.
50:24It would be great to increase that
50:27percentage and Neil Epperson's
50:29group has found his last slide,
50:31found as this was published just
50:33very recently that of the 20% of
50:36studies that they looked at that it
50:38properly about properly evaluating sex
50:40differences 72% found a difference.
50:42So that's why like if you look you
50:44will find you will likely find
50:48100%. So I tried to acknowledge all the
50:51people that have done the work in my lab,
50:54also the funding agencies
50:55I haven't talked about.
50:56These are past and present.
50:57I don't get money from all of
51:00them right now and I just wanted
51:02to end off on the organization
51:04for the study of sex differences.
51:07Please do I think about this group?
51:09It's not just for neuroscience, it's it.
51:11It is a focus more on sex.
51:13But there is a little bit of gender
51:14in the conference as well and it's
51:15going to be in beautiful Calgary, AB.
51:17So if you feel like learning about more.
51:19These do join us, so thank you very much.
51:30All right.
51:32Some lovely comments coming through on
51:34the chapter saying and wonderful talks.
51:35Thank you so much for that
51:37questions for Doctor Glia.
51:45Hi. Thank you so much for your talk.
51:47I was wondering.
51:50If you did any work and or have any
51:53sort of inklings about what chemically
51:56would make like brexanolone or I
51:59think it was Anna Keenora effective
52:02in these like postpartum symptoms
52:05that fluoxetine you know doesn't have
52:07that characteristic or something
52:08like that like what is it chemically
52:09that like might make those effective.
52:11I think I think that's a great question
52:15and I'd say that for brexanolone it's
52:17easy because it's kind of replenishing
52:18those hormones that we know.
52:20Have diminished.
52:21So I do think, remember I said oh you know,
52:23part you may or may not remember I
52:25said that part of our question has been
52:27hey does antidepressant efficacy is it,
52:28is it, does it change based on
52:31hormonal status and something.
52:33There's there's many things that are
52:35going on in the postpartum that I
52:37just don't think allows fluoxetine
52:39to do its work long term like in in
52:41our model it actually reverses the
52:43maternal care deficits really early on
52:46but for some reason it stops working so.
52:50You know,
52:50I think that that has something
52:51to do with the information.
52:53I probably don't know that's what Anakinra
52:55is doing is you know blocking those
52:57effects of IL 1 beta but allopregnanolone,
53:00I think that part of that is by
53:02that mechanism of action is by
53:05replacing those that metabolite of
53:07progesterone that's that's missing.
53:09So just my system that you know the other
53:11thing I think about a lot is plasticity.
53:13So that of course I think about the campus
53:16and we see those reductions in plasticity
53:18and it's not just us in the postpartum,
53:21it's pretty long term and things
53:23that normally would upregulate
53:24it don't necessarily.
53:26So maybe it's that maybe it's
53:27like a clamping of homeostasis
53:28really like it's just we're not,
53:30that system is not allowed to be as
53:32liable as it should be and we need that.
53:34There are many reasons to think that that's
53:38important for the efficacy of fluoxetine.
53:40Because that guy named uh.
53:43That's wrong.
53:43And Herbert,
53:44Joe Herbert at Cambridge University
53:46has also shown that you don't get that
53:50obligation and neurogenesis unless you
53:52give corticosterone in like a daily dosage.
53:55If you give a pellets or you're
53:56clamping at a certain level,
53:58you don't get an increase.
53:59That's in males.
54:00So something about that ability to.
54:04Move, be liable.
54:05I don't know how else to say that,
54:07but I think it has something
54:08to do with homeostasis.
54:11To change this. Something.
54:18The person who I always think is Allison,
54:20who's not Allison. April, I'm so sorry.
54:24That's from now on you're out.
54:25But could you please change your name
54:27because I clearly haven't encoded that.
54:29I need some better pattern
54:31separation or something.
54:31Yes, go ahead. Sorry.
54:33April, April, April.
54:36So you talked about like different?
54:40Aspects, so like hippocampus,
54:41the stresses in the immune system.
54:43I'm curious if you have looked at
54:48microglial phenotypes in the influence
54:51like in the inflammation and immune
54:53system route and postpartum depression,
54:56if you could speak on that at all.
54:58Yes, we have and we're and you're
55:02going to ask me what we found?
55:05Uh, So what happened was that particular
55:07study is the one that was anakinra.
55:10So we have some of the data.
55:11We don't have all of the data yet.
55:12And that was one of those pandemic,
55:14you know,
55:15a woman named Emily Clark started that
55:17and then the pandemic hit and she decided
55:19I'm going to go and do an MD instead,
55:21which I don't blame her.
55:23And uh, I don't remember,
55:26but it was a low end because
55:27we had to stop the study.
55:29So we'll,
55:29we'll have that information for you soon,
55:32I think.
55:33I mean microglia in general anyway are there.
55:37Then there's a,
55:38there's a change that happens
55:39at postpartum day early like by
55:418:00 and then it comes back up.
55:42It's restored really quickly.
55:43They do seem more angry.
55:45So they have that and me void shape,
55:48not reactive, but ameboid shape.
55:49So there are some changes,
55:51but they're pretty early.
55:52They don't last a long time.
55:53But I don't know how to
55:55fluoxetine what's happening,
55:56and that is something we'll look at.
55:59Yeah,
56:00we also want to do some
56:01RAC and microglia too.
56:02So that's on the,
56:04that's in the on the books, super exciting.
56:06Thank you.
56:08And of course thinking about the
56:10intergenerational transmission of
56:11mental health, Stacy Bilbo has some
56:13wonderful micro gear data. Tracy Bale.
56:18At the intersection of prenatal
56:20stress and environmental pollution.
56:23Yeah, she's got some.
56:24I love state, Stacy Bubble and
56:25Tracy Bale. I love them both.
56:27Thank you for your talk.
56:29I have just a curiosity about
56:31other medications that we know
56:33have an effect on inflammation,
56:34like statins or metformin, for example.
56:37Like, is there any research to show you know,
56:40their benefit because it seems like
56:42it's the same kind of mechanism
56:44increasing inflammatory markers.
56:46Yeah. You know, that is really an
56:49interesting question and I know,
56:51I, I, I don't know.
56:53The answer like off the top of my head.
56:54But I know there's a researcher called
56:57Hillary Brown who's in University
56:59of Toronto who looks at autoimmune
57:01disorders and Perry Natal mental
57:03illness and it it's not a clear story.
57:06I think there I think it's something oh oh.
57:11So interferon therapy I do believe
57:15causes more depressive symptoms and in
57:17females than in males and in humans.
57:20So I think that there is more
57:21of a tie to inflammation and.
57:23And females, but it's, you know,
57:25that's not depression either.
57:27So I don't know.
57:28That's a really good question though.
57:30Thank you.
57:33Just quickly check the chat
57:34and just maybe in terms of the
57:36CFOs data that you presented,
57:37just looks really fascinating.
57:39So are you aware of any data on say
57:43transcranial stimulation studies or you
57:46know insects differences in terms of
57:48the regions that need to be targeted?
57:51Non of course not enough,
57:53but the studies that are out there show
57:55that it's actually better for females than
57:57it is for women than it is for for men,
58:00which is fascinating and I'll just give you.
58:04A so I I tried to look at that because
58:06we've actually done some dread work
58:09in that negative cognitive bias.
58:10And this is what I'm really pushing for.
58:12It was just some pilot work,
58:14but it I'm not going to tell
58:15you where or anything,
58:16but it went in the opposite direction.
58:18So when we shut down.
58:22Glutamate receptors and then a certain area,
58:24it actually increased negative bias in
58:26the females and decreased it in the male.
58:28So we're really excited about.
58:29So that's why exactly why I
58:30looked at that because I wanted to
58:32see is there any evidence,
58:33but you know,
58:34like that paper like 5% of people are
58:36looking at like using sex as a variable,
58:39like they use it as a covariate
58:40of let's say we accounted for it,
58:42accounted for it by having an equal number.
58:44But that's not showing me the.
58:46So if you're doing that work,
58:48even if you're not just give like
58:50make them different colors.
58:51On the graph so I can look at it and see.
58:54And the second thing is,
58:55don't tell me you don't have the
58:57power without doing it right?
58:58So actually it can increase your power.
59:01If you have a sex difference it
59:03will increase your power.
59:04And Murshed AL 2015 they did a
59:06really good job of explaining that.
59:10Kyle Pruitt does have a question.
59:12Kyle, would you like to unmute
59:13and ask doctor glia question?
59:18I was told to look at the camera.
59:22Quick question, I'm sorry I missed the
59:251st 3 minutes of your presentation,
59:27but I wondered if you if you included
59:30a trigger warning to the vast numbers
59:34of upper academics who are now pretty
59:37convinced that sex differences don't exist.
59:41I said I don't know if you. I did talk
59:43about how I don't think it's sexist.
59:45OK, good. That's good to be warned.
59:50I also yeah, I really,
59:53I could give a whole talk
59:54about that. But yeah,
59:56I also appreciated your mantra about
59:59if you don't look you'll see the same
01:00:02thing contaminates 87% of all the
01:00:05parent child research on on variables
01:00:07and resilience because variables
01:00:09don't exist in all those studies,
01:00:12no matter what they title the paper,
01:00:14it's extremely important that it
01:00:17ruins so much wonderful research.
01:00:20And I couldn't agree more with
01:00:22your your your incredible passion
01:00:24for including it now. Thank you.
01:00:27About to say, but you have fetal sex.
01:00:29A lot of people don't include it,
01:00:30and I do think it's really important,
01:00:32especially when they're
01:00:33at inflammatory markers.
01:00:33And then don't tell me
01:00:35is it a male or female.
01:00:37We know that's going to change things,
01:00:38so I'm sure it muddies the waters.
01:00:41Thank you.
01:00:43Please join me in thanking
01:00:45Dr Galea one more time.