Yale Psychiatry Grand Rounds: "Infant Neurobehavioral Processing of the Parent and Trauma"

May 10, 2024

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May 10, 2024

Flynn Lecture: "Infant Neurobehavioral Processing of the Parent and Trauma"

Regina Sullivan, PhD,

ID11654

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00:00So sweet, Thank you for that
00:02lovely introduction and
00:03thank you for the invitation.
00:04It's a pleasure to be here.
00:05I am honored to be on a list of
00:07such incredible researches that
00:09you've had come speak with you.
00:12So thank you. You know,
00:15it's really interesting to be here
00:17to give my presentation when Charlie
00:20Greer is in the audience because
00:23he was instrumental in actually
00:25starting this area out with maternal
00:29odor and the neural circuitry in the
00:31olfactory bulb really important work.
00:33So it's lovely to see you
00:35here when I give this talk,
00:36what probably as I end my career to have.
00:39Yeah. So it's really lovely.
00:41Thank you.
00:42Let me just go through about 8 slides
00:45where I give background information.
00:47So just so you understand my approach,
00:51which is a a bit different from what
00:53one typically hears and I want you to
00:55be conscious of those distinctions.
00:57So everybody here knows that early
01:00life trauma impacts the brain,
01:02but really it's in later life that
01:05the psychiatric disorders emerge.
01:06So it's a really horrible challenge
01:09that to this day we really don't
01:12understand what the roots of the
01:14roots of that pathology are and what
01:16initiates that pathway to pathology.
01:19So that's what we're exploring.
01:21So as we do that, we try to make sure that,
01:28sorry, that was me,
01:30we try to make sure that we only
01:33use infant neurobiology to explain
01:35the infant brain.
01:37And I mention this because so much of
01:40the literature uses the adult brain
01:42to explain behaviors in the infant
01:45and it can be troublesome because
01:46the infant brain is still immature.
01:48So even with an attachment,
01:51there are different types of attachment
01:54across development and frequently
01:56you can see maternal behavior.
01:58Neurobiology used to explain
02:00infant attachment.
02:01So as I give this data,
02:04please don't upset with me if I
02:06don't cite the adult attachment
02:08data to explain the infant data.
02:10I'm just using the infant's data and
02:14some clear attendance that we use in
02:16my lab is the infant brain is not
02:18an immature version of the adult brain.
02:20The infant doesn't go out and get a job,
02:23but just do it.
02:24Not very well because their
02:25brain isn't fully matured.
02:27They have specialized behaviors
02:29that make them a great infant.
02:32So for example,
02:33the infant isn't capable of or the young
02:36child isn't capable of defending themselves,
02:39the parent does it.
02:40So the infant has its system defense system,
02:43which involves going to the parent,
02:46not activating the amygdala as we would.
02:49So that's just a classy example that I'm
02:52going to talk about today is why it's
02:55important to just look at the infant brain.
02:56So the in the brain is not an
02:58immature of a Nadel brain.
02:59Clearly documented is that even if a
03:01behavior looks the same across development,
03:04it can use a different circuit,
03:06and we've done that in my lab.
03:08So avoidance,
03:09for example,
03:10involves the amygdala in adult
03:13humans and and rodents.
03:15But in the rodent we know that
03:17it's the peripheral cortex or the
03:19olfactory cortex and the Olfactu
03:21bulb that has that information,
03:23not the amygdala.
03:24But the behavior looks the same,
03:26no behavioral transition. And finally,
03:29some brain areas look to be functioning,
03:33but they're generating a different
03:34behavior in infant than the adult.
03:36So if I were to see a circuit activated
03:38in the infant and then just use the
03:40adult literature to explain what
03:42that circuit of behavior's doing,
03:44I could be presenting misleading information.
03:46So those are the principles
03:48that we try to adhere to here.
03:52And I'm going to be talking today about
03:54just the expression of attachment,
03:57the circuitry for acquisition or learning,
04:00who is the attacker figure and the
04:02expression are very different circuits.
04:04So I'm just talking about the expression.
04:07And I will mention that there are
04:09people here doing this lovely,
04:10amazing circuit work trying to
04:13explain all of this as well.
04:15So please excuse me if I don't
04:18talk about that work,
04:19but I wish I could listen to each of
04:22them give a talk rather than me honestly
04:24because it's such amazing work anyway.
04:27So when we talk about expression,
04:29we typically say, OK,
04:30there's an attachment circuit.
04:32But the fact is when the infinite showing pro
04:35social behavior to the attachment figure,
04:38they're actually using many,
04:39many,
04:40many different behaviors.
04:41And what we know about the brain
04:44is it's likely each one of those
04:46behaviors has its own circuit.
04:47So I'm gonna be talking a lot about
04:51proximity seeking circuits and safe
04:54haven using the parent as as a as
04:59a place to go to in under threat.
05:03OK.
05:04And then finally I'd like to say
05:07that sometimes people say you
05:09can't use a rodent to explain
05:12attachment behavior in children.
05:14It's true.
05:15Attachment behaviors in humans
05:17is incredibly complex.
05:18There's a lot of cognitive baggage
05:21that that children have when
05:23they're when they're responding
05:24to their attachment figure.
05:26But the fact is, attachment theory,
05:28the guiding force of so
05:30much of the human data,
05:32is based on animals other than humans.
05:35So, for example,
05:36Bolby,
05:37the father of attachment theory,
05:39began to think of attachment as a
05:42biological circuit because of the
05:44imprinting literature on chicks.
05:45And what he saw is that imprinting
05:48looks like a innate process,
05:49but the fact is the infant birds have
05:53to learn to target their attachment
05:56figure and that activates A biological
05:59predisposed circuit for attachment.
06:02And so it's not necessarily the mother
06:05has to mother bird has to do something
06:07nurturing to to get that attachment.
06:10It's not maternal behavior at all.
06:11It's just movement.
06:13So the and we know that the quality of
06:16care in this imprinting doesn't matter.
06:18They they imprint.
06:20And then there's also work
06:22by Conrad by Harlow.
06:24I think Harlow's work is particularly
06:26important in informing attachment
06:28theory is because at that time
06:30there was this predisposition that
06:31you need to have a nurturing,
06:34loving parent to have attachment.
06:36And what Harlow showed is that's not true.
06:39The horribly abusive mothers were
06:43attached to just as strongly.
06:46It was just as difficult to break
06:48that attachment as it was when
06:50you saw a nurturing parent. So.
06:51So taking the romance out of
06:54attachment and setting it into a a
06:58theoretical framework that we can
07:00actually test and learn more about
07:03attachment has been important.
07:05So Bolby has a paradigm shifting
07:09approach that ran across species that
07:12has been really important in so much
07:16of our work understanding development.
07:18So you know attachment,
07:20when a child becomes attached to a caregiver,
07:24there are many,
07:25many behaviors that are expressed
07:27towards that attachment figure.
07:28I focus on a few One is proximity seeking,
07:32the other is homeostasis.
07:34So the immature infant child cannot
07:37have homeost perfect homeostasis.
07:39So they use the caregiver
07:41to regulate the homeostasis,
07:43cognitive function and emotion.
07:45And finally,
07:47I'll talk a lot about a safe base using
07:50the parent as A to approach safety.
07:53So I'm studying attachment in the infant,
07:56but I'm using very,
07:58very specific selective behaviors
08:01because it's complex and I feel
08:03that we have to just say,
08:04OK, it's incredibly complex.
08:05We want to understand this.
08:07We all have to listen to talks
08:09that are and read papers that
08:12are incredibly overly complex,
08:14but it's that complex,
08:15embracing that complexity I feel
08:17that will help us finally make some
08:19inroads into impacting the clinical
08:21help that we need to give children.
08:23And neuroscience hasn't been
08:25particularly successful in doing that.
08:26And I take that to heart and
08:29really try to work hard using
08:32the human literature to inform,
08:35much as like Dylan's work using
08:38that literature to help inform what
08:41we know about to help clinicians.
08:44So what we what we do know and I'll
08:47talk about today is that when there's
08:50adversity within attachment that
08:52these features of attachment towards
08:55the caregiver are are disrupted.
08:57So there's the proximity seeking
08:59is disrupted,
09:00there's decreased approach and increased
09:03avoidance regulation is disrupted.
09:04And I'm gonna give you some examples
09:07of learning and the infants has
09:09compromised use of the mother as a safe face.
09:13So the mother isn't actually
09:14doing anything to be a safe face.
09:17It's sensory stimuli that the child's
09:19picking up from the caregiver.
09:21So that sensory information
09:23that they're getting,
09:24that child is still getting the
09:26same information but can't use it.
09:28So there are neural circuits that are
09:30compromised and using sensory stimuli
09:32from the mother as a safe haven.
09:35So it's so when we talk about
09:37regulation of the infant and the
09:39caregiver regulating the infant,
09:40it's actually the infant's use
09:42of that sensory stimuli which
09:44is permitting the regulation.
09:46Does that make sense?
09:47It's a bit of a turn how we
09:49typically think of it.
09:51OK.
09:51So I'm going to use these few
09:53core features to try to better
09:56understand attachment expression,
09:58to understand the infant brain
10:00in the hopes that we'll
10:02figure out something to better inform
10:04clinical treatment of children,
10:06but also to how we how we rear
10:09children in a normal family.
10:11So we use this low bedding paradigm that was
10:14felt in my lab by Tanya Roth a long time ago.
10:19Basically all we do is we take
10:21bedding away from the mother,
10:23and the mother can't build a nest.
10:26So she repeatedly tries to build a nest and
10:29inadvertently hurts the hurts her infants.
10:31So it's not like the mother's aggressive,
10:33it's inadvertent.
10:34She gets actually almost too worrisome.
10:38She keeps fixing the nest.
10:39She but has normal maternal care.
10:43These rats do not lose weight,
10:45so they're they're not malnourished.
10:48And I will say that there's a more
10:50more stressful paradigm also called
10:53lobe and recall our scarcity,
10:55diversity,
10:55low bedding where they also
10:57have a screen under the floor
10:59and they don't clean the cage.
11:01So there's it's really ammonia
11:03smell and pretty stinky.
11:05I think that we need to embrace
11:07diversity in animal models
11:08and understand that there's a
11:10distinction between an animal model,
11:12not with malnutrition and an animal model
11:15that has adversity plus malnutrition,
11:17all are great.
11:20So,
11:23and I want to give a nod to that,
11:26these rat pups that have low bedding
11:30grow up to be aggressive and that
11:34was work done by Maya Opendoc
11:36in an in both animals in a cage.
11:39So introducing a stranger into the cage.
11:41And so these animals are aggressive.
11:43They're also antisocial,
11:46low social behavior.
11:48Interestingly, if you take the odor
11:51associated with this maltreatment
11:53and presented them to adulthood,
11:55it it repairs a poor swim test
11:57and repairs social behavior.
11:59So there's something really,
12:02really special about this odor in
12:05early life that's changing, that,
12:08that has a great deal of value
12:09not only to the baby but for the
12:12rat continues across the lifespan.
12:16OK, So for those of you who don't work
12:18with rats, I want to have this slide to
12:20tell you what a rat mother does in the
12:22cage 'cause I think this is incredibly
12:24important in understanding the literature.
12:26So their mother rat has nursing bouts
12:29and has many of these across the day.
12:32So she goes into the nest,
12:33she nurses the animal,
12:35and then when she gets too warm,
12:37she leaves the nest.
12:38So an incredibly simplistic mechanism based
12:41on the metabolic load and overheating in
12:43the female When the mother enters the nest,
12:46that's when all this rough handling produced
12:50by low bedding occurs and grooming occurs.
12:52Then in Michael Mini's paradigm
12:54with licking and grooming,
12:55this is where it occurs.
12:57So this goes on for a couple of minutes
13:00and then the mother settles down and
13:03non nutritively nurses the pups.
13:05Everybody falls asleep and that's what
13:07you see mostly in the nest is the
13:10mother with the baby rats just sleeping.
13:13Periodically the mother
13:14gives a milk ejection.
13:16It's, you know, lasts 4 milliseconds.
13:19Pups respond to it for, you know,
13:21less than a minute and then
13:23everybody goes back to sleep.
13:25And then the mother leaves the nest.
13:28A little bit of handling
13:29as she leaves the nest,
13:30but usually it's pretty rapid.
13:33And then this is repeated over
13:35and over again.
13:36So if we look at when the
13:39mother's hurting the rat pups or
13:41having normal maternal care,
13:43we're really just looking here.
13:44Oops,
13:45sorry,
13:48We're really just looking here.
13:49And otherwise everything looks normal.
13:53The only time we can identify an
13:56abused animal in the nest is when
13:58the mother's actively abusing it.
13:59Other than that,
14:00everybody the behavior looks the same.
14:03And I think this is analogous to children
14:05where you can't tell an abused child.
14:08I mean, a seasoned therapist
14:10obviously can tell things,
14:11but within the classroom, for example,
14:13it's incredibly difficult to find out who
14:16that child is unless they're stressed.
14:17And Mary Ainsworth showed decades ago
14:20in the strange situation procedure
14:22that a bit of stress can help uncover
14:24problems behaviorally in children.
14:26So, So in the nest, they look fine.
14:32And So what we did is,
14:35can we uncover deficits early in life?
14:38And we just did a simple test in a wine maze.
14:41We put maternal odor on one side and
14:44a familiar odor on the other side.
14:46Even the abused animals approach the
14:48maternal odor. It's a strong attachment.
14:52They respond a little bit less robustly.
14:55But there's nothing we can do
14:57to get rid of this attachment.
14:59No matter how horribly the mother treats the
15:02animal or how whatever we do to the animal,
15:05it remains intact.
15:07So Justice Boldb talked about maltreated
15:11children still attached to their caregiver.
15:15So we did something a
15:17little bit more intrusive.
15:18We took an anesthetized mother and
15:20measured the amount of time that the
15:23the pup stayed with the mother or not.
15:25There's no difference in the amount of time.
15:27So even the maltreated pups
15:29stay with their caregiver,
15:31their social behavior is a bit different.
15:33So remember, their social behavior towards
15:34the mother is not different in the nest,
15:36but if you stress them a bit by
15:39having an anesthetized mother,
15:41their social behavior is a bit
15:43different towards the mother.
15:45They are more likely to go behind her back,
15:47less likely to ****** attached,
15:48for example.
15:52The amygdala is causal for
15:54this social behavior deficit,
15:56and we know that corticostral increases
15:59are critical in producing the expression
16:02of this bad social behavior by the
16:05infant rats that are maltreated.
16:07Maya Opentek and John Wilson did some
16:11optogenetics suppressing the amygdala
16:13in these in the maltreated animals,
16:16and it repairs social behavior.
16:18So we know that the core of the social
16:22behavior deficit in early life is the
16:25amygdala because we can suppress it.
16:26It doesn't mean that there aren't
16:28other pieces in the network of the
16:30brain contributing to this deficit,
16:31but the amygdala is one place in that
16:35pathway where we can repair the behavior.
16:39Sorry. So here you see example of
16:44normal behavior and suppress the
16:46amygdala and the behaviors normalized.
16:49So I'm gonna go back to the nest
16:51because we really don't understand well
16:53what is this maltreating mother do.
16:55I showed you that there are
16:57limited periods of time when she
16:59is not treating the pups well.
17:01So we did some local field potential
17:04recording in the amygdala and in the and
17:06in the PFCI have a lot more data in the
17:09Pfc and that's what I'm gonna show you.
17:11But the amygdala and the prefrontal
17:13cortex mirror one another in
17:15the local field potential. So
17:20anyway, so here's for those
17:24of you unfamiliar with LFP.
17:25It's like EEG, but the electrodes
17:28placed within a specific brain area.
17:30So I'm going to show you that in red.
17:34This is where we see behavioral differences.
17:36These are in yellow or places where
17:39we see differences in LFP in the
17:42prefrontal cortex and amygdala.
17:44So where we're seeing deficits
17:45in the Pfc and the amygdala,
17:47I mean and and the behavior don't match up.
17:52The Pfc is probably not developed
17:54yet in this age animal.
17:56In fact we know that in rats that
17:58it's a late developing brain area.
18:01Anyway let me show you the data so oh sorry.
18:06OK so here we looked at the mother
18:08during a milk ejection and you can
18:11see that the control reared animals
18:14show an increase in in gamma power
18:20but the adversity rear pups don't.
18:23So the response of the animals
18:26to maternal behavior is blunted
18:29in the adversity reared animals.
18:32And this is just comparing the
18:34adversity reared and the control
18:35reared in one slide and also
18:38grooming the control animals.
18:40Reared animals show a change in power in
18:43the gamma range to the mother grooming them,
18:46which which the low bedding animals don't.
18:49So there's a fundamental difference
18:51in how these animals are responding
18:54to nurturing maternal behaviors.
18:59We don't see a different with
19:02maltreat with maltreated behaviors,
19:03shocking results to us.
19:06Honestly, if anybody had predicted
19:07what would go wrong in the brain,
19:09we'd say maltreatment would be
19:12something horrible to these infant rats,
19:15and that's where you'd see
19:16the normal differences.
19:17But the fact is, we didn't.
19:18We saw it in the nurturing behaviors.
19:21So that helps us begin to think
19:23about what's going wrong in the
19:25brain in a maltreatment situation.
19:27And I think it helps us get
19:29out of our cultural bias.
19:31Well, of course,
19:32the thing that might be most horrible is
19:34that they're being hurt by the caregiver.
19:36And this suggests that instead
19:39it's the change in the hedonic
19:41value potentially of nurturing
19:43behaviors that may be one of
19:45the things contributing to this.
19:47And I love this experiment because
19:49it went against what we our bias is
19:52when we went into the experiment.
19:54So.
19:56So the problem with doing neuroscience
19:59like this is that sometimes it doesn't
20:02make any sense to a human researcher.
20:05We have a jargon.
20:06So I was at a meeting, and Mary Dozier,
20:10who is an incredible attachment researcher,
20:13does amazing intervention
20:15work with foster parents.
20:18Lovely work, she said.
20:19You know the social behavior of your
20:21animals and our social behavior tests.
20:23Remember,
20:24I showed you they were with the mother,
20:25but there was this weird behavior,
20:27she said.
20:28It looks like a disordered attachment to me.
20:30So she helped us develop a strain
20:33situation procedure in the RAT.
20:35And we grasped this because we really
20:38and truly wanted to make an impact
20:42and present our data in a way that,
20:45in a way that actually made it,
20:48would make sense to people.
20:49So here's our rodents behavior.
20:52For those of you unfamiliar with
20:54the strain situation procedure,
20:55it's just a series of presenting the mother,
20:57removing the mother,
20:58presenting a stranger, removing a stranger.
21:00And the only data that's used in
21:02the strange situation procedure is
21:04this final reunion with the mother
21:06and it's actually a stress paradigm,
21:0920 minutes stress paradigm.
21:11So by the end of this the the
21:15kid is is a bit shaken up.
21:17Anyway,
21:18we showed here that our maltreated
21:21animals show deficits here.
21:23So not surprising.
21:25Of course we I showed you
21:26data on that already
21:30so we did local fuel
21:31potential on these animals.
21:33And here's the adversity reared animals.
21:36Here's control reared animals
21:38response to reunion with the mother.
21:40So this is the normal behavior that an
21:43animal has when they're with the mother.
21:45There's a change in the power
21:48and the and the adversity.
21:51Reared animals are not having
21:53a change in the response of
21:55the of the prefrontal cortex,
21:56so the behavior seems to be blunted.
21:59And actually we've done experiments
22:01recording from the mother,
22:02live recordings of the mother
22:04and the pup in the nest,
22:06and both of them have
22:08blunted LFP responses so
22:13we could repair both the
22:16social behavior and the LFP by
22:20decreasing stress hormone levels.
22:23Amazingly, it's just systemic stress
22:27hormones and we know that stress
22:30hormones activate the amygdala.
22:32So the idea, in fact,
22:34we have some data showing that yes,
22:36it's the amygdala being activated by the
22:38high corticostral levels and reduction
22:40of that normalizes the amygdala.
22:44So, so why is that bad and why is how
22:51does that ever get to be abnormal?
22:54A parent in humans and in rats is supposed
22:58when they're present and there's a trauma.
23:01They're supposed to be reduction
23:03of the stress hormones,
23:04social buffering, social buffering,
23:06occurs throughout the lifespan.
23:08I'll talk a little bit of that later,
23:09but in the rat pups, it's in children,
23:11it's massively strong and has
23:13massive effects on the brain
23:15that we don't see in the adult.
23:17Anyway.
23:18So here we did an experiment showing
23:20that when the mother is present and
23:23this is a normally reared animal
23:25and she's she shuts off the HPA axis
23:28at the level of the hypothalamus
23:31and it's norepinephrine from the
23:34to the hypothalamus to the PVN.
23:36Exactly that gets reduced to
23:38the mother's year.
23:39So here's an animal getting shocked alone.
23:41This is time and this is
23:42norepinephrine levels.
23:43Shock alone increased norepinephrine.
23:44Here's an odor only animal
23:46not getting shocked.
23:48And here's an animal getting
23:49shocked with its mother Looks
23:51like it's not getting shocked.
23:52So norepinephrine.
23:53The mother is blocking norepinephrine to
23:57the HPA axis and not activating the HPA axis.
24:00And that's how it works in pups.
24:03In the adult,
24:04it's a much much more complex
24:06procedure in order to socially buffer,
24:08but the rat pup has a simplistic
24:11circle circuit.
24:12OK,
24:13my open doc did a optogenetic
24:17experiment where she manipulated
24:19dopamine from the ventral
24:21tegmental area to the basolateral
24:24amygdala and showed you could.
24:26You don't need a massive
24:29change in corticostron.
24:30Change in dopamine to the amygdala
24:34could repair social behavior as well.
24:37And corticostral levels
24:38are changing dopamine.
24:39So we think of corticostron
24:41as a system wide change,
24:43but dopamine is this very targeted
24:46circuit that's also working with the
24:49courticosterone to shut down the amygdala,
24:52make sense?
24:55OK, so this is an interim summary.
24:59So what do these findings suggest?
25:02There is pup behavior circuitry.
25:04One attachment remains
25:06intact in maltreatment.
25:08The expression towards some other changes,
25:10but there is a strong attachment.
25:13I'm 2A Perturbation into social
25:15behavior deficits with the mother is
25:17causally linked to the amygdala and
25:19then next programming and then the Pfc.
25:22So remember the Pfc actually isn't
25:23mature enough to be functionally
25:25integrated into behavior in the rack up.
25:27And these are rack ups younger
25:29than 14 days of age.
25:30So we know that the Pfc in the rack isn't
25:33isn't contributing to behavior yet.
25:37It's a great way of understanding
25:39programming of the Pfc
25:43to look at a pre and area brain area
25:46that's not participating in behavior
25:48yet and to watch how maternal behavior
25:51is changing the neural activity of
25:53that brain area in a way that we know
25:57is critical for brain maturation.
25:59So anyway, so next I'm going
26:03to use some threat behavior to
26:06better understand what's going on.
26:08And I in all honesty,
26:09I did these threat experiments
26:11first and ended the social behavior.
26:14But I start with the social
26:16behavior because it's so much
26:17more clinically relevant.
26:18And now I'm gonna show you some a
26:21bit more complex threat experiments
26:23that helped really define what was
26:26going on in the in the infant rat.
26:28And without these threat experiments,
26:30I would not have found anything about
26:34the mother suppressing the amygdala.
26:36It was back.
26:38So social behavior, social buffering,
26:40the mother's social figures,
26:42ability to reduce a stress hormone levels
26:46is present throughout our lifetime.
26:48In the baby,
26:50it's just much more strong.
26:53And what I'm going to show you in
26:56these next experiments is that there's
26:58an age specific neurobehavioral
27:00transitions in social buffering and
27:02it's not really social buffering,
27:03it's complete shutting off of the
27:05stress system at the level of the HPA axis.
27:08So the mother is blocking stress
27:10hormone social buffering.
27:11It's typically just an attenuation.
27:13So anyway,
27:14and all of this was found through
27:17fear conditioning,
27:18because I started out looking
27:20at the development of learning
27:21using the olfactory system.
27:23And when I was a graduate student
27:27looking at milk odor pairings,
27:31I found out through a control
27:33group that if you tail pinch
27:36the pup while the odor was on,
27:38that they actually liked the odor.
27:41So that was the first indication
27:42that there was for me that there was
27:44something massively different about
27:45the reward system in the infant rats.
27:48So pain paired with an odor
27:50made the rat pup like the odor.
27:53And the fact is,
27:54not only did they like the odor,
27:56they use that odor for ****** attachment.
27:58So the odor became like the maternal odor.
28:03And Charlie Greer did some of
28:05that work while you were in,
28:08in Gordon's Shepherd's lab, right.
28:10And Patty Peterson was the postdoc
28:12amazing work and was the first one
28:14to show that this odor learning was
28:17changing the olfactory bulbs there.
28:22So anyway, looking at this in
28:24the fear conditioning system,
28:26I think this computer is on a timer.
28:30Yeah. So anyway, So what we figured
28:36out with fear conditioning is that
28:38there is a read period where whatever
28:40you do is a reward to the infant rat,
28:43They're going to like the odor,
28:44and the odor is going to become
28:46a new maternal odor.
28:47So there's something about massive bias
28:49in the brain for attachment learning.
28:52And this ends when pups are ten
28:54days old and it's a robust fast
28:56transition and it's dependent
28:59upon maturation of the amygdala.
29:02So before PN 10,
29:04you have this new maternal odor and this
29:08learning during the attachment fee is
29:11due to norepinephrine and the locus Aurelius.
29:14And other people had shown that the
29:16locus Aurelius has a transition where
29:18it becomes much more specialized at
29:2010 days of age and that's critical
29:23for ending the sensitive period.
29:25The other thing that happens is
29:27the amygdala becomes functional,
29:28begins to participate in fear conditioning
29:32and we think that's due to changes
29:35in GABA receptors within the amygdala.
29:38This is a slice Physiology
29:40experiment we did ages ago.
29:42I will say that the rainy lab at
29:46Emory has done this in a much more
29:48sophisticated way since then.
29:51Really lovely work.
29:52But anyway just blocking this is this is age.
29:57So as the animal gets older
30:00it you get young animal,
30:02you're an older animal,
30:04you get changes from Ltd to LLTP
30:07and picrotoxin just looking at these
30:10animals being manipulated here.
30:13So GAB is changing everything.
30:16So the next thing we figured out
30:19was that after the amygdala is
30:22present in fear conditioning,
30:23the mother can turn it off.
30:25And why we did this experiment
30:28is incredibly complicated.
30:29There was work at Levine's lab showing
30:33that corticosterone can change,
30:35the mother can change corticosterone
30:37levels in the pup,
30:39and we knew that the shock was
30:42increasing corticosterone and
30:43that the amygdala needed the
30:46corticosterone to be had plasticity.
30:48So we knew that.
30:49So we simply tried having some other present
30:53during fear Conditioning and lo and behold,
30:56she was blocking amygdala
30:58and Fear Conditioning.
30:59And it isn't.
31:00So.
31:00She's just blocking fear conditioning.
31:02Actually,
31:03what she's doing is she's reverting
31:06the pup back to the Sensitive Period.
31:08The amygdala's acting like the
31:11Sensitive period amygdala rather
31:13than functional amygdala and so
31:16pups again in this age range,
31:20these pups are learning to like the odor.
31:24So it's two things are happening
31:26suppression of amygdala and fear.
31:27And two back to odor preference learning.
31:31So and the fact is that you can
31:36toggle these circuits just with
31:38the mother present or through
31:41manipulation of of corticostron
31:44within the amygdala or within
31:47the hypothalamus in the PDN
31:51or with dopamine.
31:53So this goes away when pups are
31:56about peeing 15 to 16 and then
31:59odor shock conditioning is never
32:01shut off by the mother.
32:03Again we're working on the
32:07mechanisms for this using
32:10intracellular plasticity molecules,
32:12but with no success yet.
32:16OK so as bizarre as this sounds,
32:22Nim Tottenham was able to replicate this
32:25in the behavioral Level in Children The
32:29mothers present 4 year olds don't learn.
32:31Fear, Conditioning and Work by Dylan
32:36G has shown that maternal presence can
32:40actually turn off the amygdala in children.
32:42So as bizarre as this system sounds in
32:47wrap UPS and completely unexpected and
32:50really found through the back door has
32:54been massively helpful in understanding
32:57rapid transitions in the sensitive period.
33:00Before that we simply thought things
33:02were came on slowly and ended slowly.
33:04But here's this rapid, you see,
33:07I'm not doing anything this rapid transition.
33:11And anyway, you don't want the brain
33:15to change one day from, you know,
33:17attachment learning to fear learning.
33:19So there's sort of the mother being
33:21present is this intermediary system.
33:23So when the pups are with the mother,
33:25their attachment system is active.
33:27When they're off on their own,
33:28their fear system is activated.
33:31So and lovely work by Dylan G honestly.
33:36OK, so I told you we're working
33:39on trying to find mechanisms.
33:42So one thing we did find is that
33:44we can manipulate URK,
33:46which is an intracellular molecular
33:49cascade associated with plasticity.
33:53We have found that manipulating URK
33:55can turn on and off the circuit.
33:57So the mother seems to be changing
34:00URK within the cell and suppressing
34:05URK activation so that the pups can't
34:09can't learn is what we're finding and
34:11we can do causal experiments here.
34:13We haven't been able to figure
34:15out what ends here.
34:16We know that the mother
34:18can no longer change IRK,
34:20but a lot of changes occur
34:22as the sensitive period ends.
34:24We just haven't found.
34:27It's probably a multi faceted
34:29system honestly which is
34:35suggests our inability to find it.
34:37So I'm not going to show you data
34:39and please excuse me for that,
34:41I'm just going to tell you some
34:43things that we found in about this.
34:44But so as the mother is,
34:48we found something about the circuitry
34:52engaged at different stages of
34:53development in the rat pops being used
34:56to identify using for air conditioning.
34:59So as the mother is blocking amygdala,
35:05the signal seeming to mediate the mother's
35:08input to the amygdala is the VTA.
35:11And this was done by Maya Opendoc.
35:15And you know, you would expect
35:17that the VTA to the amygdala would
35:20have this abrupt change at 15 when
35:22the mother can no longer turn,
35:24no longer turn off the amygdala.
35:27But the fact is the VTA is staying
35:29active for a little bit longer and then
35:32with some maturation the the prefrontal
35:35cortex which is the adult system comes on.
35:39So here you have this unique infant
35:42circuit relaying information about the
35:45mother to suppress to to suppress fear.
35:48And then the social buffering
35:50circuit comes on.
35:53So adversity messes up this system.
35:58So we looked at animals that were
35:59reared with an abusive mother
36:00using the low vetting procedure,
36:02scarcity, adversity, procedure.
36:03And what they found is 1 is that the
36:08attachment the the mothers, the the,
36:10the system where anything paired with
36:12odor produces a new maternal odor that
36:15goes away earlier at a younger age.
36:17And the amygdala becomes involved
36:20in fear conditioning.
36:21So there's earlier incorporation of
36:24the amygdala and emergence of fear.
36:27Two,
36:27the mother cannot no can no longer
36:30turn off the fear system.
36:32So that made us interested in the
36:35mother as a safety signal being degraded,
36:39which we feel has massive clinical
36:41significance because we knew that
36:43in the strange situation procedure
36:45that in the reunion the child was
36:47acting poorly with the mother.
36:49But to understand that potentially
36:51the safety signal is a very discreet
36:55fixable because it's learned aspect
36:58of the caregiver is is absolutely
37:01heart warming to us
37:05and the that was done by
37:07my open doc and Patrice
37:11drummer anyway, OK,
37:13so here's are my last slides actually.
37:17So why once so this is during adversity,
37:22this attachment figure. So far.
37:24So with this adversity rearing,
37:27what are the critical variables
37:29initiating the pathology?
37:31You know the the pups are still wanting to
37:33stay with the mother still receiving this,
37:36this abnormal behavior.
37:38What is the what is the things that
37:40are going wrong in that in that system.
37:43So Maya has shown that the dopamine
37:47signal is really important.
37:50So she did this heroic experiment
37:53where for 90 minutes each day she
37:56had rat pups have adversity with a
37:59mother a sufficient to produce the
38:01short term and long term the infant
38:04and the adult outcome effects.
38:06So every day she,
38:08while she shock,
38:10gave shock to the pups with the mother,
38:12which mimics the adversity rearing.
38:17Surprisingly enough,
38:20she blocked dopamine during that 90 minutes,
38:24hurt the animals blocked dopamine
38:26within the amygdala systemically or
38:28within the amygdala, and the social
38:31behavior deficits did not emerge so.
38:34So not only is the amygdala important
38:38in the expression of the aberrant
38:40social behavior in early life,
38:42but it's also the amygdala and
38:44dopamine is important in setting
38:46up the amygdala in a way to produce
38:49that abnormal social behavior.
38:50So, so we've identified two
38:53major factors here,
38:54dopamine and stress hormones that
38:57are really important working in
38:59harmony to produce these deficits,
39:01but are also important in the expression.
39:07So we did this really bizarre experiment.
39:12It's the last thing I'm going to talk about.
39:13I'm sorry. I'm going 5 minutes over.
39:17Great. OK, great.
39:18So these are my last few slides. So,
39:22so I'm going to explain these very carefully.
39:25It's a little complex.
39:26So we know that a normal rear pup
39:29produces good social behavior, right?
39:31And we know the diversity rear pups
39:33produces abnormal social behavior.
39:35We know that it produces changes in
39:37the image of the in hippocampus,
39:39well documented at this point.
39:42And we know from many labs that
39:44those effects are enduring.
39:45OK, so we know that corticostron
39:50is elevated here and we know
39:54it's can be problematic.
39:56So what we did is we injected
40:00these normal pups,
40:02normally rear pups,
40:03with stress hormones
40:07while they're with a mother.
40:09So about a 90 minute treatment
40:12and that was sufficient to produce
40:14all of the deficits in the pups.
40:16So here's a mother engaged in
40:19absolutely normal maternal behavior,
40:22but high stress levels with normal
40:24maternal behavior was sufficient
40:27to produce these changes.
40:31And then next we took the adversity rear
40:33pups and we blocked hercorticosterone
40:36every day and we were able to prevent
40:40the amygdala and hippocampus deficits.
40:42We didn't look at every single thing in
40:45the amygdala and hippocampus obviously.
40:47So it's quite you know we will
40:49assume that there are things still
40:51going wrong in the brain.
40:53We're just focusing on the amygdala.
40:55Obviously the effects of trauma are
40:57throughout the brain and we will expect some
41:01brain areas to be corticostro independent,
41:03some not and completely different system.
41:06And I think it's important
41:08to to note that this is not,
41:10this is a very small piece of
41:13information in a complex situation.
41:15OK.
41:16So finally we did this experiment
41:19where we repeated this abusive pups,
41:23they are getting they have the
41:25natural increase in court and
41:26we've injected A pups being reared
41:28by a normal level with court.
41:30And then we also injected pups with
41:32court with an anesthetized mother.
41:34No maternal behavior whatsoever.
41:40They all produced the same deficits.
41:43The only condition that we did
41:45that produced a normal amygdala was
41:48injection of pups when they were alone.
41:53The hippocampus still changed,
41:56but the amygdala changes did not happen.
41:59So it looks like the amygdala is
42:03incredibly sensitive to combination of
42:06stress within a social context and the
42:10hippocampus just responds to the trauma.
42:12And that does explain a huge amount
42:15of variability in the literature.
42:17I will say that sometimes people have said
42:19that injecting pups with corticostrone
42:21is enough to produce problems.
42:23But in my lab we are so careful
42:28about handling the pups and our
42:30colony is gets massive oversight.
42:33We don't have a stressed colony,
42:35our animals, our mothers response.
42:37So controlling the colony,
42:39making sure it gets good animal care,
42:42we can inject court.
42:45And anyway, so
42:50I gave you a lot of information,
42:51hopefully not too much and I've
42:54hopefully placed it within a
42:56framework that lets you maintain it.
42:58But I'm going to review everything.
43:01So first, there's a sensitive
43:03period prior to amygdala maturation
43:06in the human and the rat.
43:07We know the amygdala is late developing.
43:10We don't we know in the rat that it
43:12occurs at 10 days of age in the human.
43:14We think it's around crawling.
43:18We'll never know because it's impossible
43:21to do those experiments in in children
43:23and Jill is probably the expert on that.
43:28So trauma during this time pre amygdala
43:30is engaging the attachment system.
43:36So such as in fear conditioning
43:37repaired the odor with we got an odor
43:40preference and a new maternal odor.
43:42So when the pups are a little bit
43:43older and the amygdala is activated,
43:45we have this transitional sensitive period
43:47where the amygdala responds to trauma,
43:49but if the mother's present,
43:51the mother shuts it off.
43:54So this has been identified in
43:58rodents and replicated in children,
44:00including Dylan's work and Nim,
44:04Tottenham's work.
44:06So this data helps us take that
44:09wonderful human literature and go beyond
44:12mathematical models of causation and
44:15actually test directly test causation.
44:18And I think that that's important
44:20because many things that make
44:22sense to us end up not to be true.
44:24So we know that our framework
44:26of development is incorrect.
44:28Otherwise we would have made
44:30much much much better progress in
44:32helping children than we have.
44:34So.
44:37So the mother suppresses age
44:38specific mechanisms distinct
44:40from adult social buffering.
44:41We have transition of a circuit
44:44going from the dopaminergic VTA
44:46to the Pfc used in older animals.
44:48The mother controls initiation of
44:51the HPA axis via norepinephrine from
44:54the NST and we know that the infant
44:56initiation of the HP axis is far more
44:59simplistic than it is in the adult.
45:01The adult still has norepinephrine is a major
45:04driver of the initiation of the HPA axis,
45:07but it also access to have many,
45:09many,
45:10many other pathways to activation
45:12and suppression of the HPA axis.
45:14So we may think that may be the
45:17reason why that goes away anyway.
45:20And we've identified at least
45:22one H specific intracellular
45:24molecular signal signal to block
45:27plasticity within the amygdala.
45:29That's IRC.
45:30P IRC Anyway,
45:32finally the quality of care received by
45:34the infant from the mother appears to
45:37degrade these age specific mechanisms.
45:39So the mother's ability to have high
45:42hedonic value is reduced based on
45:45pups approaching less and also the
45:48mother's inability to turn off the
45:51amygdala and stop the air conditioning.
45:54And finally understanding these age
45:56specific mechanisms supports the well
45:59documented age specific clinical approach.
46:01We already know we a clinician,
46:04a good clinician knows something
46:06already about how to about this
46:09complex attachment system and it's up
46:12to the animal researchers I think to
46:14begin to show these these mechanisms.
46:16So that's it, Major.
46:19I've given you a presentation
46:22including work spanning over 20 years.
46:25Many,
46:26many people have been involved in that work,
46:27but I think I've picked out
46:29pieces of it that I hope make a
46:33story that's understandable.
46:34So thank you so much.