Yale Psychiatry Grand Rounds: ""Translational Neurogenetics of Fear-Related Disorders: Seeking Novel Interventions for PTSD"

Transcript

• 00:00The host and, introduce,
• 00:02doctor Ressler who tell you
• 00:04just a little bit about
• 00:05his training, and he'll talk
• 00:06about, you know, a lot
• 00:06of the amazing work that
• 00:07he's done, but,
• 00:09was sort of really one
• 00:10of the early inspirations
• 00:12for what a career as
• 00:13a physician scientist could look
• 00:14like and,
• 00:15example of someone who thinks
• 00:17very broadly and deeply across,
• 00:19model systems.
• 00:21He did his undergraduate degree
• 00:23at MIT,
• 00:24went on to do his
• 00:25MD PhD at Harvard where
• 00:27he worked with Vinda Bagh
• 00:28doing some really seminal
• 00:30work that contributed to her
• 00:31Nobel Prize, and then went
• 00:33to Emory where he did
• 00:33his training,
• 00:34in psychiatry and also,
• 00:36research and,
• 00:38has had such, influence on
• 00:40the field, in terms of
• 00:41thinking about PTSD, thinking about
• 00:43translation,
• 00:45has been a leader of
• 00:47the ACNP,
• 00:48the US SOBP,
• 00:50has been in the HHMI,
• 00:51is in the National Academy,
• 00:53of Medicine. So we're really
• 00:55honored and privileged to host
• 00:56you here and really looking
• 00:57forward to, your talk.
• 01:04Thanks so much. And before
• 01:05we go, we're making sure
• 01:06we announce that this is
• 01:08an honor of of doctor
• 01:09Henninger. And and George Henninger
• 01:10is really one of the
• 01:11founders and leaders of biological
• 01:13psychiatry psychiatry for for so
• 01:15many decades, and it's really
• 01:15an honor to be able
• 01:16to be here, representing, and
• 01:17and and celebrating his
• 01:18history. So thanks.
• 01:19Thanks, doctor Heninger.
• 01:21Right? You're still out there
• 01:22doing doing experiments in the
• 01:23lab.
• 01:27Amazing
• 01:28work. Thank you, AZA. Thank
• 01:29you, John. I I feel
• 01:30like I'm, a bit of
• 01:32a homecoming.
• 01:33Last night's dinner was sort
• 01:34of a carry rest where
• 01:35this is your life. I,
• 01:37was
• 01:38with Jane Taylor who,
• 01:39I got to started to
• 01:40get to know when I
• 01:41was a resident with Mike
• 01:42Davis, shortly after he moved
• 01:44down from Yale.
• 01:46And, then worked with Shannon
• 01:47Gourley, who had been a
• 01:48postdoc with Jane for years,
• 01:50for many years when our
• 01:51labs were adjacent to each
• 01:52other and had several collaborations,
• 01:54all the way up to
• 01:54AZA, who I had the
• 01:56privilege of being sort of
• 01:57an informal mentor a little
• 01:58bit for when you were
• 01:58in Keitai's lab and with
• 01:59the MDPhD program. So, so
• 02:01thanks everybody for having me
• 02:02here today.
• 02:03I'm gonna talk about post
• 02:05traumatic stress as,
• 02:07really my passion and work
• 02:08for the last twenty five
• 02:09years or so.
• 02:10Really, from animal models, human
• 02:12genetics, human brain function, human
• 02:14behavior,
• 02:16and, hopefully,
• 02:18to how some of the
• 02:19one of the places where
• 02:20understanding neurobiology might eventually lead
• 02:22to novel treatments.
• 02:25These are my disclosures. I
• 02:27don't believe any of them
• 02:28are directly related to what
• 02:29I'm gonna be talking to
• 02:30about today,
• 02:31and I think I've officially
• 02:32been approved to be able
• 02:33to give this talk in
• 02:34a disclosed way. But if
• 02:36not, pull me off the
• 02:36thing or something. I don't
• 02:37know what it would.
• 02:39Okay.
• 02:41So trauma. So PTSD
• 02:43is the the DSM title
• 02:44of the disorder that I
• 02:46will sort of talk about,
• 02:47but, it's really trauma broadly.
• 02:50And,
• 02:51Sandra Galea, who is the
• 02:52dean of the public health
• 02:53and really been a national
• 02:54leader in public health, stated
• 02:55that trauma is a foundational
• 02:57driver in the health of
• 02:58the public. And,
• 02:59whether we look at top
• 03:01ten,
• 03:02the the cost of annual
• 03:04US and worldwide spending, whether
• 03:06we look at WHO numbers,
• 03:08However you break it down,
• 03:09we all know that mental
• 03:10disorders
• 03:11are the leading causes of
• 03:12disability,
• 03:13in the top few of
• 03:14the leading causes of death.
• 03:16And trauma, both,
• 03:18trauma from the surgical perspective
• 03:20of trauma, as well as
• 03:21trauma from the psychological perspective
• 03:23of trauma, and particularly developmental
• 03:24trauma, are some of the
• 03:26biggest risk factors for everything
• 03:27in psychiatry. We know that.
• 03:29And,
• 03:30trauma in terms of post
• 03:31traumatic stress disorder is highly
• 03:33prevalent,
• 03:34and I would argue could
• 03:35be preventable
• 03:36and understandable.
• 03:38So to get us on
• 03:39the same page of what
• 03:40I'm talking about when I
• 03:41talk about PTSD,
• 03:43so just brief epidemiology.
• 03:46So,
• 03:47things like the National Comorbidity
• 03:49Study and other very large
• 03:50studies suggest that the prevalence
• 03:51of trauma in the US
• 03:52is around five to ten
• 03:53percent. Generally, it has about
• 03:55a two to one female
• 03:56to male rate. So on
• 03:57and again, the national comorbidity
• 03:59studies will get around ten
• 04:00to twelve percent female, around
• 04:01five to seven percent male.
• 04:03What we know is it's
• 04:04much higher rates in at
• 04:05risk population.
• 04:07So, like,
• 04:08John and doctor doctor Crystal's
• 04:10work and at the National
• 04:10Center for PTSD and so
• 04:12much of the work done
• 04:13out of the Yale programs.
• 04:15We know, veteran PTSD is
• 04:17is enormously,
• 04:19large problem. But we also
• 04:21have been understanding,
• 04:22increasingly over the last twenty
• 04:23years, and some of what
• 04:24I'll talk about is our
• 04:25work in civilian populations in
• 04:27Atlanta,
• 04:27that in at risk communities,
• 04:29particularly under resourced communities, communities
• 04:31of risk,
• 04:32for poverty,
• 04:34violence, and importantly, structural racism,
• 04:37that we have also much
• 04:38higher rates of PTSD. And
• 04:39so our,
• 04:40we in our at risk
• 04:41communities, whether it be victims
• 04:43of sexual assault, whether it
• 04:44be victims of community violence,
• 04:46or, whether it be combat
• 04:47veterans, we can have rates
• 04:48of PTSD as high as
• 04:49twenty five percent.
• 04:51And one of the themes
• 04:52I'll be talking about throughout
• 04:53the day is what's the
• 04:54difference between those who go
• 04:55on to develop PTSD versus
• 04:57those who don't. And maybe
• 04:58that's one of the critical
• 04:59factors for, understanding the disorder
• 05:01and understanding interventions and treatments.
• 05:04Again, we the first month
• 05:06of trauma symptoms, we call
• 05:07acute stress disorder and that's
• 05:09because most people recover.
• 05:10You have a much higher
• 05:11percent of people who have
• 05:12PTSD like symptoms in the
• 05:14first days and weeks, but
• 05:15most people recovering. So that'll
• 05:16be one of the things
• 05:17we'll get into when we
• 05:17talk about the development of
• 05:19PTSD.
• 05:20It's tractable, I would argue,
• 05:22because we know when it
• 05:23starts, and I'll get into
• 05:24that as we go. For
• 05:26any of this, I'm I'm
• 05:27having my own little
• 05:29talking to esteemed people, and
• 05:30I'm going to get cooler
• 05:31here.
• 05:35Pardon me. Aaron's is my
• 05:36favorite medical student term. So,
• 05:38you have to have an
• 05:39event. Criterion a, you have
• 05:40that reexperiencing or avoidance.
• 05:42Criterion,
• 05:43b and c,
• 05:46negative,
• 05:47and,
• 05:49alterations in cognition and mood.
• 05:50And this is new from
• 05:51DSM four to DSM five
• 05:53where, we have both a
• 05:54sense of,
• 05:56anhedonia that's highly comorbid with
• 05:58depression, but also,
• 06:00the
• 06:01cognitive difficulties
• 06:03that we see with trauma.
• 06:04And part of the way
• 06:05of understanding that is when
• 06:06your brain is essentially in
• 06:07sort of fight or flight
• 06:08survival mode, it's very difficult
• 06:10to have top level executive
• 06:11functioning.
• 06:12And then finally, increased arousal
• 06:14sympathetic hyperactivation.
• 06:16And in many ways, the
• 06:17intrusive symptoms, re experiencing nightmares
• 06:19and flashbacks,
• 06:20are components of of memory
• 06:22that we can really understand
• 06:23with the with the modern
• 06:24technologies of engrams and and
• 06:26and understanding trauma memories. And
• 06:29the sympathetic hyperactivation,
• 06:31related to what I'll talk
• 06:32about arousal, h the hypothalamic
• 06:34pituitary adrenal axis,
• 06:36and overactivation of the sympathetic
• 06:38system. Those will be some
• 06:39of the themes that come
• 06:40up, over and over again.
• 06:42So PTSD
• 06:44is everything in psychiatry is
• 06:45a gene by environment disorder.
• 06:47And at the level of
• 06:48genetics,
• 06:50it seems that, our some
• 06:52of the psychotic syndromes and
• 06:53developmental syndromes like autism may
• 06:55be on the order of
• 06:56sixty percent, sixty to seventy
• 06:58percent genetics.
• 06:59And then,
• 07:00alcohol use disorder, depression,
• 07:02PTSD are all probably on
• 07:04the order of forty percent
• 07:05genetic risk. But they all
• 07:06have a genetic component. They
• 07:07all have, an environmental component.
• 07:10I would argue that PTSD
• 07:11is further than some in
• 07:13understanding the interplay of these
• 07:14things because everybody who studies
• 07:16PTSD from from the time
• 07:18of its first nosology inception
• 07:20in the seventies has talked
• 07:21about the trauma and we
• 07:22capture data on the trauma.
• 07:24So it's really a field
• 07:25that's embedded within trying to
• 07:27understand what the environmental component
• 07:28is, and I think that
• 07:29gives us a lot more
• 07:30power when we start to
• 07:31look at the intersection in
• 07:32model systems and in genetics
• 07:34of gene by environment interplay.
• 07:39Again, my own,
• 07:41entry level into PTSD was
• 07:43started at, in as a
• 07:45resident in the VA systems,
• 07:47but was particularly
• 07:50both impressed and saddened by
• 07:52my observations
• 07:53as an intern and resident
• 07:54at Grady Hospital in Atlanta,
• 07:56at Emory. And what was
• 07:58clear to me in the
• 07:58late nineties,
• 08:00mid to late nineties, was
• 08:01that everybody come into coming
• 08:03into so Grady's a tertiary
• 08:04care hospital. And, back then,
• 08:06before a lot of the
• 08:07modern residency rules,
• 08:09the interns were over in
• 08:10overnight
• 08:11running the psychiatry emergency room.
• 08:13So we didn't know what
• 08:14we were doing. You know,
• 08:14you do whatever the nurse
• 08:15tells you to do. But,
• 08:17but but, you know, we
• 08:18were interviewing people who were
• 08:19being brought in by the
• 08:20police and everything else. So
• 08:20basically, all of Northeast Georgia
• 08:22was coming in, who was
• 08:23brought in for mental health
• 08:24assessments were coming in there.
• 08:26So you saw everything. It
• 08:27was amazing. But what was
• 08:29also amazing to me is,
• 08:30one, I realized that I'm
• 08:31really not a very good
• 08:32diagnostician, because everybody looked like
• 08:34everything.
• 08:35Twenty five years later, you
• 08:36know, I think we're all
• 08:37wondering, well, is that how
• 08:38much is that us, and
• 08:39how much of is that
• 08:39our attempt to cluster everything
• 08:41together into the DSM?
• 08:43But what was also clear
• 08:44is from the from my
• 08:46stints at the VA, I
• 08:47was very attuned to looking
• 08:48for trauma and PTSD. We
• 08:50weren't talking about that in
• 08:51our inner city populations, but
• 08:53it was absolutely everywhere. And
• 08:55if you ask about trauma,
• 08:56it was there and it
• 08:56was
• 08:57prevalent and pervasive.
• 08:59So from there, we started
• 09:00interviewing people in our,
• 09:02central Fulton County Mental Health
• 09:03Center. So essentially, our outpatient
• 09:05clinic serving inner city Atlanta.
• 09:07In our first paper,
• 09:09about fifty percent of the
• 09:10people in the waiting rooms,
• 09:11who were generally there for
• 09:12psychosis, for bipolar, for substance
• 09:14abuse disorders,
• 09:15about fifty percent of them
• 09:17met full CAHPS criteria for
• 09:18PTSD. But only about five
• 09:20percent were we talking about
• 09:21trauma at all in their
• 09:22in their chart. So it
• 09:23was clear that this was
• 09:24a pervasive,
• 09:25almost epidemic problem that we
• 09:27weren't paying attention to. So
• 09:28from there, we started what
• 09:29became called the Grady Trauma
• 09:31Project, where we started interviewing
• 09:32people in,
• 09:33waiting rooms of the primary
• 09:35care centers at Grady Hospital.
• 09:36And this was a population
• 09:38that was about ninety percent
• 09:39African American, about five to
• 09:41eight percent, Hispanic and Asian,
• 09:43and only a few percent
• 09:44Caucasian. So it was very
• 09:46much an underrepresented,
• 09:48population from the majority white
• 09:50perspective, but very much of
• 09:51a socially,
• 09:54ice isolated in terms of
• 09:56of structural disparity,
• 09:58and impoverished population. So just
• 10:00now,
• 10:02fifteen years later, we've interviewed
• 10:03almost thirteen thousand. I think
• 10:04it's closer to fourteen thousand
• 10:06folks now, to really get
• 10:07a sense of one of
• 10:08the largest studies of civilian
• 10:10trauma,
• 10:11in the country, and particularly
• 10:12one of the largest studies
• 10:13of African American civilian trauma.
• 10:15In this population,
• 10:16over everyone was below the
• 10:18poverty line. Over forty percent,
• 10:20reported a household monthly income
• 10:21of less than five hundred
• 10:22dollars. About half knew somebody
• 10:24personally who was murdered, which
• 10:25is just a remarkable statistic.
• 10:28About half had personally been
• 10:29attacked themselves. And about a
• 10:30third each had had experiences
• 10:32of sexual assault or childhood
• 10:33maltreatment.
• 10:34Importantly, everybody had experienced high
• 10:36levels of discrimination. So in
• 10:37addition to understanding the levels
• 10:39of trauma and a lot
• 10:40of the datasets that I
• 10:41talk about, whether it be
• 10:42the neuroimaging datasets, the physiology
• 10:43datasets, as well as this
• 10:45cohort was one of the
• 10:46founding cohorts of the Psychiatric
• 10:47Genomic Consortium.
• 10:49It's now over a million
• 10:50people. But it's also one
• 10:51of the most well represented
• 10:53in terms of diversity in
• 10:54part because of the Atlanta,
• 10:56Greater Power Project.
• 10:58But it's, we also began
• 10:59to really start to understand
• 11:01the role of structural racism,
• 11:03and discrimination as one of
• 11:05the critical environmental factors leading
• 11:06to chronic stress. And so
• 11:08I'm not gonna talk much
• 11:09more about it, but just
• 11:09wanted to do a shout
• 11:10out, particularly to these folks,
• 11:11Nagaar Fani, who's associate professor
• 11:13now at Emory Nate Harnett,
• 11:15who's an assistant professor at,
• 11:16Harvard, and, Sierra Carter, who's
• 11:18an associate professor at Georgia
• 11:20State, who led many studies
• 11:21now and continue to do
• 11:22great work,
• 11:23understanding the roles of structural
• 11:25racism, racial discrimination, negative life
• 11:27experiences,
• 11:28and how that adds to
• 11:29the chronic stress issues, including
• 11:31poverty, including,
• 11:32being victims of violence,
• 11:34in at risk communities.
• 11:36So I'm happy to talk
• 11:37more about that in the
• 11:38discussion section. But critically, in
• 11:40addition to understanding
• 11:42some of the critical roles
• 11:43of structural racism that this
• 11:45has helped with, it's also
• 11:46just really provided so much
• 11:47to our understanding of the
• 11:48biology of these disorders in
• 11:50civilians.
• 11:52Okay. So that's my stint
• 11:53on epidemiology and some of
• 11:55the GDP. And, I'm just
• 11:56gonna have one slide on
• 11:57current treatments because the rest
• 11:58of it's really gonna be
• 11:59about where do we go
• 11:59from here. And, unfortunately, current
• 12:01treatments, we don't have a
• 12:02whole lot to say. So,
• 12:03again, with as with most
• 12:04things in psychiatry, we have
• 12:05two general areas. We have
• 12:07psychotherapies and we have medications.
• 12:09And our psychotherapies,
• 12:11primarily,
• 12:12are the cognitive behavioral therapy
• 12:14based therapies. And the areas
• 12:16that we understand the most
• 12:17about is prolonged exposure.
• 12:19And prolonged exposure,
• 12:21then has components,
• 12:23that are built into cognitive
• 12:25processing therapy, eye movement desensitization,
• 12:27EMDR,
• 12:28and other therapies. But all
• 12:30of these, particularly from the
• 12:31translational perspective, rely on this
• 12:33idea of desensitization,
• 12:35habituation, or extinction of fear.
• 12:38And so from a clinical
• 12:39perspective can you see it's
• 12:40okay.
• 12:41From a clinical perspective, what
• 12:43happens in these therapies, right,
• 12:44is you go into the
• 12:45therapist's office and they say,
• 12:47tell me about your trauma.
• 12:48And you're like, I don't
• 12:48wanna talk about my trauma.
• 12:50It's like, it'll it'll I
• 12:51promise you it'll be you'll
• 12:52be okay. And this will
• 12:53be good for you. So,
• 12:54you know, part of the
• 12:55more the sort of more
• 12:56modern, if you will, like
• 12:57cognitive processing, interpersonal therapies are
• 13:00there's a component of emotion
• 13:02regulation,
• 13:03training, skills training, and other
• 13:04things to help people. And
• 13:05now a lot of this
• 13:06is so you don't dissociate
• 13:07or run out of the
• 13:08room. Right? Extinction only works
• 13:10if you stay there with
• 13:11the exposure.
• 13:12But assuming that has happened
• 13:14with a good therapist, the
• 13:15patient will start telling about
• 13:16the trial. Well, I was
• 13:16walking out down this dark
• 13:18alley, and this person came
• 13:19up, and etcetera, etcetera. And
• 13:21on an on a zero
• 13:22to one hundred, and again,
• 13:23a lot of the sophistication
• 13:24of quantification
• 13:25of anxiety is still subjectively,
• 13:27you know, are you a
• 13:28hundred, gonna have a panic
• 13:29attack? Are you zero, gonna
• 13:30fall asleep?
• 13:32And, again, one of my
• 13:33themes over and over again
• 13:34is we have to have
• 13:35quantitative biomarkers to advance the
• 13:37field.
• 13:37And simple things like the
• 13:39oblong skin response could be
• 13:40very easy ways to do
• 13:41this.
• 13:42But nonetheless, so you would
• 13:44talk to your therapist. You
• 13:45would get up to, you
• 13:45know, as close to a
• 13:46hundred as as the therapist
• 13:47will as you can while
• 13:49the therapist is helping you
• 13:50stay there. And then you
• 13:52just keep there, and you
• 13:53stay there. And you talk
• 13:53more about it. And they
• 13:54ask other questions. And they're
• 13:55curious, and they're empathic, and
• 13:57they're helping you breathe. And
• 13:58what miraculously,
• 14:00over the course of minutes
• 14:01to hours, you're still there
• 14:03and talking about it, but
• 14:04some of that emotional salience
• 14:07has decreased. And it starts
• 14:08to, if anything, become even
• 14:09a little bit boring. You're
• 14:10just kinda there. And you
• 14:11get to the end of
• 14:11the session. It's like, that
• 14:12was hard, but I survived
• 14:13it. You come back the
• 14:14next day or next week.
• 14:15You said, tell me again
• 14:17what happened. And they tell
• 14:18you again. And it's still
• 14:19very upsetting, but it's not
• 14:20quite as upsetting. And they
• 14:21do that over and over
• 14:22again. And that's the basic
• 14:23process that for thirty years,
• 14:24starting with Beck and many
• 14:25others have talked and then
• 14:26and Nafoa, have talked about
• 14:28the idea of desensitizing this
• 14:29memory.
• 14:30And I'll come to, later
• 14:32talking about extinction of fear
• 14:33and how we think this
• 14:34is very similar.
• 14:36All right. So that's the
• 14:36therapies.
• 14:38EMDR is an interesting side.
• 14:40We think that likely what's
• 14:42happening with the eye movements,
• 14:43with the tapping, with the
• 14:44other things is really about
• 14:45distraction. And if you're doing
• 14:46the exposure while being distracted,
• 14:48you're less likely to dissociate.
• 14:50You're more likely to be
• 14:51able to have emotional stability
• 14:52during that time and to
• 14:53be able to have more
• 14:54success.
• 14:56Medications, we really only have
• 14:57two we only have two
• 14:58FDA approved treatments, paroxetine,
• 15:00and sertraline, Paxil, and Zoloft.
• 15:02And the rest of my
• 15:03talk will be about how
• 15:04we can do better.
• 15:05John Crystal and many folks
• 15:07coming out of the Yale
• 15:07programs, have been leaders in
• 15:09thinking about this. But critically,
• 15:11we have no FD we
• 15:12have no approved treatments that
• 15:13are based on our current
• 15:14understanding of the neurobiology.
• 15:16And that's where I think
• 15:17the gap is that is
• 15:18so fascinating.
• 15:19So our goal is to,
• 15:21take the learnings that has
• 15:23been going on for the
• 15:24last hundred plus years in
• 15:25learning and memory, in neural
• 15:27circuit neurotransmission,
• 15:29and circuit,
• 15:30processing
• 15:31to understand PTSD better and
• 15:33have targeted treatments. So
• 15:35why could we do this?
• 15:36Well, I think it's in
• 15:37part because PTSD is tractable.
• 15:38And I think in many
• 15:39ways, we can think about
• 15:40PTSD
• 15:41as a sister to, substance
• 15:43abuse,
• 15:44which is that we understand
• 15:45the neural circuitry, and that
• 15:46neural circuitry is trans, is
• 15:48is really, conserved across species.
• 15:51We know when it starts.
• 15:53By definition, it starts at
• 15:54the time of the trauma.
• 15:55And because the traumatologists
• 15:57of the world have been
• 15:58trying to understand trauma for
• 15:59a long time, we do
• 16:00have a fair amount of
• 16:00that. And we understand a
• 16:01lot about how to make
• 16:03mice afraid and stressed.
• 16:06And finally,
• 16:07it's a process of learning
• 16:08and memory. And some of
• 16:09the greatest, advances in neuroscience
• 16:11have been understanding synaptic plasticity.
• 16:14Again, a place that Yale
• 16:15is a leader in.
• 16:16And while plasticity, we often
• 16:18think of neurologically
• 16:20with loss of plasticity, such
• 16:22as Alzheimer's disease, we're increasingly
• 16:24thinking of depression as perhaps
• 16:26a disorder of loss of
• 16:28sort of metaplasticity.
• 16:29But PTSD isn't even simpler.
• 16:31It's a disorder where you
• 16:32almost overly learn this initial
• 16:34fear memory. In the same
• 16:35way, perhaps with addiction, you
• 16:37overly learn or or overly,
• 16:40sensitize
• 16:41that specific pathway and are
• 16:42unable to now regulate it
• 16:44later.
• 16:45So our goal is to
• 16:45have a molecular biology of
• 16:47PTSD
• 16:48that can lead to predictive
• 16:49biomarkers, interventions, and treatments.
• 16:51So, again, just to put
• 16:52us all on the same
• 16:53page,
• 16:55the the simplistic circuit, that
• 16:57I'll mostly talk about, though
• 16:58it's certainly much, much more
• 16:59complicated,
• 17:01is the amygdala as sort
• 17:02of the final common pathway
• 17:04that drives the fight or
• 17:05flight fear response.
• 17:06And as Joe Ledoux,
• 17:08you know, first,
• 17:10said, there's the concept of
• 17:12if pathways coming into the
• 17:13amygdala that are both conscious
• 17:15and preconscious. The,
• 17:18high road, Joe called it,
• 17:20was the classical pathway where
• 17:21sensory information goes to the
• 17:23the thalamus, the visual cortex,
• 17:24has multiple layers of visual
• 17:25cortex, and eventually gets back
• 17:27to the amygdala.
• 17:29And we know that conscious
• 17:30awareness of this, sensory pathway
• 17:32may take a half a
• 17:33second several hundred milliseconds. In
• 17:35parallel, within that very first
• 17:37preprocess signal, the visual thalamus
• 17:39sends projections to the amygdala,
• 17:41and the amygdala is firing
• 17:42off
• 17:44comparisons of does this memory
• 17:46engram match previous
• 17:48fear? For example, my snake
• 17:50represent engram representation,
• 17:52that's happening on the order
• 17:53of a hundred milliseconds. So
• 17:54a full half a second
• 17:55before we're consciously aware our
• 17:57amygdala has shot off. Can
• 17:58we ignore this, or do
• 17:59I need to run away,
• 18:00fight it,
• 18:02etcetera, etcetera. That's critical for
• 18:04evolution. One could argue it's
• 18:05been one of the primary
• 18:06drivers of evolution, being able
• 18:07to have as rapid as
• 18:08biology can create, ability to
• 18:11escape or fight.
• 18:12But I would argue in
• 18:13the modern world, dysregulated fear
• 18:15leads to our disorders of
• 18:17phobia, panic, PTSD. In a
• 18:18twenty four seven news cycle
• 18:20world, it makes all of
• 18:21these that much worse. And
• 18:22it probably drives things like
• 18:23xenophobia,
• 18:25bigotry, and
• 18:27sphere in elections. And I'll
• 18:28just leave it at that.
• 18:29We talked enough about that
• 18:30at dinner. Okay.
• 18:34But again, the amygdala is
• 18:35the area that we can
• 18:36really study. It's been conserved
• 18:37across,
• 18:38primates. It's, for the most
• 18:40part across,
• 18:41mammals and for the most
• 18:42part across vertebrates. So we
• 18:43really are talking about in
• 18:44many ways, the reptilian brain
• 18:46of survival.
• 18:47At the next level, what's
• 18:49going on? Well, decades of
• 18:51work have shown that when
• 18:52the that basic Pavlovian conditioning,
• 18:54the conditioned stimulus, the previously
• 18:56neutral stimulus that might be
• 18:58in a lab, a tone,
• 18:59or a a visual cue
• 19:01in the real world might
• 19:02be the sounds and smells
• 19:03and context of the trauma,
• 19:05the car at the time
• 19:06of the car crash, the
• 19:07smell of the person attacking
• 19:08you, the smell and sights
• 19:10of the guns in the
• 19:11in the in the,
• 19:12whether it be in the
• 19:13inner city or whether that
• 19:14be in the war zone,
• 19:15or the civilian war zone,
• 19:18compared with the trauma, the
• 19:19pain, the loud noise, the
• 19:21thing the avert the innately
• 19:22aversive stimulus.
• 19:23And that single pairing,
• 19:26through rapid plasticity,
• 19:28that we now know is
• 19:29NMDA dependent, which I'll talk
• 19:30about is BDNF dependent, is
• 19:32calcium dependent, is CREB dependent.
• 19:33All of our favorite plasticity
• 19:35molecules for decades are all
• 19:36going on in here. And
• 19:38that leads to rapid changes
• 19:39on the order of seconds
• 19:40to minutes to hours that
• 19:42essentially then,
• 19:43I think we can think
• 19:44of it almost as a
• 19:45switch that now in the
• 19:46future, this condition stimulus is
• 19:48gonna activate the same engram
• 19:50that that previously unconditioned stimulus
• 19:52would have activated.
• 19:53And either one activates from
• 19:55the lateral and basolateral to
• 19:56the central amygdala, a set
• 19:58of hardwired projections that people
• 19:59like Mike Davis when he
• 20:01was at Yale, and Joe
• 20:02Ladoux at NYU, and Mike
• 20:03Kanzolo at UCLA,
• 20:05showed essentially lead to the
• 20:07hardwired threat response,
• 20:09but they also look just
• 20:10like the panic attack response.
• 20:11So in psychiatry, as a
• 20:13resident, I was very excited
• 20:14to read some of Mike's
• 20:15reviews
• 20:16because when you look at
• 20:17this, that they knew that
• 20:19electrical or chemical stimulation of
• 20:20the amygdala in a mouse,
• 20:22a rat, or a human
• 20:23in surgery would lead to
• 20:25hardwired immediate responses of hypothalamic
• 20:28projections leading to increased heart
• 20:29rate, sympathetic response,
• 20:31blood pressure increases, the GI
• 20:33distress,
• 20:34the respiratory distress, the panting,
• 20:35the arousal, the startle response
• 20:37that Mike's famous for, the
• 20:39freezing response to the PAG,
• 20:41and then the, hypothalamic pituitary
• 20:43adrenal stress axis and cortisol.
• 20:45All of these things that's
• 20:46is that sort of massive
• 20:48panic attack
• 20:49is mediated through this fear
• 20:51response. And it's one of
• 20:52the few places, if not
• 20:53the only in our field,
• 20:54that we can directly take
• 20:56a set of human symptoms,
• 20:57the panic attack that we
• 20:58see in panic disorder,
• 20:59phobia, or PTSD with the
• 21:01trigger, and we can overlay
• 21:02them to a hardwired set
• 21:04of reflexes coming out of
• 21:06the amygdala. Fascinating. We've known
• 21:07about it for a long
• 21:08time, but we haven't yet
• 21:09as a field been able
• 21:10to take this finding and
• 21:12turn it into novel interventions
• 21:13and treatments.
• 21:15So that's one of the
• 21:16questions. And the other question
• 21:18is, even though we know
• 21:19a lot about this hardwired
• 21:21system in some people, in
• 21:22some model systems, what we
• 21:24don't know still is why
• 21:25only ten percent of people
• 21:26develop PTSD and the other
• 21:28ninety percent are are are
• 21:29resilient. And that's probably the
• 21:30bigger question. And that probably
• 21:32has more to do with
• 21:33what information's coming into the
• 21:34amygdala and these downstream,
• 21:37effector systems and how is
• 21:38that regulated by the cortical
• 21:40areas, by the hippocampal areas,
• 21:42and other things.
• 21:44So another way to breaking
• 21:45this down then is to
• 21:46try to model these systems
• 21:48across
• 21:49a dynamic time flow. So
• 21:51first of all so again,
• 21:52if we say given trauma
• 21:54x,
• 21:55why do ten percent of
• 21:56people develop PTSD and ninety
• 21:57percent of people recover? Well,
• 21:59part of that's genetic, and
• 22:00I'll spend a fair amount
• 22:01of time talking about that.
• 22:02Part of that's environmental, and
• 22:03I'll talk about that. But
• 22:04again, one example is childhood
• 22:06trauma. We know that someone
• 22:07with childhood trauma, when they're
• 22:09an adult, if they have
• 22:10an interpersonal attack or a
• 22:11car crash, they're a lot
• 22:12more likely to develop something
• 22:13like PTSD or trauma related
• 22:15depression, etcetera.
• 22:17We know that something about
• 22:18the trauma consolidation
• 22:20period, what the level of
• 22:21trauma, if it's an interpersonal
• 22:22trauma, it's more risky than
• 22:24if it's a non interpersonal
• 22:25trauma.
• 22:26And if one has likely
• 22:28disrupted sleep,
• 22:29has poor social connections,
• 22:31has a more high stress
• 22:33response, etcetera, those are all
• 22:35things that may predispose someone
• 22:37down that path. And I'll
• 22:38talk more about that. But
• 22:39then in the in the
• 22:40days and weeks in that
• 22:42transition between acute stress to
• 22:44chronic stress, there's also something
• 22:45critical that's going on.
• 22:47During the early expression of
• 22:49fear, be it the intrusive
• 22:50memories, the nightmares, the flashbacks,
• 22:52the avoidance, the sympathetic response,
• 22:54all of these things,
• 22:55there's different cognitions and those
• 22:57seem to further drive sensitization
• 23:00towards PTSD or recovery. So
• 23:01for a few examples, people
• 23:03with PTSD will generalize. I
• 23:04was afraid of that person
• 23:05in that alley at that
• 23:06time. Then I kinda didn't
• 23:08wanna go out at night.
• 23:09Then I didn't wanna be
• 23:10around men.
• 23:11Now I don't really wanna
• 23:12leave my house or my
• 23:13bedroom. The world has become
• 23:14more and more dangerous and
• 23:15less and less safe through
• 23:16generalization, which is probably in
• 23:18part a working memory hippocampal
• 23:20process.
• 23:21That's in contrast to discrimination.
• 23:24There are safe places and
• 23:25dangerous places, but I can
• 23:26I can discriminate those in
• 23:28a in an emotionally valiant
• 23:30discriminatory way? So that's an
• 23:31important area of distinction.
• 23:33The other idea is that,
• 23:34doc, every time I talk
• 23:36about this, it gets worse
• 23:37and worse. Why would I
• 23:37wanna do exposure therapy?
• 23:39We think about this in
• 23:40many ways as sensitization, which,
• 23:42again, Joe Ladoux and Cree
• 23:43Nader restarted the field of
• 23:44reconsolidation.
• 23:46And we're increasingly thinking about
• 23:47sensitization as when that fear
• 23:49is reactivated,
• 23:50and then you escape. Then
• 23:52you you have the that
• 23:53memory. It's resupported. It's resensitized.
• 23:55It's reconsolidated.
• 23:57You don't hold on to
• 23:58it long enough to extinguish.
• 24:00And I'll end with some
• 24:01of our old work about
• 24:02desychoserine,
• 24:02which I think may be
• 24:03telling us some important clues
• 24:05about ketamine and psychedelics
• 24:07with if we can enhance
• 24:08plasticity,
• 24:09we've gotta make sure we're
• 24:10enhancing plasticity going down the
• 24:11extinction pathway and not just
• 24:13the reconsolidation or sensitization pathway,
• 24:16and that may be critical.
• 24:17So I'll end with that.
• 24:19But, so overall, I'll spend
• 24:21the next, I guess, twenty
• 24:23minutes or so talking about
• 24:25several different stories. One, how
• 24:27we can understand consolidation, both
• 24:28at the human level and
• 24:30one example in mouse models
• 24:32of how understanding consolidation could
• 24:33lead to novel treatments and
• 24:34interventions. Second, just, briefly, some
• 24:36of the really exciting work
• 24:37that's been going on for
• 24:38a decade now, but starting
• 24:39to come to fruition of
• 24:40large scale genetics. Much of
• 24:41what's done by been done
• 24:42by the Glertner lab here,
• 24:44the million veteran programs and
• 24:45others in the PGC.
• 24:50We now have over a
• 24:51million samples and are really
• 24:52starting to have a genetic
• 24:53architecture of PTSD.
• 24:55That's really exciting because we
• 24:56can start to bring that
• 24:57together with the human post
• 24:58mortem molecular genetics, as well
• 25:00as the rodent. And really
• 25:01say what's conserved in these
• 25:02pathways that we can really
• 25:03follow and target.
• 25:05And then finally, a new
• 25:06area of work,
• 25:07that's a little bit of
• 25:08a side, but pointing to
• 25:09some of the same pathways
• 25:10and same,
• 25:12molecules
• 25:13is stress related aggression. Again,
• 25:14we talk about the fight
• 25:15or flight, but we almost
• 25:16never really talk about the
• 25:17fight.
• 25:19But, we know there's this
• 25:20concept, and that's mediate cycles
• 25:22of violence. A lot of
• 25:23those cycles of violence that
• 25:24lead to that,
• 25:26community violence is tra is
• 25:27untreated trauma. And by understanding
• 25:30what's mediating that could get
• 25:31give us new clues into
• 25:32how we'd help stem that
• 25:34tide.
• 25:35And then I'll end with
• 25:36coming back to what's the
• 25:37difference between sensitization and extinction,
• 25:39and how by enhancing plasticity,
• 25:41maybe in a targeted way,
• 25:43either through targeting with specific
• 25:44kinds of therapies or targeting
• 25:46it by better understanding the
• 25:47neural circuits,
• 25:49could we have better treatments
• 25:50for chronic PTSD?
• 25:52So consolidation.
• 25:54So this idea of
• 25:56memories
• 25:57not being permanent immediately, but
• 25:58rather going through a period
• 25:59of short term memory to
• 26:00long term memory, and then
• 26:02long term memory being reactivated
• 26:04with working memory,
• 26:05and then being,
• 26:07able to be reconsolidated
• 26:08or extinguished or critical concepts
• 26:10that I'll come to. And
• 26:12a lot of our understanding
• 26:13of of early consolidation came
• 26:15from Jim McGaw and folks
• 26:16like that. Jim worked for
• 26:18decades in this area a
• 26:19lot based on context, fear
• 26:20of learning, and rats. But
• 26:21what he showed was that
• 26:22you could have short term
• 26:23memories, again, translated long term
• 26:26memories, of course, like people
• 26:27like Eric,
• 26:28Candel, and Paul Gringard, and
• 26:30others got a Nobel Prize
• 26:31for some of these concepts.
• 26:32But Jim, was able to
• 26:34show is at least in
• 26:35in simple models, in this,
• 26:36you know, held up a
• 26:37cause of Aplysia and everything
• 26:38else, that when a memory
• 26:40type event happened, whether that
• 26:41be in an Aplysia, Drosophila,
• 26:43or a mammalian brain, there's
• 26:45short term memory events,
• 26:47possibly short term genes that
• 26:48lead to long term genes
• 26:49that lead to very long
• 26:50term genes that lead to
• 26:51structural changes, dendrite
• 26:53and axonal changes, etcetera.
• 26:56My first work with Mike
• 26:57Davis Hefter, he'd come down
• 26:58from Yale.
• 26:59I, came from Linda Buxauab
• 27:01and sort of my my
• 27:03skill was I knew how
• 27:03to do molecular cloning in
• 27:05in situ, and I really
• 27:06wanna do something in emotion.
• 27:07When I learned about the
• 27:08amygdala, I was like, this
• 27:09is really cool, and there's
• 27:10very few people doing molecular
• 27:12biology of the amygdala in
• 27:13the late nineties. So we,
• 27:14I cloned about thirty different
• 27:16genes related to synap that
• 27:17were known related to LTP
• 27:18and synaptic plasticity. And we
• 27:19started looking at them in
• 27:20the amygdala after fear host
• 27:22of
• 27:23genes were changed quite robustly,
• 27:23and they fell into the
• 27:23the the same
• 27:24predicted pathways. We found immediate
• 27:25early genes, like FOS and
• 27:25JUNE and others,
• 27:28that came up within the
• 27:29first
• 27:29minutes and were associated with
• 27:31CREB. We
• 27:38then found genes like BDNF
• 27:39and a number of structural
• 27:40plasticity genes that came up
• 27:42hours later. And we found
• 27:43a number of things that
• 27:44were inhibitory related, that were
• 27:46transiently downregulated and then came
• 27:47back up.
• 27:49So all this could be,
• 27:50was happening in the amygdala.
• 27:52But how can we study
• 27:53consolidation in humans?
• 27:55And this started in emergency
• 27:57departments. And the idea again
• 27:58was, wouldn't it right now,
• 28:00if you have chest pain
• 28:01or arm numbness, you know
• 28:03to go to the emergency
• 28:04room. And with the right
• 28:05cardiovascular test or EKG
• 28:07or MRI,
• 28:08they can diagnose early stroke
• 28:10or early heart attack. And
• 28:11with the right intervention,
• 28:13you can take this early
• 28:14biological
• 28:15risk and prevent the long
• 28:17term sequelae of heart damage
• 28:19or brain damage.
• 28:20What if we understood enough
• 28:21about the biology of psychological
• 28:23trauma that if we identified
• 28:25those who were most at
• 28:26risk in the emergency department,
• 28:28could we prevent that very
• 28:29early stress or early acute
• 28:31stress from transforming into long
• 28:33term PTSD?
• 28:34And I think we can,
• 28:35but how do we do
• 28:35that? So we started studies
• 28:37at Emory.
• 28:38These data,
• 28:39were robust enough to get
• 28:40us a large, contract,
• 28:42U01 with NIH and the
• 28:43DOD,
• 28:44led by Sam MacLean, Kerrison
• 28:46Kona, Ron Kessler, and myself
• 28:47called the Aurora Project. And
• 28:49we enrolled over five thousand
• 28:50people across about twenty different
• 28:52emergency rooms in the US,
• 28:53and collected as much data
• 28:55as we possibly could. And
• 28:56so so that that included
• 28:58blood data in the ER,
• 28:59all the ER related data,
• 29:00galvanic skin response, other physiology
• 29:02data in the ER, in
• 29:03addition to neuroimaging
• 29:04data on a subset within
• 29:06the first weeks. And then
• 29:07we followed people up for
• 29:08a whole year with all
• 29:09the cool,
• 29:10watch based data and phone
• 29:12based active and passive data
• 29:14that we could. And we're
• 29:14still even though this officially
• 29:16ended several years ago, we're
• 29:17still
• 29:18diving through the data, and
• 29:19it's now publicly available if
• 29:20anybody wants to collaborate.
• 29:23Some of the early findings
• 29:25were that things like amygdala
• 29:27or anterior cingulate and for,
• 29:29for the mouse people, anterior
• 29:31cingulate, we think is associated
• 29:33is similar to prelimic,
• 29:34cortex.
• 29:36These, we knew were associated
• 29:37with long term fear and
• 29:38threatened PTSD.
• 29:40And we all they're also
• 29:41predictive early in the aftermath
• 29:42of trauma of later PTSD.
• 29:44So this is led by
• 29:45Jenny Stevens, who's now an
• 29:46associate professor at Emory and
• 29:47leads the imaging component of
• 29:49Aurora.
• 29:50And the amygdala activation to
• 29:52fearful faces in the ER
• 29:54at about two weeks after
• 29:55trauma is very predictive of
• 29:57later PTSD,
• 29:58three months and six and
• 29:59twelve months after trauma. And
• 30:01similarly, the anterior cingulate that
• 30:03in many studies, has coactivation
• 30:05of amygdala,
• 30:07shows a similar pattern.
• 30:09In contrast, the hippocampus tends
• 30:11to go with the,
• 30:12subgenual cortex. And they tend
• 30:14to be associated with down
• 30:15regulating,
• 30:16amygdala or at least core
• 30:17inversely correlated with amygdala activation.
• 30:20That seems to be, inversely
• 30:22associated with PTSD.
• 30:24So this is using a,
• 30:26a go no go, hippocampal
• 30:28inhibition task.
• 30:30And what we find what
• 30:31Sonavang Ruiz, who's assistant professor
• 30:33at Emory found is that
• 30:34activation more activation of hippocampus
• 30:37was associated with less PTSD
• 30:38symptoms. So this is a
• 30:40two week imaging scan,
• 30:41was less associated with three
• 30:43month and six month PTSD.
• 30:44So we're seeing the circuits
• 30:45in the directions we'd expect
• 30:47to very early after trauma
• 30:48when we're still calling this
• 30:49acute stress and not long
• 30:51term stress.
• 30:52For the sympathetic locus coeruleus
• 30:55and and adrenergic fans in
• 30:56the house,
• 30:58This was one of our
• 30:59most exciting findings that still,
• 31:01we're trying to, figure out
• 31:02what the next steps are.
• 31:04So MRI is fine. It's
• 31:05hard to do on everybody,
• 31:07and it's hard to analyze.
• 31:09ESENSE is a very inexpensive,
• 31:12so AZA and anybody else
• 31:13doing human naturalistic studies,
• 31:16this is a great tool.
• 31:17It it plugs into an
• 31:18iPhone, costs about a hundred
• 31:19bucks. You can use it
• 31:20multiple times, and gives you
• 31:22lab relay labs,
• 31:24as good as Biotech based,
• 31:26Galvanic skin response data. And
• 31:28we plugged it in on
• 31:29people's phones often while they
• 31:30were waiting on their neck
• 31:31board with their neck boards
• 31:32to for their neck spine
• 31:34to be cleared in the
• 31:35ED after a motor vehicle
• 31:37crash.
• 31:38And we simply ask them,
• 31:39what brought you into the
• 31:40hospital?
• 31:41And the galvanic skin response
• 31:43before that question and after
• 31:44that question was highly predictive
• 31:46of PTSD six months and
• 31:47twelve months later.
• 31:48And so, again, what we
• 31:49think this is is just
• 31:51like McGough said, we know
• 31:52that that the adrenergic systems
• 31:54involved in in threat consolidation
• 31:56and early adrenergic hyperactivation
• 31:58is likely one of the
• 31:59predictors of later PTSD. And
• 32:01I think Steve Southwick had
• 32:02some of the earliest data
• 32:03on,
• 32:04on the role of hyperadrenergic
• 32:06systems in PTSD.
• 32:08So those are some of
• 32:09the things. I'm not I
• 32:10could spend an hour a
• 32:11couple hours going through AURORA
• 32:12data on all the different
• 32:13kinds of metrics we're trying
• 32:15to provide. But the idea
• 32:16is, can we use predictive
• 32:17analytics from large scale studies
• 32:19to really start to understand
• 32:21the blood based biomarkers, physiological
• 32:23biomarkers that can predict long
• 32:24term PTSD
• 32:25in the very short term
• 32:26after trauma. But what do
• 32:27we do with that data?
• 32:28How do we intervene?
• 32:31Well, I think that's where,
• 32:32in some ways, our model
• 32:33systems can come into play.
• 32:34And so in parallel,
• 32:36we were studying what are
• 32:37the,
• 32:38so I I showed you
• 32:39some of the early data
• 32:40of
• 32:41amygdala based, transcription factors changing
• 32:44after fear conditioning. A decade
• 32:45later, we could do, RNA
• 32:47arrays. And now we can,
• 32:48of course, do lots of
• 32:49detailed RNA Seq and single
• 32:50cell Seq. But some of
• 32:52the, one of the most
• 32:53the early findings that we
• 32:54were really excited about was
• 32:56neurokinin b or tachykinin two.
• 32:58So Raul Lendero, who's now
• 32:59at,
• 33:00Barcelona,
• 33:01was looking at genes that
• 33:03were,
• 33:04that really differentiated,
• 33:06con control condition versus those
• 33:08who were consolidating fear in
• 33:10a tone shot paradigm in
• 33:12mice. And one of those
• 33:13interesting genes was tachykinin two.
• 33:14And he found that that
• 33:15was significantly increased shortly after
• 33:17trauma, but returned to normal.
• 33:18So that's kind of like
• 33:19we'd expect with that medium,
• 33:21consolidation,
• 33:22set of genes.
• 33:23It was associated with paired
• 33:25learning, but not unpaired stress.
• 33:26So it seemed to be
• 33:27associative learning specific.
• 33:29And it was located in
• 33:30a really interesting place. So
• 33:31in the in the whole
• 33:32temp
• 33:33temporal lobe, the only place
• 33:34it's really expressed is the
• 33:35central medial amygdala.
• 33:37And this is the part
• 33:38of the amygdala that's projecting
• 33:39down to all these brainstem
• 33:40hardwired
• 33:41projections. So it's a critical
• 33:42area. It's a good time
• 33:43course.
• 33:44And there were drugs.
• 33:46So a sanitant was a
• 33:48a known drug that was
• 33:49available and had been, tested
• 33:50actually in schizophrenia decades earlier.
• 33:52And Raul showed that both
• 33:54systemically or intraamigulally,
• 33:57with cannulation,
• 33:58that it blocked that blocking
• 33:59this pathway that was naturally
• 34:01associated with consolidation
• 34:02led to a decrease or
• 34:04blockade in fear consolidation. So
• 34:06if you did tone shot
• 34:07pairings and saw was measuring
• 34:08freezing in mice, gave the
• 34:09drug systemically or intramigally, and
• 34:11then tested them afterwards,
• 34:13those who received the antagonist
• 34:15had significantly less fear.
• 34:17He then also showed that
• 34:18if he overexpress the drug
• 34:20with a virus, he could
• 34:21get significantly more fear. So
• 34:22he could push and pull
• 34:23it in both directions.
• 34:25And if he did the
• 34:26combined experiment,
• 34:28where he, took four groups
• 34:29of animals with or without
• 34:30drug, with or without viral
• 34:32overexpression,
• 34:33he could replicate the drug
• 34:35alone, would, decrease the fear.
• 34:37The virus alone, increase the
• 34:38fear. And the drug plus
• 34:40the virus normalize the fear.
• 34:42So from a pharmacological
• 34:43perspective, we could push it
• 34:44and pull it in both
• 34:45directions from a genetic perspective.
• 34:47Don't have time to show
• 34:48you, but he did DREDS
• 34:49and optogenetics
• 34:50in these cell populate same
• 34:51cell populations with TACT3 pre
• 34:53drivers and could push and
• 34:54pull the threat consolidation in
• 34:56both directions. So a lot
• 34:57of data that this was
• 34:58a critical molecular pathway in
• 34:59a critical specific set of
• 35:01cells.
• 35:02In parallel, Moriel Zavowski, who's
• 35:04at Utah now, and David
• 35:05Anderson Group at Caltech, also
• 35:07identified TACT2 in the medial
• 35:08and central amygdala
• 35:09associated with chronic social stress.
• 35:11So now we're having convergent
• 35:12data from different labs that
• 35:14this is an important pathway.
• 35:16And,
• 35:17ongoing work now is, looking
• 35:19at how this pathway modulation
• 35:22may help block fear consolidation.
• 35:24And because there are drugs
• 35:25available, there's a potential path
• 35:26forward. And just our own
• 35:28little,
• 35:29foray into identifying better antagonists,
• 35:32more potent,
• 35:33and with potential
• 35:36composition of matter. So that
• 35:37industry might be actually interested
• 35:38in doing a study that
• 35:39would be helpful to humans.
• 35:41We've been,
• 35:42identifying
• 35:43a whole set of novel
• 35:44compounds that all act on
• 35:46the tach three, tach two
• 35:48receptor that may be useful
• 35:49antagonists. So all of this
• 35:51is in,
• 35:52the path the the as
• 35:54an example of saying, identifying
• 35:56new pathways related to threat
• 35:58consolidation
• 35:59may lead to a whole
• 36:00new pharmacology
• 36:01specific around,
• 36:03consolidation. So that in the
• 36:04aftermath of trauma,
• 36:06if we apply,
• 36:08new biomarkers to really understanding
• 36:10who's most at risk for
• 36:11later PPSC,
• 36:12could we target the tachykinin
• 36:14system? I'll show you a
• 36:15little bit about neurotensive later.
• 36:17There's interesting evidence about targeting
• 36:19the cortisol system. So there's
• 36:20many different pathways. As a
• 36:21field, we have to triage
• 36:22and understand which of these
• 36:24make the most sense, have
• 36:25the best data, but there's
• 36:27a real path forward for
• 36:28potentially,
• 36:29in
• 36:31early prevention of PTSD.
• 36:34Okay. Another way of getting
• 36:36at this is what are
• 36:36the genetics? And so again,
• 36:38I argue that about the
• 36:39twin studies and then later,
• 36:41genetic studies suggest about up
• 36:43to forty percent of the
• 36:44risk for PTSD,
• 36:45is genetically mediated. This is
• 36:47the GWAS,
• 36:49Manhattan plot, of part of
• 36:51individual SNPs
• 36:52associated with PTSD risk across
• 36:55over a million,
• 36:56samples now. And this includes
• 36:57the million veterans program with
• 36:59about ninety five loci. So
• 37:00it's a really exciting time.
• 37:01It wasn't that long ago,
• 37:03that,
• 37:04schizophrenia was here and and
• 37:06PTSD had maybe one.
• 37:08But it's really, you know,
• 37:09sticking with the
• 37:11perseverance of the field and
• 37:13finding, and a lot of
• 37:14this is Kirsten Conan,
• 37:16scratching every, piece of dirt
• 37:18in the world to find
• 37:19who's got PTSD samples. We've
• 37:20been able to pull all
• 37:21this together.
• 37:22Our little favorite I think
• 37:24it's just my favorite. I
• 37:25think it's funny, and I'm
• 37:25not sure anybody else does.
• 37:27But, with schizophrenia, it took
• 37:29you know, the the the
• 37:30best biology we had for
• 37:31schizophrenia was dopamine. And the
• 37:33dopamine receptor came up as
• 37:34number, I think, hundred and
• 37:35fifty something in the schizophrenia
• 37:37GWAS.
• 37:39And with, PTSD,
• 37:41with freeze two, we had
• 37:43a hit, on chromosome seventeen
• 37:45that included the CRH locus.
• 37:46And I'll dive more into
• 37:48what that means.
• 37:49And then that has remained
• 37:50quite strong at freeze three.
• 37:52So we like to say
• 37:53that it took schizophrenia one
• 37:54hundred and fifty to find
• 37:55the pathway they felt confident
• 37:56in. And we got it
• 37:57in our top ten. So,
• 37:59so maybe this is saying
• 38:00something about decades of work
• 38:02on the hypothalamic pituitary acts
• 38:04as being involved in stress
• 38:05and PTSD.
• 38:06It's nice validation in that.
• 38:08This has worked, from your
• 38:10own Joel Gartner and and
• 38:11the Yale, and National Center
• 38:13for PTSD,
• 38:14along with Murray Stein and
• 38:15colleagues have really been leaders
• 38:16in this area as well.
• 38:18And the the largest freeze
• 38:19includes MVP, but before the
• 38:21freeze three, this was the
• 38:22MVP dataset,
• 38:23with their really nice, chromosomal
• 38:25plot of these genes. And
• 38:27while there's many exciting new
• 38:28pathways and again, I'm not
• 38:30gonna talk about a lot
• 38:31of them because we could
• 38:32go down those paths and
• 38:32we're they're all we're just
• 38:34starting to figure out what
• 38:35they are. And now trying
• 38:36to figure out how to
• 38:37triage them. There are several
• 38:38that are particularly relevant to
• 38:40things we already know in
• 38:41neuroscience.
• 38:42One is related to stress
• 38:43and HPA regulation,
• 38:44and I'll talk more about
• 38:45the CRH locus. And then
• 38:47lots related to glutamatergic
• 38:49plasticity and gabbroplasticity
• 38:50that we're starting to
• 38:55the the the the holy
• 38:56grail for us would be
• 38:57to find at least some
• 38:58set of genes that fits
• 38:59within some set of cells
• 39:00that is in a circuit
• 39:02we understand that is chained
• 39:03with trauma so that we
• 39:04could really pull the whole
• 39:05story together. And I'll try
• 39:06to say a little bit
• 39:07of that now. But to
• 39:08remind you,
• 39:10the CR HR1 locus, so
• 39:11CR HR1 is the is
• 39:13the main stimulatory
• 39:14GS coupled G protein receptor
• 39:17for corticotropin releasing hormone, which
• 39:19is released by the amygdala,
• 39:20by the bed nucleus, or
• 39:21the c atrial terminalis,
• 39:22by the hypothalamus. From the
• 39:24hypothalamus, it causes ACTH release
• 39:26from the, pituitary gland,
• 39:28causing the adrenals to release
• 39:30cortisol and epinephrine back to
• 39:32the sympathetic response I just
• 39:33showed you in PTSD.
• 39:36And cortisol response,
• 39:38it will be the theme
• 39:39of a lot of other
• 39:40things. We've understood that there's
• 39:41dysregulation of HPA
• 39:43in PTSD,
• 39:45since some of the very
• 39:46first biological work by Rachel
• 39:48Yehuda, Dennis Charney, Steve Southwick,
• 39:49and others in the early
• 39:51nineteen eighties at,
• 39:52Yale showing dysregulation of the
• 39:54HP access with PTSD and
• 39:56depression.
• 39:57But how do we triage
• 39:58this? So we've got genetic
• 40:00data, but that's obviously
• 40:01only correlation with one part
• 40:03of it. How do we
• 40:04pull that back to neuroscience?
• 40:07So the other area that
• 40:09of of really great progress,
• 40:11in the field,
• 40:12and is is neuroscience. And
• 40:14particularly, single cell sequencing and
• 40:16our and post mortem RNA
• 40:17sequencing.
• 40:18So, shout out to, Matthew
• 40:20Durgenti and, and John and
• 40:22many folks here as well
• 40:24who've been doing a lot
• 40:24with the,
• 40:26with the various national center
• 40:28post mortem datasets.
• 40:30And,
• 40:31just some data from Nikos
• 40:32Daskalakis and our group, and
• 40:34collaborators,
• 40:35from very recently, the large
• 40:37PsycINFO
• 40:37data sets,
• 40:39combine one of the largest
• 40:40data sets of postmortem,
• 40:42one hundred,
• 40:42PTSD brains, one hundred depression
• 40:44brains, one hundred control brains,
• 40:46with both whole brain, I
• 40:48mean, regional specific RNA seq,
• 40:49and then a subset of
• 40:51single cell sequencing.
• 40:52And this is a huge
• 40:53dataset. I'm not gonna go
• 40:54into all of that other
• 40:55than to say there's starting
• 40:56to be some intersection of
• 40:58large scale genetics with human
• 41:00brain biology
• 41:01with, neuroscience.
• 41:03And one example,
• 41:05is this is looking at
• 41:06RNA across multiple brain regions.
• 41:08Again, medial prefrontal cortex, hippocampus,
• 41:10and amygdala,
• 41:11and seeing differential expression of
• 41:13a number of different genes,
• 41:14and particularly inflammatory
• 41:15TNF, interleukin,
• 41:17and interferon pathways, along with
• 41:19stress pathways.
• 41:20And then single cell sequencing
• 41:22cluster analysis,
• 41:23in, different regions, including the
• 41:26DLPFC,
• 41:27in which we're also seeing,
• 41:28corticotropin releasing hormone receptor,
• 41:30differentially expressed. So again, back
• 41:32to the CRH one we
• 41:33see genetically.
• 41:34And, across, stress related disorders
• 41:36including depression, seeing f k
• 41:38b p five, which is
• 41:39a gene that regulates cortisol,
• 41:42glucocorticoid receptor activation. And I'll
• 41:43come back to that in
• 41:44a minute.
• 41:46And just to pull some
• 41:47of that together, Nikos' group
• 41:48showed,
• 41:49last year,
• 41:51in the in the American
• 41:51Journal that,
• 41:53RNase in a different set
• 41:55of brain data,
• 41:56RNA Seq, associated with increased
• 41:59CRH,
• 42:00and as well as FKBP
• 42:02five in cortex with PTSD
• 42:04and depression. And then they
• 42:05were able to recapitulate this
• 42:07in,
• 42:08IPS induced neurons.
• 42:10And that if you, with
• 42:11IPS induced neurons, activate those
• 42:13cells with cortisol, you get
• 42:15mixed overlap with quite a
• 42:16few of the genes, including
• 42:17interleukin genes, TNF genes, and
• 42:19cortisol related f k b
• 42:21p five
• 42:22in induced neurons activated by
• 42:24cortisol.
• 42:26Take home point, we're starting
• 42:27to be at least a
• 42:28subset of intersection between large
• 42:30scale genetics, target showing specific
• 42:33inflammatory and HPA genes with
• 42:35brain expression and PTSD
• 42:37of inflammatory and stress genes
• 42:39with induced neurons with cortisol
• 42:41and inflammatory and stress genes.
• 42:43So maybe that just means
• 42:44that anytime you get stressed,
• 42:46you get this set of
• 42:46things and it's not that
• 42:47interesting. Or maybe it means
• 42:49that at least in some
• 42:50of these pathways, we're onto
• 42:51something that's really robust across
• 42:53species and circuits.
• 42:56Just a a little bit
• 42:57of the historical data,
• 43:00validating or replicating some of
• 43:02the role of these pathways.
• 43:03So this is what c
• 43:04r CRH is also CRF
• 43:05in the literature historically.
• 43:07If you overexpress
• 43:08CRH in the rodent amygdala,
• 43:10you get
• 43:11significantly increased startle. So, again,
• 43:13startle is one of those
• 43:14core symptoms of PTSD,
• 43:16and one of the ways
• 43:17we can study the threat
• 43:18response across mammals.
• 43:20If you increase activation of
• 43:22the CRH pathway, in this
• 43:23case, it's physiologically
• 43:25by knocking down GABA receptors.
• 43:27So you're basically disinhibiting
• 43:28the CRH pathway.
• 43:30You get increased CORT, so
• 43:32you increase HPA axis. But
• 43:34critically, you get deficits and
• 43:36extinction. Animals learn to be
• 43:37afraid just fine with fear
• 43:39conditioning, but you then extinguish
• 43:40them and they stay afraid
• 43:42for long, again, another core
• 43:43deficit in PTSD.
• 43:46I'm not gonna go through
• 43:47all of these, but just
• 43:48to remind us that, FKBP
• 43:51five is a gene that,
• 43:52has been understood for a
• 43:53while to be critical to
• 43:54cortisol regulation. It's an intracellular,
• 43:58chaperone that binds the glucocorticoid
• 44:00receptor.
• 44:01And Isabel Bender and I
• 44:02showed,
• 44:03fifteen years ago that differential
• 44:05genetic versions appear to be
• 44:07associated
• 44:08with stress. In particular,
• 44:10childhood trauma as a risk
• 44:11factor for PTSD
• 44:13could be in part stratified
• 44:15by different genetic versions of
• 44:17FKBP5.
• 44:18And the,
• 44:19the genetic version of FKBP5
• 44:21associated with more PTSD
• 44:23was also associated with more
• 44:24amygdala activation,
• 44:25less hippocampal activation,
• 44:27more attentional bias for threat,
• 44:30more, differential epigenetics,
• 44:32and other markers of PTSD.
• 44:35And while this hasn't yet
• 44:37survived GWAS,
• 44:38it survived meta analysis of
• 44:40about twenty thousand samples. And
• 44:41we think part of the
• 44:42issue is that the biology
• 44:45for gene by environment interaction
• 44:47at GWASO still hasn't really
• 44:49been figured out statistically.
• 44:50And,
• 44:52the the term is you
• 44:53get too much, QQ plot
• 44:53or genetic inflation genomic inflation
• 44:53when you include
• 44:55the
• 44:57the environmental variable in g
• 44:58by e. So we don't
• 44:59really, I think, know how
• 44:59to
• 45:00best interrogate GWAS data yet
• 45:02at the level of gene
• 45:03by environment. So I would
• 45:04say the jury is still
• 45:05out whether FKBP five will
• 45:07survive or are skilled genetics
• 45:07or not.
• 45:13That said, there's
• 45:14dozens of studies showing that
• 45:16FKBP five modulation and,
• 45:18is all alters emotion responding
• 45:21threat and fear and anxiety
• 45:22related behaviors in mice.
• 45:25So I wanna leave you
• 45:26with this section with with
• 45:28my work with our working
• 45:29hypothesis
• 45:30for one way of understanding
• 45:32gene by environment mechanisms,
• 45:34related to amygdala and stress
• 45:36pathways.
• 45:37So So that we can
• 45:38think of the amygdala, back
• 45:39to Joe Ledoux's picture, as
• 45:41always sort of on online,
• 45:44being modulated when it can
• 45:45be by prefrontal cortex and
• 45:46hippocampus.
• 45:47But receiving preprocessed
• 45:49external sensory information
• 45:51rapidly, comparing that to its
• 45:52internal memory engrams, and making
• 45:54these rapid, pre conscious decisions
• 45:56about, do I fight, flight,
• 45:58or freeze?
• 46:00Or am I resilient, and
• 46:01do I ignore it?
• 46:03But we know
• 46:04that work by people like
• 46:06Regina Sullivan has shown that
• 46:07early developmental cortisol, early stress
• 46:10leads to a sensitized amygdala.
• 46:12We also know that genetic
• 46:14alteration modifications
• 46:16in the FKBP five in
• 46:18terms of leukaryoticoid
• 46:19receptor feedback
• 46:20and CRH receptors and, that
• 46:22really that are at the
• 46:23top of the HPA axis,
• 46:24both alter amygdala sensitization.
• 46:27And so I raise hypothesis
• 46:29is does early life stress
• 46:31leading to increased developmental cortisol
• 46:33in the combination of genetic
• 46:35risks in the HPA axis
• 46:36that make you more sensitive
• 46:37during development
• 46:39lead to a more sensitized
• 46:40amygdala and limbic system. So
• 46:42then later in development, when
• 46:43trauma occurs, are more likely
• 46:45to respond in a stress
• 46:46sensitive way. And we can
• 46:48then translate in that to
• 46:49human terms, childhood maltreatment, poverty,
• 46:51violence, exposure, experience, racism,
• 46:53combined with biological risk factors
• 46:56may be part of the
• 46:57story of gene by environment.
• 46:58So a long way to
• 46:59go, but I think a
• 46:59tractable hypothesis.
• 47:03Wanna deviate and talk about
• 47:04stress related aggression,
• 47:06the fight in fight or
• 47:07flight.
• 47:09Again,
• 47:10cycles of violence is one
• 47:11of the things we know
• 47:12exists, but we don't really
• 47:14know what to do about
• 47:14it.
• 47:16In our own Duke Grady
• 47:17trial project study about halfway
• 47:19through with about four thousand
• 47:20people,
• 47:22we found that,
• 47:23those who had active PTSD
• 47:26were more likely to report
• 47:27having,
• 47:29a history of of of
• 47:30violent related behavior
• 47:32and arrests
• 47:33or prisons for violence. So
• 47:34there's a high rates of
• 47:35arrest, a lot of which
• 47:36had to do with mental
• 47:37health or with structural racism.
• 47:39But if you separate that
• 47:40out, there's a comp component
• 47:41there.
• 47:44So it there's a general
• 47:46hypothesis in the field that
• 47:47we've sort of stayed away
• 47:48from, but we can't, I
• 47:49think, avoid
• 47:50that history of violence exposure,
• 47:52particularly in development,
• 47:54leads to PTSD and other
• 47:55trauma symptoms. And particularly in
• 47:57males, this can lead into
• 47:59a subset to dysregulated aggression,
• 48:01and that may be part
• 48:02of that cycle.
• 48:04So the question is, can
• 48:05we use preclinical models to
• 48:06understand this a little bit?
• 48:08And so Emily Newman,
• 48:10came to my lab being
• 48:11well known already from her
• 48:12graduate work in Klaus Michiek
• 48:13as one of the leaders
• 48:14in understanding how to study
• 48:16aggression in females. So it
• 48:17was very hard to get
• 48:18female mice to fight, and
• 48:19she figured out how to
• 48:20do it and has a
• 48:20whole very interesting
• 48:22literature on female aggression.
• 48:24But we also were very
• 48:25interested in,
• 48:26developmental components in adults about
• 48:28what how does stress and
• 48:30aggression interact.
• 48:31And so we were really
• 48:32serendipitously
• 48:33found this when we were
• 48:34looking at if we, use
• 48:35GCaMP. So calcium imaging to
• 48:37understand what's going on in
• 48:38the central amygdala CRF specific
• 48:40cells. So again, these are
• 48:41the CRF cells that are
• 48:42part of this whole pathway
• 48:43we've been talking about. And
• 48:45we were doing a bunch
• 48:45of things. And interestingly, they
• 48:47don't care a whole lot
• 48:47about fear per se. And
• 48:48this fits with,
• 48:50Larry Zweifel's work at University
• 48:52of Washington that showed
• 48:53that threat by itself is
• 48:55not that activating to the
• 48:57central amygdala neurons, but it
• 48:58seems to be mod more
• 48:59moderate labels of threat. And
• 49:01separately, we had shown they
• 49:02seem to care more about
• 49:02extinction of fear than they
• 49:03do, fear consolidation
• 49:05themselves. So there's something about
• 49:06this nuanced behavior that these
• 49:08are doing that's not just
• 49:09the threat response.
• 49:10Well, it turns out they're
• 49:11super sensitive to, stress related
• 49:14aggression.
• 49:15So if we measure calcium
• 49:16imaging and are measuring,
• 49:18the delta f signal of
• 49:19these, and we have mice,
• 49:21that are either,
• 49:24it's either either nothing at
• 49:26all, they just are quiet.
• 49:27If they're being attacked by
• 49:28an aggressive opponent, so it's
• 49:30a defensive bite, they don't
• 49:31care. But if they've previously
• 49:33been stressed and are acting
• 49:34in an offensive
• 49:35way to aggress the other
• 49:36animal, you get this huge
• 49:38calcium signal.
• 49:40And she showed that this
• 49:41calcium signal not only
• 49:43happens at the time of
• 49:44that, sort of stress related
• 49:46offensive aggression, it's actually predictive
• 49:48of it.
• 49:49And so she could show
• 49:50both the peak size,
• 49:52during the bout and predicting
• 49:54the bout, was predictive of
• 49:56aggression.
• 49:58And,
• 49:59so she did a bunch
• 50:01of studies. I don't have
• 50:01time. I'm just gonna show
• 50:02you really one,
• 50:04that asked not only does
• 50:05it correlate do these cells
• 50:06correlate with predicting offensive aggression,
• 50:09can you block activity of
• 50:10these cells and does that
• 50:11block the offensive stress related
• 50:13offensive aggression? So she used,
• 50:16CRH,
• 50:18CRE,
• 50:19with combined with a a
• 50:20a dread virus, a chemogenetic
• 50:22virus. In this case,
• 50:24inhibitory dread.
• 50:26And so the video on
• 50:27the left shows the so
• 50:29this is a within animal
• 50:30control. So the same mouse
• 50:32that got the inhibitory dread
• 50:33but is now getting saline,
• 50:37the, c fifty seven is
• 50:39attacking the other and this
• 50:40is all done with deep
• 50:40lab cut, and other digital
• 50:42phenotyping. But you can see,
• 50:44this is one example of
• 50:45many attacks.
• 50:47But if the same animal
• 50:48was now given the DCZ
• 50:49to activate the inhibitory dread
• 50:51only in these CRF neurons,
• 50:53it would come up. It
• 50:54would approach it just as
• 50:55much. It would sniff. It
• 50:56would do everything else.
• 51:00But it would it would
• 51:00just wander right. So it
• 51:02essentially looks like it transformed
• 51:03this aggression into just a
• 51:05so a a nonaggressive social
• 51:07interaction.
• 51:13So to quantify these data,
• 51:16that she showed that so
• 51:17in each of these, it's
• 51:18the same animal before and
• 51:20after DCZ,
• 51:22in the CRE animal versus
• 51:23in the control virus versus
• 51:24the CRE. It doesn't affect,
• 51:26general approach.
• 51:28It doesn't affect the initial
• 51:29contact,
• 51:30but it completely wipes out
• 51:32the switch from the contact
• 51:33to the attack.
• 51:34And, she's now shown,
• 51:36that if you do optogenetic
• 51:38immediate feedback, so you can
• 51:39essentially lab see these cells,
• 51:42and then give out the
• 51:42genetic inhibition
• 51:44right at the time that
• 51:45those cell activity would predict
• 51:47the aggression. They can very
• 51:48dynamically inhibit that response. And
• 51:50in the contrast, if you
• 51:51use an excitatory dread, they
• 51:53show
• 51:54unnatural aggressive behaviors. They fight
• 51:56a lot more and they
• 51:57even aggress,
• 51:58females.
• 51:59So it's it's, I think,
• 52:00a very interesting model.
• 52:03So in summary, it raises
• 52:05the question. It was CRH
• 52:06in the central amygdala particularly
• 52:08important for the fight and
• 52:09fight or flight.
• 52:10Separate set of questions. We
• 52:11and many others have data
• 52:12on CRH and the amygdala
• 52:14related to suicide,
• 52:15in post mortem brains. And
• 52:16there's a law on psychodynamic
• 52:18theory about suicidality being aggression
• 52:20turned inward. Don't know what
• 52:21to do with that, but
• 52:22it's something to think about.
• 52:25Alright. I'll spend my last
• 52:26maybe five minutes on,
• 52:28wrapping up with thinking about
• 52:29the extinction versus sensitization,
• 52:32dilemma. And if you already
• 52:34have trauma, you already have
• 52:35PTSD,
• 52:37what can we do about
• 52:38it?
• 52:39And wouldn't it be great
• 52:40if we could make extinction
• 52:41exposure work better, more efficiently,
• 52:43more robustly?
• 52:45So again, this is our
• 52:46clinical, desensitization
• 52:48or habituation curve. It maps
• 52:49under the Pavlovian definition of
• 52:51extinction of fear,
• 52:53And we know it's NMDA
• 52:54dependent, and I'll show you
• 52:55why. So some of the
• 52:56first data that it was
• 52:57NMDA dependent. So I talked
• 52:58early on about the amygdala
• 53:00during fear consolidation uses all
• 53:02these known plasticity mechanisms.
• 53:04Turns out, Mike Davis' group
• 53:05had shown that extinguishing fear,
• 53:07taking this already existing fear
• 53:08memory, and now extinguishing it
• 53:10requires new learning. Mark Bowden
• 53:12showed behaviorally that it was
• 53:13new learning,
• 53:14not not at the ratio
• 53:16of the original learning, and
• 53:17that new learning was a
• 53:18new inhibitory learning.
• 53:20Bill Falls, when he was
• 53:21with Mike Davis in the
• 53:22early nineties, showed that this
• 53:23was an NBA dependent. So
• 53:24they trained rats to be
• 53:25afraid. In this case, they
• 53:26had rats in a dark
• 53:27box, and every time they
• 53:28got a light, they got
• 53:29a foot shock. And then
• 53:30we're measuring the animal's fear
• 53:31with startle. So this is
• 53:33a lot of startle with
• 53:34when the lights were on.
• 53:35They then got sixty lights
• 53:37in the absence of any
• 53:37shocks. That's extinction or exposure
• 53:39therapy for the rats. They
• 53:40don't care about the lights
• 53:41anymore. And then if they
• 53:42did that same experiment with
• 53:44the extinction with AP five,
• 53:45one of the, known MDA
• 53:47antagonists,
• 53:48and then tested them again
• 53:49off of drug, they were
• 53:50just as afraid as they
• 53:51ever were. So it looked
• 53:52like you had to have
• 53:53active NMDA plasticity to enhance
• 53:55extinction. We now know that's
• 53:57also LTP dependent.
• 53:58A decade later,
• 54:00we showed that we could
• 54:01enhance this process by enhancing
• 54:02NMDA function. So d cycloserine
• 54:05is a known partial
• 54:07agonist of the NMDA receptor.
• 54:08It's expressed in the NMDA
• 54:09receptor, of course, is most
• 54:10densely expressed in the amygdala,
• 54:11hippocampus, and other areas involving
• 54:13learning and memory.
• 54:15If you partially, if you
• 54:16act agonize NMDA,
• 54:18at the time of giving,
• 54:20a partial extinction. So in
• 54:21this case, thirty lights, you
• 54:22could make the extinction work
• 54:24as well as if they
• 54:25had had full extinction by
• 54:26enhancing NMDA function at the
• 54:28time of exposure therapy.
• 54:30We used desicloserine
• 54:31because it was already It
• 54:32was FDA approved in humans.
• 54:33It had been used for
• 54:34tuberculosis.
• 54:35And with Barbara Rothbaum, a
• 54:36leader of exposure therapy
• 54:38in a full range of
• 54:39anxiety disorders,
• 54:41we first showed that you
• 54:42could enhance exposure therapy for
• 54:43fear of heights, in a
• 54:45virtual reality
• 54:46paradigm. And so we could
• 54:47make humans,
• 54:49have as much decrement in
• 54:50fear
• 54:51after only two exposure sessions
• 54:53as they normally would have
• 54:54after six or eight exposure
• 54:55therapy sessions by combining the
• 54:57exposure with the cycloserine in
• 54:59a double blind placebo controlled
• 55:00way. So humans like rats
• 55:02could have an improved extinction
• 55:04with the cycloserine.
• 55:06So this was really exciting
• 55:07for the field. It was
• 55:08before we had the ketamine
• 55:10miracle.
• 55:11And it was at a
• 55:12time,
• 55:13when there was possibility of
• 55:14an of combining
• 55:16drugs that could enhance learning
• 55:17with exposure therapy. And for
• 55:19a while, it looked really
• 55:20good. There were a couple
• 55:21of, studies on improving
• 55:23social anxiety exposure, improving OCD
• 55:25exposure,
• 55:26and even PTSD and panic.
• 55:29But,
• 55:30as with many things in
• 55:31the field, things that looked
• 55:32too too good to be
• 55:33true early on don't always
• 55:34hold up. And, larger meta
• 55:36analysis and larger studies started
• 55:38to not find a positive
• 55:39association. So what was going
• 55:41on? Did we was it
• 55:42all file drawer effect? Was
• 55:43it all,
• 55:45early,
• 55:46false positives?
• 55:47Was there or was it,
• 55:48the later drug wasn't sourced
• 55:50from the same place? Were
• 55:51we not doing the therapy
• 55:52the right way?
• 55:54The field kind of struggled
• 55:55with this for more than
• 55:56five years.
• 55:57One of the things that,
• 55:58was found from Adam Guastela's
• 56:00work in social anxiety
• 56:02was that people who got
• 56:03had good within session extinction
• 56:05and got desycloserine
• 56:07got much better. But if
• 56:09they did not have good
• 56:09within session extinction,
• 56:11they even got they got
• 56:12had no change or even
• 56:13got a little worse. So
• 56:14it said, is there something
• 56:16going on here about combining
• 56:17plasticity with learning? And about
• 56:19the same time, Barry Everett,
• 56:20a leader with,
• 56:23from the English groups in
• 56:24learning and memory with Trevor
• 56:25Robbins and others,
• 56:27did the specific study related
• 56:28to reconsolidation,
• 56:30which had been thought to
• 56:31be NMDA dependent and extinction.
• 56:33And they showed that d
• 56:34cycloserine
• 56:35could potentiate
• 56:36both of these learning processes.
• 56:38So DCS potentiated both the
• 56:40extinction and the reconsolidation
• 56:41of fear conditioning,
• 56:43depending on the length of
• 56:44the extinction memory reconsolidation
• 56:45session. So the take home
• 56:47message of this in a
• 56:48lot of other studies was
• 56:49the strength of the memory,
• 56:50whether you're activating
• 56:52the reconsolidation
• 56:53microcircuit or the extinction microcircuit
• 56:55could both be enhanced, but
• 56:57they would have the opposite
• 56:58behavioral effect. And maybe that's
• 56:59what was going on. So
• 57:01in the last few years,
• 57:01as people have tried to
• 57:02either combine DCS with drugs
• 57:05that would preferentially
• 57:06drive extinction,
• 57:07like perhaps hydrocortisone
• 57:09or doing it with differential
• 57:10timing, there's been more success.
• 57:12And partly, I'm saying this
• 57:13not because necessarily d cycloserine's
• 57:15gonna go anywhere at this
• 57:16point. But as we think
• 57:18about other drugs that enhance
• 57:19plasticity robustly,
• 57:21do we have something to
• 57:22learn from the story of
• 57:23d cycloserine?
• 57:24Ketamine, I think, for people
• 57:26is is, of course, everyone,
• 57:27I think, I'm sure here
• 57:28knows. At first, it's a,
• 57:30paradox. Ketamine's an antagonist in
• 57:32d cycloserine and agonists. What's
• 57:33going on, and why would
• 57:34an antagonist of NMDA receptors
• 57:36enhance plasticity?
• 57:38I think one of the
• 57:38learning theories from doctor Dumont,
• 57:40the late great doctor Dumont
• 57:41himself, and weasel Matej and
• 57:43others, was that ketamine may
• 57:44preferentially,
• 57:45as opposed to AP five,
• 57:46which blocks NMDA receptors potently
• 57:49everywhere, ketamine in certain doses
• 57:50may preferentially block NMDA receptors
• 57:52on inhibitory neurons compared to
• 57:54excitatory neurons. In the synaptic
• 57:57triad,
• 57:57then the right dose of
• 57:58ketamine,
• 57:59the sub sub anesthetic dissociative
• 58:02ketamine dose may lead to
• 58:04hyperactivity
• 58:05of the of the pyramidal
• 58:07neuron leading to an LTP,
• 58:09NMDA dependent LTP BDNF release
• 58:12through,
• 58:12preferential disinhibition
• 58:14of these cells.
• 58:15And people both here at
• 58:17Yale, Jerry, Sanacora, and many
• 58:18others in John's group, as
• 58:20well as Adrianna Feder and
• 58:21Dennis at,
• 58:23at Mount Sinai show that
• 58:24not only does ketamine help
• 58:25in rapid suicidality, rapid depression
• 58:28and PTSD symptoms, combining ketamine
• 58:30with exposure therapy may lead
• 58:32to a faster,
• 58:33enhancement of learning.
• 58:35But I would argue that
• 58:37we have to be careful
• 58:38because enhancing plasticity, whether it
• 58:40be through d cycloserine or
• 58:41ketamine at the NMDA level,
• 58:43BDNF or other prosthesogens, maybe
• 58:45psychedelics,
• 58:46we may be at risk
• 58:47for enhancing reconsolidation
• 58:49as much as we are
• 58:50extinction. We have to figure
• 58:51out how to target that.
• 58:52And I'll finish in one
• 58:53minute. I know I'm running
• 58:54a little bit late.
• 58:55Could we are these all
• 58:57the same circuits and is
• 58:57it hopeless?
• 58:59Or are these are there
• 59:00different microcircuits mediating reconsolidation extinction?
• 59:03And if we understood those,
• 59:04could we target them?
• 59:07Andreas Luthy's work, who's been
• 59:08a leader in the in
• 59:09the molecular circuitry of fear
• 59:11suggests that these are different
• 59:13circuits.
• 59:14So they this is a
• 59:15study from about a decade
• 59:17ago recording
• 59:18mouse neurons in the amygdala
• 59:20with fear conditioning and extinction.
• 59:21And the take home point
• 59:23is about fifty percent of
• 59:24the neurons
• 59:25respond to tone in a
• 59:26tone shock pairing.
• 59:27And about half of those,
• 59:28they called fear neurons. They
• 59:30don't care about the tone
• 59:31initially.
• 59:32After tone shock pairing, they
• 59:34fire with the tone. After
• 59:35extinction of fear, they stop
• 59:37firing. So these cells look
• 59:38like the behavior, and so
• 59:40the the
• 59:42the histogram bars are the
• 59:43behavior and the dots are
• 59:44the cell firing. They fire
• 59:46with when the animal is
• 59:47fearful, and they don't fire
• 59:49when they're not. But another
• 59:50set of cells they called
• 59:51extinction or fear off neurons
• 59:53don't care about the tone,
• 59:54don't care about the tone
• 59:55after fear conditioning, but then
• 59:57start firing once that tone
• 59:58has been extinguished. So it's
• 59:59a set of cells that
• 01:00:00seem to hold that extinction
• 01:00:01inhibitory memory. And it raises
• 01:00:03the question of, are these
• 01:00:04distinct cells and can we
• 01:00:05molecularly target them? And one
• 01:00:07of the exciting areas of
• 01:00:09the last decade has been
• 01:00:10really identifying a whole set
• 01:00:11of molecular markers of amygdala
• 01:00:13cells that we can now
• 01:00:13both see in mice and
• 01:00:14we're starting to identify in
• 01:00:15humans with single cell sequencing.
• 01:00:17And and can we target
• 01:00:19specific fear of neurons?
• 01:00:21And so one, example of
• 01:00:22this is
• 01:00:23a subset of the pyramidal
• 01:00:25neurons in the amygdala is
• 01:00:26marked by the thi one
• 01:00:27developmental gene. But it's not
• 01:00:28all the pyramidal neurons. It's
• 01:00:30only about thirty percent of
• 01:00:31the CaM kinase positive pyramidal
• 01:00:33neurons. And it turns out
• 01:00:34when you activate these optogenetically,
• 01:00:36you block the canonical flow
• 01:00:38through of the fear circuit
• 01:00:39from the lateral amygdala to
• 01:00:41the central amygdala.
• 01:00:42Interestingly, not only does it
• 01:00:43have that paradoxical
• 01:00:45behavior,
• 01:00:46they don't project to the
• 01:00:47central. The classic canonical pathway
• 01:00:49is that the excitatory neurons
• 01:00:50and the BLA project to
• 01:00:51the central and that's that
• 01:00:53fear reflex. These don't. They
• 01:00:54project preferentially to the ventral
• 01:00:56accumbens and to the intra
• 01:00:57limbic rather than the prelimic.
• 01:00:59So these are looking like
• 01:01:00a positively valent subset of
• 01:01:02cells.
• 01:01:03When you activate these cells
• 01:01:05optogenetically,
• 01:01:06instead of enhancing freezing, you
• 01:01:07get this robust decrement in
• 01:01:09fear. And it looks like
• 01:01:10you block fear consolidation.
• 01:01:12If you, and this works
• 01:01:14whether you do it optogenetically
• 01:01:15or chemogenetically,
• 01:01:16and if you inhibit them,
• 01:01:17you get the opposite effect.
• 01:01:18So if you inhibit so
• 01:01:19these are now putative
• 01:01:20fear off cells that we
• 01:01:22can activate. They look like
• 01:01:23fear inhibiting cells and extinction
• 01:01:25enhancing cells. If you inhibit
• 01:01:26them, you get the opposite.
• 01:01:28So Ken McCullough and our
• 01:01:29group then did RNA,
• 01:01:31trap to say, can we
• 01:01:32identify other molecular markers or
• 01:01:34targets in this fear of
• 01:01:36population?
• 01:01:37And there are many of
• 01:01:37them, but one really exciting
• 01:01:39one was the neurotensin receptor
• 01:01:40too.
• 01:01:41There was no behavioral data
• 01:01:43about this in the literature.
• 01:01:44We didn't know anything about
• 01:01:45the drug, but we hypothesized
• 01:01:46that because this is a
• 01:01:47cell, that's a GS coupled
• 01:01:49stimulatory receptor in fear off
• 01:01:51neurons, that if we got
• 01:01:52an agonist to activate the
• 01:01:54cell, we would descend we
• 01:01:55would decrease fear. And lo
• 01:01:56and behold, we've got one
• 01:01:57of the most robust fear
• 01:01:58blockade effects we'd seen. So
• 01:02:00it suggests that we're and
• 01:02:02and then finally,
• 01:02:03Azizia's lab, Keitai, in parallel
• 01:02:06with this had shown that
• 01:02:07neurotensin
• 01:02:07is mediating valence modulation in
• 01:02:09the amygdala.
• 01:02:10So it suggests that we're
• 01:02:11starting to get to the
• 01:02:12point in our understanding of
• 01:02:13molecular
• 01:02:14cell mechanisms that we can
• 01:02:15combine with rodent amygdala, human
• 01:02:17amygdala, RNAseq with genetics to
• 01:02:19really triage and prioritize
• 01:02:21gene pathways that may preferentially
• 01:02:23enhance or inhibit fear and
• 01:02:25may give us new targets.
• 01:02:27So with that, I will
• 01:02:28end with reminding you PTSD
• 01:02:31is not one thing. It
• 01:02:31is many things.
• 01:02:33Only about ten percent of
• 01:02:34people after trauma develop PTSD,
• 01:02:36and our understanding of genetics
• 01:02:37consolidation and multidetermine behaviors can
• 01:02:40help us put all these
• 01:02:41pieces together again. And we
• 01:02:42probably have to think about
• 01:02:43something different in early fear
• 01:02:45consolidation and risk than we
• 01:02:46do in what we do
• 01:02:47after the fear trauma has
• 01:02:48already been developed.
• 01:02:49Simplistically,
• 01:02:50the amygdala is being regulated
• 01:02:52by hippocampus and prefrontal cortex.
• 01:02:53The brakes have fallen off
• 01:02:54in PTSD.
• 01:02:56Our current treatments
• 01:02:57to retrain the brain, if
• 01:02:58you will, but they don't
• 01:02:59do it very well. Our
• 01:03:00current medications
• 01:03:02don't work very well at
• 01:03:02all, but they help decrease
• 01:03:03symptoms. Our futures may really
• 01:03:05target these therapies. And there's
• 01:03:07a whole host of tractable
• 01:03:09ways to potentially target this
• 01:03:11with the idea that precision
• 01:03:12medicine approach to trauma and
• 01:03:14psychiatric disorders may be tractable
• 01:03:15and feasible if we continue
• 01:03:17to understand neurogenetics
• 01:03:18and circuits. So with that,
• 01:03:19thanks so much for your
• 01:03:20attention, and look forward to
• 01:03:22discussion and questions.