SOME THOUGHTS ABOUT INTERGENERATIONAL TRAUMA, EPIGENETICS, AND RESILIENCE
Rachel Yehuda, Ph.D.
Coverage
of epigenetic intergenerational trauma data is often sensationalized
Biological changes after trauma can aid in coping with challenges rather than compounding their effects
Intergenerational Trauma
The idea that the effects of extreme stress can be “passed” on to future generations.
Intergenerational trauma helps explain exaggerated responses to adversity
Current Trauma Effects
Earlier Trauma Effects
Parental Trauma
Effects
Ancestral Trauma Effects
The fact of intergenerational trauma creates a mandate to promote healing and resilience
But the biological findings don’t always support the idea of compounded adversity.
In some cases, they suggests that we develop protective mechanisms , or ones that help us adapt.
The Intergenerational Paradox
Parental or ancestral trauma may heighten vulnerability, but the epigenetic adaptations may simultaneously facilitate coping mechanisms.
Trauma increases susceptibility for psychological distress, but also produces adaptations that help us cope with them.
Some biological alterations reflect mobilization of healing mechanisms
Cortisol
Cortisol Levels in Combat Veterans and Holocaust Survivors were similar
But these two groups differed in a significantly important way.
Specialized
Treatment Program for Holocaust Survivors
Established in 1993 at the Icahn School of Medicine at Mount Sinai
% Prevalence
Holocaust offspring had more mental health diagnoses
X2=18.11, p<.001
Yehuda et al. J. Psychiatric Research, 35:2261, 2001
Glucocorticoid receptors are proteins to which cortisol binds to exert its effects
Glucocorticoid Receptors are more sensitive in PTSD
Evidence for greater sensitivity of these receptors:
1) Larger number of glucocorticoid receptors in PTSD
2) Lower cortisol levels following synthetic glucocorticoid administration
3) Altered circadian rhythm of cortisol and other hormones
4) Greater immune response in blood to glucocorticoid administration in vitro
5) Greater brain glucose response to glucocorticoid injections with FDG – PET
6) Greater sensitivity of induced neurons (reprogrammed from stem cells) to glucocorticoid administration.
Why is it important:
Because this has major implications for how the body might respond to stress
Cortisol regulates its own production through Negative Feedback Inhibition
Yehuda, N Engl J Med 2002;346:108-114
In PTSD, there is an enhanced negative feedback inhibition. This biology allows earlier detection threat and quicker and more efficient responses, but perhaps at a cost…
If Glucocorticoid Receptors are more responsive, here’s what might happen during “Fight or Flight”
Amygdala signals brain to activate SNS and HPA axis to release adrenaline and cortisol.
Cortisol inhibits its own release via negative feedback and inhibits the SNS.
Cortisol
If Glucocorticoid Receptors are more responsive, here’s what might happen during “Fight or Flight”
Amygdala signals brain to activate SNS and HPA axis to release adrenaline and cortisol.
Cortisol inhibits its own release via negative feedback and inhibits the SNS.
Cortisol
Adrenaline Hyperarousal Hypervigilance Overconsolidation of memory
Intrusive memories Avoidance Distress
Lower cortisol levels associate with PTSD risk factors like prior trauma
What is the mechanism for how experience resets glucocorticoid receptor?
Epigenetics is the science of how genes are regulated
Increased methylation generally impedes RNA transcription, whereas less methylation enhances gene expression.
Epigenetic marks function as switches to attenuate or amplify gene expression. Some epigenetic changes are ‘heritable’.
Cytosine Methylation of DNA
CH3
Epigenetic changes are both heritable and enduring
Epigenetic marks are heritable because they survive cell division.
They are enduring because they require special enzymes for their removal.
Epigenetics provides a fascinating insight into how environmental factors leave lasting imprints on our DNA
Daughter cells are identical to parent cell.
Much like epigenetic marks survive cell division, trauma survivors carry within them the enduring imprints of the past Epigenetics provides a mechanism for understanding how the past shapes our present and future.
“I’m not the same person I used to be” or “I don’t live in the past, the past lives in me”
Epigenetic changes on the GR might calibrate the feedback loop.
Methylation
Gene Expression
Cortisol
.59; df=35;p=.003
partial r = -.52; ;p=.002
Variations in maternal care were underpinned by epigenetic change in offspring brain
M Meaney
Maternal PTSD may confer additional in utero effects
Women pregnant on 9/11 with PTSD had lower cortisol levels and so did their 7 month old infants.
PTSD-(n=46) PTSD+(n=52) Yehuda et al., J Clin Endocrinol Metab. Jul;90(7):4115-8,
There was a significant effect of trimester on infant cortisol levels
First Second Third PTSDPTSD+
(F=10.56, df=1,8, p=0.012),
Yehuda et al., J Clin Endocrinol Metab. Jul;90(7):4115-8, 2005.
J Seckl
During pregnancy, an enzyme expressed in the placenta helps protect the fetus from overexposure to excessive maternal glucocorticoids
Enzyme metabolizes cortisol into inactive cortisone.
Enzyme is more active in first two trimesters; this protects fetal brain from neurotoxic effects.
Much less active in 3rd trimester to help promote lung development.
Considering maternal behavior and in utero affects, do trauma exposures in father shape offspring biology?
A Lehrner
Maternal and Paternal PTSD associate differently with cortisol and glucocorticoid receptor sensitivity
(F1,86=5.98, p=.016)
Maternal PTSD
Maternal and Paternal PTSD associate differently with methylation of the glucocorticoid receptor promotor
PTSD
F1,87=6.0, p=.016, interaction
Maternal
Male pass stress-related changes to male offspring via sperm
•Published: 01 December 2013
B.Dias
K Ressler
Epigenetic change can survive cell division in meiosis
Meiosis produces reproductive cells (gametes) with half the number of chromosomes as the parent.
Meiosis occurs at different times for males and females
Females: Meiosis begins in fetal development. Females are born with primary oocytes, that are arrested at prophase 1 until puberty. Oogenesis occurs during ovulation.
Males: Meiosis begins at puberty –spermatogenesis occurs throughout reproductive life. This might offer a window into understanding sex differences and developmental windows.
Studying Holocaust parents and their own children
FKBP5 – previously identified as one of 23 differentially expressed genes
FKBP5 is a regulator of the GR
EB Binder
Early experience programs the FKBP5 gene
There was a methylation effect in the same location on a specific region of the FKBP5 gene in Holocaust survivors and their own children
Holocaust survivors Holocaust offspring Not genotype dependent
There was a significant positive correlation between methylation in Holocaust survivors and their children
Anxiety disorders were less common in offspring of mothers exposed in childhood
NoCurrentAnxietyDisorder
YesCurrentAnxietyDisorder
Control
Effects of
maternal childhood exposure may
confer some adaptive advantages of offspring. Bierer et al., Am J Psychiatry , 2020.
Holocaust offspring also showed changes 11--HSD, but only if their mothers were younger than 12 when exposed
Bierer et al., Psychoneuroendocrinology 48:1-10, 2014
LM Bierer
Effects in offspring are opposite of parents
Holocaust Control Holocaust Survivors Holocaust Offspring
Yehuda, Bierer et al, J Psychiatric Res. 43(9): 877,2009
Bierer et al., Psychoneuroendocrinology 48:1-10, 2014
‘In utero’ programming of cortisol metabolism from Holocaust survivors
to children
Just as young mothers mounted a biological adaptation to starvation, the fetus accommodates in utero to conditions of high cortisol.
OFFSPRING ARE NOT ALWAYS PASSIVE RECIPIENTS OF MATERNAL TRAUMA EFFECTS They are adapting.
Epigenetic ‘inheritance’ is not the story of how trauma results in permanent generational damage
• How parental experiences can prepare offspring for challenges similar to those that parents have encountered.
• Offspring can dynamically respond to parental effects allowing future change.
• Environmental change can further alter stress-related epigenetic change.
• Epigenetic intergenerational effects reflect the ability of the offspring to adapt.
The alternative: not being able to adapt.
Stress-related epigenetic changes may change further following successful treatment in PTSD
The drug probably did not directly reverse the epigenetic alterations.
The experience of therapy created an environment where change could occur.
Psychedelic-assisted psychotherapy
• Using a psychedelic to induce a non-ordinary state that is conducive to reflecting, instead of avoiding, negative affect or material
• The non-ordinary state promotes curiosity introspection, selfcompassion, and insight – it is a catalyst.
• Ancestral presence can often be part of a medication session.
Mice were “treated” with a fear extinction paradigm – think “exposure for rodents” –and no longer feared cherry blossoms. Offspring were not more sensitive and did not show epigenetic alterations.
Resilience is the ability to respond and adapt in the face of adversity
• It’s not the opposite of psychopathology.
• It’s not about bouncing back.
• It’s about change and transformation.
Kintsugi: healing and growth can come from adversity, transforming what was once broken into something uniquely beautiful and valuable.
The fact that we can transform to meet environmental challenge is the superpower. That is resilience.
Resilience: the elephant in the room
• Often, its our environments that are broken, not our biology, and we have to continue to survive the threats of that environment.
• Many continue to live in environments that reinforce the biology of trauma.
– It’s hard to turn of hypervigilance if it is still necessary because of how you live now.
As clinicians we need to distinguish between someone who is traumatized by the past and someone who is living in an ongoing environment of threat and stress.
Back to Joseph
Linda M. Bierer
Amy Lehrner
Heather Bader
Nikos Daskalakis
Janine Flory
Iouri Makotkine
Michael Meaney
Jonathan Seckl
Elizabeth Binder
Routing Yang
Rasha Hammamieh
Charles Marmar
Kristen Brennand
Carina Seah
Joseph Buxbaum