By Omar Kassem, Spring 2021.
Brain development and maturation are modulated by an interaction between environmental conditions and genes. Early childhood is a critical period of brain development, which renders it highly vulnerable to disorganizing environmental influences. Sustained or adverse early-life stress (ELS), such as childhood trauma or caregiver deprivation, affects neuron and network development in specific brain regions causing long-term structural and functional changes in the brain. Brain regions involved in emotional processing, such as the amygdala, cognitive regions such as the hippocampus and prefrontal cortex, as well as networks involved in social behaviors seem to be particularly vulnerable to the impact of stress. ELS-induced long-lasting changes in these regions increase susceptibility to emotional disorders and psychiatric illnesses, which indeed has been reported in many human studies.
Understanding the biological changes that early childhood adversity can cause in the brain is essential to intervene and reverse some of those long-lasting effects. It is also important to note that the brain is so complex, and the effects of ELS are diverse and profound. Thus, many studies were conducted on animal models to understand the different biological effects of ELS on brain networks, neurons’ properties, and genome. Understanding the neural underpinnings of the relationship between ELS and the mental health of the victims is of great value in the pursuit of possible treatments and intervention. Moreover, better understanding of caregiver-related stress effects on child development provides a lot of useful insights for improving orphanage systems.
The long-term effects of ELS stem from the fact that developmental processes that organize circuits and connectivity patterns are still occurring throughout childhood. Therefore, unlike the effects of stress on adult cognitive functions that are reversible, ELS can often permanently impact these processes and systems, yet behavioral and pharmacological interventions can still be effective. In humans, the development of the hippocampus and limbic circuit, involved in cognitive and emotional functions, takes place largely after birth and continues for years into adolescence. An epidemiological study conducted on post-institutionalized adolescents showed that chronic early life stress, being raised in orphanages, is associated with a reduced volume of prefrontal cortex and hippocampus. Remarkably, this study was conducted on adolescents years after exposure but the impact of ELS was still significant. Further studies in mice showed that ELS can interfere with connections that form between neurons to form networks, which causes cognitive deficits that could persist into adulthood.
Similarly, ELS, in the form of caregiver deprivation, has been shown to affect the development of the amygdala, which is highly involved in emotion processing and learning. One key study did an fMRI scan of brain activity of children adopted from orphanages in a behavioral paradigm where they were anticipating an aversive stimulus. In this paradigm children were instructed to “go” to a neutral cue, and “not go” to a rare threat cue. ELS-exposed preadolescents were more wary and took longer to approach a neutral cue when anticipating a potential threat, indicating that the disorganized care of the orphanage experience can alter emotional and behavioral regulation. FMRI data showed that only activity in the amygdala differentiated the ELS-exposed children from the control group when anticipating an aversive stimulus. These findings help explain the epidemiological association between the institutional rearing of children and psychiatric disorders. Moreover, they gesture towards the importance of providing stable caregiver interaction, in orphanages and families, to preserve children’s mental and neurological wellbeing.
Many studies have attempted to understand the neuron-level impacts of ELS that cause the observed brain activity changes and behavioral patterns. The two main influences are changes in the electrical properties and myelination of neurons, myelin being the fatty layer that surrounds and insulates neurons. One study used adolescent social isolation of rats to investigate the electrical properties of a specific type of neurons in the amygdala. This study revealed that the stressed group showed a significant increase in neuron excitability, meaning that neurons were more easily and frequently firing, in comparison to control rats. This effect was mediated by a decrease in SK potassium channel activity. Using drugs to enhance SK channel activity and normalize neuron excitability reduces anxiety-related behaviors, which provides insights for potential therapeutic drugs that could elevate symptoms.
Another study attempted to investigate the effect of altered brain activity during early development, and how that could induce long-term changes similar to those observed in children that face early childhood adversity. This study showed that using drugs to decrease the activity of the prefrontal cortex of mice during development reproduces the cellular and behavioral defects induced by repeated ELS: increased behaviors associated with anxiety and depression, a persistent decrease in neuronal activity, and early differentiation of oligodendrocyte precursors (OPCs), cells that will be responsible for producing the myelin surrounding neurons. Conversely, restoring normal neuronal activity in the prefrontal cortex in mice undergoing early maternal separation leads to the disappearance of short-term memory deficits, depressive behaviors, and oligodendrocyte development. However, behavioral disorders associated with anxiety persisted. The same study revealed that ELS is associated with changes in myelination and oligodendrocyte maturation. ELS induces premature maturation of oligodendrocytes. Additionally, early maturation of OPCs has been reported in young adults who were sexually assaulted in childhood. These results suggest that early emotional adversity could lead to expedited maturation in brain regions associated with emotion processing, which comes with a short-term advantage, processing the immediate emotional disturbances, and a long-term deficit. The decrease in OPCs could lead to a decrease in quantity and plasticity of myelination later in life. This falls in line with human studies associating institutionalized rearing with a decline in white matter volume, which is related to the volume of the fatty myelin layer surrounding axons. These studies provide evidence for accelerated maturation of emotion circuitry following ELS. Whether these changes come at the cost of lagged development of other systems is still unknown, and is of great importance for improving the lives of individuals with histories of ELS.
The study of epigenetic changes in neurons has provided substantial insight into the biological impacts of ELS in the brain. Epigenetics refers to the regulation of gene expression without altering the genetic code itself. Epigenetic modifications involve adding a chemical modification to the DNA or histone proteins, which the DNA is wrapped around, to change its chemical properties and 3D shape in the cell. By making the DNA more tightly or loosely packed, epigenetic machinery can regulate the accessibility of the genome, thus regulating the expression of genes. These modifications are added by a writer protein and removed by an eraser.
One key study found that early-life stress in mice induces epigenetic changes in a particular type of neuron in the depression-associated region nucleus accumbens, making mice more vulnerable to stress later in life. They then showed that increasing modification levels on the DNA is sufficient to induce depression-like behaviors in mice, in other words inducing an ELS-like phenotype. Conversely, decreasing the modification levels reversed the depression-like behaviors in response to stress. These results demonstrate the deficits associated with ELS on an epigenetic level and suggest that therapeutic intervention that normalizes DNA epigenetic modification could be a promising treatment. The same study tested the effect of using a drug that inhibits the enzyme responsible for this modification, to interfere with ELS disruptions. Treated mice indeed showed reduced modification levels in their genome and improved behavioral performance.Many epigenetic studies have revealed that some epigenetic modifications could be heritable, potentially making future generations more vulnerable to disruptions that parents experienced. The question of whether epigenetic changes that happen in response to early life adversity could be inherited is another interesting perspective that could have implications for parents with a history of ELS.
Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10: 434–445.
Chen, Y. & Baram, T. Z. Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks. Neuropsychopharmacology 41, 197–206 (2016).
Malter Cohen M, Jing D, Yang RR, Tottenham N, Lee FS, Casey BJ (2013). Early-life stress has persistent effects on amygdala function and development in mice and humans. Proc Natl Acad Sci USA 110: 18274–18278.
Sandi C, Haller J (2015). Stress and the social brain: behavioural effects and neurobiological mechanisms. Nat Rev Neurosci 16: 290–304
Kim JJ, Diamond DM (2002). The stressed hippocampus, synaptic plasticity and lost memories. Nat Rev Neurosci 3: 453–462.
Joëls M, Baram TZ (2009). The neuro-symphony of stress. Nat Rev Neurosci 10: 459–466.
Brown AS, Susser ES, Lin SP, Neugebauer R, Gorman JM (1995). Increased risk of affective disorders in males after second trimester prenatal exposure to the Dutch hunger winter of 1944-45. Br J Psychiatry 166: 601–606
Bremner JD, Southwick SM, Johnson DR, Yehuda R, Charney DS (1993). Childhood physical abuse and combat-related posttraumatic stress disorder in Vietnam veterans. Am J Psychiatry 150: 235–239
Chen, Y. & Baram, T. Z. Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks. Neuropsychopharmacology 41, 197–206 (2016)
Lewis, C. R. & Olive, M. F. Early life stress interactions with the epigenome: potential mechanisms driving vulnerability towards psychiatric illness. Behav Pharmacol 25, 341–351 (2014).
Early life stress and brain function: Activity and connectivity associated with processing emotion and reward. NeuroImage 209, 116493 (2020).
Kronman, H. et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nat Neurosci (2021) doi:10.1038/s41593-021-00814-8.
Brunson KL, Chen Y, Avishai-Eliner S, Baram TZ (2003). Stress and the developing hippocampus: a double-edged sword? Mol Neurobiol 27: 121–136
Ivy AS, Rex CS, Chen Y, Dubé C, Maras PM, Grigoriadis DE et al (2010). Hippocampal dysfunction and cognitive impairments provoked by chronic earlylife stress involve excessive activation of CRH receptors. J Neurosci 30: 13005–13015.
Shonkoff JP (2011). Protecting brains, not simply stimulating minds. Science 333:982–983.
Hodel AS, Hunt RH, Cowell RA, Van Den Heuvel SE, Gunnar MR, Thomas KM (2015). Duration of early adversity and structural brain development in postinstitutionalized adolescents. Neuroimage 105: 112–119.
Wang, X.-D. et al. Forebrain CRF₁ modulates early-life stress-programmed cognitive deficits. J Neurosci 31, 13625–13634 (2011).
Brunson KL, Kramár E, Lin B, Chen Y, Colgin LL, Yanagihara TK, Lynch G, Baram TZ et al (2005). Mechanisms of late-onset cognitive decline after early-life stress. J Neurosci 25: 9328–9338.
Nemeroff, C. & Dunlop, B. 688. The CRH-1 Receptor Antagonist Saga in Mood and Anxiety Disorders: The Good, the Bad and the Ugly. Biological Psychiatry 81, S279 (2017).
Kumar, A., Rinwa, P., Kaur, G. & Machawal, L. Stress: Neurobiology, consequences and management. J Pharm Bioallied Sci 5, 91–97 (2013).
Fareri, D. S. & Tottenham, N. Effects of early life stress on amygdala and striatal development. Dev Cogn Neurosci 19, 233–247 (2016).
Cohen, M. M. et al. Early-life stress has persistent effects on amygdala function and development in mice and humans. PNAS 110, 18274–18278 (2013).
Ellis, B.H., Fisher, P.A., Zaharie, S., 2004. Predictors of disruptive behavior, developmental delays anxiety, and affective symptomatology among institutionally reared romanian children. J. Am. Acad. Child Adolesc. Psychiatry43, 1283–1292
Zeanah, C.H., Egger, H.L., Smyke, A.T., Nelson, C.A., Fox, N.A., Marshall, P.J., 2009.Institutional rearing and psychiatric disorders in romanian preschool children.Am. J. Psychiatry 166, 777–785.
Teissier, A. et al. Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms. Molecular Psychiatry 25, 1159–1174 (2020).
Rau, A. R., Chappell, A. M., Butler, T. R., Ariwodola, O. J. & Weiner, J. L. Increased Basolateral Amygdala Pyramidal Cell Excitability May Contribute to the Anxiogenic Phenotype Induced by Chronic Early-Life Stress. J Neurosci 35, 9730–9740 (2015).
Teissier, A. & Gaspar, P. Comment le stress précoce altère le comportement à l’âge adulte. Med Sci (Paris) 36, 218–221 (2020).
Teissier, A. et al. Early-life stress impairs postnatal oligodendrogenesis and adult emotional behaviour through activity-dependent mechanisms. Molecular Psychiatry 25, 1159–1174 (2020).
Nelson, C. A. Hazards to Early Development: The Biological Embedding of Early Life Adversity. Neuron 96, 262–266 (2017).
Tanti, A. et al. Child abuse associates with an imbalance of oligodendrocyte-lineage cells in ventromedial prefrontal white matter. Mol Psychiatry 23, 2018–2028 (2018).
Kronman, H. et al. Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nature Neuroscience 1–10 (2021) doi:10.1038/s41593-021-00814-8.