Reported early life stress is associated with increased risk for mood disorders and suicidal behavior.
Early life stress is thought to reorganize the developing brain and behavior of children, sometimes with adverse consequences for stress response.
Many types of stress can occur early in life. One set of stressors are beyond parental control, including malnutrition, natural disasters, and death or separation from family members. A second set of early stressors, which are perhaps more potent, include poor parental care, such as deprivation or neglect;4 and physical or sexual abuse, often by someone other than a parent.3 Abuse or neglect early in life is reported to reprogram individual behavioral and physiological stress adaptation in humans4–7 and animal models.8–12
We review what is known about how stressful early life experiences may increase an individual’s risk for committing suicide, and consider how early adversity may reprogram an individual’s response to stress, thereby increasing the risk for negative outcomes.
Early Trauma and Stress Programming
Stress response encompasses the behavioral and physiological processes that should maintain homeostasis in response to environmental challenges.13 Behavioral response to stress tends to be stable in adults and can include activation (impulsive or action-orientated) to inhibited (anxious, depressed or despairing) coping styles.14,15 The physiological stress pathway includes the coordination of the autonomic nervous system, which provides a fast response to the stressor, increasing heart rate and decreasing metabolism, and stimulating epinephrine release from the adrenal medulla with the hypothalamic pituitary adrenal medulla (HPAm) axis.16,17 Excitatory inputs from the medial prefrontal cortex (PFC)18 and brainstem nuclei19,20 and inhibitory inputs from the ventromedial PFC18 via the hippocampus and amygdala, stimulate release of corticotropin-releasing hormone (CRH) from the hypothalamus.16 That in turn stimulates the pituitary to secrete adrenocorticotropin, which in turn causes release of cortisol from the adrenal cortex (HPAc) in response to stress or to maintain metabolic homeostasis. Cortisol feeds back on the hypothalamus, pituitary, hippocampus, amygdala, and mPFC to inhibit the HPAc axis.16
Early adversity has been linked with enduring alterations in behavioral and physiological regulation in response to stress. Poor maternal care in particular has been linked to behavioral dysregulation during stress (either enhanced emotionality or greater inhibition) in human infants.5,6,21,22 This has been demonstrated in children reared by adoptive (ie, not biologically related) parents,6 suggesting that the environmental component of early adversity is potent in its effects. In rats, higher rates of good quality care (maternal arch-backed nursing, licking and grooming) lead to decreased startle response to novelty and increased open-field exploration (indicating adaptability to a stressor) in biologically (BIO) reared and cross-fostered (FOSTER) infant rats.8,9
Similar results have been demonstrated in nonhuman primates. Macaque juveniles with high scores on the Relationship Quality Index in infancy (indicating amicable mother-infant interactions) appear to cope better with later maternal separation and novel group formation.10 Juveniles reared with less protective mothers are more likely to engage in risky behavior.11,12
The infant hypothalamic-pituitary-axis (HPA) is also sensitive to maternal behavior, such that poorer care has been linked with both higher cortisol responses to stress6,7 and a flattened diurnal rhythm of cortisol due to higher trough secretion levels in humans.23 Similarly, rat offspring that receive poor quality maternal care exhibit reduced sensitivity to glucocorticoid feedback contributed to by low glucocorticoid receptor (GR) expression in the hippocampus, and resulting in enhanced HPA response to physical stressors.8,9
This work has been confirmed and extended using a maternal deprivation paradigm in rats. Maternal deprivation in infant rodents results in reduced GR gene expression; this contributes to excessive corticosterone release in adulthood when stressed, and greater mineralocorticoid receptor gene expression resulting in lower resting corticosterone levels.24
Early Trauma and Suicidal Behavior
Childhood adversity has been associated with psychiatric disorders or psychopathology linked with risk for suicide such as major depressive disorder25 and impulsivity.2,3 If stress reprogramming plays a role in the effects of early adversity on risk for depression, impulsivity/aggression, and suicidal behavior, we would expect that these outcomes would be associated with stress response dysregulation in such clinical populations. In fact, this has been repeatedly demonstrated.
Major depressive disorder (MDD) is characterized by abnormal behavioral and physiological responses to stress. Severe MDD has been associated with enlarged adrenal glands, hypersecretion of cortisol, dexamethasone suppression resistance (indicating that the HPA feedback loop may be disrupted), and elevated levels of CRH.25 Dexamethasone resistance and cortisol hypersecretion have also been linked with suicide,26,27 and higher rate of relapse of major depression, which puts depressed individuals at increased risk for suicide.
Impulsivity, a proposed psychological risk factor for suicide, has also been linked with abnormal response to stress.27 When impulsive individuals are stressed, they are more likely to consume alcohol27,28 or other drugs.29 This may reflect greater use of avoidant stress coping strategies.30 Impulsive individuals show lower HPA activity as measured by resting levels of salivary cortisol31 and plasma cortisol.32 Thus, impulsive individuals, who are at greater risk for suicidal behavior, have some evidence of dysregulated behavioral and physiological stress responses.
There is some evidence that suicidal individuals have difficulty regulating stress response, but more investigation in this area is required. Adolescents with proactive stress coping skills have a lower risk of suicidal ideation and suicide attempts.33 Higher plasma cortisol has been observed in suicidal patients.26,27,34 Intriguingly, inhaled corticosteroid use prescribed for rhinitis has been associated with lower suicide rates, suggesting that corticosteroids may inhibit suicidal impulses potentially by suppressing neuro-inflammatory processes, although more research is required.35
Posttraumatic stress disorder (PTSD) is associated with greater risk of suicidal behavior and is characterized by abnormal HPA function involving GR over-expression and low levels of cortisol indicating an upregulation of the feedback inhibition by higher levels of cortisol.27 PTSD may be due to adult onset trauma or childhood trauma, but in either case, there is a recalibration of the HPA axis stress response system. Whether stress dysregulation linked with suicide combines with a pre-existing abnormal response and an early stress, resulting in impulsivity or major depression, or is a direct consequence of early stress and becomes a predictor of suicidal behavior in at-risk individuals, is not yet known.
Some of the relationship between early trauma, stress adaptation, and suicidal behavior may arise from epigenetic processes. In a rat model of early stress, one group has demonstrated that hippocampal GRs are associated with behavioral and physiological stress reactivity changes in adulthood, and adulthood GR expression is lower in infants that experience poorer maternal care.9
Researchers have recently confirmed that expression of GRs is lower in suicide victims who reported childhood abuse, compared with no-abuse suicides and controls.36 Intriguingly, an identical mechanism has recently been demonstrated in both rats and humans: greater methylation within a specific CpG island in the GR promoter region in hippocampal DNA occurs following early life stress in rodents that in turn inhibits GR expression.36,37
Early Stress, Suicide, and Serotonin
Although the role of epigenetic mechanisms in the link between early stress and suicide remains to be more fully elucidated, the mechanisms of translation between early adversity and adult psychopathology likely include interactions among multiple neural pathways. Identifying the molecular pathways that may mediate the risk conferred by early life stress will help identify potential targets for intervention and treatment of at-risk individuals. In addition to the best-studied stress response system, the HPA axis, other stress responsive systems include monoamine neurotransmitter systems, including the serotonin (5-HT) system, and the noradrenergic system, including the sympathetic nervous system. Since multiple interactions have been demonstrated between the HPA and serotonin systems, we might expect the serotonin system to also play a prominent role in the effects of early life stress on subsequent suicide risk.
For example, bidirectional connections exist between serotonergic neurons of the raphe nuclei and the CRH containing neurons,38 a major center for HPA regulation, and drugs that cause serotonin release or raise intra-synaptic levels, result in HPA activation by adrenocorticotropic hormone and cortisol release.39
Serotonin system abnormalities have been linked with both recurrent major depression40 and aggression/impulsivity.41,42 Serotonin transporter 5-HTT, in particular, may modulate the association between early trauma and psychiatric outcomes.43,44 5-HTT regulates reuptake of 5-HT from the synaptic cleft, and is the target of the most commonly prescribed antidepressants, selective serotonin reuptake inhibitors (SSRIs).
There is evidence that 5-HTT expression plays a role in the effect of early adversity on risk for stress-related major depression in adulthood. Environmental challenges early in life disrupt the expression and/or function of 5-HTT. Rats experiencing maternal or nutritional deprivation exhibit lower 5-HTT protein in the raphe nuclei, the location of all serotonergic neuron cell bodies.45 Human adults with major depression who report physical or sexual abuse in childhood, and adolescent rhesus macaques that experienced early maternal deprivation or nursery rearing, exhibit decreased 5-HTT binding as indexed by positron emission tomography in limbic brain regions in adulthood.44,46
Maternally deprived, or “nursery-reared” infants, as well as infants who experience aggression from their mothers, are unable to upregulate peripheral 5-HTT in response to stress-ors at 3 to 4 months of age.47 Correspondingly, lower post-stressor 5-HTT expression predicts emotion dysregulation in infant rhesus macaques, just as lower 5-HTT expression or binding are linked with human psychopathology (MDD,44 and impulsivity).42
Serotonin function in specific brain areas may contribute to the link between early stress, suicide, and its endophenotypes. Two important affected structures are the midbrain, the site of the serotonin raphe nuclei, and the amygdala.44,48 Individual differences in amygdalar expression of 5-HTT have been linked with emotion processing,49 indicating that 5-HTT expression in specific brain regions may influence psychological outcomes during stress.
Further, structural variation in the 5-HTT gene moderates amygdala response to fearful stimuli,50 such that lower expressing 5-HTT alleles are associated with greater amygdala activation in a task matching fearful faces. It is possible that this association may disrupt global neural synchrony: Decreased functional coupling between amygdala and anterior cingulate cortex (ACC) has been observed in low expressing 5-HTT allele carriers51 and in individuals with mood disorders.52 Correspondingly, lower expressing alleles are associated with poorer outcomes in adulthood in those reporting childhood adversity. Those outcomes include stress-related onset of major depression and suicidal behavior for the first time in the mid-20s.43 Lower 5-HTT binding or expression may indeed be a risk factor for both mood disorders and suicidal behavior: 5-HTT binding is lower in the ventromedial cortex and anterior cingulate and midbrain of suicidal depressed compared with nonsuicidal depressed.53 Whether this link predicts stress response in suicidal individuals is not yet known.
Other aspects of the monoamine system may also play a role in the association between early stress and suicide: the TPH2 gene is the rate-limiting enzyme in the synthesis of serotonin in brain and is reported to be associated with risky decisions in a gambling task and that could reflect the kind of impaired decision-making that leads to aggressive behaviors and to suicide attempts in major depression.54 So there may be both direct gene effects as well as gene-environment interactions involving the serotonin system that result in enduring developmental effects on brain circuits related to decision-making and mood regulation. Norepinephrine (NE), another monoamine, may also play a role in stress programming and suicide risk. NE metabolites are altered in arsonists and suicide victims.55 Future work will establish whether NE may mediate some of the association between early stress and suicidal behavior.
Critical Periods for Stress Programming
The developmental timing of early stress may determine its potential effects on risk for suicide. The effects of early stress appear to be most potent before the age of 16 years.3,43 Studies reporting effects of early trauma have typically examined outcomes of adversity experiences before this age.3,43
One reason that children may be most sensitive to adversity in early life is that neurodevelopment continues at this stage in both the HPA and serotonin pathways. For example, it is possible that 5-HTT dysregulation at a critical point in emotional development shapes neural and psychological trajectories. The developmental impact of 5-HTT availability on adult behavior and mood has been demonstrated to depend on lower expression during a critical period: 5-HTT blockade with an SSRI early in infancy in mice56 and perhaps in humans57 results in a depressive phenotype or enhanced emotional responsivity in adulthood.
These effects may be due to permanent downregulation of 5-HTT when 5-HTT expression is disrupted early in life,58 but not necessarily in adulthood.59 They could also result in downstream effects such as on brain structure or neural circuits that in turn endure into adulthood.
If early stress exerted similar long-term effects on 5-HTT expression and behavior, we would expect to observe 5-HTT dysregulation early in life. Lower post-stressor 5-HTT expression is observed in infant rhesus macaques that experience early life stress (maternal deprivation or maltreatment) and is associated with behavioral disinhibition at an early stage in development.47
These findings suggest that 5-HTT impairment in mice, whether induced pharmacologically or by stress at a critical period in development, may lead to lifelong dysregulation of neural 5-HTT expression or other downstream changes in neural circuitry and an adult depressive phenotype.
Genetic, epigenetic, and gene-environment interactions are emerging as a compelling set of potential causes of adult psychopathology including suicidal behavior. Clearly, more research is needed to further elucidate the detailed mechanistic links between early stress, HPA and serotonin system function, stress coping, and suicidal behavior. The results of such studies will help to identify potential targets for prevention and reduction of risk for adult psychopathology and suicidal behavior.
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