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1. Stress by age at exposure - early childhood stress

1. Stress by age at exposure - early childhood stress

Early childhood stress increases susceptibility to mental health problems such as ADHD, depression, anxiety and addiction1

Early childhood stress causes changes in cortisol concentrations and cortisol metabolism.

  • Girls with a history of sexual abuse were found to have higher cortisol levels and altered cortisol concentrations in their saliva.
  • Early childhood stress (especially if chronic) can lead to increased cortisol concentrations in the blood.
  • Rats that were separated from their mothers at an early age or received less care still show an increased basal cortisol level as adults, an increased release of cortisol in response to acute stress, increased activity of the HPA axis (stress axis) and more stress symptoms.

Early childhood stress causes various changes in the brain that can last a lifetime. This particularly affects the areas of the brain that are responsible for stress response and emotional processing. The hippocampus, which is responsible for memory and the regulation of the stress hormone cortisol, shows an altered receptor density as a result of early childhood stress. Epigenetic changes in the glucocorticoid receptor gene NR3C1 can lead to a reduced number of cortisol receptors and thus to permanently increased cortisol levels in the brain.
The dopaminergic system, which is responsible for reward processing, is altered by early childhood stress. The motivation to pursue rewards can decrease along with dopamine levels in the striatum. The serotonin balance in the brain can be disrupted, which impairs neuronal development and emotion regulation. Early childhood stress can downregulate the sympathetic nervous system.
Prenatal maternal stress affects the migration and maturation of GABAergic cells and reduces the number of GABA-A and benzodiazepine receptors, which impairs cortical functions. A high level of maternal affection can reverse these changes.

Early stress causes further

  • an increased susceptibility to oxidative stress
  • an altered immunological stress response
  • epigenetic changes that influence gene expression
  • Shortened telomeres and reduced telomerase activity
  • a reduced brain volume in adulthood
  • Changes in the blood-brain barrier
  • an altered sensitivity to sedative hypnotics
  • increased startle reflex.

Stress in early childhood and adolescence (puberty) can also influence the remission of ADHD, whereby a high level of stress is associated with a more severe progression of ADHD into adulthood.

1.1. Stress during certain phases of brain development is particularly harmful

During the

  • prenatal development
  • Infancy
  • Childhood
  • Adolescence (puberty)

people are particularly vulnerable to stressors. During these critical periods, stressors can have lifelong effects such as persistent cacostasis (dyshomeostasis). During these periods, individuals are also particularly susceptible to a favorable environment that can trigger hyperstasis and lead to the development of resistance to stressors in adulthood.2
Therefore, there is a considerable difference between stress occurring during a developmental phase of a brain region and stress occurring outside this phase (especially after the end of brain development, in humans at around 24 years of age).

Examples:

  • Epigenetic demethylation of the FKPB5 gene, which modulates the sensitivity of glucocorticoid receptors3 is only mediated by stress during the differentiation and proliferation phase of neurons, but no longer in mature neurons.4
  • If excessive stress occurs during the developmental phase of the HPA axis, this increases the sensitivity of the HPA axis by permanently reducing the threshold values for the onset of the stress response.5 This impairs the ability to respond appropriately to stress6 and can lead to pathologically altered reactions to stressors in later life (including anxiety disorders, depression, autism and schizophrenia).

An example from the animal world: a certain species of bird lives by collecting and hiding nuts. For one year, an animal needs around 10,000 nuts, the hiding places of which it has to remember. These memory processes are carried out by the hippocampus. These birds have an above-average sized hippocampus. The hippocampus of birds experiences a developmental spurt between the 60th and 100th day of life. Animals that were only fed nut meal during these days were unable to take advantage of this developmental boost. Their hippocampus remained smaller than that of other specimens. In addition, they were unable to develop the ability to hide and find the required number of nuts for the rest of their lives, even if they were fed nuts from the 100th day of life.

The dopaminergic and noradrenergic systems, which are particularly important for attention, motor skills and stress resistance, develop especially in the first years of life (from conception to around 3 years of age) and again in middle adolescence. Negative environmental influences (stress) are therefore particularly harmful to the dopaminergic and noradrenergic systems during this period.

This is done in several ways, among others:

  • Early stress causes defective development of the dopaminergic pathways of the nucleus accumbens.7
  • Children who were exposed to a stressful environment or insecure attachment in the first 6 years of life suffer permanent damage in dopaminergic and serotonergic regions of the brain.8

Based on Rensing et al.’s description of the two-hit model, according to which mental disorders such as anxiety disorders, depression, autism and schizophrenia can be traced back to damage in adolescence that affects already damaged stress systems,9 it would be conceivable to view ADHD as the result of the first hit.
The assumption of ADHD as a first hit for other disorders may be contradicted by a study that found no increased specificity of symptoms of a disorder with increasing disorder severity.10

Stress levels during puberty can lead to an increase in early childhood stress levels.11 Another study shows that adults who reported more than five ADHD symptoms from their childhood were more likely than average to develop mental disorders or addiction.12

1.2. Age at exposure to stress determines type of mental disorder

It is not only the type and intensity of early childhood stress, but also the timing of the stress that determines the later disorder pattern. This is due to the fact that the development of the mammalian brain follows a specific chronological sequence. The individual brain regions do not develop simultaneously, but in their own time windows. In one phase of development, the respective brain regions are considerably more susceptible to external disturbances.

  • Cortisol treatment during pregnancy reduced the sensitivity of corticoid receptors in the PFC of newborn monkeys, with the timing of cortisol administration determining in which parts of the PFC this occurred. In adult monkeys, reduced receptor sensitivity due to cortisol administration was no longer observed.13
  • Severe maternal anxiety in pregnancy during the 12th to 22nd week after the last menstrual period significantly increased the risk of ADHD-HI, while severe anxiety during the 32nd to 40th week did not increase the risk.14 In contrast, a study found no increased psychiatric disorders at 9 years of age in children of women exposed to one month of repeated rocket fire on civilians during the 2006 Lebanon war.15 It is possible that one month of repeated stress is not a sufficiently intense stressor.
  • The developmentally oldest brain regions in the brain stem, which control the basic mechanisms of life and which develop first, are susceptible to very early disorders, which then often end fatally.
    Cortical areas of the brain that are not essential for survival and that develop later are susceptible to disorders that occur at slightly later stages of development.16
  • The specific effects of prolonged exposure to stress on the brain, behavior and cognition depend on the timing and duration of exposure to stress and, in part, on an interaction between gene effects and early childhood exposure to stress. These differences may explain why stress leads to different mental disorders at different times of life.17
  • Traumatic experiences before the age of 12 (such as the loss of a parent through death or permanent separation) increase the risk of later depressive illness, while traumatic experiences afterwards increase the risk of PTSD1819
  • Traumatic experiences before the age of 6 showed different dexamethasone/CRH test results than traumatic experiences at a later age.20
  • Prolonged emotional maltreatment in childhood correlated (as the only type of maltreatment) with a deviating (here: reduced) cortisol response to acute stressors with increasing adulthood.21
  • Sexual abuse at the age of 3 to 5 or at the age of 11 to 13 reduced the volume of the hippocampus, while sexual abuse at the age of 14 to 16 reduced the volume of the PFC.22
  • Extensive and long-term monitoring of 733 patients with various personality disorders showed that the different intensity and timing of early childhood stress also contributes to the differentiation of the disorders.23 All those affected were victims of early childhood stress: 73% of the 733 participants reported early childhood abuse, 82% early childhood neglect.
  • Changes in dopaminergic transmission in the mesolimbic, mesocortical and nigrostriatal systems caused by stress and high glucocorticoid concentrations prenatally and in the first years of life are probably determined by the ontogenetic developmental state of these brain regions at the time of stress exposure.24
  • The type and timing of early childhood stress exposure, for example, are likely to differentiate the environmental development of ADHD and borderline.25

The main developmental periods in which the respective brain regions are particularly vulnerable are (in years of life)26

  • Amygdala left: 0.5 to 2 years
  • Hippocampus: 3-527 and 11-14 years
  • Dorsal anterior cingulate cortex: 7-9 and 17-x years
  • Interiorer long fasciculus: from 7 years
  • Thalamus: 7-9 and 13-15 years
  • Corpus callosum: 9-10 years27
  • Ventromedial PFC: 8-10 and 14-16 years
  • Amygdala right: from 10 years
  • Visceral cortex: from 11 years of age
  • PFC (volume): 8-15 years28 14-16 years27

Gender-specific differences had to be taken into account. In girls, the amygdala developed much earlier than in boys, in whom an increase in amygdala volume could still be observed in adulthood.29

1.3. Early childhood stress

Early stress increases the risk of mental disorders.3031 Childhood emotional, physical or sexual abuse as well as trauma cause a long-lasting (beyond the period of abuse) profound disturbance of stress regulation.32 There is some evidence that children whose mothers were exposed to particular stress during pregnancy have a persistently increased vulnerability to mental disorders.33
Children of women exposed to repeated civilian rocket fire within one month during the 2006 Lebanon war were not found to have increased psychiatric disorders at the age of 9 years.15 This suggests that one month of repeated stress is not a sufficiently chronic stressor to damage the unborn child.

Rat pups separated from their mother at an early age have a long-lasting increased physiological and behavioral stress response to further stressors. The threshold for the onset of the stress response is reduced.34 The same applies to rat pups whose mothers showed weak nursing behavior.3536
A study of adopted ADHD sufferers also deals with the question of how much of ADHD is inherited and how much is acquired.37

Even with early childhood stress, it depends on the degree to which it is beneficial or detrimental. Very brief handling (removing baby rats from their mother by holding them in the hand) is a beneficial stimulus, mainly because it increases the rate of maternal licking and grooming. Prolonged periods of separation of newborn rats from the mother are stressful, especially because they attenuate maternal licking and grooming,38 which is associated with oxytocin release.

1.3.1. Behavioral changes due to early stress

Early childhood stress affects the brain and body for a lifetime. For example, early physical or sexual abuse causes lifelong behavioral and pathophysiological problems.3940 Similarly, cold and indifferent families or chaos in the home environment lead to lasting emotional problems in children.4142

1.3.1.1. ADHD and PTSD most common disorders in childhood stress

ADHD and PTSD are the most commonly diagnosed disorders in sexually abused children. There is a high degree of symptom overlap and comorbidity between ADHD, PTSD and sexual abuse.43
Early childhood stress, particularly adverse care experiences such as child abuse (MALT), is a risk factor for ADHD4445 46 47 , but also other psychopathologies such as ASD47, anxiety, depression and addiction. Childhood abuse was found to triple the risk of ADHD.48

1.3.1.2. Risk of depression increased by early stress

Early childhood stress changes brain structure and brain function and increases the risk of depression later in life.4950

1.3.1.3. PTSD/PTBS risk increased by early stress

Early stress increases the risk of later post-traumatic stress disorder,4950

1.3.1.4. Obesity and cardiovascular disease risk increased by early stress

Early stress increases the risk of obesity and cardiovascular disease.5152

1.3.1.5. Risk of stress intolerance increased by early stress

Early stress increases the likelihood of increased subjective sensitivity to stress in adulthood, which is associated with an increased risk of anxiety disorders and depression.53

The development of increased sensitivity to stress appears to be gene-dependent. Early childhood stress increases stress resilience, exploration and less anxious behavior in male Cdh13 + / + - and Cdh13 +/- mice. In mice with Cdh13 - / -, however, early childhood stress caused delayed habituation, no reduction in anxiety-like behavior and reduced fear extinction.54

1.3.1.6. Risk of attention and learning problems increased by early stress

Early childhood (non-sexual) maltreatment impairs attention at the age of 14 and 21.55

Impaired latent learning and attention deficit due to early childhood stress correlates with changes in the cholinergic system in relation to the muscarinic and nicotinic receptors.56

Spatial learning and memory problems due to early childhood stress correlate with neurophysiological changes in the brain

  • NMDA receptor57
  • GABA-A receptor57
  • Serotonergic system58
  • Hippocampus: impairment of neurogenesis58
1.3.1.7. Risk of aggression disorder increased by early stress

The social isolation of rodents in the first few days after weaning causes increased aggression,57 linked to various neurophysiological correlates:

  • Noradrenergic system, beta-2-adrenoceptor5960
  • Neurosteroid system
    • Allopregnanolone6162
  • GABAergic system
    • GABA-B-1a receptor63
  • Serotonergic system
    • 5HT-2C receptor6465
  • Glutamatergic system
    • AMPA receptor65
1.3.1.8. Risk of hyperactivity increased by early stress

The social isolation of rodents in the first few days after weaning causes increased motor activity,6657 linked to various neurophysiological correlates:

  • Dopaminergic system
    • PFC67
    • Nucleus accumbens67
      • Reduced dopamine level in the tissue, increased dopamine turnover68
    • Striatum
      • Reduced dopamine level in the tissue, increased dopamine turnover68
  • Serotonergic system67
    • Nucleus accumbens
      • Reduced basal serotonin turnover66
  • Glutamatergic system
    • AMPA receptor69
1.3.1.9. Increased risk of anxiety disorders due to early childhood stress

Early childhood stress causes anxiety memory deficits,57, which are neurophysiologically linked to

  • Cholinergic system
    • Muscarinic receptor7071
  • Signaling systems associated with neuroplasticity70
  • Egr-1 system71
1.3.1.10. Impaired social behavior and early childhood stress

Early childhood stress causes deficits in social behavior that are neurophysiologically linked to the dopaminergic system and there to the D1 receptor.70

1.3.2. Neurophysiological changes due to early stress

Exposure to early childhood stress38

  • Activates the stress response systems and changes their molecular organization, which alters their sensitivity to response and reaction
  • Influences myelination, neural morphology, neurogenesis and synaptogenesis
  • Causes permanent functional consequences, such as
    • Attenuated development of the left hemisphere
    • Reduced feedback between right and left hemisphere
    • Increased electrical irritability within the circuits of the limbic system
    • Reduced functional activity of the cerebellar vermis.
  • Increased risk for the development of e.g.
    • PTSD
    • Depression
    • Borderline
    • Dissociative identity disorder
    • Drug abuse.

The various brain regions differ in their sensitivity, which depends in part on genetics, gender, time, development rate and density of the glucocorticoid receptor.38

1.3.2.1. Early stress makes the HPA axis (stress axis) more sensitive

Early childhood stress “programs” the HPA axis for life,7238 by means of epigenetic mechanisms.73

A comprehensive meta-analysis of 210 studies on biochemical substances (biomarkers) in ADHD indicated that the hypothalamic-pituitary-adrenal axis (HPA axis) is affected or dysregulated in ADHD (in addition to the brain’s monoamine system).74

Prenatal maternal stress affects the child’s brain and behavior. Stressful life events, natural disasters, maternal anxiety or depression increase the risk of emotional, behavioral and/or cognitive problems in the child, such as depression, anxiety, ADHD of conduct disorder. Studies on the biological correlates and mediators of these findings suggest that the HPA axis plays a role in mediating the effects of maternal stress on the fetal brain and that maternal stress is associated with changes in the limbic and frontotemporal networks and the functional and microstructural connections that link them. Maternal stress correlates with a thinner cortex and enlarged amygdala in children.75 Prenatal maternal stress increases the risk of premature birth and shortened telomere length.

1.3.2.1.1. Early stress alters endocrine stress responses of the HPA axis

Permanent changes in the HPA axis in the unborn child may be the key mechanism that explains the link between prenatal stress, adverse birth outcomes (especially low birth weight) and increased susceptibility to various diseases later in adulthood.

  • Stress before birth and into early childhood has a potentially lifelong impact on HPA axis responses in psychological and pharmacological terms.767778798081828384
  • In adulthood, there are significant correlations between childhood trauma, psychiatric symptoms in adulthood and HPA axis responses to psychological and pharmacological stress.858681
  • Interruptions in care during infancy and chronic stress change the later stress response of the HPA axis and cause increased vulnerability to mental disorders.87
  • In humans, early experiences of stress also lead to permanent damage to the stress regulation systems, making them particularly susceptible to mental disorders as a result.8889
1.3.2.1.2. Change in the CRH system

Rats separated from their mother at an early age or less cared for by their mother showed90

  • More than doubled CRH levels on inflammation
  • Reduced density of CRH receptor binding in the anterior pituitary gland
  • Changes in extrahypothalamic CRH systems
    • 59% increase in CRH receptor binding sites in the raphe nuclei
    • Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86

Young monkeys that grew up under early attachment stress had increased CRH and decreased adrenaline levels at the age of 4 years.9192

The social isolation of rodents in the first days after weaning causes functional changes in the CRH system.93

1.3.2.1.3. Change in the ACTH stress response

In one study, sexually abused girls were found to have reduced basal ACTH levels and reduced ACTH responses to CRH stimulation, while the cortisol response was unremarkable.94

Early experiences of stress can lead to disturbances in the ACTH receptor systems, which prevent the experience of anxiety from being extinguished and thus cause long-term stress. This can be improved by administering ACTH.95 In our opinion, the change in ACTH receptor systems could possibly be a consequence of a down/upregulation response. ⇒ Downregulation / upregulation

Rats separated from their mother at an early age or less cared for by their mother show90

  • Elevated basal ACTH levels
  • Increased ACTH levels due to acute stress
  • More than doubled CRH levels to inflammation
  • Reduced density of CRH receptor binding in the anterior pituitary gland
  • Changes in extrahypothalamic CRH systems
    • 59% increase in CRH receptor binding sites in the raphe nuclei
    • Increase in immunoreactive CRH concentrations in the parabrachial nucleus by 86
  • Behavioral abnormalities such as96
    • Increased anxiety
    • Anhedonia
    • Increased alcohol preference
    • Sleep disorders
    • Cognitive impairments
    • Increased sensitivity to pain
1.3.2.1.4. Changes in cortisol due to stress in early childhood
1.3.2.1.4.1. Changes in corticoid receptors due to early stress
  • Rats that were separated from their mothers for a longer period of time at an early age had an increased messenger RNA density of the hippocampal mineralocorticoid receptor, while the glucocorticoid receptor messenger RNA density was reduced in the PFC as well as in the hippocampus.97 This shift causes impaired deactivation of the HPA axis by cortisol at the GR at the end of the stress response. This confirms that early childhood stress triggers the mechanism of downregulation with respect to the cortisol receptors relevant for acute stress responses, while the diurnal feedback regulation of the HPA axis (which regulates basal cortisol levels outside of an acute stress response via the mineralocorticoid receptors) is hardly altered.98

  • Intense stressful experiences in childhood cause epigenetic changes (methylation) in the NR3C1 glucocortioid receptor gene. These changes result in a reduced number of docking sites for the hormone cortisol in the brain.99 This results in a permanently elevated cortisol level in the brain because the existing cortisol cannot dock. The brain is therefore in a permanent state of alert.

  • Early childhood stress permanently alters the expression of cortisol receptors in the hippocampus and the response of the HPA axis to acute and chronic stress **** .100101

  • Desensitized corticoid receptors also have an influence on other reaction chains, including the noradrenergic and adrenergic systems.102

  • Epidemiologic and preclinical studies have shown that the disruption of the HPA axis in ADHD may result from excessive cortisol exposure in the fetal and early postnatal period (early childhood stress). Glucocorticoid administration at this stage of life may permanently alter glucocorticoid receptors in the brain, causing dysregulation of HPA axis activity, disturbances in the biosynthesis of neurotransmitters and their receptors, and alterations in intracellular pathways. Glucocorticoids (cortisol) increase the activity of the dopaminergic system. Reduced expression of glucocorticoids could thus cause hypofunction of the dopaminergic system.103

  • Early stress alters the functionality of the glucocortioid (cortisol) receptors (here: in the hippocampus). This impairs the inhibition of the HPA axis after a stress reaction. The expression of glucocortioid (cortisol) receptors is enhanced by higher serotonin levels, which in turn is moderated by higher cAMP levels.104 This causes changes in the HPA axis into adulthood.105

  • Early childhood stress in mice alters stress coping behavior in adulthood and in adult male offspring. The behavioral changes are accompanied by increased glucocorticoid receptor (GR) expression and decreased DNA methylation of the GR promoter in the hippocampus. DNA methylation is also reduced in sperm of exposed males in adulthood. If animals with genetic exposure grow up without early childhood stress in a safe environment with many opportunities for social contact (enriched environment), no behavioral changes are observed. At the same time, the aforementioned changes in GR gene expression and DNA methylation in the hippocampus of the male offspring are reversed.106

  • Caring brood care in rat pups in the first week causes methylation of promoters involved in the expression of genes that influence stress responses and behavior throughout life (positive here).107
    In genetically identical rats, only different brood care showed a different expression of the stress systems:

    • Rat pups that received little grooming and physical attention from their mothers developed lower levels of the transcription factor NGFI-A (also known as EGR1) in the hippocampus. This resulted in increased methylation and thus lower expression of the glucocorticoid receptor gene (GR gene) in the hippocampus.108
      A lower GR expression level in the hippocampus correlates in adulthood with108
      • Increased basal glucocorticoid level (in mice: corticosterone, in humans: cortisol)
      • Increased glucocorticoid stress response
      • More anxious behavior
      • In females: less brood care of their own children
    • Rat pups that received a lot of grooming and physical care from their mother developed a higher level of the transcription factor NGFI-A (EGR1) in the hippocampus. This results in reduced methylation and thus higher expression of the glucocorticoid receptor gene (GR gene) in the hippocampus.108
      A higher GR expression level in the hippocampus correlated in adulthood with108
      • Lower basal glucocorticoid level (in mice: corticosterone, in humans: cortisol)
      • Lower glucocorticoid stress response
      • Less anxious behavior
      • In females: increased brood care of their own children
  • In adult rats that were separated from their mother once for 24 hours at the age of 6, 9 or 12 days, the cortisol feedback mediated by the GR was deficient and impaired.109 In addition to a simultaneous increase in MR and decrease in GR in the hippocampus, there was also increased activation of the adrenal gland as a result of increased ACTH levels.110

  • Intense stressful experiences in childhood cause epigenetic changes (methylation) in the NR3C1 glucocorticoid receptor gene. These changes result in a reduced number of glucocorticoid receptors (GR) in the brain.99 This results in a permanently elevated cortisol level because the existing cortisol cannot dock. The brain is therefore in a permanent state of alert.

  • Maternal neglect and chronic stress inhibit the development of glucocorticoid receptors in the hippocampus. This

    • Reduces the stress-dampening effect of cortisol at the end of the stress response of the HPA axis
    • Increases CRF and vasopressin mRNA levels in the hypothalamus
      • Production of the stress hormones ACTH and corticosterone was increased.

    The authors conclude that early stress programs stress regulation and primes the mammalian brain to be more anxious and to have an increased noradrenergic, corticosteroid and vasopressin response to stress.111112

1.3.2.1.4.2. Changes in the cortisol stress response due to early childhood stress
  • Rats that were separated from their mothers after birth showed an overactive stress hormone response of the HPA axis to acute stressors as adult animals,113114 while the response of the HPA axis outside acute stress situations showed no deviating stress hormone levels.98
  • Low birth weight correlates with aberrant salivary cortisol responses to acute psychosocial stress in male boys and adults.11511681
  • Salivary and plasma cortisol responses to pharmacologic stimulation are associated with birth weight and gestational age.11711881
  • Intense family problems in early childhood correlate with the cortisol response to unknown situations. This is seen as an indication of a gene-environment interaction.11981
  • There are significant (albeit only slight) correlations between infant attachment styles and salivary cortisol responses to acute stress in adulthood120121 122 81 and between attachment behavior in adulthood and salivary cortisol responses in relationship conflict situations.12381
  • Children whose mothers used cocaine during pregnancy showed an altered (usually flattened) cortisol response to stress. If experiences of violence were added, this effect intensified.124
  • Early childhood stress causes permanent changes in the HPA axis, which are reflected in altered basal and stress-induced cortisol levels. Children with internalizing problems often show elevated cortisol levels in response to acute stressors, while adults who have experienced early childhood psychological stress often show decreased basal cortisol levels and increased ACTH responses to acute stress.125
  • Monkeys that grew up in groups of peers without a mother showed more elevated cortisol levels in response to multiple 4-day isolation as a stressor than monkeys that had grown up with their mother. They also showed a greater affinity for addiction.126
1.3.2.1.4.3. Early stress changes basal daily cortisol levels
  • Children who grew up in an orphanage showed a cortisol level development throughout the day that showed almost no changes. Compared to children raised in families, the morning increase in cortisol levels (CAR) was absent, as was a decrease in cortisol levels throughout the day. The more pronounced the changes in cortisol levels were throughout the day, the greater the resilience to mental disorders.125
  • A flatter daily cortisol level was associated with an increased risk of mental disorders. A higher amplitude of the cortisol curve throughout the day was associated with improved stress management.87
  • Prenatal stress increased the unborn child’s cortisol levels for the rest of its life.127
  • Childhood maltreatment led to striking changes in the HPA axis in macaques in the first six postnatal months44
    • Higher plasma cortisol levels
    • Higher cortisol accumulation in the hair
    • Increased HPA activity
    • Prolonged activation of the HPA axis
    • Increased level of emotional reactivity
1.3.2.1.5. Changes in vasopressin (AVP) due to early childhood stress

Early stress experience in mice (on the 10th day of life) caused DNA hypo-methylation, which reduced the vasopressin release of the gene responsible for this throughout life and supported a permanent hyperactivation of the HPA axis.128

1.3.2.2. Dopamine system - permanent damage due to early childhood stress

Early childhood stress (e.g. postnatal deprivation, maternal separation) led to reduced motivation to pursue rewards and reduced mesolimbic dopamine levels in the striatum in adult rats and monkeys.129 Monkeys with early childhood stress experience also showed reduced interest in rewards. However, reward consumption remained unchanged. Increased noradrenaline degradation substances were found in the urine.130

In humans, early childhood stress is also associated with reduced reward-related activity in the ventral striatum131, which is associated with increased symptoms of anhedonia,132 although the data did not differentiate between reward expectation and reward receipt. It is conceivable that reduced reactivity to rewards received in particular correlates with anhedonia or depression.

Maltreated adolescents showed reduced dopaminergic activation of the pallidum (part of the striatum) during reward anticipation with simultaneously stronger symptoms of depression.133

Further studies confirm that early childhood stress (without a direct link to depression) correlates with reduced activation of the striatum during reward anticipation, but not during reward maintenance.134135 This is consistent with the changes in ADHD with respect to both reward anticipation and reward maintenance. Neurophysiological correlates of reward in ADHD

Stress and high glucocorticoid levels prenatally and in the first years of life appear to alter developmental programs that ensure dopaminergic transmission in the mesolimbic, mesocortical and nigrostriatal systems. The induced changes are probably determined by the ontogenetic developmental state of these brain regions at the time of stress exposure and their stability appears to be associated with increased lifetime susceptibility to psychiatric disorders, including drug addiction.24 A change in the mesolimbic dopamine system triggered by chronic (social) stress is also being discussed as a cause of schizophrenia.136 Early childhood neglect correlated with increased mesolimbic dopamine release in the ventral striatum in response to acute stress.137
With regard to ADHD, a lifelong change in the dopaminergic system and the HPA axis (changes in the amount of MR and GR receptors that control the activity and deactivation of the HPA axis) has been demonstrated in children whose mothers were treated with cortisol for a longer period during pregnancy.138 The ADHD symptoms described in these children are therefore associated with changes in the HPA axis.

  • Early exposure to cortisol led to long-term changes in dopamine synthesis through adaptive responses. A cortisol receptor agonist (here: dexamethasone) promoted PACAP mRNA transcription, cell proliferation and DA synthesis, while a cortisol receptor antagonist inhibited this.139
  • Early stress caused defective development of the dopaminergic pathways of the nucleus accumbens.7
  • Children who were exposed to a stressful environment and insecure attachment in the first 6 years of life suffered permanent damage in dopaminergic and serotonergic regions of the brain.140
  • Early stress in combination with corresponding gene variants caused a sensitization of the dopamine system, making it more susceptible to acute stress, which leads to progressive dysregulation.141
  • Social stress in adolescence increased the number of dopamine transporters in mice.142 Increased DAT is typical for ADHD.
    • Mice that were separated from their mothers as newborns showed a reduced number of DAT in the nucleus accumbens and striatum as well as other changes in the dopamine system.143144
  • An altered function of the DAT is involved in ADHD and ASD. Within the first few months of life, environmental influences can epigenetically alter the expression of the DAT.145
  • Early childhood separation from the mother led to lifelong changes in the dopaminergic system in rats.146147

The social isolation of rodents in the first days after weaning from the mother causes reproducible, long-term changes57

  • Behavior:
    • Neophobia148
    • Disturbed sensorimotor gating148
    • Aggression148
    • Cognitive rigidity148
  • Neurophysiological:
    • Reduced PFC volume148
    • Reduced synaptic plasticity148
      • In the cortex
      • In the hippocampus
    • Hyperfunction of the mesolimbic dopaminergic system in the nucleus accumbens148
      • Increased presynaptic dopamine function
      • Increased serotonin function
    • Hypofunction of the mesocortical dopamine system148
    • Attenuated serotonin function in148
      • PFC
      • Hippocampus
    • Functional changes in the dopaminergic system in
      • Amygdala
        • Increased basal dopamine turnover149
      • Infralimbic mPFC
        • Reduced basal dopamine metabolism149

Rhesus monkeys that grew up without a mother and only with peers showed increased levels of the dopamine metabolite homovanillic acid (HVA) in response to social separation.150

1.3.2.3. Noradrenaline system - permanent damage due to early childhood stress

Separation of rat pups from their mothers increased GABA receptor-mediated release of norepinephrine in SHR rats (a model of ADHD-HI and ADHD-C), while this was decreased in Wystar-Kyoto rats (considered a control model of non-ADHD).151
Early childhood separation from the mother led to lifelong changes in the noradrenergic and dopaminergic systems in rats.146
Maternal stress (restriction for 1 h per day on day 15-21 of pregnancy) in rats led to a decrease in the hypothalamic noradrenaline and blood plasma corticosterone response to acute stress in adult male offspring.152

Monkeys separated from their mothers in early childhood showed a reduced basal noradrenaline level in the cerebrospinal fluid. This correlated with impaired social behavior, impulsivity, increased aggression and decreased interest in tasty rewards.153
Other monkeys with early childhood stress experience showed a reduced interest in rewards. However, reward consumption remained unchanged. Increased noradrenaline metabolites were found in the urine.130 Increased degradation substances in the urine indicate a reduced level in the brain.

Rhesus monkeys that grew up without a mother and only with peers showed reduced levels of the noradrenaline metabolite 3-methoxy-4-hydroxyphenylglycol (MHPG) in response to social separation.150

Epigenetic environmental factors such as prenatal stress appear to be able to impair the development of the noradrenergic system. This can increase the risk of ASD.154
The catalytic enzyme HSD11B2 (11 β-hydroxysteroid dehydrogenase-2), which inactivates cortisol, is downregulated in the placenta in the middle of pregnancy. This increases the receptivity of the fetal brain to cortisol.155 While stress and nutritional deprivation can decrease HSD11B2 expression through increased methylation, hypoxia decreases HSD11B2 expression via other mechanisms.156157 This can result in significant changes in the noradrenergic system.

A further, but possibly non-causal, connection between stress and the noradrenaline system is established via MeCP2.
In the MeCP2 mutant mouse model of Rett syndrome, the HPA axis is overactivated, presumably due to increased expression of the CRH gene, leading to abnormal stress responses. MeCP2 binds the CRH promoter, which is normally enriched with methylated CpG dinucleotides.158 MeCP2 deficiency impairs the noradrenergic system and causes respiratory distress. The administration of noradrenaline improves this.159
Reduced MECP2 expression was found in 11 of 14 ASD sufferers and in 2 of 2 ADHD sufferers.160 A case study also reported a connection with ADHD.161 SHR and PCB-contaminated rats showed changes in the MECP2 gene.162 Offspring of rat mothers given alcohol showed reduced MECP2 expression.163164 Alcohol during pregnancy massively increases the risk of ADHD.

1.3.2.4. Serotonin system - permanent damage due to early childhood stress

Serotonin influences the developing brain. During certain stages of brain development, 5-HT, in conjunction with other transmitters, regulates brain cytoarchitecture and nodal connectivity by modulating a variety of developmental processes, including neuronal progenitor cell proliferation, migration and differentiation, maturation of postmitotic neurons, and apoptosis. Environmental factors that alter serotonergic modulation during development or variation in genes involved in 5-HT signaling can cause disorders associated with defective innervation, circuit formation, and network connectivity.165

Acute and chronic stress influences serotonergic communication:

  • Acute stress increased the gene expression of the 5-HT7 receptor in the CA1 region of the hippocampus,166 while the gene expression of the 5-HT1A receptor decreased167
  • Corticosterone dose-dependently influences 5-HT1A receptor-mediated responses in the rat hippocampus in vitro and in vivo: activation of only the high-affinity mineralocorticoid receptor suppresses 5-HT1A receptor-mediated responses, while additional activation of lower-affinity glucocorticoid receptors enhances the effect of 5-HT.168
  • Glucocorticoid-mediated chronic stress downregulated 5-HT1A receptors in the hippocampus in animals.168

Rhesus monkeys that grew up without a mother and only with peers showed150

  • Without stress
    • Lower 5-HIAA concentrations in the cerebrospinal fluid
  • As a reaction to social distancing
    • Higher 5-HIAA concentrations in the cerebrospinal fluid
1.3.2.5. Changes in the vegetative nervous system (sympathetic / parasympathetic nervous system)

Early childhood stress experiences are associated with a down-regulation of the sympathetic nervous system, but probably not with a change in parasympathetic cardiovascular stress reactivity in adulthood.169

1.3.2.6. Changes in the cortex / PFC
  • Adults with early emotional maltreatment showed a reduced volume of mPFC.170
  • Animal experiments have shown that emotional experience in the first years of life causes structural neuronal changes (wiring patterns in the prefrontal-limbic circuits) in the brain that are retained throughout life.171172173
  • Maltreated children and adolescents show structural developmental damage, in174
    • Cortex
    • Orbifrontal cortex (reduced volume in institutionalized children)
      The disorders of the amygdala and the orbifrontal cortex correlate with social and emotional regulation disorders (including increased anxiety).
      Neuronal emotion processing and emotion regulation remain altered into adulthood.175176177
  • After stressing newborn rats, they showed developmental disorders of the neuronal systems of the PFC. These animals had a significantly higher stress response behavior with increased anxiety and orientation difficulties at an older age.178
  • Early sexual abuse caused a thinner cortex in the regions representing the genital area.179
  • Prenatal maternal stress correlates with a thinner cortex in children.180 A delay in the first cortex thickness maximum is considered a sign of developmental disorders.
1.3.2.7. Early childhood stress alters connectivity of the thalamus

The spatial distribution of global connectivity is highest in the regions of salience and default mode networks, and the severity of early childhood stress experience predicted increased global connectivity of the left thalamus.181

Early childhood stress changes how the amygdala is addressed by the thalamus.182

1.3.2.8. Early childhood stress changes the amygdala

Maltreated children and adolescents exhibit structural developmental damage, e.g. in:174

  • Amygdala (increased volume in children at home)
    The disorders of the amygdala and the orbitofrontal cortex correlate with social and emotional regulation disorders (including increased anxiety).
  • Neuronal emotion processing and emotion regulation remain altered into adulthood.175176177
  • Prenatal maternal stress correlates with an enlarged amygdala in children.180
1.3.2.9. Hippocampus
  • Early stress reduces the amplitude of long-term potentiation in the hippocampus.
    Rodents exposed to early stress showed dendritic atrophy in hippocampal cells and reduced amplitude of long-term potentiation in the CA3 region of the hippocampus, leading to deficits in memory formation.183
  • Prolonged exposure to stress alters brain structures involved in cognition and mental health. In the prenatal period and the first years of life, the hippocampus (up to 2 years) and amygdala (up to 8 years) are particularly vulnerable to prolonged stress.17
  • Rats that were separated from their mothers for a longer period of time at an early age had an increased messenger RNA density of the hippocampal mineralocorticoid receptor, while the glucocorticoid receptor messenger RNA density was reduced in the PFC as well as in the hippocampus.97 This shift causes impaired deactivation of the HPA axis by cortisol at the GR at the end of the stress response. This confirms that early childhood stress triggers the mechanism of downregulation with respect to the cortisol receptors relevant for acute stress responses, while the diurnal feedback regulation of the HPA axis (which regulates basal cortisol levels outside of an acute stress response via the mineralocorticoid receptors) is hardly altered.98
  • Exposure to glucocorticoids (stress hormones) during hippocampal development in pregnancy influences the starting point of the stress response through epigenetic changes via mRNA and methylation.184
  • Another study also describes epigenetic changes in the hippocampus due to early childhood stress.185
1.3.2.10. Corpus callosum

Abused children and adolescents exhibited structural developmental damage, including in the corpus callosum.174

Like all myelinated regions, the corpus callosum is potentially susceptible to early childhood stress, as high concentrations of stress hormones suppress glial cell division, which is critical for myelination.186 The size of the corpus callosum is strongly influenced by early experience in a sex-specific manner. Handling led to a significantly larger width of the corpus callosum in male rats.187

When male monkeys are raised in isolation, this weakens the development of the corpus callosum and causes a4 reduced size, which correlates with defects in certain learning tasks.112

Childhood traumas such as severe neglect or abuse appear to correlate with a significant reduction in the mean proportions of the corpus callosum, particularly in boys.188189 The corpus callosum is said to be more susceptible to neglect in boys and more susceptible to sexual abuse in girls.112

1.3.2.11. Early childhood stress and GABA

Prenatal maternal stress delays the migration of GABAergic cell precursors from their site of origin in the medial ganglionic eminence (in the forebrain) to their destination in the cortex.190191 This GABAergic cell migration is crucial for subsequent cortical function, e.g. in schizophrenia.190192193 The subsequent maturation of GABAergic cells is also influenced by prenatal stress and correlates with altered social and anxiety-like behavior after prenatal stress. An IL-6 antagonist was able to prevent a maternal stress-induced delay in the migration of GABAergic cell precursors in mice.190191194190

The social isolation of rodents in the first few days after weaning causes functional changes in the GABAergic system5759195

Early childhood stress due to prolonged separation from the mother, endotoxins or neglect (e.g. due to less attentive breastfeeding) changes the molecular composition of the supramolecular complex of gamma-aminobutyric acid (GABA)-benzodiazepine and benzodiazepine. This had the following effects:196112

  • Reduced (high-affinity) GABA-A receptors in the amygdala and locus coeruleus
  • Reduced benzodiazepine receptors in the amygdala centrally and laterally, in the PFC, in the locus coeruleus and in the nucleus tractus solitaricus
  • Reduced mRNA levels for the GABA-A-gamma-2 receptor, which binds with high affinity to benzodiazepine, in the amygdala nuclei, locus coeruleus and nucleus tractus solitaricus.

Handling (briefly holding newborns), on the other hand, increased all three levels. It is known that brief handling leads to increased maternal care and affection, which causes increased oxytocin levels (instead of decreased oxytocin levels due to severe stress).

Here too, the offspring of mothers who showed a high level of affection also showed this as adults:197

  • More benzodiazepine receptors in the amygdala (central, lateral, basolateral) and locus coeruleus
  • More alpha2-adrenoceptors in the locus coeruleus
    • This reduces feedback inhibition of the noradrenergic neurons
  • Fewer CRH receptors in the locus coeruleus
  • A significantly lower level of anxiety in response to new stimuli
    Anxiety and fear are mediated by reduced GABAergic inhibition of the amygdala. The GABAergic inhibition of the amygdala is influenced by, among other things
    • Noradrenergic projections from the locus coeruleus to the PFC
    • CRH projections from the amygdala to the locus coeruleus (anxiety-increasing)
    • Endogenous benzodiazepines (anxiolytic)

The authors conclude that maternal care during infancy serves to “program” behavioral responses to stress in the offspring by altering the development of the neural systems that mediate anxiety.197112

1.3.2.12. FKBP5

The glucocorticoid receptor (GR) is present in almost all cells and is a corticosteroid-dependent transcription factor. In the hormone-free state, it is present in the cell in a complex with heat shock protein 90 and a number of other helper proteins such as FKBP51, which influence steroid signal transduction. 198

  • Stress in the developmental phase of the HPA axis increases the activity of the FKBP5 gene through an epigenetic change (methylation). In adults, however, trauma does not cause methylation of this gene. FKBP5 is also thought to play a role in aggression.199200 The epigenetically altered variant of FKBP5 causes a permanent deterioration in stress regulation in those affected.
  • Carriers of the FKBP5 genotypes rs1360780 or rs3800373 have a significantly increased risk of depression if they have been exposed to traumatizing events, such as physical violence, sexual abuse or serious accidents. Without such stressful events, the probability of depression is unchanged.201 In the case of such stress, the shutdown of the HPA axis normally triggered by cortisol at the end of the stress response is impaired. As a result, the HPA axis is not shut down properly and remains permanently activated.
    This effect is a phenotypic description of ADHD-HI (with hyperactivity).
1.3.2.13. Increased susceptibility to oxidative stress

Early and long-term stress increases vulnerability to oxidative stress.202

1.3.2.14. Change in the immunological stress response (Kindling effect)

Moderate and severe childhood maltreatment (MAL) correlates positively with the overall change in the stress response of the cytokine IL-6 as well as the maximum IL-6 concentration during TSST.203

Traumatic experiences in childhood cause increased CRP levels.204
This could be due to the kindling effect. Earlier activation of cytokines (proteins that fight inflammation) leads to a more intensive cytokine response when they are activated again.
Kindling hypothesis of depression. Since cytokines can influence the neurotransmitter systems, early childhood cytokine intoxications cause long-lasting changes in the catecholamine systems (dopamine, noradrenaline, serotonin).
For example, even low doses of the cytokine IL-2 in newborn mice led to permanently reduced dopamine levels in the hypothalamus in adulthood.205

1.3.2.15. Epigenetic changes due to early stress

Epigenetic changes describe mechanisms by which the expression of genes and thus their activity are influenced. The effect of an epigenetic change can therefore occur in any of the ways described so far, e.g. a change in the cortisol receptors or a change in the dopaminergic system.

1.3.2.15.1. Changes in DNA methylation

Early childhood stress experiences can contribute to the development of ADHD via DNA methylation. However, DNA methylation correlating with externalizing behaviors appears to be the consequences of problematic behaviors reinforced by early childhood stress experiences rather than the epigenetic basis of such behaviors. Externalizing behavior methylation risk scores correlated with smaller gray matter volumes in medial orbitofrontal and anterior/middle cingulate cortices. These brain regions are associated with ADHD.206
Children who grew up in institutions show significant changes in DNA methylation compared to children who grew up in families. These changes in DNA methylation can explain around 7 to 14% of the changes in behavior.207

1.3.2.15.2. Shortened telomeres, reduced telomerase

Stress in the first 4 years of life, the time when the brain develops most rapidly, leads to shortened telomeres, the DNA repeats at the chromosome ends. Cortisol and oxidative stress increase telomere shortening and inhibit telomerase (the enzyme that repairs telomeres).208209210 Shortened telomeres cause altered behavior. However, it is less likely that certain later behaviors influence telomere length, since telomere shortening occurs primarily in the first years of life and hardly ever occurs in adults. The length of telomeres significantly influences the expression of genes. A comprehensive and illuminating account can be found in Bateson, Nettle. Prenatal maternal stress correlates with shortened telomere lengths in children.21121221375

  • Behaviors that are promoted by shortened telomeres are213
    • Impulsiveness
      • Impatience
      • Devaluation of removed rewards
    • Willingness to take risks
    • Food
      • Higher BMI
      • Quantity
      • Frequency
    • Addictive behavior
      • Smoking
      • Alcohol consumption
    • Stress reactivity
      • Higher blood pressure
      • Higher basal cortisol level (in healthy children)
      • Higher cortisol stress responses
      • More internalizing symptoms
    • Neurotic personality traits
    • Pessimistic personality traits
    • Avoidance of physical activity
  • Behaviors that are promoted by longer telomeres are213
    • Physical activity
1.3.2.16. Reduced brain volume in adulthood due to early deprivation

Deprivation in the first years of life (here: in Romanian children in institutions) resulted in a reduced brain volume in adulthood. This cannot be reversed even through an enriched environment (here: adoption).214

1.3.2.17. Altered development of the blood-brain barrier

Early childhood stress in rats led to an altered development of the blood-brain barrier by increasing caveolae-mediated transport in brain endothelial cells.215

1.3.2.18. Further neurophysiological changes due to early childhood stress
  • Reduced sensitivity to sedative hypnotics
    (shortened loss of the righting reflex)
    • CRH system
      • CRH receptor195
    • Noradrenergic system195
    • GABAergic system216
    • Allopregnanolone61217
  • Increased susceptibility to picrotoxin-induced convulsions
    • GABAergic system
      • GABA-A receptor218
    • Allopregnanolone218
  • Increased startle reflex66
  • Impaired prepulse inhibition66
  • Increased food collecting behavior (food hoarding)66
  • Reduced susceptibility to GABAergic drugs
    • Such as pentobarbital and diazepam
  • Histochemical changes in oligodendrocyte maturation and myelination219 and dendritic spine density in the mPFC220
  • Downregulation of the biosynthetic pathway of allopregnanolone
    • Allopregnanolone is a neurosteroid with positive allosteric modulatory activity against the GABA-A receptor.22161

1.4. Stress in childhood and adolescence prevents remission of ADHD

A study of stress levels in children with ADHD found that severe stress levels in childhood and adolescence were associated with more severe ADHD-HI or ADHD-I progression into adulthood, while children with low stress levels often showed remitting ADHD.222
Conversely, studies on the age-dependent effects of enriched environments in rodents show that youth is a very vulnerable age segment. Positive effects are already evident in childhood. However, the greatest benefit was observed in middle adolescence. Enriched environments resulted in improved selective and auditory sustained attention performance, increased exploration and food-gathering behavior as well as a significant decrease in corticosterone levels and reduced anxiety levels.223


  1. Lee SH, Jung EM (2023): Adverse effects of early-life stress: focus on the rodent neuroendocrine system. Neural Regen Res. 2024 Feb;19(2):336-341. doi: 10.4103/1673-5374.377587. PMID: 37488887. REVIEW

  2. Chrousos (2009): Stress and disorders of the stress system. Nat Rev Endocrinol. 2009 Jul;5(7):374-81. doi: 10.1038/nrendo.2009.106. PMID: 19488073. REVIEW

  3. Binder, Bradley, Liu, Epstein, Deveau, Mercer, Tang, Gillespie, Heim, Nemeroff, Schwartz, Cubells, Ressler (2008): Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults. JAMA 2008; 299: 1291–305.

  4. Klengel, Mehta, Anacker, Rex-Haffner, Pruessner, Pariante, Pace, Mercer, Mayberg, Bradley, Nemeroff, Holsboer, Heim, Ressler, Rein, Binder (2013): Allelespecific FKBP5 DNA demethylation mediates gene-childhood trauma interactions. Nat Neurosci 2013; 16: 33–41.

  5. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 119

  6. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 120

  7. Lesting (2005): Adaptive Reifung von Dopamin und Serotonin im Nucleus accumbens, der integrativen Schnittebene zwischen Emotion und Bewegung, Seite 3, mit weiteren Nachweisen

  8. Braun, Helmeke, Poeggel, Bock (2005) Tierexperimentelle Befunde zu den hirnstrukturellen Folgen früher Stresserfahrungen, S. 44 – 58 in: Egle, Hoffmann, Joraschky (Hrsg.) Sexueller Missbrauch, Misshandlung, Vernachlässigung. 3. Auflage, Schattauer – inzwischen gibt es die 4. Auflage, 2016

  9. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper, Moleküle, Seite 293 f.

  10. Groen, Wichers, Wigman, Hartman (2019): Specificity of psychopathology across levels of severity: a transdiagnostic network analysis. Sci Rep. 2019 Dec 4;9(1):18298. doi: 10.1038/s41598-019-54801-y. n = 1.933

  11. Heim, Binder (2012): Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol; 2012; 233: 102–11

  12. Richter, Spangenberg, Ramklint, Ramirez (2019): The clinical relevance of asking young psychiatric patients about childhood ADHD symptoms. Nord J Psychiatry. 2019 Sep 26:1-7. doi: 10.1080/08039488.2019.1667427.

  13. Heijtz, Fuchs, Feldon, Pryce, Forssberg (2010): Effects of antenatal dexamethasone treatment on glucocorticoid receptor and calcyon gene expression in the prefrontal cortex of neonatal and adult common marmoset monkeys; Behav Brain Funct. 2010; 6: 18. doi: 10.1186/1744-9081-6-18; PMCID: PMC2858712

  14. Van den Bergh, B. R.H. and Marcoen, A. (2004), High Antenatal Maternal Anxiety Is Related to ADHD Symptoms, Externalizing Problems, and Anxiety in 8- and 9-Year-Olds. Child Development, 75: 1085–1097. doi:10.1111/j.1467-8624.2004.00727.x

  15. Barzilay, Lawrence, Berliner, Gur, Leventer-Roberts, Weizman, Feldman (2019): Association between prenatal exposure to a 1-month period of repeated rocket attacks and neuropsychiatric outcomes up through age 9: a retrospective cohort study. Eur Child Adolesc Psychiatry. 2019 Nov 4. doi: 10.1007/s00787-019-01426-1. n = 14.053

  16. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 294

  17. Lupien, McEwen, Gunnar, Heim (2009): Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009; 10: 434–45.

  18. Maercker, Michael, Fehm, Becker, Margraf (2004): Age of traumatisation as a predictor of posttraumatic stress disorder or major depression in young women. Brit J Psychiatry 2004; 184: 482–7.

  19. Agid, Shapira, Zislin, Ritsner, Hanin, Murad, Troudart, Bloch, Heresco-Levy, Lerer (1999): Environment and vulnerability to major psychiatric illness: a case control study of early parental loss inmajor depression, bipolar disorder and schizophrenia. Mol Psychiatry 1999; 4: 163–72.

  20. Heim, Mletzko, Purselle, Musselman, Nemeroff (2008): The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol Psychiatry 2008; 63: 398–405. zitiert nach Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 53

  21. Carpenter, Tyrka, Ross, Khoury, Anderson, Price (2009): Effect of childhood emotional abuse and age on cortisol responsivity in adulthood. Biol Psychiatry 2009; 66: 69–75.

  22. Andersen, Teicher (2008): Stress, sensitive periods and maturational events in adolescent depression. Trends Neurosci 2008; 31: 183–91.

  23. Skodol, Gunderson, Shea, McGlashan, Morey, Sanislow, Bender, Grilo, Zanarini, Yen, Pagano, Stout (2005): THE COLLABORATIVE LONGITUDINAL PERSONALITY DISORDERS STUDY (CLPS): OVERVIEW AND IMPLICATIONS, J Pers Disord. 2005 Oct; 19(5): 487–504. doi: 10.1521/pedi.2005.19.5.487; PMCID: PMC3289284; NIHMSID: NIHMS349849, Kapitel: ANTECEDENTS

  24. Rodrigues, Leão, Carvalho, Almeida, Sousa (2011): Potential programming of dopaminergic circuits by early life stress; Psychopharmacology, March 2011, Volume 214, Issue 1, pp 107–120

  25. Weiner, Perroud, Weibel (2019): Attention Deficit Hyperactivity Disorder And Borderline Personality Disorder In Adults: A Review Of Their Links And Risks. Neuropsychiatr Dis Treat. 2019 Nov 8;15:3115-3129. doi: 10.2147/NDT.S192871. eCollection 2019.

  26. Teicher (2015): Sensitive periods and the neurobiological and psychiatric consequences of childhood abuse. Plenarvortrag 17. Tagung der Deutschsprachigen Gesellschaft für Psychotraumatologie. Innsbruck 26.2–28.2.2015 zitiert nach Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 38

  27. Teicher, Abuse and Sensitive Periods, Blogbeitrag, December 14, 2008 (Zugriff 27.12.17

  28. Giedd, Lalonde, Celano, White, Wallace, Lee, Lenroot (2009): Anatomical brainmagnetic resonance imaging of typically developing children and adolescents. J Am Acad Child Adolesc Psychiatry 2009; 48: 465–470.

  29. Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 52

  30. Zitnik, Curtis, Wood, Arner, Valentino (2016): Adolescent Social Stress Produces an Enduring Activation of the Rat Locus Coeruleus and Alters its Coherence with the Prefrontal Cortex. Neuropsychopharmacology. 2016 Apr;41(5):1376-85. doi: 10.1038/npp.2015.289.

  31. McEwen (2008): Understanding the potency of stressful early life experiences on brain and body function. Metabolism. 2008 Oct;57 Suppl 2:S11-5. doi: 10.1016/j.metabol.2008.07.006.

  32. Heim, Direktorin des Instituts für Medizinische Psychologie an der Charité, Berlin, im Interview, zitiert aus Weber, Ohrfeigen für die Seele, Süddeutsche Zeitung 15.10.2015, Seite 16

  33. Bindt, Huber, Hecher (2008): Vorgeburtliche Entwicklung. In: Grundlagen körperlicher und psychischer Entwicklung. In: Herpertz-Dahlmann (Hrsg.) (2008): Entwicklungspsychiatrie: biopsychologische Grundlagen und die Entwicklung psychischer Störungen, Schattauer, Seite 100

  34. Plotsky, Thrivikraman, Nemeroff, Caldji, Sharma, Meaney (2005): Long-term consequences of neonatal rearing on central corticotropinreleasing factor systems in adult male rat offspring. Neuropsychopharmacology 2005; 30: 2192–204.

  35. Meaney (2001): Maternal Care, gene expression, and the transmission of individual differences in stress reactivity across generations. Annu Rev Neurosci; 2001; 24: 1161–92.

  36. Parent, Zhang, Caldji, Bagot, Champagne, Pruessner, Meaney (2005): Maternal Care and Individual Differences in Defensive Responses

  37. Sellers, Harold, Smith, Neiderhiser, Reiss, Shaw, Natsuaki, Thapar, Leve (2019): Disentangling nature from nurture in examining the interplay between parent-child relationships, ADHD, and early academic attainment. Psychol Med. 2019 Dec 16:1-8. doi: 10.1017/S0033291719003593. n = 345

  38. Teicher, Andersen, Polcari, Anderson, Navalta (2002): Developmental neurobiology of childhood stress and trauma. Psychiatr Clin North Am. 2002 Jun;25(2):397-426, vii-viii. doi: 10.1016/s0193-953x(01)00003-x. PMID: 12136507.

  39. Felitti, Anda, Nordenberg, Williamson, Spitz, Edward, Koss, Marks (1998): Relationship of childhood abuse and household dysfunction to many of the leading causes of death in adults. The Adverse Childhood Experiences (ACE) Study. Am J Prev Med. 1998 May;14(4):245-58.

  40. Heim, Nemeroff (2001): The role of childhood trauma in the neurobiology of mood and anxiety disorders: preclinical and clinical studies. Biol Psychiatry. 2001 Jun 15;49(12):1023-39.

  41. Repetti, Taylor, Seeman (2002): Risky families: family social environments and the mental and physical health of offspring. Psychol Bull. 2002 Mar;128(2):330-66.

  42. Evans, Gonnella, Marcynyszyn, Gentile, Salpekar (2005): The role of chaos in poverty and children’s socioemotional adjustment. Psychol Sci. 2005 Jul;16(7):560-5.

  43. Weinstein, Staffelbach, Biaggio (2000): Attention-deficit hyperactivity disorder and posttraumatic stress disorder: differential diagnosis in childhood sexual abuse. Clin Psychol Rev. 2000 Apr;20(3):359-78. doi: 10.1016/s0272-7358(98)00107-x. PMID: 10779899.

  44. McCormack KM, Howell BR, Higgins M, Bramlett S, Guzman D, Morin EL, Villongco C, Liu Y, Meyer J, Sanchez MM (2022): The developmental consequences of early adverse care on infant macaques: A cross-fostering study. Psychoneuroendocrinology. 2022 Sep 27;146:105947. doi: 10.1016/j.psyneuen.2022.105947. PMID: 36242820.

  45. Grossman A, Avital A (2023): Emotional and sensory dysregulation as a possible missing link in attention deficit hyperactivity disorder: A review. Front Behav Neurosci. 2023 Mar 2;17:1118937. doi: 10.3389/fnbeh.2023.1118937. PMID: 36935890; PMCID: PMC10017514. REVIEW

  46. Humphreys KL, Zeanah CH (2015): Deviations from the expectable environment in early childhood and emerging psychopathology. Neuropsychopharmacology. 2015 Jan;40(1):154-70. doi: 10.1038/npp.2014.165. PMID: 24998622; PMCID: PMC4262894. REVIEW

  47. Nicolaides NC, Kanaka-Gantenbein C, Pervanidou P (2023): Developmental Neuroendocrinology of Early-Life Stress: Impact on Child Development and Behavior. Curr Neuropharmacol. 2023 Aug 10. doi: 10.2174/1570159X21666230810162344. PMID: 37563814.

  48. Briscoe-Smith AM, Hinshaw SP (2006): Linkages between child abuse and attention-deficit/hyperactivity disorder in girls: behavioral and social correlates. Child Abuse Negl. 2006 Nov;30(11):1239-55. doi: 10.1016/j.chiabu.2006.04.008. PMID: 17097140; PMCID: PMC1934403. n = 228

  49. Kaufman, Plotsky, Nemeroff, Charney (2000): Effects of early adverse experiences on brain structure and function: clinical implications. Biol Psychiatry. 2000 Oct 15;48(8):778-90.

  50. Vermetten, Schmahl, Lindner, Loewenstein, Bremner (2006): Hippocampal and amygdalar volumes in dissociative identity disorder. Am J Psychiatry. 2006 Apr;163(4):630-6.

  51. Dong, Giles, Felitti, Dube, Williams, Chapman, Anda (2004): Insights into causal pathways for ischemic heart disease: adverse childhood experiences study. Circulation. 2004 Sep 28; 110(13): 1761-6.

  52. Anda, Felitti, Bremner, Walker, Whitfield, Perry, Dube, Giles (2006): The enduring effects of abuse and related adverse experiences in childhood. A convergence of evidence from neurobiology and epidemiology. Eur Arch Psychiatry Clin Neurosci. 2006 Apr;256(3):174-86.

  53. McLaughlin, Kubzansky, Dunn, Waldinger, Vaillant, Koenen (2010): Childhood social environment, emotional reactivity to stress, and mood and anxiety disorders across the life course. Depress Anxiety. 2010 Dec;27(12):1087-94. doi: 10.1002/da.20762. PMID: 21132844; PMCID: PMC3074636.

  54. Kiser, Popp, Schmitt-Böhrer, Strekalova, van den Hove, Lesch, Rivero (2018): Early-life stress impairs developmental programming in Cadherin 13 (CDH13)-deficient mice. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 27. pii: S0278-5846(18)30276-8. doi: 10.1016/j.pnpbp.2018.08.010.

  55. Boyd, Kisely, Najman, Mills (2019): Child maltreatment and attentional problems: A longitudinal birth cohort study. Child Abuse Negl. 2019 Sep 13;98:104170. doi: 10.1016/j.chiabu.2019.104170.

  56. Ouchi, Ono, Murakami, Matsumoto (2013): Social isolation induces deficit of latent learning performance in mice: a putative animal model of attention deficit/hyperactivity disorder. Behav Brain Res. 2013 Feb 1;238:146-53. doi: 10.1016/j.bbr.2012.10.029.

  57. Matsumoto, Fujiwara, Araki, Yabe (2019): Post-weaning social isolation of mice: A putative animal model of developmental disorders. J Pharmacol Sci. 2019 Oct 25. pii: S1347-8613(19)35719-6. doi: 10.1016/j.jphs.2019.10.002.

  58. Ibi, Takuma, Koike, Mizoguchi, Tsuritani, Kuwahara, Kamei, Nagai, Yoneda, Nabeshima, Yamada (2008): Social isolation rearing‐induced impairment of the hippocampal neurogenesis is associated with deficits in spatial memory and emotion‐related behaviors in juvenile mice. Journal of Neurochemistry, 105: 921-932. doi:10.1111/j.1471-4159.2007.05207.x

  59. Matsumoto, Ojima, Watanabe (1995): Noradrenergic denervation attenuates desipramine enhancement of aggressive behavior in isolated mice. Pharmacol Biochem Behav. 1995 Mar;50(3):481-4.

  60. Matsumoto, Ojima, Ohta, Watanabe (1994): Beta 2- but not beta 1-adrenoceptors are involved in desipramine enhancement of aggressive behavior in long-term isolated mice. Pharmacol Biochem Behav. 1994 Sep;49(1):13-8.

  61. Matsumoto, Pinna, Puia, Guidotti, Costa (2005): Social isolation stress-induced aggression in mice: a model to study the pharmacology of neurosteroidogenesis. Stress. 2005 Jun;8(2):85-93.

  62. Pinna, Dong, Matsumoto, Costa, Guidotti (2003): In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2035-40.

  63. Araki, Hiraki, Nishida, Kuramoto, Matsumoto, Yabe (2016): Epigenetic regulation of dorsal raphe GABA(B1a) associated with isolation-induced abnormal responses to social stimulation in mice. Neuropharmacology. 2016 Feb;101:1-12. doi: 10.1016/j.neuropharm.2015.09.013.

  64. Yu, Xu, Xue, An, Li, Chen, Yu, Sun, Ma, Tang, Xiao, Yin (2018): 5-HT2CR antagonist/5-HT2CR inverse agonist recovered the increased isolation-induced aggressive behavior of BALB/c mice mediated by ADAR1 (p110) expression and Htr2c RNA editing. Brain Behav. 2018 Feb 7;8(3):e00929. doi: 10.1002/brb3.929. eCollection 2018 Mar.

  65. Shimizu, Kurosawa, Seki (2016): The role of the AMPA receptor and 5-HT(3) receptor on aggressive behavior and depressive-like symptoms in chronic social isolation-reared mice. Physiol Behav. 2016 Jan 1;153:70-83. doi: 10.1016/j.physbeh.2015.10.026.

  66. [Heidbreder, Weiss, Domeney, Pryce, Homberg, Hedou, Feldon, Moran, Nelson (2000): Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience. 2000;100(4):749-68.)](https://www.ncbi.nlm.nih.gov/pubmed/11036209/

  67. Ago, Araki, Tanaka, Sasaga, Nishiyama, Takuma, Matsuda (2013): Role of social encounter-induced activation of prefrontal serotonergic systems in the abnormal behaviors of isolation-reared mice. Neuropsychopharmacology. 2013 Jul;38(8):1535-47. doi: 10.1038/npp.2013.52.

  68. Eells, Misler, Nikodem (2006): Early postnatal isolation reduces dopamine levels, elevates dopamine turnover and specifically disrupts prepulse inhibition in Nurr1-null heterozygous mice. Neuroscience. 2006 Jul 21;140(4):1117-26.

  69. Araki, Ago, Hasebe, Nishiyama, Tanaka, Oka, Takuma, Matsuda (2014): Involvement of prefrontal AMPA receptors in encounter stimulation-induced hyperactivity in isolation-reared mice. Int J Neuropsychopharmacol. 2014 Jun;17(6):883-93. doi: 10.1017/S1461145713001582.

  70. Okada, Fujiwara, Mizuki, Araki, Yabe, Matsumoto (2015): Involvement of dopaminergic and cholinergic systems in social isolation-induced deficits in social affiliation and conditional fear memory in mice. Neuroscience. 2015 Jul 23;299:134-45. doi: 10.1016/j.neuroscience.2015.04.064.

  71. Okada, Matsumoto, Tsushima, Fujiwara, Tsuneyama (2014): Social isolation stress-induced fear memory deficit is mediated by down-regulated neuro-signaling system and Egr-1 expression in the brain. Neurochem Res. 2014 May;39(5):875-82. doi: 10.1007/s11064-014-1283-5.

  72. Barker (1991): The foetal and infant origins of inequalities in health in Britain. J. Public Health Med., 1991, 13, 64–68

  73. Darnaudéry, Maccari (2008): Epigenetic programming of the stress response in male and female rats by prenatal restraint stress. Brain Res Rev. 2008 Mar;57(2):571-85. doi: 10.1016/j.brainresrev.2007.11.004. PMID: 18164765. REVIEW

  74. Scassellati, Bonvicini, Faraone, Gennarelli, (2012): Biomarkers and Attention-Deficit/Hyperactivity Disorder: A Systematic Review and Meta-Analyses; JOURNAL OF THE AMERICAN ACADEMY OF CHILD & ADOLESCENT PSYCHIATRY VOLUME 51 NUMBER 10 OCTOBER 2012 www.jaacap.org, Seite 1003, S. 1012

  75. Lautarescu, Craig, Glover (2020): Prenatal stress: Effects on fetal and child brain development. Int Rev Neurobiol. 2020;150:17-40. doi: 10.1016/bs.irn.2019.11.002. Epub 2019 Dec 14. PMID: 32204831. REVIEW

  76. Huizink, Mulder, Buitelaar (2004): Prenatal stress and risk for psychopathology: specific effects or induction of general susceptibility? Psychol. Bull. 130, 115—142.

  77. Luecken, Lemery (2004): Early caregiving and physiological stress responses. Clin. Psychol. Rev. 24, 171—191

  78. Weinstock (2005): The potential influence of maternal stress hormones on development and mental health of the offspring. Brain Behav. Immun. 19, 296—308

  79. Luecken, Appelhans (2006): Early parental loss and salivary cortisol in young adulthood: the moderating role of family environment. Dev. Psychopathol. 18, 295—308

  80. Entringer, Kumsta, Hellhammer, Wadhwa, Wüst (2009): Prenatal exposure to maternal psychosocial stress and HPA axis regulation in young adults. Hormones and Behavior, Volume 55, Issue 2, February 2009, Pages 292-298, https://doi.org/10.1016/j.yhbeh.2008.11.006

  81. Kudielka, Hellhammer, Wust (2009): Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge; Psychoneuroendocrinology, 34, 2-18., Absatz 2.7.

  82. Panzer (2008): African Journal of Psychiatry – The neuroendocrinological sequelae of stress during brain development : the impact of child abuse and neglect : review article; African Journal of Psychiatry, Volume 11, Issue 1, Feb 2008, p. 29 – 34

  83. Teicher, Andersen, Polcari, Anderson, Navalta, Kim (2003): The neurobiological consequences of early stress and childhood maltreatment; Neuroscience & Biobehavioral Reviews, Volume 27, Issues 1–2, January–March 2003, Pages 33-44

  84. Grizenko, Shayan, Polotskaia, Ter-Stepanian, Joober (2008): Relation of maternal stress during pregnancy to symptom severity and response to treatment in children with ADHD; J Psychiatry Neurosci. 2008 Jan; 33(1): 10–16. PMCID: PMC2186370

  85. Heim, Newport, Heit, Graham, Wilcox, Bonsall, Miller, Nemeroff (2000): Pituitary-adrenal and autonomic responses to stress in women after sexual and physical abuse in childhood. JAMA 284, 592—597.

  86. Heim, Mletzko, Purselle, Musselman, Nemeroff (2008): The dexamethasone/corticotropin-releasing factor test in men with major depression: role of childhood trauma. Biol. Psychiatry 63, 398—405.

  87. Sjögren, Leanderson, Kristenson (2006): Diurnal saliva cortisol levels and relations to psychosocial factors in a population sample of middle-aged Swedish men and women.International journal of behavioral medicine13(3):193-200

  88. Heim, Shugart, Craighead, Nemeroff (2010): Neurobiological and psychiatric consequences of child abuse and neglect. Dev Psychobiol 2010; 52: 671–90.

  89. Heim, Binder (2012): Current research trends in early life stress and depression: review of human studies on sensitive periods, gene-environment interactions, and epigenetics. Exp Neurol; 2012; 233: 102–11.

  90. Ladd, Owens, Nemeroff (1996): Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 1996; 137: 1212–18.

  91. Coplan, Andrews, Rosenblum, Owens, Friedman, Gorman, Nemeroff (1996): Persistent elevations of cerebrospinal fluid concentrations of corticotropin-releasing factor in adult nonhuman primates exposed to early-life stressors: implications for the patho-physiology of mood and anxiety disorders. Proc Natl Acad Sci 1996; 93: 1619–23.

  92. Coplan, Smith, Altemus, Scharf, Owens, Nemeroff, Gorman, Rosenblum (2001): Variable foraging demand rearing: sustained elevations in cisternal cerebrospinal fluid corticotropin-releasing factor concentration in adult primates. Biol Psychiatry 2001; 50: 200–4.

  93. Hodge, Butcher (1975): Catecholamine correlates of isolation-induced aggression in mice. Eur J Pharmacol. 1975 Mar;31(1):81-93.

  94. De Bellis, Chrousos, Dorn, Burke, Helmers, Kling, Trickett, Putman (1994): Hypothalamic–pituitary–adrenal axis dysregulation in sexually abused girls. J. Clin. Endocrinol. Metab. 78, 249–255, n = 26

  95. Massey, Lerner, Holmes, Scott, Hernan, (2016):ACTH Prevents Deficits in Fear Extinction Associated with Early Life Seizures; Front Neurol. 2016; 7: 65. doi: 10.3389/fneur.2016.00065; PMCID: PMC4852169

  96. Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 48

  97. Ladd, Huot, Thrivikramm, Nemeroff, Plotsky (2004): Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation. Biol Psychiatry. 2004 Feb 15;55(4):367-75.

  98. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 121

  99. Berndt (2013): Resilienz, S. 150

  100. Weaver, Diorio, Seckl, Szyf, Meaney (2004): Early environmental regulation of hippocampal glucocorticoid receptor gene expression: characterization of intracellular mediators and potential genomic target sites. Ann N Y Acad Sci. 2004 Jun;1024:182-212.

  101. Kudielka, Hellhammer, Wust (2009): Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge; Psychoneuroendocrinology, 34, 2-18.

  102. Rensing, Koch, Rippe, Rippe (2006): Mensch im Stress; Psyche, Körper Moleküle; Elsevier (jetzt Springer), Seite 297

  103. Budziszewska, Basta-Kaim, Kubera, Lasoń (2010); [Immunological and endocrinological pattern in ADHD etiopathogenesis]. Przeglad Lekarski [01 Jan 2010, 67(11):1200-1204], PMID:21442976

  104. Meaney, Diorio, Francis, Weaver, Yau, Chapman, Seckl (2000): Postnatal handling increases the expression of cAMP-inducible transcription factors in the rat hippocampus: the eff ects of thyroid hormones and serotonin. J Neurosci 2000; 20: 3926–35

  105. Seckl, Meaney (2004): Glucocorticoid programming. Ann N Y Acad Sci. 2004 Dec;1032:63-84.

  106. Gapp, Bohacek, Grossmann, Brunner, Manuella, Nanni, Mansuy (2016): Potential of Environmental Enrichment to Prevent Transgenerational Effects of Paternal Trauma

  107. Kaffman, Meaney (2007): Neurodevelopmental sequelae of postnatal maternal care in rodents: clinical and research implications of molecular insights. J Child Psychol Psychiatry 2007; 48(3–4): 224–44.

  108. Feder, Nestler, Charney (2009): Psychobiology and molecular genetics of resilience. Nat Rev Neurosci. 2009;10(6):446-57.

  109. De Kloet, Vreugdenhil, Oitzl, Joels (1998): Brain corticosteroid receptor balance in health and disease. Endocr Rev, 1998 Jun, 19(3), 269-301

  110. Vázquez, Van Oers, Levine, Akil (1996) Regulation of glucocorticoid and mineralocorticoid receptor mRNAs in the hippocampus of the maternally deprived infant rat. Brain Res. 1996 Aug 26;731(1-2):79-90.

  111. Liu, Diorio, Tannenbaum, Caldji, Francis, Freedman, Sharma, Pearson, Plotsky, Meaney (1997): Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress. Science. 1997 Sep 12;277(5332):1659-62. doi: 10.1126/science.277.5332.1659. PMID: 9287218.

  112. Teicher, Andersen, Polcari, Anderson, Navalta (2002): Developmental neurobiology of childhood stress and trauma. Psychiatr Clin North Am. 2002 Jun;25(2):397-426, vii-viii. doi: 10.1016/s0193-953x(01)00003-x. PMID: 12136507. REVIEW

  113. Rots, Jong, Workel, Levine, Cools, De Kloet (1996): Neonatal Maternally Deprived Rats have as Adults Elevated Basal Pituitary-Adrenal Activity and Enhanced Susceptibility to Apomorphine; J. Neuroendocrinol., 8, 501-506.

  114. Buuse, Garner, Koch (2003): Neurodevelopmental animal models of schizophrenia: effects on prepulse inhibition. Curr Mol Med. 2003 Aug;3(5):459-71.

  115. Wüst, Entringer, Federenko, Schlotz, Hellhammer (2005): Birth weight is associated with salivary cortisol responses to psychosocial stress in adult life. Psychoneuroendocrinology 30, 591—598

  116. Jones, Godfrey, Wood, Osmond, Goulden, Phillips (2006): Fetal growth and the adrenocortical response to psychological stress. J. Clin. Endocrinol. Metab. 91, 1868—1871

  117. Kajantie, Eriksson, Barker, Forsen, Osmond, Wood, Andersson, Dunkel, Phillips (2003): Birthsize, gestational age and adrenal function in adult life: studies of dexamethasone suppression and ACTH1-24 stimulation. Eur. J. Endocrinol. 149, 569—575.

  118. Ward, Syddall, Wood, Chrousos, Phillips (2004): Fetal programming of the hypothalamic—pituitary—adrenal (HPA) axis: low birth weight and central HPA regulation. J. Clin. Endocrinol. Metab. 89, 1227—1233.

  119. Ouellet-Morin, Boivin, Dionne, Lupien, Arsenault, Barr, Perusse, Tremblay (2008): Variations in heritability of cortisol reactivity to stress as a function of early familial adversity among 19-month-old twins. Arch. Gen. Psychiatry 65, 211—218

  120. Luecken (1998): Childhood attachment and loss experiences affect adult cardiovascular and cortisol function. Psychosom. Med. 60, 765—772

  121. Luecken (2000): Parental caring and loss during childhood and adult cortisol responses to stress.Psychol.Health 15,841—851.

  122. Quirin, Pruessner, Kuhl (2008): HPA system regulation and adult attachment anxiety: individual differences in reactive and awakening cortisol. Psychoneuroendocrinology 33, 581—590

  123. Powers, Pietromonaco, Gunlicks, Sayer (2006): Dating couples’ attachment styles and patterns of cortisol reactivity and recovery in response to a relationship conflict. J. Pers. Soc. Psychol. 90, 613—628

  124. Lester, Lagasse, Shankaran, Bada, Bauer, Lin, Das, Higgins (2010): Prenatal cocaine exposure related to cortisol stress reactivity in 11-year-old children. J Pediatr. 2010 Aug;157(2):288-295.e1. doi: 10.1016/j.jpeds.2010.02.039.

  125. Tarullo, Gunnar (2006): Child maltreatment and the developing HPA axis. Horm. Behav. 50: 632-639

  126. Fahlke, Lorenz, Long, Champoux, Suomi, Higley (2000): Rearing Experiences and Stress-Induced Plasma Cortisol as Early Risk Factors for Excessive Alcohol Consumption in Nonhuman Primates. Alcoholism: Clinical and Experimental Research, 24: 644–650. doi:10.1111/j.1530-0277.2000.tb02035.x, n = 97

  127. Koehl, Darnaudéry, Dulluc, Van Reeth, Le Moal, Maccari (1999): Prenatal stress alters circadian activity of hypothalamo-pituitary-adrenal axis and hippocampal corticosteroid receptors in adult rats of both gender. J. Neurobiol. 1999, 40, 302–315

  128. Murgatroyd, Patchev, Wu, Micale, Bockmühl, Fischer, Holsboer, Wotjak, Almeida, Dietmar Spengler (2009): Dynamic DNA methylation programs persistent adverse effects of early-life stress. Nature Neuroscience volume 12, pages 1559–1566, 2009

  129. Pizzagalli (2014): Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393-423. doi: 10.1146/annurev-clinpsy-050212-185606. PMID: 24471371; PMCID: PMC3972338.

  130. Pryce, Dettling, Spengler, Schnell, Feldon (2004): Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring. Biol Psychiatry. 2004 Jul 15;56(2):72-9. doi: 10.1016/j.biopsych.2004.05.002. PMID: 15231438.

  131. Hanson, Albert, Iselin, Carré, Dodge, Hariri (2016): Cumulative stress in childhood is associated with blunted reward-related brain activity in adulthood. Soc Cogn Affect Neurosci. 2016 Mar;11(3):405-12. doi: 10.1093/scan/nsv124. PMID: 26443679; PMCID: PMC4769626.

  132. Corral-Frías, Nikolova, Michalski, Baranger, Hariri, Bogdan (2015): Stress-related anhedonia is associated with ventral striatum reactivity to reward and transdiagnostic psychiatric symptomatology. Psychol Med. 2015;45(12):2605-17. doi: 10.1017/S0033291715000525. PMID: 25853627; PMCID: PMC4700837.

  133. Dennison, Sheridan, Busso, Jenness, Peverill, Rosen, McLaughlin (2016): Neurobehavioral markers of resilience to depression amongst adolescents exposed to child abuse. J Abnorm Psychol. 2016 Nov;125(8):1201-1212. doi: 10.1037/abn0000215. Erratum in: J Abnorm Psychol. 2017 Jan;126(1):136. PMID: 27819477; PMCID: PMC5119749.

  134. Dillon, Holmes, Birk, Brooks, Lyons-Ruth, Pizzagalli (2009): Childhood adversity is associated with left basal ganglia dysfunction during reward anticipation in adulthood. Biol Psychiatry. 2009 Aug 1;66(3):206-13. doi: 10.1016/j.biopsych.2009.02.019. PMID: 19358974; PMCID: PMC2883459.

  135. Mehta, Gore-Langton, Golembo, Colvert, Williams, Sonuga-Barke (2010): Hyporesponsive reward anticipation in the basal ganglia following severe institutional deprivation early in life. J Cogn Neurosci. 2010 Oct;22(10):2316-25. doi: 10.1162/jocn.2009.21394. PMID: 19929329.

  136. Selten, van der Ven, Rutten, Cantor-Graae (2013): The social defeat hypothesis of schizophrenia: an update. Schizophr Bull. 2013 Nov;39(6):1180-6. doi: 10.1093/schbul/sbt134. Epub 2013 Sep 23. PMID: 24062592; PMCID: PMC3796093. REVIEW

  137. Pruessner, Champagne, Meaney, Dagher (2004): Dopamine release in response to a psychological stress in humans and its relationship to early life maternal care: a positron emission tomography study using [11C]raclopride. J Neurosci. 2004 Mar 17;24(11):2825-31. doi: 10.1523/JNEUROSCI.3422-03.2004. PMID: 15028776; PMCID: PMC6729514.

  138. Kapoor, Petropoulos, Matthews (2007): Fetal programming of hypothalamic-pituitary-adrenal (HPA) axis function and behavior by synthetic glucocorticoids. Brain Res Rev. 2008 Mar;57(2):586-95.

  139. McArthur, McHale, Dalley, Buckingham, Gillies (2005): Altered mesencephalic dopaminergic populations in adulthood as a consequence of brief perinatal glucocorticoid exposure. Journal of Neuroendocrinology 17(8):475-82 · September 2005

  140. Braun, Helmeke, Poeggel, Bock (2005): Tierexperimentelle Befunde zu den hirnstrukturellen Folgen früher Stresserfahrungen, S. 44 – 58 in: Egle, Hoffmann, Joraschky (Hrsg.) Sexueller Missbrauch, Misshandlung, Vernachlässigung. 3. Auflage, Schattauer. 2016 erschien die 4. Auflage

  141. Simpson, Morud, Winiger, Biezonski, Zhu, Bach, Malleret, Polan, Ng-Evans, Phillips, Kellendonk, Kandel (2014): Genetic variation in COMT activity impacts learning and dopamine release capacity in the striatum; Learn Mem. 2014 Apr; 21(4): 205–214. doi: 10.1101/lm.032094.113, PMCID: PMC3966542

  142. Iñiguez, Aubry, Riggs, Alipio, Zanca, Flores-Ramirez, Hernandez, Nieto, Musheyev, Serrano (2016): Social defeat stress induces depression-like behavior and alters spine morphology in the hippocampus of adolescent male C57BL/6 mice. Neurobiol Stress. 2016 Aug 21;5:54-64. eCollection 2016 Dec.

  143. Brake, Zhang, Diorio, Meaney, Gratton (2004): Influence of early postnatal rearing conditions on mesocorticolimbic dopamine and behavioural responses to psychostimulants and stressors in adult rats. Eur J Neurosci. 2004 Apr;19(7):1863-74. doi: 10.1111/j.1460-9568.2004.03286.x. PMID: 15078560.

  144. Meaney, Brake, Gratton (2002): Environmental regulation of the development of mesolimbic dopamine systems: a neurobiological mechanism for vulnerability to drug abuse? Psychoneuroendocrinology. 2002 Jan-Feb;27(1-2):127-38. doi: 10.1016/s0306-4530(01)00040-3. PMID: 11750774.

  145. Green, Eid, Zhan, Zarbl, Guo, Richardson (2019): Epigenetic Regulation of the Ontogenic Expression of the Dopamine Transporter. Front Genet. 2019 Nov 4;10:1099. doi: 10.3389/fgene.2019.01099. eCollection 2019.

  146. Matthews, Hall, Wilkinson, Robbins (1996): Retarded acquisition and reduced expression of conditioned locomotor activity in adult rats following repeated early maternal separation: effects of prefeeding, d-amphetamine, dopamine antagonists and clonidine. Psychopharmacology (Berl). 1996 Jul;126(1):75-84. doi: 10.1007/bf02246414. PMID: 8853220.

  147. Hall, Wilkinson, Humby, Robbins (1999): Maternal deprivation of neonatal rats produces enduring changes in dopamine function. Synapse. 1999 Apr;32(1):37-43. doi: 10.1002/(SICI)1098-2396(199904)32:1<37::AID-SYN5>3.0.CO;2-4. PMID: 10188636.

  148. Fone, Porkess (2008): Behavioural and neurochemical effects of post-weaning social isolation in rodents-relevance to developmental neuropsychiatric disorders. Neurosci Biobehav Rev. 2008 Aug;32(6):1087-102. doi: 10.1016/j.neubiorev.2008.03.003. PMID: 18423591.

  149. Heidbreder, Weiss, Domeney, Pryce, Homberg, Hedou, Feldon, Moran, Nelson (2000): Behavioral, neurochemical and endocrinological characterization of the early social isolation syndrome. Neuroscience. 2000;100(4):749-68.

  150. Wood, Gabrielle, Hunter, Skowbo, Schwandt, Lindell, Barr, Suomi, Higley (2021): Early Rearing Conditions Affect Monoamine Metabolite Levels During Baseline and Periods of Social Separation Stress: A Non-human Primate Model (Macaca mulatta). Front Hum Neurosci. 2021 Apr 9;15:624676. doi: 10.3389/fnhum.2021.624676. PMID: 33897393; PMCID: PMC8062724.

  151. Sterley, Howells, Russell (2013): Maternal separation increases GABA(A) receptor-mediated modulation of norepinephrine release in the hippocampus of a rat model of ADHD, the spontaneously hypertensive rat. Brain Res. 2013 Feb 25;1497:23-31. doi: 10.1016/j.brainres.2012.12.029.

  152. Reznikov, Nosenko (1995): Catecholamines in steroid-dependent brain development. J Steroid Biochem Mol Biol. 1995 Jun;53(1-6):349-53. doi: 10.1016/0960-0760(95)00073-9. PMID: 7626479.

  153. Kraemer, Ebert, Schmidt, McKinney (1989): A longitudinal study of the effect of different social rearing co 5-89. doi: 10.1016/0893-133x(89)90021-3. PMID: 2477005.

  154. Mehler MF, Purpura DP (2009): Autism, fever, epigenetics and the locus coeruleus. Brain Res Rev. 2009 Mar;59(2):388-92. doi: 10.1016/j.brainresrev.2008.11.001. PMID: 19059284; PMCID: PMC2668953. REVIEW

  155. Holmes MC, Abrahamsen CT, French KL, Paterson JM, Mullins JJ, Seckl JR (2006): The mother or the fetus? 11beta-hydroxysteroid dehydrogenase type 2 null mice provide evidence for direct fetal programming of behavior by endogenous glucocorticoids. J Neurosci. 2006 Apr 5;26(14):3840-4. doi: 10.1523/JNEUROSCI.4464-05.2006. PMID: 16597738; PMCID: PMC6445356.

  156. Zhu P, Wang W, Zuo R, Sun K (2019): Mechanisms for establishment of the placental glucocorticoid barrier, a guard for life. Cell Mol Life Sci. 2019 Jan;76(1):13-26. doi: 10.1007/s00018-018-2918-5. PMID: 30225585.

  157. Alikhani-Koopaei R, Fouladkou F, Frey FJ, Frey BM (2004): Epigenetic regulation of 11 beta-hydroxysteroid dehydrogenase type 2 expression. J Clin Invest. 2004 Oct;114(8):1146-57. doi: 10.1172/JCI21647. PMID: 15489962; PMCID: PMC522246.

  158. McGill BE, Bundle SF, Yaylaoglu MB, Carson JP, Thaller C, Zoghbi HY (2006): Enhanced anxiety and stress-induced corticosterone release are associated with increased Crh expression in a mouse model of Rett syndrome. Proc Natl Acad Sci U S A. 2006 Nov 28;103(48):18267-72. doi: 10.1073/pnas.0608702103. PMID: 17108082; PMCID: PMC1636379.

  159. Viemari JC, Roux JC, Tryba AK, Saywell V, Burnet H, Peña F, Zanella S, Bévengut M, Barthelemy-Requin M, Herzing LB, Moncla A, Mancini J, Ramirez JM, Villard L, Hilaire G (2005): Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice. J Neurosci. 2005 Dec 14;25(50):11521-30. doi: 10.1523/JNEUROSCI.4373-05.2005. PMID: 16354910; PMCID: PMC6726028.

  160. Nagarajan RP, Hogart AR, Gwye Y, Martin MR, LaSalle JM (2006): Reduced MeCP2 expression is frequent in autism frontal cortex and correlates with aberrant MECP2 promoter methylation. Epigenetics. 2006 Oct-Dec;1(4):e1-11. doi: 10.4161/epi.1.4.3514. PMID: 17486179; PMCID: PMC1866172.

  161. Suter B, Treadwell-Deering D, Zoghbi HY, Glaze DG, Neul JL (2014): Brief report: MECP2 mutations in people without Rett syndrome. J Autism Dev Disord. 2014 Mar;44(3):703-11. doi: 10.1007/s10803-013-1902-z. PMID: 23921973; PMCID: PMC3880396.

  162. DasBanerjee T, Middleton FA, Berger DF, Lombardo JP, Sagvolden T, Faraone SV (2008): A comparison of molecular alterations in environmental and genetic rat models of ADHD: a pilot study. Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1554-63. doi: 10.1002/ajmg.b.30877. PMID: 18937310; PMCID: PMC2587509.

  163. Kim P, Park JH, Choi CS, Choi I, Joo SH, Kim MK, Kim SY, Kim KC, Park SH, Kwon KJ, Lee J, Han SH, Ryu JH, Cheong JH, Han JY, Ko KN, Shin CY (2013): Effects of ethanol exposure during early pregnancy in hyperactive, inattentive and impulsive behaviors and MeCP2 expression in rodent offspring. Neurochem Res. 2013 Mar;38(3):620-31. doi: 10.1007/s11064-012-0960-5. PMID: 23283698.

  164. Kim P, Choi CS, Park JH, Joo SH, Kim SY, Ko HM, Kim KC, Jeon SJ, Park SH, Han SH, Ryu JH, Cheong JH, Han JY, Ko KN, Shin CY (2014): Chronic exposure to ethanol of male mice before mating produces attention deficit hyperactivity disorder-like phenotype along with epigenetic dysregulation of dopamine transporter expression in mouse offspring. J Neurosci Res. 2014 May;92(5):658-70. doi: 10.1002/jnr.23275. PMID: 24510599.

  165. Lesch, Waider (2012): Serotonin in the Modulation of Neural Plasticity and Networks: Implications for Neurodevelopmental Disorders. Neuron VOLUME 76, ISSUE 1, P175-191, OCTOBER 04, 2012 DOI:https://doi.org/10.1016/j.neuron.2012.09.013

  166. Yau et al. 2001 nach Jørgensen (2007): Studies on the neuroendocrine role of serotonin. Dan Med Bull. 2007 Nov;54(4):266-88.

  167. Lopez et al. 1999 nach Jørgensen (2007): Studies on the neuroendocrine role of serotonin. Dan Med Bull. 2007 Nov;54(4):266-88.

  168. Meijer, Kortekaas, Oitzl, de Kloet (1998): Acute rise in corticosterone facilitates 5-HT1A receptor-mediated behavioural responses. European Journal of Pharmacology, Volume 351, Issue 1, 1998, Pages 7-14, ISSN 0014-2999, https://doi.org/10.1016/S0014-2999(98)00289-1.

  169. Winzeler, Voellmin, Hug, Kirmse, Helmig, Princip, Cajochen, Bader, Wilhelm (2017): Adverse childhood experiences and autonomic regulation in response to acute stress: the role of the sympathetic and parasympathetic nervous systems; Anxiety, Stress & Coping Vol. 30 , Iss. 2,2017; n = 118

  170. Van Harmelen, van Tol, van der Wee, Veltman, Aleman, Spinhoven, van Buchem, Zitman, Penninx, Elzinga (2010): Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment. Biol Psychiatry 2010; 68: 832–8.

  171. Newport, Stowe, Nemeroff (2002): Parental Depression: Animal Models of an Adverse Life Event; American Journal of Psychiatry 2002 159:8, 1265-1283

  172. https://de.wikipedia.org/wiki/Trauma_(Psychologie)#Kindesmisshandlung

  173. Berndt (2013): Resilienz, S. 149 ff

  174. Egle, Joraschky, Lampe, Seiffge-Krenke, Cierpka (2016): Sexueller Missbrauch, Misshandlung, Vernachlässigung – Erkennung, Therapie und Prävention der Folgen früher Stresserfahrungen; 4. Aufl., Schattauer, S. 51, mit weiteren Nachweisen

  175. Tottenham, Hare, Millner, Gilhooly, Zevin, Casey (2011): Elevated amygdala response to faces following early deprivation. Dev Sci 2011; 14: 190–204.

  176. Weber, Miller, Schupp, Borgelt, Awiszus, Popov, Elbert, Rockstroh (2009): Early life stress and psychiatric disorder modulate cortical responses to affective stimuli. Psychophysiology 2009; 46: 1234–43. n = 70

  177. Matz, Junghöfer, Elbert, Weber, Wienbruch, Rockstroh (2010): Adverse experiences in childhood influence brain responses to emotional stimuli in adult psychiatric patients. Int J Psychophysiol 2010; 75: 277–86. n = 46

  178. Müller, Candrian, Kropotov (2011): ADHS – Neurodiagnostik in der Praxis, Springer, Seite 85

  179. Heim, Mayberg, Mletzko, Nemeroff, Pruessner (2013): Decreased cortical representation of genital somatosensory fi eld aft er childhood sexual abuse. Am J Psychiatry 2013; 170: 616–23.

  180. Lautarescu, Craig, Glover (2020): Prenatal stress: Effects on fetal and child brain development. Int Rev Neurobiol. 2020;150:17-40. doi: 10.1016/bs.irn.2019.11.002. PMID: 32204831. REVIEW

  181. Philip, Tyrka, Albright, Sweet, Almeida, Price, Carpenter (2016): Early life stress predicts thalamic hyperconnectivity: A transdiagnostic study of global connectivity. J Psychiatr Res. 2016 Aug;79:93-100. doi: 10.1016/j.jpsychires.2016.05.003.

  182. Danielewicz, Hess (2016): Early life stress alters synaptic modification range in the rat lateral amygdala. Behav Brain Res. 2014 May 15;265:32-7. doi: 10.1016/j.bbr.2014.02.012.

  183. Brunson, Kramár, Lin, Chen, Colgin, Yanagihara, Lynch, Baram (2005): Mechanisms of late-onset cognitive decline after early-life stress. J Neurosci. 2005 Oct 12;25(41):9328-38.

  184. Provençal, Arloth, Cattaneo, Anacker, Cattane, Wiechmann, Röh, Ködel, Klengel, Czamara, Müller, Lahti; PREDO team, Räikkönen, Pariante, Binder (2019): Glucocorticoid exposure during hippocampal neurogenesis primes future stress response by inducing changes in DNA methylation. Proc Natl Acad Sci U S A. 2019 Aug 9. pii: 201820842. doi: 10.1073/pnas.1820842116.

  185. Köhler, Gröger, Lesse, Guara Ciurana, Rether, Fegert, Bock, Braun (2019): Early-Life Adversity Induces Epigenetically Regulated Changes in Hippocampal Dopaminergic Molecular Pathways. Mol Neurobiol. 2019 May;56(5):3616-3625. doi: 10.1007/s12035-018-1199-1.

  186. Lauder (1983): Hormonal and humoral influences on brain development. Psychoneuroendocrinology. 1983;8(2):121-55. doi: 10.1016/0306-4530(83)90053-7. PMID: 6137852. REVIEW

  187. Berrebi, Fitch, Ralphe, Denenberg, Friedrich, Denenberg (1988): Corpus callosum: region-specific effects of sex, early experience and age. Brain Res. 1988 Jan 12;438(1-2):216-24. doi: 10.1016/0006-8993(88)91340-6. PMID: 3345428.

  188. Teicher, Ito, Glod, Andersen, Dumont, Ackerman (1997): Preliminary evidence for abnormal cortical development in physically and sexually abused children using EEG coherence and MRI. Ann N Y Acad Sci. 1997 Jun 21;821:160-75. doi: 10.1111/j.1749-6632.1997.tb48277.x. PMID: 9238202.

  189. De Bellis, Keshavan, Clark, Casey, Giedd, Boring, Frustaci, Ryan (1999): Bennett Research Award. Developmental traumatology. Part II: Brain development. Biol Psychiatry. 1999 May 15;45(10):1271-84. doi: 10.1016/s0006-3223(99)00045-1. PMID: 10349033. n = 105

  190. Gumusoglu, Fine, Murray, Bittle, Stevens (1995): The role of IL-6 in neurodevelopment after prenatal stress. Brain Behav Immun. 2017 Oct;65:274-283. doi: 10.1016/j.bbi.2017.05.015.

  191. Stevens, Su, Yanagawa, Vaccarino (2013): Prenatal stress delays inhibitory neuron progenitor migration in the developing neocortex. Psychoneuroendocrinology. 2013 Apr;38(4):509-21. doi: 10.1016/j.psyneuen.2012.07.011.

  192. Volk, Lewis (2013): Prenatal ontogeny as a susceptibility period for cortical GABA neuron disturbances in schizophrenia. Neuroscience. 2013 Sep 17;248:154-64. doi: 10.1016/j.neuroscience.2013.06.008.

  193. Muraki, Tanigaki (2015): Neuronal migration abnormalities and its possible implications for schizophrenia. Front Neurosci. 2015 Mar 10;9:74. doi: 10.3389/fnins.2015.00074.

  194. Lussier, Stevens (2016): Delays in GABAergic interneuron development and behavioral inhibition after prenatal stress. Dev Neurobiol. 2016 Oct;76(10):1078-91. doi: 10.1002/dneu.22376.

  195. Ojima, Matsumoto, Tohda, Watanabe (1995): Hyperactivity of central noradrenergic and CRF systems is involved in social isolation-induced decrease in pentobarbital sleep. Brain Res. 1995 Jun 26;684(1):87-94.

  196. Caldji, Francis, Sharma, Plotsky, Meaney (2000): The effects of early rearing environment on the development of GABAA and central benzodiazepine receptor levels and novelty-induced fearfulness in the rat. Neuropsychopharmacology. 2000 Mar;22(3):219-29. doi: 10.1016/S0893-133X(99)00110-4. PMID: 10693149.

  197. Caldji, Tannenbaum, Sharma, Francis, Plotsky, Meaney (1998): Maternal care during infancy regulates the development of neural systems mediating the expression of fearfulness in the rat. Proc Natl Acad Sci U S A. 1998 Apr 28;95(9):5335-40. doi: 10.1073/pnas.95.9.5335. PMID: 9560276; PMCID: PMC20261.

  198. Hausch (2008): FKBP51 – ein neues Zielprotein zur Behandlung von Depression, Forschungsbericht 2008 – Max-Planck-Institut für Psychiatrie

  199. Klengel, Max Plank Institut für Psychiatrie, München, n = 2000

  200. Berndt (2013): Resilienz, S. 151

  201. Ising (2012): Stresshormonregulation und Depressions­risiko – Perspektiven für die antidepressive Behandlung; Forschungsbericht (importiert) 2012 – Max Planck Institut für Psychiatrie

  202. Schiavone, Colaianna, Curtis (2015): Impact of Early Life Stress on the Pathogenesis of Mental Disorders: Relation to Brain Oxidative Stress; Current Pharmaceutical Design, Volume 21, Number 11, April 2015, pp. 1404-1412(9).

  203. Carpenter, Gawuga, Tyrka, Lee, Anderson, Price (2010): Association between Plasma IL-6 Response to Acute Stress and Early-Life Adversity in Healthy Adults; Neuropsychopharmacology (2010) 35, 2617–2623

  204. Danese, Moffitt, Harrington, Milne, Polanczyk, Pariante, Poulton, Caspi (2009): Adverse Childhood Experiences and Adult Risk Factors for Age-Related Disease, Depression, Inflammation, and Clustering of Metabolic Risk Markers. Arch Pediatr Adolesc Med. 2009;163(12):1135-1143. doi:10.1001/archpediatrics.2009.214

  205. Kabiersch, Furukawa, del Rey, Besedovsky (1998): Administration of interleukin-1 at birth affects dopaminergic neurons in adult mice. Ann N Y Acad Sci. 1998 May 1;840:123-7.

  206. Sun Y, Jia T, Barker ED, Chen D, Zhang Z, Xu J, Chang S, Zhou G, Liu Y, Tay N, Luo Q, Chang X, Banaschewski T, Bokde ALW, Flor H, Grigis A, Garavan H, Heinz A, Martinot JL, Paillère Martinot ML, Artiges E, Nees F, Orfanos DP, Paus T, Poustka L, Hohmann S, Millenet S, Fröhner JH, Smolka MN, Walter H, Whelan R, Lu L, Shi J, Schumann G, Desrivières S (2022): Associations of DNA Methylation With Behavioral Problems, Gray Matter Volumes, and Negative Life Events Across Adolescence: Evidence From the Longitudinal IMAGEN Study. Biol Psychiatry. 2022 Jun 22:S0006-3223(22)01356-7. doi: 10.1016/j.biopsych.2022.06.012. PMID: 36241462.

  207. Naumova, Rychkov, Kornilov, Odintsova, Anikina, Solodunova, Arintcina, Zhukova, Ovchinnikova, Burenkova, Zhukova, Grigorenko (2019): Effects of early social deprivation on epigenetic statuses and adaptive behavior of young children: A study based on a cohort of institutionalized infants and toddlers. PLoS One. 2019;14(3):e0214285. doi:10.1371/journal.pone.0214285

  208. Choi, Fauce, Effros (2008): Reduced telomerase activity in human T lymphocytes exposed to cortisol. Brain Behav Immun. 2008 May;22(4):600-5. doi: 10.1016/j.bbi.2007.12.004.

  209. von Zglinicki (2002): Oxidative stress shortens telomeres. Trends Biochem Sci. 2002 Jul;27(7):339-44.

  210. Haussmann, Marchetto (2010): Telomeres: Linking stress and survival, ecology and evolution; Current Zoology 56 (6): 714−727, 2010

  211. Gottschling, Aparicio, Billington, Zakian (1990): Position effect at S. cerevisiae telomeres: reversible repression of Pol II transcription. Cell. 1990 Nov 16;63(4):751-62.

  212. Robin, Ludlow, Batten, Magdinier, Stadler, Wagner, Shay, Wright (2014): Telomere position effect: regulation of gene expression with progressive telomere shortening over long distances. Genes Dev. 2014 Nov 15;28(22):2464-76. doi: 10.1101/gad.251041.114.

  213. Bateson, Nettle (2018): Why are there associations between telomere length and behaviour? Philos Trans R Soc Lond B Biol Sci. 2018 Mar 5; 373(1741): 20160438. doi: 10.1098/rstb.2016.0438; PMCID: PMC5784059; PMID: 29335363

  214. Mackes, Golm, Sarkar, Kumsta, Rutter, Fairchild, Mehta, Sonuga-Barke; ERA Young Adult Follow-up team. (2020): Early childhood deprivation is associated with alterations in adult brain structure despite subsequent environmental enrichment. Proc Natl Acad Sci U S A. 2020 Jan 7;117(1):641-649. doi: 10.1073/pnas.1911264116.

  215. Gómez-González B, Escobar A. Altered functional development of the blood-brain barrier after early life stress in the rat. Brain Res Bull. 2009 Aug 14;79(6):376-87. doi: 10.1016/j.brainresbull.2009.05.012. PMID: 19463912.

  216. Matsumoto, Puia, Dong, Pinna (2007): GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders. Stress. 2007 Mar;10(1):3-12.

  217. Araki, Nishida, Hiraki, Matsumoto, Yabe (2015): DNA methylation of the GC box in the promoter region mediates isolation rearing-induced suppression of srd5a1 transcription in the prefrontal cortex. Neurosci Lett. 2015 Oct 8;606:135-9. doi: 10.1016/j.neulet.2015.08.031.

  218. Matsumoto, Nomura, Murakami, Taki, Takahata, Watanabe (2003): Long-term social isolation enhances picrotoxin seizure susceptibility in mice: up-regulatory role of endogenous brain allopregnanolone in GABAergic systems. Pharmacol Biochem Behav. 2003 Jul;75(4):831-5.

  219. Makinodan, Rosen, Ito, Corfas (2012): A critical period for social experience-dependent oligodendrocyte maturation and myelination. Science. 2012 Sep 14;337(6100):1357-60. doi: 10.1126/science.1220845.

  220. Silva-Gómez, Rojas, Juárez, Flores (2003): Decreased dendritic spine density on prefrontal cortical and hippocampal pyramidal neurons in postweaning social isolation rats. Brain Res. 2003 Sep 5;983(1-2):128-36.

  221. Dong, Matsumoto, Uzunova, Sugaya, Takahata, Nomura, Watanabe, Costa, Guidotti (2001): Brain 5alpha-dihydroprogesterone and allopregnanolone synthesis in a mouse model of protracted social isolation. Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2849-54.

  222. Hartman, Rommelse, van der Klugt, Wanders, Timmerman (2019): Stress Exposure and the Course of ADHD from Childhood to Young Adulthood: Comorbid Severe Emotion Dysregulation or Mood and Anxiety Problems. J Clin Med. 2019 Nov 1;8(11). pii: E1824. doi: 10.3390/jcm8111824. n = 609

  223. Korkhin, Zubedat, Aga-Mizrachi, Avital (2019): Developmental effects of environmental enrichment on selective and auditory sustained attention. Psychoneuroendocrinology. 2019 Oct 19;111:104479. doi: 10.1016/j.psyneuen.2019.104479.