Early life experiences can have an outsized effect on brain development and neurobiological health.
New research is showing that those effects can be passed down to subsequent generations, reporting that the infant children of mothers who had experienced childhood emotional neglect displayed altered brain circuitry involved in fear responses and anxiety.
The study appears in Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.
“These results show that our brain development is not only shaped by what happens in our own life, but is also impacted by things that happened to our parents before we were even conceived,” said lead author of the study, Cassandra Hendrix, Ph.D., Department of Pyschology, Emory University, Atlanta, GA, U.S..
Dr. Hendrix and her colleagues studied 48 Black mother-infant pairs starting in the first trimester of pregnancy. Mothers were given a questionnaire to assess childhood trauma (experiences of early abuse or neglect).
The mothers were also evaluated for current, prenatal stress levels, and for anxiety and depression. One month after birth, infants underwent a brain scan using resting-state functional magnetic resonance imaging, a non-invasive technology that could be used while the babies slept naturally.
“These remarkable results leverage our ability to image the brain and its functioning very early in life,” said Cameron Carter, MD, Editor of Biological Psychiatry: Cognitive Neuroscience and Neuroimaging.
The researchers focused on brain connections between the amygdala, which is central to processing fearful emotions, and two other brain regions: the prefrontal cortex and the anterior cingulate cortex.
Both areas play a key role in regulating emotions. Babies whose mothers experienced childhood emotional neglect had stronger functional connections between the amygdala and the cortical regions.
After controlling for mothers’ current stress levels, the researchers found that the more emotional neglect a mother had experienced during her own childhood, the more strongly her baby’s amygdala was connected to the frontal cortical regions.
Physical abuse or neglect of the mother were not correlated with the stronger connectivity. The findings suggest that childhood emotional neglect has intergenerational effects on brain structure and function.
The significance of the stronger connection remains unclear, said Dr. Hendrix. “The neural signature we observed in the 1-month-old infants of emotionally neglected mothers may be a mechanism that leads to increased risk for anxiety, or it could be a compensatory mechanism that promotes resilience in case the infant has less supportive caregivers.
In either case, emotional neglect from a mother’s own childhood seems to leave behind a neural signature in her baby that may predispose the infant to more readily detect threat in the environment almost from birth. Our findings highlight the importance of emotional support early in life, even for subsequent generations.”
“The findings add to evidence of the intergenerational consequences of early life adversity, such as maternal neglect,” added Dr. Carter. “Future studies that follow children longitudinally will help us understand the functional significance of these changes in brain function in terms of the emotional and social development of children of mothers who experienced early neglect.”
Neurobiological consequences of early life stress
While strong arguments have been made for using one type of conceptualization over another [14, 15, 47], careful examination of this literature suggests that there are commonalities in findings across the two approaches. Here, we focus on some general recent themes across this literature with implications for human development.
Early life stress is consistently associated with altered functioning of the hypothalamic pituitary adrenal (HPA) axis and autonomic nervous system [33, 54, 64]. These systems are critical to facilitating motived psychological and behavioral responses to the environment, particularly environmental threats and challenges [65, 66].
Additionally, growing evidence suggests that early life stress is associated with alterations in the immune system and inflammatory activity, which is increasingly implicated in producing shifts in individuals’ behavioral responses to their environment [46, 67].
Together, these changes in peripheral physiological systems are critical for facilitating adaptive responses to threat and challenge. In addition, altered activity of these systems is associated with negative mental and physical health consequences after stress exposure [68,69,70].
The effects of early life stress on these peripheral stress response systems are thought to be a result of altered neural plasticity in circuits integral to stress responses, including the prefrontal cortex (PFC), hippocampus, amygdala, and striatal circuits [15, 71]. There is also a growing corpora of research implicating epigenetic changes in the regulation of many of these effects [34, 72].
Many of these changes have been hypothesized to represent adaptive responses to environments of high threat which become problematic within the broader social context [73, 74]. Below, we review the current state of the literature linking early life stress to altered brain function, and some of the potential hormonal, psychophysiological, neural, and genetic mechanisms thought to support these effects.
Neural consequences of early life stress and their proposed mediating mechanisms
Alterations in prefrontal–hippocampal–amygdala circuits
Research in both non-human animals and humans suggests that early life stress is linked to pronounced effects on the development of prefrontal–hippocampal–amygdala circuits. These circuits play an important role in facilitating peripheral stress responses through the release of corticotrophin reducing hormone (CRH) and glucocorticoids and regulation of the autonomic nervous system [9, 75].
Additionally, these circuits are implicated in emotion processing, self-regulation, and memory and learning [76,77,78]. Rodents exposed to abusive maternal behaviors or maternal separation as pups show decreased dendritic arborization throughout the PFC and hippocampus [79, 80].
Experiences of chronic restraint stress in adult rodents result in increased dendritic arborization in the amygdala [81, 82], and there is some evidence for similar effects in the amygdala after experiences of stress as pups . In association with these structural changes, rodents demonstrate modifications in synaptic signaling and epigenetic changes in the hippocampus and amygdala [34, 84,85,86].
These changes in synaptic structure and signaling are thought to produce increased sensitivity to threat in the environment, through decreased regulation of the amygdala by the PFC and hippocampus [87, 88]. Additionally, they have been associated with increased anxiety and depressive-like behaviors in animals after experiences of early life stress [89,90,91,92].
Changes in hippocampal synaptic plasticity have also been linked to altered memory and learning processes, with rodents’ demonstrating reduced spatial memory [93, 94] and enhanced threat learning [95, 96].
The changes throughout the PFC, hippocampus, and amygdala and their associated effects on behavior, memory, and learning appear to be at least partially mediated by chronic exposure to CRH and glucocorticoids induced by chronic stress [93, 97,98,99].
For example, rat pups exposed to chronic stress in the form of fragmented maternal behaviors demonstrate augmented expression of CRH in the hippocampus and memory deficits. Blocking CRH receptors resulted in improved memory performance and prevented dendritic atrophy in the hippocampus .
Chronic maternal separation stress in mice is associated with decreases in glucocorticoid receptor mRNA in the brain, especially so in the amygdala, which is in turn associated with alterations in anxiety-like and social behaviors. Restoring the glucocorticoid receptor mRNA deficit in the amygdala reverses the changes in anxiety and social behavior . Additionally, in male mice, enhanced freezing behavior in the context of a conditioned threat paradigm after exposure to fragmented maternal behaviors can be reversed by blocking glucocorticoid receptors .
In humans, similar changes in brain structure and function after experiences of stress in childhood are evidenced in the amygdala, PFC, and hippocampus. Indeed, one of the most reliable findings in children exposed to early life stress is reduced hippocampal volume [29, 53, 56].
Reduced hippocampal volume in children exposed to a range of different types of early life stress, including abuse, neglect, and living in poverty, has been linked to increased symptoms of psychopathology [101,102,103,104]. Additionally, changes in hippocampal volume are thought to be associated with deficits in learning processes in children who experience early life stress [7, 105, 106].
A growing literature also indicates that early life stress is associated with changes in amygdala and PFC reactivity to emotional stimuli as well as altered connectivity between the two regions [51, 52, 107]. Cumulative stress, severe neglect from early institutionalization, and abuse have all been associated with heightened amygdala reactivity to emotional images [28, 108, 109]. This heightened reactivity appears to be at least partially a result of altered PFC–amygdala connectivity, leading to increased sensitivity to emotionally salient cues [107, 110, 111].
Indeed, children with a history of maltreatment, which includes emotional, physical, and sexual abuse and emotional and physical neglect, appear to demonstrate atypical connectivity between the amygdala and inferior frontal gyrus , and children growing up in poverty is associated with atypical ventrolateral PFC–amygdala connectivity .
Longitudinal work suggests that children exposed to various forms of early life stress demonstrate an atypical trajectory of age-related changes in PFC–amygdala connectivity as compared to peers who were not exposed to early life stress . The strength of PFC–amygdala connectivity appears to mediate the relationship between maltreatment exposure and anxiety and depressive symptoms [114, 115].
Structural and functional alterations in PFC–hippocampal–amygdala circuits in individuals exposed to various forms of early life stress suggests that alterations in these circuits play an important role in the relationship between early life stress and its effects on development.
As with non-human animals, there is also evidence that changes in CRH and glucocorticoid function may partially mediate the neural effects described above [34, 54]. Indeed, there is some evidence that humans demonstrate similar epigenetic changes in glucocorticoids to those observed in non-human animals, and these alterations are associated with changes in the hippocampus, symptoms of psychopathology, and altered learning processes [72, 116,117,118].
Additionally, abnormal hypothalamic pituitary adrenal responsivity is often observed after a variety of experiences of early life stress, including poverty, family violence, maltreatment, and institutional deprivation, although this varies with age [54, 68].
This, in parallel with the animal literature demonstrating that extended exposure to glucocorticoids leads to hippocampal atrophy and dysregulation of the HPA axis [119, 120], has given rise to the hypothesis that chronic activation of the HPA axis through exposure to severe and/or extended stress leads to neural alterations in the PFC, hippocampus, and amygdala.
This in turn produces dysregulation in systems responsible for responding to potential threats and challenges in the environment [64, 71]. This dysregulation of stress response systems can lead to increased risk for both mental and physical health issues [121,122,123].
The effects of early life stress on PFC–hippocampal–amygdala circuitry are thought to be in part related to alterations in emotion processing produced by the types of early inputs children in high stress environments experience. Relative to non-maltreated children, children who experience physical abuse have heightened perceptual and physiological sensitivity to angry facial expressions [124, 125] and are more likely to perceive emotional situations as demonstrating anger as early as preschool age .
Physically abused children also more readily categorize faces that are morphed between two different emotions as angry  and require less perceptual information to identify faces as angry than non-maltreated children . Additionally, physically abused children show biases to angry faces during cognitive tasks.
They respond more quickly to angry faces during a Go/No-Go paradigm  and seem to require greater cognitive resources to disengage their attention from angry faces, showing delayed disengagement when angry faces served as invalid cues in a selective attention paradigm .
Children who are exposed to extreme threat appear to preferentially attend to and identify facial movements that are associated with threat, such as a scowling facial configuration [125, 128,129,130,131], and more reliably track the trajectory of facial muscle activations that signal threat .
This close attention to cues of anger likely shapes how abused children understand what facial movements mean. For example, one study found that 5-year-old abused children tended to believe that almost any kind of interpersonal situation could result in an adult becoming angry; by contrast, most non-abused children understand that anger is likely in particular interpersonal circumstances .
Studies of maltreated children (including those who experience neglect and other forms of abuse) also show less accurate identification of facial emotions in general [41, 131] and particular difficulty identifying positive emotions .
In addition, these children demonstrate abnormalities in the expression and regulation of emotions . Neglected children show delays in perceiving emotions in the ways that adults do . Maltreated children also show higher levels of rumination (repeatedly dwelling on past negative experiences), which has been associated with an attention bias to sad faces  and may contribute to risk for depressive symptomatology.
The combination of difficulties with emotional recognition, expression, and regulation may increase children’s risk for a broad range of maladaptive outcomes. For example, misreading others’ facial emotion might impair peer interactions, while problematic emotion regulation and expression may contribute to rumination and/or aggressive behavior.
The effects of maltreatment on children’s recognition of and attention to emotion are thought to, in part, be shaped by the broader environment in which they are raised. Children who grow up in environments where emotional interactions with caregivers are highly atypical have different developmental trajectories than do those growing in more consistently nurturing environments .
Parents from these high-risk families signal emotions unclearly, and express more anger [14, 29, 137, 138]. Together, this suggests that exposure to increased levels of potential threat alters children’s perceptual processes such that they become more likely to perceive situations others may not find threatening as threat, likely resulting in extending activation of prefrontal–hippocampal–amygdala circuits and associated peripheral stress response systems.
Alterations in prefrontal–striatal dopaminergic circuits
Recent evidence suggests that early life stress also has a range of negative effects on dopaminergic circuits involved in motivation, specifically those related to reward processing [138, 139]. Animal models of early life stress have been associated with changes in circuits classically implicated in motivation to obtain and pursue rewards, including the ventral striatum, prefrontal cortex, and amygdala [140, 141].
Chronic repeated separation of rodent pups from their mothers alters the number of dopaminergic glial cells, affects rate of cell proliferation and death, and promotes aberrant dopaminergic signaling in the ventral tegmental area and substantia nigra in adulthood [142,143,144].
Additionally, alterations in maternal care have been associated with reduced connectivity between the PFC and caudate putamen  as well as structural and functional alterations in the nucleus accumbens [79, 146]. These changes have been linked to increased anhedonia-like behaviors [147, 148] and altered sensitivity to reward, both hyper- and hyposensitivity depending on the paradigm utilized [149, 150]. As with changes in the hippocampus and amygdala, chronic exposure to glucocorticoids, through interactions with dopaminergic neurons, appears to play an important role in mediating some of these effects [151,152,153].
In humans, disruptions during reward processing have been observed in the nucleus accumbens, ventral tegmental area, ventral striatum, and PFC after experiences of early life stress [154,155,156,157], and these disruptions are associated with depressive and anxiety symptoms in adolescents and adults [158,159,160,161] as well as altered reward learning [11, 15].
Specifically, children who experienced maltreatment demonstrate decreased striatal, orbitofrontal cortex, and hippocampal activation during reward learning , and children with high early life stress demonstrate decreased activation of the putamen and insula when anticipating future losses .
Additionally, in children exposed to early life stress, ventral striatal activation has been demonstrated to mediate variation in reward related learning . Importantly, these circuits are highly connected with both the amygdala and prefrontal cortex, which together play a key role in psychological and behavioral responses to stress, emotional and social learning, and self-regulatory processes [163, 164]. These disruptions likely then place children at increased risk for maladaptive behaviors, along with negative mental and physical health outcomes later in life.
reference link: https://jneurodevdisorders.biomedcentral.com/articles/10.1186/s11689-020-09337-y
More information: Cassandra L. Hendrix et al, Maternal childhood adversity associates with frontoamygdala connectivity in neonates, Biological Psychiatry: Cognitive Neuroscience and Neuroimaging (2020). DOI: 10.1016/j.bpsc.2020.11.003