Maternal neglect generate abnormal activation of the brain’s auditory cortex – parvalbumin neurons

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The brain undergoes dramatic change during the first years of life.

Its circuits readily rewire as an infant and then child encounters new sights and sounds, taking in the world and learning to understand it.

As the child matures and key developmental periods pass, the brain becomes less malleable–but certain experiences create opportunities for parts of the adult brain to rewire and learn again.

Cold Spring Harbor Laboratory (CSHL) scientists have been studying one such period of transformation in mice: the time during which an adult female first learns to recognize and respond to the distress cries of young mouse pups.

The research, reported January 7, 2020 in the Journal of Neuroscience, suggests that the same mechanisms that enable rapid learning during early development come into play when a period of heightened learning is triggered during adulthood.

The findings hint at potential therapeutic strategies for a rare neurodevelopmental disorder called Rett syndrome, in which the adult brain may be unable to benefit from the rewiring opportunities.

A few years ago, CSHL Associate Professor Stephen Shea and colleagues discovered that female mice that lack two functional copies of a gene called Mecp2 failed to learn to retrieve distressed young.

The scientists traced this parental neglect to the abnormal behavior of a group of neurons in the brain’s auditory cortex called parvalbumin (PV) neurons. PV neurons are inhibitory neurons: their signals dampen the activity of other brain cells.

During development, the signals of PV neurons help close the critical periods during which the brain is most receptive to change.

This shows neurons


Abnormal behavior of parvalbumin (PV) neurons (in red) in the auditory cortex of the mouse brain manifests as parental neglect. Normal activity of PV neurons depends on the Mecp2 gene, without which female mice can’t learn to respond to distress cries of young pups. Image is credited to Shea lab/CSHL, 2020.

The latest work from the Shea team, led by postdoctoral researchers Billy Lau and Keerthi Krishnan, and conducted in collaboration with CSHL Professor Josh Huang, took a closer look at how exposure to the young pups changes signaling within the auditory cortex of female mice.

By monitoring the activity of individual cells in this part of the brain, the researchers found that when Mecp2 is intact, inhibitory signaling from PV neurons decrease following exposure to an encounter with pups.

This inhibitory signaling allows other neurons in the circuit to become more responsive to the young animals’ cries. “The inhibitory networks sort of back off and allow the excitatory activity to be stronger,” Shea explains.

It’s not yet known exactly how pups trigger these changes in the female mice, but they occurred as long as MECP2 was present–even in mice that had never been pregnant. In female mice whose Mecp2 genes were impaired, however, the PV neurons’ signals remained strong.

In humans, mutations in Mecp2 cause Rett syndrome. Children with Rett syndrome appear develop normally for the first several months of life, but later begin to lose language and motor skills.

The new findings from Shea’s team support previous evidence that PV neurons are particularly vulnerable to loss of MECP2. This suggests that these cells or the circuits they are involved in may be appropriate targets for drug development.

It also suggests that patients with Rett syndrome may be most responsive to treatment during certain developmental periods.

Shea says prior to pup exposure, cells in the auditory cortex behaved the same in the brains of mice with impaired Mecp2 as they did in other mice. “That suggests that Mecp2 is specifically important during windows of heightened learning. That principle might guide treatments that are focused in time, at certain developmental milestones.”


The long-term consequences of exposure to adversity in infancy have been well documented, especially its effects on a child’s development and increased vulnerability for later mental health problems (Kessler et al., 2010; Carr et al., 2013; Reuben et al., 2016).

While adversities such as chronic neglect or abuse have been extensively described in the literature, the negative consequences of exposure to intimate partner violence (IPV) are less well documented. Primary reasons for the dearth of findings are that cases of IPV often go unreported out of fear of consequences or get palliated by the individuals involved.

IPV as defined by the Centers for Disease Control and Prevention is one intimate partner exercising coercive control over the other, including physical and sexual violence, as well as threats of physical or sexual violence, and emotional abuse in the context of physical and sexual violence (Saltzman et al., 1999; Breiding et al., 2015).

As the official definition suggests, most research has focused on the effects of IPV on women, also, child exposure to IPV is often treated different from child maltreatment. Yet, an estimated 10%–20% of children living in the US are annually exposed to IPV (Carlson, 2000). A Canadian incidence study indicated that up to 34% of substantiated investigations into child abuse and neglect were characterized as child exposure to IPV (Trocmé, 2010).

Research is exceptionally scarce on the effects of exposure to IPV during the perinatal phase and infancy, even though the assumed harm is significant enough for the WHO to recommend standardized screening for IPV during pregnancy and to call for increased research on prevention for IPV’s adverse effects (World Health Organization, 2011).

Research shows that exposure to adversity over the first 5 years of life can have lasting effects on brain development (Perry, 2002; Fox et al., 2010; Bick and Nelson, 2016). Throughout this sensitive period, interactions with the primary caregivers are a vital learning environment and a primary developmental context. Both positive and negative experiences alike affect the socio-emotional and cognitive development of the child and maturation of associated brain structures (Schore, 2001).

Two critical aspects of the interaction with the primary caregivers are essential for brain development:

(1) a secure ongoing relationship or attachment between caregiver and child; and

(2) a sensitive co-regulation with the caregiver in the presence of a stressor to help the child to develop and increase its capacity for independent emotion regulation.

A secure ongoing relationship to a caretaker(s) is fundamental for successful development. Critically, a secure relationship buffers the infant’s hormonal stress response and therefore, protects the developing brain from harmful effects of stress hormones (Gunnar and Donzella, 2001; Tronick, 2017).

In contrast, a lack of self-experienced security for the child leads to an increased risk for behavioral problems (Dozier et al., 2001; Belsky and Fearon, 2002) and decreased environmental exploration which compromises the development of cognitive skills associated with school readiness (Moss et al., 1993). Ongoing caregiver relationships that do not provide a sense of safety fail to buffer the hormonal stress responses exposing the infants’ brain to adverse stress effects (Zeanah and Gleason, 2010).

Emotion regulation refers to the child’s ability to modulate and adjust to her levels of arousal (Cole et al., 2004). The frontal lobe, central for the development of emotion regulation, undergoes a period of rapid growth and synaptic excess around 6–18 months of age, making this a critical period for the infant to learn how to respond to emotions (Dawson, 1994; Nelson and Bosquet, 2004).

Until self-regulation of emotion is well developed the caregivers are a source of external regulation for the child, hence the caregivers play a vital role in the development of emotion regulatory behaviors. Sensitive responding to the child’s regulatory needs by a caregiver helps the child to regulate stress and to better control stress hormones.

This, in turn, helps the child to learn how to regulate herself more effectively. Emotion regulation skills are necessary for the child for learning and focus attention, essential skills to excel in school (Perry, 2001; Cook et al., 2017). By contrast, insensitive caretaking compromises the child’s regulation of arousal and stress.

Simply put, a distressed or highly aroused child does not feel safe and is unable to engage with people or objects in the world (Wittling and Schweiger, 1993; Schore, 2001; Cook et al., 2017). Thus, less optimal regulation by a caretaker(s) can become toxic for the child. In sum, these early experiences of sensitive regulation or insensitive maltreatment and dysregulation are critical for the child’s development be it good or ill (Sroufe and Rutter, 1984; Tronick, 2017).

Exposure to IPV can influence both the infant and the caretaker, interfering with the dyadic co-regulation of emotions. IPV can disrupt the caregiver’s ability for optimal caregiving as they may have difficulty regulating their own emotions in the context of violence or are affected by IPV-related psychopathology such as depression and anxiety (Letourneau et al., 2011; Pels et al., 2015).

Several studies find that IPV leads to poor mother-infant attachment. Women who experienced IPV during pregnancy or in the first postpartum year had weaker attachments to their infants, perceived their infants as more difficult, and had more doubts about their parenting qualities compared to women not exposed to IPV (Zeitlin et al., 1999; Huth-Bocks et al., 2004; Quinlivan and Evans, 2005). This corroborates research indicating that exposure to IPV is a risk factor for the development and maintenance of secure attachments between mother and child (Sims et al., 1996; Zeanah et al., 1999).

Exposure to IPV During the Perinatal Period

Increasing evidence indicates that self-reported IPV during pregnancy and the perinatal period is associated with poor health outcomes for the fetus, newborn, and infant up to 1 year postpartum (Cokkinides et al., 1999; Boy and Salihu, 2004; Coker et al., 2004; Rosen et al., 2007; Sarkar, 2008).

Exposure to violence increases significant risk factors during the perinatal period, such as a four-times as high risk for antepartum hemorrhage, a condition that can be fatal for the unborn (Janssen et al., 2003; Han and Stewart, 2014).

Well established as well are increased risk for low birth weight (Lipsky et al., 2003; Silverman et al., 2006; Rosen et al., 2007), intrauterine growth restriction (Janssen et al., 2003), preterm delivery (Lipsky et al., 2003; Sarkar, 2008), and overall increased fetal morbidity (for review see Boy and Salihu, 2004; Donovan et al., 2016).

Furthermore, maternal high-stress levels during pregnancy, for example, due to exposure to IPV can affect the fetus and its neurohormonal chemistry. The womb is a shared environment with the mother and experiences that affect her can, in turn, affect the developing fetus. For example, the placenta produces an enzyme (11beta-hydroxysteroid dehydrogenase type 2) that breaks down cortisol to an inactive form, protecting the developing fetal brain from its harmful effects.

During pregnancy exposure to high-stress contexts increase maternal cortisol along with a downregulation of the enzyme can result in more cortisol reaching the fetus. This exposure can lead to changes in behavioral development (O’Donnell et al., 2009; Davis and Sandman, 2010; Conradt et al., 2013; Ramborger et al., 2018), a larger infant cortisol response, a slower rate of recovery after experiencing a stressor (Davis et al., 2011), as well as make the infant more susceptible to stress later in life (Davis and Sandman, 2010).

Conradt found that high stress during pregnancy leads to epigenetic changes in both the mother and the infant and reduced attentional capacities in infants at 4 months of age (Conradt et al., 2013). While only two studies have looked at the stress exposure of women exposed to IPV during pregnancy, both found a significant increase in self-reported stress levels (Chambliss, 2008) and higher levels of the stress hormone cortisol (Han and Stewart, 2014) related to IPV during pregnancy.

Exposure to IPV During Infancy and Early Childhood

IPV has a high incidence (70%–80%) to occur during the first year postpartum when at least one incident of IPV during pregnancy was reported (Martin et al., 2001; Charles and Perreira, 2007).

Symptoms of Trauma and Psychopathology

In the absence of language, trauma is difficult to diagnose in young infants. Nonetheless, symptoms reported in infants exposed to IPV are consistent with the definition of trauma in the Zero to Three (Organization) and DC: 0-3R Revision Task Force (2005), which provides diagnostic classification criteria for mental health disorders in infancy and early childhood. Descriptions of infants exposed to IPV include eating problems, sleep disturbances, and mood disturbances (Layzer et al., 1986).

Clinical studies find poor sleeping habits, poorer general health, higher irritability, and increased screaming and crying (Alessi and Hearn, 2007). A study looking at multiple forms of traumata in infants, including IPV, found that trauma due to witnessing a threat to a caregiver was related to the most severe symptoms and increased hyperarousal and fear (Scheeringa and Zeanah, 1995; Zeanah and Gleason, 20102015).

Moreover, the number of trauma symptoms shows an association with the number of IPV episodes witnessed (Bogat et al., 2006), indicating that an accumulation of trauma symptoms with the accumulation of IPV incidents witnessed by the infant. Next to symptoms of increased arousal, fear, and aggression, interference with development was the most frequently reported symptom of trauma in infants who witnessed severe forms of IPV.

For example, the temporary loss of an already acquired developmental skill, such as toilet training or even language. An exceptional study that observed 1-year-old infants in an experimentally simulated situation of adult conflict found that children who previously were exposed to IPV at home as infants showed increased behavioral distress compared to children who had no previous exposure.

The finding is indicative of an increased sensitivity to stress as a result of IPV in the first year of life (DeJonghe et al., 2005). Next to a much-needed increase in clinical assessment and longitudinal monitoring of IPV, experimental studies of simulated IPV combined with neurologic and neurohormonal measures on infants and children would greatly advance our understanding how IPV influences the development of regulatory skills and sensitivity to stress.

“Violence becomes traumatic when the victim does not have the ability to consent or dissent, which, in turn, is linked with the universal experience of helplessness and hopelessness engendered by victimization” (Sluzki, 1993, p 179).

Exposure to violence, such as IPV, has been recognized as a stressor with a magnitude to produce long-term consequences, including PTSD symptoms in children. Preschool children exposed to IPV show more behavior problems (Hughes, 1988) and significantly lower self-esteem than do older, school-aged children exposed to IPV (Elbow, 1982).

Experiencing abusive violence in the home interferes with the child’s developing sense of security and belief in a safe, just world and exceeds the child’s capacity for self-regulation. Evidence shows that exposure to IPV increases the child’s attention towards threatening stimuli, a behavioral pattern that is known to increase the risk to develop internalizing problems, including social and general anxiety, social withdrawal and depression (Kiel and Buss, 2011; Luebbe et al., 2011; Miller, 2015).

Externalizing and behavioral problems in children exposed to IPV are also reported to be elevated compared to unexposed (Graham-Bermann and Perkins, 2010). Thus, the age of first exposure to violence along with the cumulative amount of violence witnessed both have a significant effect and increase the risk for the development of externalizing behavior (Graham-Bermann and Perkins, 2010).

There is a significant overlap in psychosocial problems of children who either witnessed IPV or were physically abused themselves. A meta-analysis reported that both groups showed significantly more adverse psychological outcomes compared to children who were neither exposed to IPV nor physically abused themselves at home (Kitzmann et al., 2003). In sum, it appears that any violence, including exposure to IPV at home can have detrimental effects on children’s mental health.

Cognitive Development

Witnessing IPV does not only affect socio-emotional development, several studies have found an impact on a child’s IQ and cognitive functions, such as memory (Jouriles et al., 2008; Graham-Bermann et al., 2010).

A study on 1,116 twins found that childhood exposure to IPV was related to a decreased IQ compared to unexposed children, and the severity and number of violent episodes exposed to at home were associated with a greater decrease in IQ.

Another study found that children who witnessed IPV on average had an 8-point lower IQ than unexposed children, even when controlling for possible confounding variables suggesting an interplay between trauma-related distress and cognitive skills in children who witnessed IPV at home (Delaney-Black et al., 2002; Koenen et al., 2003). As with emotional development, a longitudinal study found that severe compromising cognitive effects are cumulative and that repeated and increased exposure to IPV was predictive of school engagement (Schnurr and Lohman, 2013).

Impact of IPV on Brain Development

Adverse childhood experiences, including exposure to IPV, have measurable effects on multiple areas of the brain. Even though there is no study looking directly at the effect of exposure to IPV on the brain during infancy, we can look at retrospective studies of different brain structures maturing during infancy and early childhood. Exposure to adverse experiences, including IPV, affects the development of the Hypothalamus-Pituitary-Adrenal (HPA) axis and brain structures related to witnessing itself (auditory and visual cortex).

The HPA Axis

Adversity has been reported to affect the development of the HPA Axis. The HPA axis is a critical stress response system, enabling appropriate responding to stressors and the return of the body to homeostasis. While this stress response is essential and helpful to adapt to everyday stressors appropriately, a chronic activation due to chronic exposure to stress can predispose to psychological, immune and metabolic alterations, and associated detrimental effects due to exposure to excess glucocorticoids.

In infancy and childhood, the HPA axis and cortisol reactivity are still maturing (Gunnar and Donzella, 2001), making the system vulnerable to adverse experiences (Tarullo and Gunnar, 2006). More important, changes due to high-stress exposure during this critical time of maturation may not only be long-lasting but also be harder to treat as a normal functioning may never have been established.

During infancy and early childhood, the production of the stress-hormone cortisol appears to be buffered and insensitive to a number of stressors. In both, humans and rodents, maternal caregiving has been identified as a primary factor in the infants HPA hyporesponsivity (Lupien et al., 2009).

This buffering effect through the caregiver likely protects the infant brain from the harmful effects of high levels of cortisol and is therefore even more critical in high-stress environments such as ones in which there is chronic exposure to IPV.

In humans, sensitive caregiving and co-regulation have been shown to contribute to lower levels of cortisol, while lower quality of care or insecure attachment, as often reported for children with exposure to IPV, are often associated with elevated levels of the stress-hormone (Spangler and Grossmann, 1993; Nachmias et al., 1996; Dettling et al., 2000; Ahnert et al., 2004; Müller et al., 2015).

One study reported that salivary cortisol levels in 1-year-old infants are negatively correlated with electroencephalogram (EEG) potentials, indicating that brain activity is directly affected by elevated levels of cortisol (Gunnar and Nelson, 1994).

Chronic high levels of cortisol lead to cell death, especially in those brain structures with a high density of glucocorticoid receptors (Virgin et al., 1991). For example, cell death has been found in humans taking high-dose cortisol medication (e.g., for asthma).

Adults and children showed decreased verbal memory, and a decline in explicit memory, both cognitive functions that are related to the hippocampus (Bender et al., 1991; Newcomer et al., 1994), and the observed effects were dose-dependent. That a medical form of cortisol can have such a severe impact on cognitive performance strongly suggests that stress-linked cortisol concentrations due to chronic exposure to IPV or any high-stress environment can have harmful consequences for the developing brain of the infant.

Auditory and Visual Cortex

Witnessing even just verbal abuse between caregivers as part of IPV, without physical violence, can have observable impacts on the developing brain. Magnetic resonance imaging (MRI) scans show differences in gray matter density in the arcuate fasciculus in the left superior temporal gyrus, an area involved in language processing, with a reduction in young adults who reported witnessing parental verbal abuse starting at the age of 3–13 years.

In a similar sample, diffusion tensor imaging (DTI) scans found a significant reduction of white matter volume in temporal gyrus associated with exposure to verbal abuse. Critically, these reductions showed a significant correlation to verbal IQ and language comprehension (Choi et al., 2009; Tomoda et al., 2011).

The visual cortex processes emotional stimulation and information. Strikingly, repeated visual exposure to IPV was related to reduced volume in the visual cortex and diminished connections between visual cortex and limbic system.

Most important, the observed reductions in brain volume and intra-neuronal connections were directly associated to the chronicity of exposure before the age of 12 (Choi et al., 2012; Tomoda et al., 2012). These findings indicate that early exposure to IPV, such as witnessing verbal abuse between caregivers could have affected the integrity of specific brain 


Source:
Cold Spring Harbor Laboratory
Media Contacts:
Sara Roncero-Menendez – Cold Spring Harbor Laboratory

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