The locus coeruleus (LC)-norepinephrine/SNS system becomes activated indirectly through the central amygdala when the hypothalamus releases CRH in response to a stressor. The activation of the locus coeruleus causes an increase in the release of norepinephrine throughout the brain, resulting in symptoms of PTSD and anxiety. The locus coeruleus is an older brain structure that increases sympathetic nervous system activation (SNS). This is part of the autonomic nervous system that controls the “fight or flight or freeze” response. The catecholamines (epinephrine, dopamine, and norepinephrine) and corresponding increased activity in the SNS work to prepare people for action by redistributing blood away from the skin, intestines, and kidneys and to the brain, heart, and skeletal muscles. It also redirects energy through a central dopamine mechanism that obstructs the prefrontal cortex, going from thinking and planning mode to survival and alertness mode. Studies on adults and children overall have constantly highlighted the overwhelming activity of the locus coeruleus (LC)-norepinephrine/SNS system that is connected with childhood trauma and PTSD. On the other hand, the lack of regulation of the system that stems from trauma can be related to antisocial behavior and dissociation.

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The LHPA Axis is instrumental in regulating the body's response to stress and is the most explored biological stress system amongst animals and humans. The activation of the LHPA axis triggers the hypothalamus to produce corticotrophin-releasing hormone (CRH). This is also known as a corticotrophin-releasing factor (CRF), a vital interceder of the stress response. CRH is referred to when explaining the job of the neuroendocrine system, while CRF is referred to when explaining the job as a neurotransmitter. CRH is known to stimulate the release of adrenocorticotrophic hormone (ACTH) by attaching to CRH receptors in the anterior pituitary. The ACTH then attaches to the G protein-couple receptors in the adrenal cortex, specifically in the zona fasciculata of the adrenal glands. ACTH encourages the secretion of cortisol, a glucocorticoid hormone detrimental to the central nervous system (CNS). Cortisol initiates glucocorticoid and mineralocorticoid receptors that are located throughout the brain. The glucocorticoid receptors act as transcription factors and control gene expression for metabolism, immune function, and cognitive and brain development. CRF is part of the stress response, learning, and memory. Cortisol controls the stress response system in the hippocampus and medial prefrontal cortex (mPFC).

The Neurobiology of Biological Stress Systems Limbic-Hypothalamic-Pituitary-Adrenal (LHPA) Axis

De Bellis, M. D., & Zisk, A. (2014). The biological effects of childhood trauma. Child and adolescent psychiatric clinics of North America, 23(2), 185–vii. https://doi.org/10.1016/j.chc.2014.01.002

References for the Biological Effects of Childhood Trauma

Being exposed to severe stress and trauma in youth can disrupt the regulatory processes of the LHPA axis across the lifespans of animals and humans. For animals, introducing CRF at a young age can produce an impediment in later life that surrounds erased cognitive function, a reduced number of CA3 hippocampal neurons, and a decreased branching of hippocampal pyramidal neurons. While there is info on the LHPA system that is dysregulated in youth exposed to trauma, the cortisol regulation seems contradictory. No differences in cortisol response, blunted cortisol, or increased cortisol concentration have been reported in maltreated children and adults. The ACTH shows how these findings were both blunted and increased levels were reported in maltreated depressed children and adults.

The LHPA Axis and Childhood Trauma

The Locus Coeruleus-Norepinephrine/Sympathetic Nervous System (SNS)/Catecholamine System and Childhood Trauma

Serotonin is a principal element within the stress response system. Serotonergic neurons project repetitiously from the central serotonin raphe nuclei in the midbrain to important cortical and subcortical brain regions that play detrimental roles in regulating emotions, behaviors, cognitive function, motor function, appetite, and the regulation of many physiological processes. Serotonin is a vital regulator of morphogenetic activities during early brain development, as it influences cell proliferation, migration, and differentiation. This then influences the child's brain development. Having disruptions in serotonin's regulatory functioning can be linked with several psychopathological disorders that are seen in children and adults who have experienced childhood trauma. It has been found that early trauma dysregulates serotonin in humans. This is due to the short allele of the serotonin transporter gene promoter polymorphism (5-HTTLPR) interacting with maltreatment in developing childhood depression. Children who ended up having homozygous short alleles ended up being more susceptible to depression only if there was maltreatment experienced. This is because the short allele deals with reduced transcriptional activity of serotonin, and there is less central serotonin in the brain.

The Serotonin System and Childhood Trauma

Oxytocin is vital in interpersonal relationships as it regulates an individual's sexual response and milk production. The hormone governs a broader range of social interactions, such as social memory and cognition, emotion recognition, empathy, and attachment. The Oxytocin system is also involved in regulating the body's response to stress. Research demonstrates how adverse life circumstances can disrupt the body's regulation of oxytocin. Research has also highlighted how there are gender differences related to the relationship between childhood trauma and oxytocin regulation. In terms of oxytocin responses to experimental stress for both abused boys and girls, girls had higher levels of oxytocin and decreased levels of cortisol after being exposed to physical abuse. For boys, there was no difference in hormone response to the stress. Further study in women found that those who were exposed to early maltreatment had lower levels of oxytocin, which highlights the possible relationship, considering the maltreatment was emotional abuse.

The Oxytocin System and Childhood Trauma

Activating the immune system includes the creation of cytokines, which help with inflammatory reactions to infections or pathogens in the body. While one of the main effects of the inflammatory responses is to make the physical symptoms of sickness, the activation of cytokines that help inflammation are involved in depression. This ends up being an expected outcome of early trauma. A study ended up providing evidence that supports the relationship between pro-inflammatory cytokines and heightened levels of depression and anxiety in adolescents. There have been higher levels of plasma antinuclear antibody titers found in sexually abused girls, which indicates that being exposed to that form of trauma and stress can discourage the body from suppressing B lymphocytes. This results in there being higher levels of antibody titers that are found in girls who are abused. Other studies have found that children who have been exposed to a more significant number of these adverse childhood risk factors had an increase in age-related disease risk in their adulthood. The increased activation of cytokines and dysregulation of the immune system, along with the other biological stress response systems that happen in response to early adversity, can end up leading to hypertension, accelerated atherosclerosis, metabolic syndrome, impaired growth and immune system suppression, and poorer medical health in adults who have child trauma histories.

The Immune System and Childhood Trauma

Cross-sectional studies that examined maltreatment trauma in childhood have shown lower IQs and inadequacies in language and academic achievements. The connection between early trauma and IQ has been displayed through twin studies, where domestic violence was linked with a lower IQ for children who had been exposed. In addition to lower IQs, other areas of cognitive functioning affected were complex visual attention, visual memory, language, verbal memory, problem-solving, and more. Longitudinal prospective studies that involve adolescents and adults who are exposed to childhood maltreatment are up to par with cross-sectional studies and have shown lower IQ scores and deficiencies in reading abilities. Research on the effects of early trauma on cognitive function shows that early trauma is connected with adverse cognitive development and that it is displayed in negative and delayed brain development.

The Effect of Childhood Trauma on Neuropsychological Functioning and Cognitive Development

1. Being exposed to cumulative life stress was found to be linked with poorer spatial working memory performance and lower volumes of white and gray matter in the prefrontal cortex amongst those who were not maltreated. On the other hand, cerebral and cerebellar volumes are smaller in abused and neglected youth. Having smaller cerebral volumes was also linked with having PTSD trauma earlier, and it was negatively linked to the duration of abuse. Some of the PTSD symptoms that are related to intracranial volume and total corpus callosum measures are intrusive thoughts, avoidance, hyperarousal, and dissociation. 
2. Low socioeconomic status influences brain maturation through ecological variables. Children who had PTSD from maltreatment had smaller intracranial, cerebral, and prefrontal cortex, prefrontal cortical white matter, and right temporal lobe volumes. Regarding brain volumes, larger lateral ventricles were only found in maltreated males. This highlights how males are more susceptible to the neurotoxic effects of childhood maltreatment.
3. Areas of executive function show how there is adverse brain development in children who have maltreatment-related PTSD. Evidence also highlights how a decrease in N-acetylaspartate (NAA) concentrations is linked to an increase in metabolism and a loss of neurons. Childhood maltreatment hurts the brain networks that allow a person’s ability to think and regulate their sense of self, motivations, and behaviors.
4. The hippocampus is an essential part of memory. Studies have found that children who have been mistreated and adolescents who have PTSD or subthreshold PTSD showed no differences in limbic structures. There have also been functional brain differences in the amygdala and hippocampus within maltreated youth, suggesting that hippocampal atrophy is a dormant effect of childhood maltreatment.
5. Childhood maltreatment is linked with adverse brain reward region development. This includes recognizing emotions and social cognition. In adults who were verbally abused, they had reduced fractional anisotropy. In adults who were sexually abused, there were connections with reductions in the hippocampus corpus callosum or frontal cortex, mainly if it occurred in developmental age periods. 
6. Neuroimaging studies of adults who have PTSD have decreased levels of executive and attentional function, as reflected by a decrease in activation in the dorsal control networks. They also increase the amygdala and hippocampus activation, along with other areas of the affective emotional networks. This means that they have dorsal control network deficits and have PTSD as adults. 
7. Specific types of abuse and neglect add to the intergenerational cycle of emotional and behavioral problems and addiction due to the higher level of T2 relaxation time. 
8. Genetic factors are also involved with childhood trauma as they influence brain structure and function. Those with the Val66MET polymorphism of brain-derived neurotrophic factor (BDNF) and who experienced child maltreatment ended up being more likely to have depressive disorders and a smaller hippocampus.
9. There are gender differences in terms of how maltreatment affects brain development. For boys who have PTSD they had smaller cerebral volumes and larger lateral ventricular volumes. Based on the type of trauma that was experienced also, neglect led to a smaller corpus callosum in boys, while sexual abuse led to a smaller corpus callosum in girls.

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