Child and Adolescent Psychiatric Clinics of North America
Long-term effects of childhood abuse on brain and neurobiology☆
Section snippets
Hypothalamic-pituitary-adrenal axis and early stress
The HPA axis and hippocampus are particularly sensitive to stress. Stress is associated with activation of the HPA axis. Corticotropin-releasing factor (CRF) is released from the hypothalamus, with stimulation of adrenocorticotropin hormone (ACTH) release from the pituitary, which results in glucocorticoid release from the adrenal. This release, in turn, has a negative feedback effect on the axis at the level of the pituitary and central brain sites, including hypothalamus and hippocampus. In
Effects of stress on the hippocampus
The hippocampus, a brain area involved in learning and memory, is particularly sensitive to the effects of stress [15], [16]. The hippocampus has an inhibitory effect on the HPA axis [17] so that hippocampal lesions are predicted to result in hypercortisolemia. Psychosocial stress with associated elevated levels of glucocorticoids resulted in decreased dendritic branching and neuronal loss in the CA3 region of the hippocampus [18] and an inhibition of neuronal regeneration [19] in the
Noradrenergic systems
Accumulated evidence suggests a relationship between alterations in noradrenergic brain systems and stress [28]. Most noradrenergic cell bodies are located in the locus coeruleus, a nucleus in the dorsal pons region of the brain stem, with a dense network of axons that extend throughout the cerebral cortex and to multiple cortical and subcortical areas, including hippocampus, amygdala, thalamus and hypothalamus, bed nucleus of stria terminalis, nucleus accumbens, and descending projections that
Dopaminergic systems
The three major dopaminergic neuronal systems include nigrostriatal (projection from substantia nigra to striatum), mesolimbic (projection from midbrain to nucleus accumbens), and mesocortical/mesoprefrontal (projection from midbrain to prefrontal cortex) systems. Dopamine innervation of the medial prefrontal cortex seems to be particularly vulnerable to even mild and brief stress. Preclinical studies support the fact that acute and chronic stress may have a negative impact on the normal
Serotonin
Most serotonin neurons in the brain area are located in the dorsal raphe (midbrain) with projections to cortical and subcortical areas. Animals exposed to various stressors, including footshock, tail shock, tail pinch, and restraint stress, have produced an increase in serotonin turnover in the medial prefrontal cortex [43], [44], nucleus accumbens, amygdala, lateral hypothalamus, and locus coeruleus [45]. Chronic electric shock that produced learned helplessness behavioral deficits was
Endogenous benzodiazepines
Endogenous benzodiazepines also play an important role in stress response and anxiety. Benzodiazepine receptors are present throughout the brain, with the highest concentration in cortical gray matter. Benzodiazepines potentiate and prolong the synaptic actions of the inhibitory neurotransmitter gamma aminobutyric acid (GABA). Central benzodiazepine receptors and GABA receptors are part of the same macromolecular complex. These receptors have distinct binding sites, although they are
Neuropeptides and amino acids
Exposure to stress has marked effects on the activity of a number of other central nervous system (CNS) neuropeptides systems [53]. The neuropeptides that are considered to mediate the response to stress, based on preclinical studies, are CRF, endogenous opioid peptides, neurotensin, somatostatin, cholecystokinin, neuropeptide Y, and others, such as substance P, vasopressin, oxytocin, vasointestinal polypeptide, and thyrotropin-releasing hormone. Neuropeptides account for neurotransmission at a
The neurobiology of early stress in children
The few studies of the effects of early stress on neurobiology conducted in clinical populations of traumatized children generally have been consistent with findings from animal studies. Research in traumatized children has been complicated by issues related to psychiatric diagnosis and assessment of trauma [60]. Some studies have not specifically examined psychiatric diagnosis, whereas other studies have focused on children with trauma and depression and still other studies have focused on
Neuroimaging studies of childhood abuse
Neuroimaging studies have provided a map for the neural circuitry of early childhood abuse [3]. The development of animal models for early stress has provided a model for the neural circuitry of the lasting effects of childhood abuse (Fig. 1). These studies have implicated the hippocampus, a brain area involved in new learning and memory. The medial prefrontal cortex also has been implicated in the stress response. Medial prefrontal cortex in the human consists of several related areas,
Summary
Early stress is associated with long-term alterations in brain circuits and systems that mediate the stress response. Early stressors have lasting effects on the HPA axis and norepinephrine systems. Other brain systems that are involved include benzodiazepine, opiate, dopaminergic, and various neuropeptide systems. These neurochemical systems modulate function in brain regions, including the hippocampus, amygdala, and prefrontal cortex. Long-term alterations in these brain regions are
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The work presented in this article was supported by grants from the NIMH (MH56120), the Emory Conte Center for Early Life Stress, and the Department of Veterans Affairs.