Memory

One of the most prominent symptoms of PTSD is the persistence of troubling trauma-memories that appear resistant to extinction. To understand the key role that memory plays in the development of PTSD, the current chapter presents a review of theoretical models for memory encoding, processing, learning, and extinction. The preclinical literature that has informed our understanding of the toxic relationship between chronic elevation of stress hormones such as glucocorticoids and memory is examined. Consideration of cognitive and neuroimaging studies on adults and children illustrates the long-term consequences of traumatic stress on the neurofunctional structures involved in memory, such as the hippocampus and LHPA axis. The variance in these effects, attributable to their timing and context, is discussed, and suggests that stress may preprogram subsequent memory performance when it is experienced during the critical period of brain development.

Evidence for a hyporesponsive limbic-hypothalamic-pituitary-adrenal axis following early-life repetitive hypoglycemia in adult male rats

The developing limbic-hypothalamic-pituitary-adrenal (LHPA) axis is highly vulnerable to programming by early-life environmental factors, including exposure to synthetic glucocorticoids and nutrient deficiencies. Early-life repetitive hypoglycemia (RHG) is a common complication of insulin therapy for type-1 diabetes that may have long-term consequences in adulthood. Recent observations in a rat model of early RHG suggest persistent changes in LHPA axis function, including changes in relevant hormones and affective behaviors, which support a hyperresponsive LHPA axis. Thus, we hypothesized that early RHG would alter the expression of key genes regulating LHPA axis function in adulthood. The present study employed a rat model of insulin-induced RHG spanning postnatal days (P)24–28, a neurodevelopmental equivalent of early childhood in humans, to assess the long-term effects on mRNA levels for proteins relevant to the LHPA function and the corticosterone responses to ACTH stimulation of dispersed adrenocortical cells in vitro and restraint stress in vivo at adulthood. This early RHG model resulted in a hyporesponsive LHPA axis characterized by impaired corticosterone response, increased hippocampal glucocorticoid and mineralocorticoid receptor (GR and MR), decreased hypothalamic corticotropin-releasing hormone, increased adrenal steroidogenic-acute-regulatory protein and GR, and decreased adrenal MR, melanocortin-type-2 receptor and low-density lipoprotein receptor expression. Our findings highlight a complex environmental-gene interaction between RHG and LHPA axis during development that influences regulation of this axis in adulthood. The findings are consistent with the developmental origins of disease and underscore the influences of early-life events on the programming of a major regulatory system.

Low cortisol and a flattening of expected daytime rhythm: Potential indices of risk in human development

Since the work of Hans Selye, stress has been associated with increased activity of the limbic–hypothalamic– pituitary–adrenocortical (LHPA) axis. Recently, a number of studies in adults have shown that this neuroendocrine axis may be hyporesponsive in a number of stress-related states. Termed hypocortisolism, the paradoxical suppression of the LHPA axis under conditions of trauma and prolonged stress presently challenges basic concepts in stress research. Adverse conditions that produce elevated cortisol levels early in life are hypothesized to contribute to the development of hypocortisolism in adulthood. However, as reviewed in this paper, hypocortisolism also may be a common phenomenon early in human childhood. Although preliminary at this point, the ubiquity of these findings is striking. We argue that developmental studies are needed that help explicate the origins of low cortisol and to determine whether the development of hypocortisolism is, in fact, preceded by periods of frequent or chronic activation of the LHPA axis. We also argue that developmental researchers who incorporate measures of salivary cortisol into their studies of at-risk populations need to be aware of the hypocortisolism phenomenon. Lower than expected cortisol values should not necessarily be relegated to the file drawer because they contradict the central dogma that stress must be associated with elevations in cortisol. Lastly, we note that evidence of low cortisol under adverse early life conditions in humans adds to the importance of understanding the implications of hypocortisolism for health and development.

Prediction of Outcome in Depressed Patients by Weekly Monitoring with the Dexamethasone Suppression Test

Forty-three depressed patients in hospital were studied with weekly dexamethasone suppression tests (DSTs) and were followed as out-patients for at least three months after discharge. The detection rate of patients with LHPA axis dysfunction increased from 41% with a single DST to 59% with serial DSTs. There was a poor correlation between weekly post-dexamethasone cortisol levels and Hamilton depression rating scores. In patients with evidence of LHPA axis dysfunction, a DST at discharge discriminated effectively between a good and a poor outcome group; persistent non-suppression was strongly linked with a relapse of depression in the first three months after discharge. In general, our results support previous claims that the DST is a state marker for depressive illness.