Stress and the Hypothalamic-Pituitary-Adrenal Axis

In the hippocampus, when the MRs are predominantly activated, the formation of new declarative memories is supported by the mechanism of longterm potentiation. Under low levels of acute stress, there may even be some improvement in this function. However, when stress levels and the associated increases in circulating corticosteroid levels cause more activation of the GRs, there is interference with forming new memories.

This pattern of low levels of stress improving performance and higher levels of stress disrupting performance has sometimes been descriptively referred to as an inverted-U relationship. Slight elevations in stress hormones are also associated with enhanced attention and motivation, both important for performing well on memory and higher-order cognitive tasks but impairing the recall of previous memories. These latter actions appear to be mediated by both ß-adrenergic and cholinergic receptors in the basolateral complex of the amygdala.

Stress and the Hypothalamic-Pituitary-Adrenal Axis in Animal Studies. Prolonged HPA overactivity is also associated with cognitive decline and hippocampal atrophy in rats. Rodents exposed to stress paradigms or administered large doses of corticosterone have been reported to have atrophy of the hippocampal neurons and increased sensitivity to toxins, but this could not be replicated in pigtailed macaque monkeys exposed to high doses of cortisone for 12 months. Species differences may be important because these primates proportionately have far fewer hippocampal GRs than rodents.

Stress and Hypothalamic-Pituitary-Adrenal Axis in Normal Aging. The hippocampus plays a major role in learning and memory performance, in particular in declarative (conscious and voluntary) memory. It is susceptible to damage from intense prolonged stress. Cortisol production increases during stress, and long-term exposure to high levels of cortisol causes atrophy and impaired neurogenesis in the hippocampus. There is also evidence of hippocampal atrophy as a function of aging, and HPA overactivity is associated with cognitive decline and hippocampal atrophy in normal elderly.

There are a variety of measures of HPA activity: simple plasma cortisol and salivary cortisol measures have been used, but there is much variation in these over the course of a day. Urinary cortisol may be a more reliable measure of cortisol secretion over time, and some studies have determined that cerebrospinal fluid (CSF) cortisol more accurately reflects cortisol levels in the central nervous system.

Another widely used measure of HPA activity is the dexamethasone (DST) test (DST is a synthetic glucocorticoid). DST is typically administered to individuals in the evening, and plasma cortisol levels are measured the following day in the morning or afternoon. Ordinarily, DST suppresses the HPA axis, and plasma cortisol levels will be low the day after DST administration. Failure to suppress the HPA axis (nonsuppression) is evidence of a loss of normal feedback control and homeostasis.

There is some evidence suggesting gender differences in the role of cortisol overproduction in cognitive and memory dysfunction in normal elderly individuals. One study has found that increases in urinary cortisol excretion are significantly associated with declines in memory performance over 2.5 years in healthy elderly women but not in men. Furthermore, women who showed a decrease in urinary cortisol excretion showed significant improvement in memory performance over time.

These findings highlight the possibility that damage to the structure and functioning of the brain from hypercortisolemia might be reversible, at least for healthy elderly women, although it is believed that prolonged and repeated exposure to glucocorticoids increases the risk of irreversible damage.

Indeed, longitudinal examinations of cortisol levels and declarative memory performance reveal that elderly individuals with high and increasing cortisol levels over periods ranging from 1 to 3 years show significantly greater impairments in declarative memory performance and significantly greater hippocampal atrophy than do individuals who show decreases or low and smaller increases in cortisol levels over time.

The amount of hippocampal atrophy in elderly individuals with high and increasing levels of cortisol was found to be equivalent to that of older adults exhibiting mild cognitive impairment (MCI). Although cortisol levels, on average, increase with aging, there is much interindividual variability in cortisol production in the elderly, with some individuals actually showing decreases in cortisol levels over time.