McEwen-Induced Modulation of Endocrine History: A Partial Review

In endless facets of physiology, there are points of homeostatic balance, such that too much or too litttle of something can both be deleterious (i.e., an "inverse U" pattern). This is particularly true when considering glucocorticoids (GCs), the adrenals steroid secreted during stress. In the first part of this paper, I review a number of realms in which a paucity and an excess of GCs are both damaging. Some findings are classical (for example, concerning GC effects upon body weight), while some are quite recent and have considerable implications for both physiology and pathophysiology (for example, inverse U's of GC actions in the realm of immunity and neuronal survival). The second part of the review considers the far thornier issue of how such inverse U's of GC actions are generated on a cellular and molecular level. One solution that has evolved, primarily in the hippocampus within the nervous system, involves the presence of two different types of receptors for GCs within the same cells; so long as the two receptors have very different affinities and mediate opposing effects on some cellular endpoint, an inverse U will emerge. The second solution, found in a number of peripheral tissues, involves GCs having opposing effects on the amount of some signal being generated (e.g., an immune cytokine) and the sensitivity of target tissues to that signal; under conditions that appear to be physiologically relevant, inverse U's emerge from this pattern as well. The final section of this review considers the enormous role played by Bruce McEwen in the emergence of this literature. I suggest that while much of this obviously has to do with the facts that have come from his group, another substantial contribution is from his steadying and supportive personality, the veritable embodiment of homeostatic balance.     

Developmental and sex-related differences in preschoolers' affective decision making

This study investigated developmental and sex-related differences in affective decision making, using a two-deck version of Children's Gambling Task administered to 3- and 4-year-old children. The main findings were that 4-year-old children displayed better decision-making performance than 3-year-olds. This effect was independent of developmental changes in inductive reasoning, language, and working memory. There were also sex differences in decision-making performance, which were apparent only in 3-year-old children and favored girls. Moreover, age predicted awareness of task and the correlation between the latter and decision-making performance was significant, but only in 4-year-old children. This study thus indicates that there is a remarkable developmental leap in affective decision making, whose effects are apparent around the age of 4, which according to our results, also marks the age when the correlation of declarative knowledge and decision-making performance becomes significant.     

Semantic priming effects on picture and word processing

The effects of semantic priming on picture and word processing were assessed under conditions in which subjects were required simply to identify stimuli (label pictures or read words) as rapidly as possible. Stimuli were presented in pairs (a prime followed by a target), with half of the pairs containing members of the same semantic category and half containing unrelated concepts. Semantic relatedness was found to facilitate the identification of both pictures (Experiment 1) and words (Experiment 2), and obtained interactions of semantic relatedness and stimulus quality in both experiments suggested that semantic priming affects the initial encoding of both types of stimuli. In Experiment 3, subjects received pairs of pictures, pairs of words, and mixed pairs composed of a picture and a word or of a word and a picture. Significant priming effects were obtained on mixed as well as unmixed pairs, supporting the assumption that pictures and words access semantic information from a common semantic store. Of primary interest was the significantly greater priming obtained in picture-picture pairs than in word-word or mixed pairs. This suggests that, in addition to priming that is mediated by the semantic system, priming may occur in picture-picture pairs that results from the overlap in visual features common to the pictorial representations of objects from the same semantic category.     

Perceived burdensomeness and suicide ideation in older adults

Older adults have the highest risk of death by suicide in the United States. Improving our understanding of the factors that lead to increased risk of suicide in older adults will greatly inform our ability to prevent suicide in this high-risk group. Two studies were conducted to test the effect of perceived burdensomeness, a component of the interpersonal-psychological theory of suicide (Joiner, 2005), on suicide ideation in older adults. Further, gender was examined as a moderator of this association to determine if perceived burdensomeness exerted a greater influence on suicide ideation in males. The results of these studies suggest that perceived burdensomeness accounts for significant variance in suicide ideation, even after predictors such as depressive symptoms, hopelessness, and functional impairment are controlled. Gender did not moderate the association. The implications of these findings for treatment of older adults with suicide ideation and elevated suicide risk are discussed.     

Stress, Glucocorticoids, and Damage to the Nervous System: The Current State of Confusion

An extensive literature demonstrates that glucocorticoids (GCs), the adrenal steroids secreted during stress, can have a broad range of deleterious effects in the brain. The actions occur predominately, but not exclusively, in the hippocampus, a structure rich in corticosteroid receptors and particularly sensitive to GCs. The first half of this review considers three types of GC effects: a) GC-induced atrophy, in which a few weeks' exposure to high GC concentrations or to stress causes reversible atrophy of dendritic processes in the hippocampus; b) GC neurotoxicity where, over the course of months, GC exposure kills hippocampal neurons; c) GC neuroendangerment, in which elevated GC concentrations at the time of a neurological insult such as a stroke or seizure impairs the ability of neurons to survive the insult. The second half considers the rather confusing literature as to the possible mechanisms underlying these deleterious GC actions. Five broad themes are discerned: a) that GCs induce a metabolic vulnerability in neurons due to inhibition of glucose uptake; b) that GCs exacerbate various steps in a damaging cascade of glutamate excess, calcium mobilization and oxygen radical generation. In a review a number of years ago, I concluded that these two components accounted for the deleterious GC effects. Specifically, the energetic vulnerability induced by GCs left neurons metabolically compromised, and less able to carry out the costly task of containing glutamate, calcium and oxygen radicals. More recent work has shown this conclusion to be simplistic, and GC actions are shown to probably involve at least three additional components: c) that GCs impair a variety of neuronal defenses against neurologic insults; d) that GCs disrupt the mobilization of neurotrophins; e) that GCs have a variety of electrophysiological effects which can damage neurons. The relevance of each of those mechanisms to GC-induced atrophy, neurotoxicity and neuroendangerment is considered, as are the likely interactions among them.