Sapolsky RM. Stress, the aging brain, and mechanisms of neuron death. MIT Press, Cambridge 1992

This monograph by a pioneer looks at the neuroendocrine axes and dysfunction there associated with the regulation of hormones secreted by the adrenal gland during stress. Animal studies are used, such as the aging rat, where glucocorticoids are secreted in excess because of age-related damage in the hippocampal area of the brain. Useful summaries and guides to material in forthcoming chapters make this an accessible book for understanding stress mechanisms. This book links possible pathways through which the psychological stress of relative deprivation in a society, typified by low control, may result in disease.

Table of Contents

Part I The glucocorticoid cascade hypothesis

Chapter 1: The stress-response and the emergence of stress-related disease

• stressors are physiological or psychological perturbations that throw us out of homeostasis
• stress-response is set of neural & endocrine adaptations that help reestablish homeostasis, which are similar despite varied stressors
• prolonged stress causes damage to stress-response, over-activation produces stress-related diseases, (steroid dm, hypertension, peptic ulcers, reproductive impairment, immunosuppressions
• speculation on aging interacting with stress
• impaired capacity to respond to stress
• stress (esp. prolonged), can accelerate degenerative affects of aging

Chapter 2: An Introduction to the Adrenocortical Axis

• CRF most important secretagog's of ACTH, others vasopressin, oxytocin, catecholamines. & CRF released in 15 seconds of neural event, glucocorticoids release in few minutes, and inside cell, increase or decrease transcription of particular genes
• glucocorticoids block energy storage, mobilize energy from storage sites, increase cardiovascular tone & inhibit anabolic processes (growth, reproduction, inflammation & immunity)
• feedback inhibition (end-product control) to brain, which must measure concentrations of circulating glucocorticoids

Chapter 3: Glucocorticoid Concentrations in the Aged Rat: A Problem of 
     Hypersecretion

• aged rats appear to be capable of secreting glucocorticoids in response to various stressors, indeed there is excessive secretion, because of failure of negative inhibition of adrenocortical axis by glucocorticoids,

Chapter 4: The problem of receptor loss

• the failure of negative inhibition of adrenocortical axis by glucocorticoids, appears to be due to loss of receptors in the aging hippocampus

Chapter 5: The Hippocampus as a Mediator of Glucocorticoid Feedback Regulation

• Aged rat hypersecretes glucocorticoids and is feedback resistant because of the loss of hippocampal neurons and hippocampal corticosteroid receptors that are a normal part of aging

Chapter 6: Glucocorticoid Neurotoxicity

• Hippocampal neurons die because of the extent of glucocorticoid exposure over the lifetime.
• Prolonged diminution of glucocorticoid exposure over the lifetime slows down hippocampal senescence.
• This is termed the glucocorticoid cascade

Part II How does a neuron die?

Chapter 7: Glucocorticoids Endanger Hippocampal Neurons

Chapter 8: A brief interlude: Programmed Cell Death

Chapter 9: Metabolic Chaos I: The mediators of necrotic neuronal injury

Chapter 10: Metabolic Chaos II: The role of energy failure in necrotic neuronal injury

Chapter 11: How do glucocorticoids endanger the hippocampal neuron?

Part III How depressing is all of this?

Chapter 12: Individual differences and adrenocortical function: Why do some  individuals secrete more glucocorticoids than others?

• Why is psychological stress stressful?

• loss of control is at forefront of psychological stress
• lack of predictability is major stimulant of adrenocortical axis
• Social Status, personality and adrenocortical function

• Phenomenon of social dominance

• within social species, individuals within the group typically "know" where they stand with respect to other individuals, leading to dominance hierarchies
• among primates, dominance hierarchies define one's social rank
• life for a subordinate animal is filled with problems ranging from petty harassment, in which one's nose is rubbed rudely in one's lack of social status, to extremely serious forms of menage -- unpredictable and injuries attacks, insufficient food, inability to depend on finding a safe spot when a predator attacks
• collectively, these social stressors incorporate many features of psychological stress-- lack of control, of predictability, and of outlets for frustration

• Glucocorticoid secretion in subordinate individuals

• low rank should be associated with adrenocortical hyperactivity (he finds in baboons)
• Mechanisms underlying the hypersecretion in subordinate animals
• notion that subordinate individuals are subject to more social stressors and are initiating more stress responses at the central nervous system level
• subordinate primates are more likely to show some pathologies or markers of pathology that are sensitive to glucocorticoid overexposure, and in stable hierarchies, they have more atherosclerotic occlusion, lower high density lipoprotein-cholesterol concentrations, and fewer total circulating lymphocytes.

• social ranks can change over time
• physiological correlates of dominance depend on the sort of society in which the dominance occurs
• The physiological correlates of dominance may be more related to personality than to the dominance itself.
• Perinatal experience, genetics and adult adrenocortical function

• Human and primate studies

• Early environmental influences on adult adrenocortical function in the rodent
• Genetics influences on adrenocortical function in the rodent
• behavioral traits are stable over time, suggesting roles for early experience and genetics on the adrenocortical axis

• Changes in Adrenocortical function and rate of hippocampal degeneration during aging

Summary:

• why might two organisms differ in amounts of glucocorticoids they secrete (basally, during stress or following)

• Psychological stress
• Two organisms may differ in amount of stressors to which they are exposed, or they may perceive the same stressor differently

• Factors that make for psychological stress include:

• loss of control
• loss of predictability
• loss of outlets for frustration
• perception of things worsening, independent of the actual physical reality

• Social Status
• physiological correlates of rank are highly modulated by individual personality of the animal
• for advantageous adrenocortical profiles to be seen, an organism must not only have the psychological advantages of rank available, but must have the personality that allows the perception of those advantages

• Perinatal Experience, Genetics and Adult Adrenocortical Function

• cause of personality differences exist early in development
• infant humans & primates show strong individual differences in how aversive they find novelty to be, how exploratory they are in novel settings, how social extroverted they are, etc.
• these personality differences appear to be relatively stable into adulthood
• individuals who are more aversively reactive to and less exploratory in novel settings hypersecrete glucocorticoids, and cross-fostering studies show these are attributable to mothering style much more than genetics
• neonatal handling produces adults who secrete less glucocorticoids basally and are more sensitive to feedback regulation, & this centers on hippocampus

• show that in paired comparisons, stress-sensitive and stress-resistant strains do not differ under basal, nonstressed conditions or during major physical stressors. but in response to ambiguous psychological stressors, more sensitive strains have higher blood pressure, less ability to learn, higher rates of defecation (a sign of anxiety in rats), less spontaneous exploration, and relatively enhanced glucocorticoid secretion

Do these differences matter?

• yes, they can alter the rate at which degenerative glucocorticoid cascade emergences during aging

Chapter 13 Interventions at the Time of Neurological Insults

• what can be done to decrease endangering effects of glucocorticoids immediately following a major neurological insult?
• use metyrapone to block effects of corticosteroidogenesis
• use corticosteroid receptor antagonists
• supplement neurons with additional energy substrates to protect them from steroids

Chapter 14 Is this relevant to the human?

• Does the primate hippocampus inhibit the adrenocortical axis?
• Will stress down-regulate corticosteroid receptors in the primate hippocampus and thus cause feedback resistance?
• not known (for primates), but when they are chronically stressed, they become feedback resistant
• Can stress damage the primate hippocampus
• "limbic atrophy" in untreated Cushing's patients, and in concentration camp survivors
• Normal human aging
• there is marked feedback resistance in aged humans under certain testing conditions, although initially, it was thought that adrenocortical function was relatively normal in the aged human
• Depression
• ~50% of those with major depression show some feature of glucocorticoid hypersecretion
• hypercorticalism associated with psychotic depression, more vegetative depressions and depressions in aged subjects
• given the predisposing role of stress in many depressions, such stressors may down-regulate corticosteroid receptor number in the hippocampus and thus cause hypersecretion
• humans may differ markedly in their concentrations of hippocampal corticosteroid receptors prior to the stressor, in their sensitivity to stress-induced down-regulation, and in the threshold of down-regulation at which hypersecretion occurs
• one might posit that prolonged hypercortisolism during chronic depression can cause hippocampal damage
• Alzheimer's Disease
• Alcoholic Neurotoxicity
• acute & chronic exposure stimulates glucocorticoid secretion
• Neurological insults and the clinical use of corticosteroids
• not known whether glucocorticoids exacerbate neurological insults in primate or human hippocampus, but this is seen in a number of rodent species
• interventions in preceding chapter might be considered
• caution against use of exogenous corticosteroids in such circumstances
• where clinical benefits of corticosteroid use (in controlling edema) have been overemphasized in neurological literature, & when such treatments are indeed efficacious, nonglucocorticoid substitutes (mannitol, progesterone, 21-aminosteroids) are useful as well

Keywords

• behavioral factors
• cortisol
• glucocorticoids
• hierarchy
• psychosocial factors
• relative deprivation
• risk factor
• social cohesion
• social networks
• social stratification
• stress