Sex, stress and the hippocampus: allostasis, allostatic load and the aging process

Abstract

The adaptive responses of the body that maintain homeostasis in response to stressors can be called “allostasis”, meaning “achieving stability through change”. Mediators produced by the immune system, autonomic nervous system (ANS) and hypothalamo–pituitary–adrenal(HPA) axis produce allostasis. The brain also shows allostasis, involving the activation of nerve cell activity and the release of neurotransmitters. When the individual is challenged repeatedly or when the allostatic systems remain turned on when no longer needed, the mediators of allostasis can produce a wear and tear on the body and brain that has been termed “allostatic load”. Examples of allostatic load include the accumulation of abdominal fat, the loss of bone minerals and the atrophy of nerve cells in the hippocampus. Studies of the hippocampus as a target of stress and sex hormones have revealed a considerable degree of structural plasticity and remodeling in the adult brain that differs between the sexes. Three forms of hippocampal structural plasticity are affected by circulating hormones: (1) repeated stress causes remodeling of dendrites in the CA3 region; (2) different modalities of stress suppress neurogenesis of dentate gyrus granule neurons; (3) ovarian steroids regulate synapse formation during the estrous cycle of female rats. All three forms of structural remodeling of the hippocampus are mediated by hormones working in concert with excitatory amino acids (EAA) and NMDA receptors. EAA and NMDA receptors are also involved in neuronal death that is caused in pyramidal neurons by seizures, by ischemia and by severe and prolonged psychosocial stress. The aging brain seems to be more vulnerable to such effects, although there are considerable individual differences in vulnerability that can be developmentally determined. Moreover, the brain retains considerable resilience in the face of stress, and estrogens appear to play a role in this resilience. “Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging.” This review discusses the current status of work on underlying mechanisms for protection and damage.

Introduction

Individual differences in the aging process can be conceptualized as an accumulation of wear and tear of daily experiences and major life stressors which interact with the genetic constitution and predisposing early life experiences [52], [164], [175]. The neuroendocrine system, autonomic nervous system (ANS) and immune system are mediators of adaptation to challenges of daily life, referred to as “allostasis”, meaning “maintaining stability through change” [178]. Physiological mediators such as adrenalin from the adrenal medulla, glucocorticoids from the adrenal cortex and cytokines from cells of the immune system act upon receptors in various tissues and organs to produce effects that are adaptive in the short run but can be damaging if the mediators are not shut off when no longer needed. When release of the mediators is not efficiently terminated, their effects on target cells are prolonged, leading to other consequences that may include receptor desensitization and tissue damage. This process has been named “allostatic load” [121], [127], and it refers to the price the tissue or organ pays for an overactive or inefficiently managed allostatic response. Therefore, allostatic load refers to the “cost” of adaptation.

The brain is the master controller of the three systems noted above and is also a target of these systems, subject to both protection and damage. Allostasis also applies not only to circulating hormones but also to organs and tissues of the body. In the nervous system, neurotransmitters are released by neuronal activity, and they produce effects locally to either propagate or inhibit further neural activity. Neurotransmitters and hormones are usually released during a discrete period of activation and then are shut off, and the mediators themselves are removed from the intracellular space by reuptake or metabolism in order not to prolong their effects. When that does not happen, however, there is allostatic load and the brain is at increased risk for damage [103].

The processes of allostasis and allostatic load have been described and measured for metabolic and cardiovascular changes that are associated with obesity, Type 2 diabetes and cardiovascular disease [171]. However, the same type of elevated and prolonged secretion of glucocorticoids during aging has also been associated with impairment of cognitive function in rodents [92], [93], [165] and in humans [104], [105], [170]. Moreover, the endogenous excitatory amino acid neurotransmitters appear to play a major role in these changes [165] even though they are also an essential part of normal synaptic neurotransmission and plasticity. Their actions lead to the formation of excess free radicals that can damage nerve cells, leading to the search for agents that can interfere with free radical production or enhance free radical quenching. The “glucocorticoid cascade hypothesis” of aging [94], [120], [165], [166] is an example of a theory of aging that emphasizes the pivotal nature of aging of key brain structures such as the hippocampus, a brain region involved in key aspects of episodic, declarative, spatial and contextual memory and also in regulation of autonomic, neuroendocrine and immune responses. Agents that are protective against accelerated aging should be judged for their ability to protect key brain structures such as the hippocampus from the effects of a variety of insults, many of which involve excitotoxicity and damage from reactive oxygen species and free radicals. The “glucocorticoid cascade hypothesis” of aging is a prime example of allostatic load since it recognizes feed forward mechanism that gradually wears down a key brain structure, the hippocampus, while the gradually disregulated HPA axis promotes pathophysiology on tissues and organs throughout the body.

In spite of its vulnerability to allostatic load, the brain retains considerable resilience in the face of challenges to adapt through allostasis. Studies on the hippocampus reveal a number of types of structural plasticity, ranging from neurogenesis in the dentate gyrus to remodelling of dendrites to the formation and replacement of synapses. These changes, along with compensatory neurochemical and neuroendocrine responses, provide the brain with a considerable amount of resilience. This has led to a search for agents that help the brain maintain its resilience as it ages.

This article discusses allostasis and allostatic load in the brain in relation to the aging process and a number of brain disorders in which there is overactivity of stress mediators that causes brain dysfunction. Specifically, this article summarizes research on the protective and damaging effects of adrenal steroids and estrogens on the brain, particularly on the hippocampus. It also discusses the topic of neuroprotection and the potential value of estrogens and flavonoids as anti-oxidants in promoting allostasis and enhancing resilience and countering the allostatic load promoted by excitatory amino acids and other agents that promote the generation of free radicals such as the β-amyloid protein. “Resilience is an example of successful allostasis in which wear and tear is minimized, and estrogens exemplify the type of agent that works against the allostatic load associated with aging.” Before entering full-force into this discussion, it is important to review briefly the role of the biological mediators of stress in the protective and damaging aspects of stress on the brain and body and to discuss the terms “allostasis” and “allostatic load”.