Environmental and social stresses have deleterious effects on reproductive function in vertebrates. Global climate change, human disturbance and endocrine disruption from pollutants are increasingly likely to pose additional stresses that could have a major impact on human society. Nonetheless, some populations of vertebrates (from ®sh to mammals) are able to temporarily resist environmental and social stresses, and breed successfully. A classical trade-off of reproductive success for potential survival is involved. We de®ne ®ve examples. The stress-response plays a key role in allowing an organism to survive the acute challenge to homeostasis that constitutes the typical stressor. Energy is mobilized from storage sites and diverted to exercising muscle, cardiovascular tone is enhanced, long-term and costly anabolism is suppressed until a more auspicious time, and cognition is sharpened. However, following the pioneering work of Hans Selye in the 1930s, it is clear that an excess of stress can have pathogenic effects on metabolism, vascular function, growth, tissue repair, immune defences, and even the health of some neurones.Among the most consistently adverse consequences of prolonged stress is disruption of reproductive physiology and behaviour (Figs 1 and 2). Whether one is a clinician trying to understand a patient's loss of libido, a wildlife biologist grappling with how habitat degradation translates into decreased fertility of wild populations, or a conservationist faced with an endangered species refusing to mate in a zoo enclosure, stress must be considered in the equation. As a result of considerable research, a great deal is known about the neuroendocrine bases by which the stress-response can impair reproduction (Figs 1 and 2).In this review, we consider the general mechanisms by which such suppression occurs. More importantly, we provide examples where this yoking of stress and reproductive impairment does not occur. Such exceptions to the broad physiological effects of stress are not restricted to the reproductive axis. As an interesting recent precedent, socially subordinate mice subject to numerous bite wounds during ®ghting become resistant to the immunosuppressive effects of stress and glucocorticosteroids. The authors

In the laboratory rat and guinea pig, glucocorticoids (GCs), the adrenal steroids that are secreted during stress, can damage the hippocampus and exacerbate the hippocampal damage induced by various neurological insults. An open question is whether GCs have similar deleterious effects in the primate hippocampus. In fact, we showed that sustained and fatal stress was associated with preferential hippocampal damage in the vervet monkey; however, it was not possible to determine whether the excessive GC secretion that accompanied such stress was the damaging agent. The present study examines this possibility. Pellets of cortisol (the principal GC of primates) were stereotaxically implanted into hippocampi of 4 vervet monkeys; contralateral hippocampi were implanted with cholesterol pellets as a control. One year later at postmortem, preferential damage occurred in the cortisol-implanted side. In the cholesterol side, mild cell layer irregularity was noted in 2 of 4 cases. By contrast in the cortisol-exposed hippocampi, all cases had at least 2 of the following neuropathologic markers: cell layer irregularity, dendritic atrophy, soma shrinkage and condensation, or nuclear pyknosis. Damage was severe in some cases, and was restricted to the CA3/CA2 cellfield. This anatomical distribution of damage, and the cellular features of the damage agree with that observed in instances of GC-induced toxicity in the rodent hippocampus, and of stress-induced toxicity in the primate hippocampus. These observations suggest that sustained GC exposure (whether due to stress, Cushings syndrome or exogenous administration) might damage the human hippocampus.

The hippocampus of the rat loses neurons with age, a loss which may eventuate in some of the functional impairments typical of senescence. Cumulative exposure to corticosterone (CORT) over the lifespan may be a cause of this neuronal loss, as it is prevented by adrenalectomy at mid-age. In this study, we demonstrate that prolonged exposure to CORT accelerates the process of cell loss. Rats were injected daily with sufficient CORT to produce prolonged elevations of circulating titers within the high physiological range. Animals treated for 3 months (chronic subjects) resembled aged rats in a number of ways. First, both groups had extensive and persistent depletions of CORT receptors in the hippocampus; in the case of chronic rats, no recovery of receptor concentrations occurred 4 months after the end of steroid treatment. Second, autoradiographic analysis revealed that the receptor depletion was due, in part, to a loss of CORT-concentrating cells, especially in the CA3 cell field. Remaining cells bound significantly less [3H]corticosterone than did those of control rats. Finally, analysis of size distributions of hippocampal cell bodies indicated that chronic subjects lost neurons of the same size as those lost in the aged hippocampus. Furthermore, chronic subjects also had increased numbers of small, darkly staining cells of CA3; these corresponded in size to the dark glia whose numbers increase in the aged hippocampus, and which are thought to infiltrate in response to neuronal damage or destruction. Thus, this study supports the hypothesis that cumulative exposure to CORT over the lifespan may contribute to age-related loss of neurons in the hippocampus, and that prolonged stress or exposure to CORT accelerates this process.

Previous studies have demonstrated that overexpression of the proto-oncogene bcl-2 can protect neuron and neuron-like cell lines from growth factor deprivation, calcium ionophores, glutamate excitotoxicity, hypoglycemia, free radicals, and lipid peroxidation. To determine whether Bcl-2 exhibits a similar protective effect in CNS neurons, we generated defective herpes simplex virus (HSV) vectors capable of overexpressing Bcl-2 in primary cultures and in the intact brain. Infection of hippocampal cultures with Bcl-2 vectors enhanced neuron survivorship after exposure to adriamycin, a potent oxygen radical generator. Furthermore, dichlorofluorescein measurements indicated that there was a significant reduction in the accumulation of oxygen radicals associated with this insult. Bcl-2 vectors also enhanced survival in cultured neurons after exposure to glutamate and hypoglycemia. Most significantly, the in vivo delivery of the vector protected neurons against adriamycin toxicity in the dorsal horn of the dentate gyrus and focal ischemia in the striatum.

Glucocorticoids appear capable of damaging or destroying hippocampal neurons. There is a progressive loss of such neurons with age, and the process can be prevented by adrenalectomy at mid-age or accelerated by prolonged exposure to high circulating titers of glucocorticoids. The present study examines possible mechanisms for this steroid action. Rats were either adrenalectomized, intact, or treated with corticosterone (CORT) sufficient to produce prolonged elevations of titers in the high physiological range. After 1 week, unilateral hippocampal microinfusions were made with either kainic acid (KA) or 3-acetylpyridine (3-AP). Doses of these hippocampal neurotoxins were chosen to produce small-sized lesions. Treatment with CORT exacerbated the extent of damage following neurotoxin infusion, whereas adrenalectomy attenuated the damage. Additional studies eliminated some potential mechanisms for this phenomenon. CORT did not directly alter the intrinsic toxicity of the compounds but, rather, altered the sensitivity of target cells to them. As evidence, no potentiation of damage in CORT-treated animals occurred in KA-sensitive brain regions lacking CORT receptors. Since CORT did not increase the diffusion or binding of [3H]KA in the hippocampus, it appears unlikely that CORT potentiated toxin-induced damage by influencing the specific mechanism of action of any toxin. Finally, the general nature of the CORT potentiation of damage was supported by the markedly different postulated mechanisms of toxicity of KA and 3-AP. We hypothesize that CORT exerts its extensive catabolic effects upon target cells to produce generalized metabolic vulnerability in hippocampal neurons possessing high concentrations of CORT receptors, thereby sensitizing them to varied metabolic insults.

Glucocorticoids (GCs), the adrenal steroids secreted during stress, endanger the hippocampus, compromising its ability to survive neurological insults. GCs probably do so by disrupting energetics in the hippocampus, thus impairing its ability to contain damaging fluxes of excitatory amino acids and calcium. Superficially, these observations suggest that stress itself should also exacerbate the toxicity of neurological insults. However, most studies have involved unphysiologic GC manipulations, limiting speculations about the endangering effects of stress. In this study, rats were infused with the excitotoxin kainic acid (KA) after either having been adrenalectomized and replaced with a range of physiologic concentrations of GCs, or having been stressed intermittently. We observed that within the CA3 region, increasing CORT concentrations exacerbated the KA-induced neuron loss, the extent of tau immunoreactivity, and of spectrin proteolysis. The transitions from low to high basal GC concentrations and from high basal to stress GC values were both associated with significant exacerbation of neuron loss and tau immunoreactivity; the extent of spectrin proteolysis was less sensitive to increments in GCs. As would be expected from these data, exposure to intermittent stress prior to KA infusion also exacerbated neuron loss, tau immunoreactivity, and spectrin proteolysis in CA3. Thus, physiological elevations of GCs, and stress itself, can exacerbate hippocampal neuron loss and the attendant degenerative markers following an excitotoxic insult. Of significance, seizure and hypoxia-ischemia provoke considerable GC stress responses, which may thus worsen the resultant damage. Furthermore, a number of neuropsychiatric disorders, as well as aging, are associated with elevated basal GC concentrations, which may endanger the hippocampus in the event of neurological insult.

Glucocorticoids (GCs) can damage neurons of the hippocampus, the principal target tissue in the brain for the hormone. Hippocampal neuron loss during aging in the rat is accelerated by prolonged GC exposure and decelerated by adrenalectomy. GCs appear to damage these neurons indirectly by inducing a state of vulnerability and thus impairing their capacity to survive a variety of metabolic challenges. As such, high physiological concentrations of the steroid increase hippocampal damage induced by an antimetabolite toxin, an excitotoxin, or hypoxia-ischemia. Conversely, adrenalectomy attenuates the damage caused by these insults. This study suggests that GCs endanger hippocampal neurons by impairing their energy metabolism. Neurons are extremely vulnerable to such disruption, all the insults potentiated by GCs either impair energy production or pathologically increase energy consumption, and GCs inhibit glucose utilization in the hippocampus. Administration of different brain fuels--glucose, mannose, fructose, or the ketone beta-hydroxybutyrate--reduced hippocampal damage induced by coadministration of GCs and either of 2 different neurotoxins (kainic acid and 3-acetylpyridine). This appeared to be due to a reduction in the damaging synergy between GCs and the toxin; as evidence, a dose of mannose that attenuated damage induced by kainic acid plus GCs failed to reduce damage induced by the same dose of kainic acid alone. Glucose (whose utilization is noncompetitively inhibited by GCs) and fructose (which does not readily penetrate the blood-brain barrier) were less effective at reducing damage than the other 2 fuels.

Inhibition of the adrenocortical axis by glucocorticoids (GCs) occurs at both hypothalamic and suprahypothalamic sites. In the rat, the hippocampus has been shown to be an essential suprahypothalamic site. The present study shows that the hippocampal system serves a similar role in the nonhuman primate. Bilateral lesions that included the hippocampal formation and the parahippocampal cortex; the hippocampal formation, parahippocampal cortex, and the amygdala; or the fornix all produced GC hypersecretion in cynomolgus monkeys. The hypersecretion occurred throughout the day. Moreover, these lesions were also associated with dexamethasone resistance (i.e., GC hypersecretion following administration of the synthetic GC dexamethasone). The hypersecretion could not be attributed to acute surgical trauma, because neither circumscribed lesions of the amygdala nor conjoint lesions of the perirhinal and parahippocampal cortex produced adrenocortical abnormalities. Finally, in agreement with data derived from the rat, the GC hypersecretion following hippocampal lesions was transient. Secretory activity returned to normal levels by 6-15 months in all operated groups. Thus, the primate hippocampal system appears to share some neuroendocrine functions with the rodent.