Until that clock is reset, cortisol secretion and hunger, as well as sleepiness and wakefulness, occur at inappropriate times of day in the new location. Acute stress also enhances the memory of earlier threatening situations and events, increases the activity of the immune system, and helps protect the body from pathogens. Cortisol and epinephrine facilitate the movement of immune cells from the bloodstream and storage organs, such as the spleen, into tissue where they are needed to defend against infection.
Glucocorticoids do more than help the body respond to stress. They also help the body respond to environmental change.
In these two roles, glucocorticoids are in fact essential for survival. For Educators Log in. The GR can also bind or tether itself to other DNA-bound transcription factors and modulate their ability to change gene expression Figure 2.
This adds an additional layer of control, because gene accessibility and transcription factor expression and activity are cell-specific and dynamically regulated. For example, liver-specific transcription factors such as HNF4 hepatocyte nuclear factor 4 facilitate GR binding to and regulation of metabolic genes, whereas macrophage-specific transcription factors such as PU. Glucocorticoid responses are therefore fine-tuned to consider context.
This is how glucocorticoids can control metabolism in liver, activation of macrophages, and promote death of T-cells. This explains why the GR and glucocorticoids is a potent inhibitor of inflammation only when required: i. Glucocorticoids through the GR are therefore perfectly adapted to integrate incoming signals from other pathways in order to respond appropriately to each specific challenge.
We still have a long way to go in order to fully understand the whole spectrum of glucocorticoid action. However, we now have some insight into how, by adding a few additional points of control, glucocorticoids can co-ordinate diverse cellular effects to reach a common goal: the restoration of balance following stress.
The Endocrinologist. Issue Winter Stress and the adrenal patient: safety first, please! Stress in the world of finance The lymphocytolytic actions of GCs are central in treatment of lymphocytic leukemias and lymphomas.
During prolonged exposure to GC therapy, they may contribute to immunosuppression. Physiologically, their role may be to facilitate both negative and positive selection of the T cell repertoire 95 , , and to remove potentially toxic activated cells Despite evidence of the suppressive actions of GC stretching back decades, enhancement of immune functions by GCs has been reported, and some recent results are striking.
Jefferies , argues for the importance of enhancing effects—which he ascribes to permissive actions—and laments their neglect in clinical practice. He cites instances where physiological doses of GCs improve the condition of patients or experimental animals, e. Which immune functions are enhanced in such cases is unclear. As Jefferies notes, one that has been observed fairly consistently in vitro is the stimulation of immunoglobulin synthesis by cultured B cells — For such stimulation, GCs generally are required early in a culture, consistent with them being permissive.
Some of these effects could be secondary to GC modulation of cytokine production or activity, such as the shift from T helper 1 and 2 cells Th1 to Th2 cells already mentioned, or the induction of cytokine receptors described below However, inhibition of immunoglobulin production in culture has also been reported occasionally , and GCs inhibit some of the steps preceding B cell differentiation to antigen-secreting state and suppress immunoglobulin production in whole organisms Thus, the physiological role of these influences on B cell functions is difficult to evaluate.
While most reports indicate that GCs suppress T cell function, enhancement has been observed in humans and rats. Barber et al. They gave cortisol as hemisuccinate in 6-h intravenous infusions that raised plasma cortisol levels to the micromolar range, corresponding to high stress-induced levels.
GCs can also enhance T cell responses in rats in vivo and vitro , — Corticosterone in vitro at all concentrations suppressed the mitogenic response of cultured cells from either adrenalectomized or sham-operated rats, an effect blocked by RU at n m. However, RU at 50 n m changed the suppression by 10 n m corticosterone to stimulation Similar observations were obtained with splenic lymphocytes, stimulated with either concanavalin A , or with the more specific stimulus of anti-T cell antigen receptor In the experiments with anti-T cell antigen receptor, corticosterone had to be added within the first hour of stimulus to enhance; enhancement seemed to be due to increased expression of IL-2 receptors on T cells.
In other experiments, even brief preexposure to corticosterone or aldosterone with subsequent washing out of the steroid enhanced the response to concanavalin A several days later From these and other results, Wiegers et al.
GCs also play permissive and suppressive roles in the acute-phase response, a general systemic response to immune and inflammatory reactions triggered by injury and infection , GCs enhance the hepatic acute-phase response by increasing sensitivity to mediators, while suppressing the overall response by inhibiting mediator production A final example of GC-induced immune enhancement comes from an unexpected reinterpretation of classic data.
Even relatively minor increases in GC concentrations can deplete circulating leukocytes. This has typically been interpreted as a decline in immune competence, as most evidence suggested that such leukocytes were being sequestered, inactive, in immune tissues. However, such depletion might instead involve diversion of circulating leukocytes to local areas of need such as in inflamed skin , — In an example of immune activation, delayed-type hypersensitivity DTH , acute stress experienced immediately before the administration of an antigen to the skin significantly enhances a cell-mediated immune response directed against the antigen [while, in contrast, chronic stress over a period of weeks suppresses the DTH response ].
We now consider these GC actions in the context of the criteria. The criterion of conformity—do GCs have effects on the immune system that are similar to, opposite to, or different from the more rapid stress-responsive hormones? As discussed, the first wave of immune responses to various stressors is one of activation.
Thus, the criterion of time course suggests that the inhibitory effects of GCs upon immunity and inflammation should be viewed as suppressive, whereas the more recently appreciated enhancing effects are permissive. Furthermore, the fact that the enhancing effects of GCs in rats are seen with low levels of the hormone and can be mediated by the MR supports the permissive scenario of such enhancement occurring under basal conditions in place at the onset of a stressor.
In contrast, the requirement for higher concentrations of GCs and GR involvement for the emergence of the inhibitory effects supports the picture of suppressive actions occurring as GC concentrations rise into the stress-induced range.
The criteria of subtraction and replacement—is there an overshoot of immunity or inflammation in circumstances of diminished adrenocortical activity, and can the overshoot be counteracted with GCs? The earliest such report came in , with the observation by Kepinov discussed in Ref. Adrenalectomy has also long been known to cause the thymus and other lymphoid organs to hypertrophy.
Flower et al. Moreover, the response of normal rats is enhanced by administration of RU Bacterial endotoxin-induced sepsis in rats causes GC secretion secondary to the actions of cytokines upon the adrenocortical axis , , adrenalectomy significantly increases fever and mortality induced by the sepsis, and GCs reverse these effects 81 , , Adrenalectomized rats, and intact rats treated with RU, developed substantially higher levels of plasma IL-6 than control rats after injection of endotoxin, an effect attenuated by administration of GCs 81 , In some circumstances, basal GC concentrations do not prevent immune or inflammatory overshoot; stress concentrations of GCs must be attained 81 , Miller et al.
A striking example of inflammatory overshoot is the Lewis rat, in which cytokines such as IL-1 fail to stimulate CRH synthesis or secretion so that an inflammatory stressor does not stimulate GC secretion. Lewis rats are exceptionally susceptible to experimental arthritis induced with streptococcal cell wall polysaccharide when compared with Fischer rats, and can be protected by treatment with GCs , Similarly, Fischer rats, normally resistant to experimental arthritis, become susceptible when GC actions are blocked with RU , or adrenalectomy 78 , Lewis rats are also very sensitive to carrageenin-induced inflammation 72 and to induction of experimental allergic encephalomyelitis EAE , a model of multiple sclerosis In normal rats the stressor of induction of EAE triggers substantial GC secretion, most probably via the stimulating actions of cytokines, and adrenalectomy significantly increases EAE-induced mortality; this increased mortality is prevented by administration of GCs that produce circulating concentrations in the stress range, but not in the basal range , , Immune overshoot also occurs in obese strain chickens that spontaneously develop autoimmune thyroiditis 99 , , Their hypothalamic-pituitary-adrenal HPA axes are resistant to cytokine activation 79 ; furthermore, the biological potency of any secreted GCs is greatly decreased because of a doubling of circulating transcortin concentrations Clinical reports show parallels to these findings.
Moreover, unilateral adrenalectomy to remove an adrenocortical adenoma can cause a flare-up of autoimmune thyroid disease ; whether the adrenalitis or thyroid disease in these two cases is more readily triggered in circumstances of stress is not known. Furthermore, individuals with inflammatory arthritis i. The criterion of homeostasis—do GC effects in this realm during stress make sense? As noted, one response of many GC physiologists has been to relegate them to pharmacology. Other attempts at incorporating them into physiology now appear quite unsatisfactory, such as the speculation that immunity is suppressed to spare energy during the prototypical physical stressor or that GC-induced lymphocytolysis provides substrate for gluconeogenesis and tissue repair More recent work has helped clarify the homeostatic logic of the immunosuppressive effects of GCs, as well as their predominance at higher concentrations and only after the first wave of the stress response.
Immunosuppression is logically viewed as suppressing the stress response to an infectious stressor to decrease the likelihood of autoimmune overshoot. Antigenic challenges to the immune system trigger polyclonal responses, raising the risk of autoimmunity where epitopes recognized by some of the clones overlap with those of normal body constituents.
This is due to the preferential targeting by GCs of lymphocytes that are less active or that produce antibodies with lower affinities for the antigen , Consistent with this role of GCs, after an infectious stressor, GC concentrations peak when the antiantigen response peaks 80 , , which may be days later.
Another argument for the homeostatic value of GC suppression is that many cytokines induced by stressors can be toxic in excess, independent of their stimulation of immune and inflammatory reactions, and thus their levels need to be controlled , Thus, the criterion of homeostasis suggests that the enhancing effects of GCs be viewed as permissive, while the delayed inhibiting effects of GCs be viewed as permissive, while the delayed inhibiting effects are suppressive.
Why were enhancing, permissive effects of GCs so rarely observed in earlier studies? Surprisingly, the results of Barber et al. Classical permissive effects, such as those on gluconeogenesis or cardiovascular functions, have generally been elicited with basal levels of GCs in subjects with subnormal or no GCs. This illustrates the earlier point that permissive effects probably have dose-response relations similar to other GC effects, but whose effects at high doses of GCs are usually obliterated by suppressive effects.
In the experiments of Barber et al. Wiegers et al. They also suggest that in the other studies, high and prolonged GC exposure may have suppressed enhancing effects. Thus, if permissive effects on T cell functions are generally mediated by MRs, a reinterpretation may be necessary of experiments in which administration of RU exacerbates immune or inflammatory responses.
Exacerbation has usually been interpreted as being caused simply by blocking of suppressive GC actions, but could also be due partly to RU uncovering permissive enhancement by GCs through MRs. Synthetic GC agonists like dexamethasone, which are often used for immunosuppression both experimentally and clinically, would be unlikely to reveal permissive effects through MRs since they are effective immunosuppressants at much lower concentrations than corticosterone or cortisol and would activate MRs much less than the natural GCs.
Finally, another reason for the dearth of earlier reports of permissive effects of GCs on T cell functions may be that not all T cell-mediated responses require permissive enhancement. Enhancement by GCs via up-regulation of hormone, cytokine, and growth factor receptors has been proposed to underlie permissive activation of several physiological systems , , , Such effects could also account for the generally beneficial influences of GCs in culture media GC inhibition of production of mediators that act through many of these receptors is initially paradoxical.
However, a simple mathematical model shows that combined stimulating and inhibitory effects, even with identical dose-response curves, generate a bell-shaped dose-response curve according to which GCs activate homeostatic mechanisms permissively at basal levels reached during normal diurnal variation and suppress them at stress-induced levels Fig.
The bell-shaped curve generated via GC receptors extends GC influences over a wide concentration range, which is even further extended at low concentrations if permissive GC actions are mediated via MRs, as just described for T cell mitogenesis.
Although there is no time axis in the figure, permissive actions should be thought of as preceding, and suppressive actions as following, a stressor. Regulation by GCs of defense mechanisms through permissive and suppressive GC actions.
The two bell-shaped curves are derived from a mathematical model of a GC-regulated defense mechanism composed of a mediator, its receptor, and the mediator-receptor complex that generate activity 6. Cortisol is assumed to permissively induce mediator receptors via either GC receptors GRs or mineralocorticoid receptors MRs , and to suppress mediator levels via GRs. Thus, with increasing cortisol concentrations, activity first rises over the basal cortisol range as mediator receptors increase but then decreases as mediator levels are suppressed by cortisol in the stress-induced range.
Cortisol actions are calculated using a K d of cortisol for GRs of 30 n m , and of cortisol for MRs of 0. Approximate values are given for ranges of basal diurnal and stress-induced free cortisol concentrations in humans.
Conclusions: With infectious stressors, immune activation precedes and contributes to the eventual increase in GC concentrations at which suppressive effects occur. Furthermore, GC deficiency is associated with pathological overshoot of inflammatory and immune responses; GC secretion induced by stress protecst against this overshoot, sculpting and restraining the immune response.
Even complete absence of GC activity does not diminish inflammatory and immune responses, as would be expected if permissive GC actions were required to enhance or "prime" those responses. Thus, most GC actions on immune and inflammatory reactions are suppressive, even under conditions of exposure to basal GC concentrations, while evidence is mounting that permissive actions also play important roles. Thus, it appears that GCs present in advance can permissively help mediate the immune activation demonstrable during the first moments of response to a variety of stressors, whereas stress-induced GCs later act to rein in that same activation.
The early phases and endocrine mediators of the metabolic stress response have been understood for decades Fig. Blood glucose levels are elevated rapidly, in part by mobilization from existing stores, and by inhibition of further storage through a rapid insulin resistance ; thus, energy is diverted from storage sites to exercise muscle.
These changes are brought about by catecholamines, glucagon, and GH. The preeminent effect of GCs upon metabolism is their ability to increase circulating glucose concentrations. This is accomplished through a number of mechanisms. One, discussed later, is via stimulation of appetite by low levels of GCs In addition, when GCs are present for hours before the stressor, there is 1 the stimulation of glycogenolysis and gluconeogenesis by glucagon and catecholamines that constitute the immediate stress response; 2 stimulation of hepatic gluconeogenesis and glycogen deposition; and 3 inhibition of peripheral glucose transport and utilization reviewed in Refs.
In addition, GCs mobilize lipids through lipolysis in fat cells, and amino acids through inhibition of protein synthesis and stimulation of proteolysis in various muscle types. The criteria yield a clear interpretation of these GC actions. By the criterion of conformity, GCs help to mediate permissively the metabolic stress response, synergizing with catecholamines, GH, and glucagon to stimulate lipolysis and to elevate circulating glucose concentrations by stimulating glycogenolysis and gluconeogenesis cf.
Epinephrine and glucagon act quickly, whereas GCs act slowly to enhance and prolong for several hours the increase in blood glucose due to epinephrine or glucagon A similar conclusion is reached by applying the criteria of time course and subtraction: during a physical stressor, Addisonian and adrenalectomized individuals are impaired in mobilizing the necessary energy substrates, a defect corrected with maintenance doses of GCs.
As early an investigator as Selye showed that this impaired capacity to mobilize substrates becomes fatal during stress when the organism is already food deprived.
Furthermore, from the standpoint of homeostasis, it makes abundant sense for the metabolic stress response to be one of mobilization of substrate stores and their diversion to the subset of tissues that need them.
With regard to the slower stimulation of gluconeogenesis and inhibition of peripheral glucose utilization by stress-induced GCs, they clearly supplement the permissive actions and may be responsible for extending and prolonging the stress response.
They can therefore be categorized as stimulatory. Stimulation of liver glycogen deposition, however, which similarly takes a few hours, can have little influence on the stress response, but by restoring glycogen levels prepares for the next one. It thus is best classified as preparative.
All four criteria suggest that during a prototypical stressor, GCs help mediate the metabolic response through both permissive and stimulating actions and also have preparative actions. These actions appear to arise from a mixture of monotonic and biphasic effects over the GC dose range. For example, GC inhibition of glucose uptake is monotonic Fat depletion is stimulated by GCs over their entire dose range In contrast, the muscle-wasting effects of GCs appear to occur only in the stress range These mediating GC actions should be viewed as both permissive and stimulatory.
The preparative GC stimulation of hepatic glycogen deposition gives a classic monotonic dose-response curve. These interpretations of the roles of GCs in metabolic stress responses differ from those in Ref.
This shift in interpretation can be understood by distinguishing between the effects of GCs upon metabolism, and those of GC-induced insulin secretion. During the normal daily fluctuations of fasting and feeding, of repose and activity, each with their associated metabolic demands, and after injury or during disease states, the metabolic actions of GCs are intertwined with those of insulin and certain other hormones.
In these interactions a central physiological variable is the level of blood glucose, which must be kept from falling below some threshold for normal brain function and may have to be raised acutely to satisfy a sudden need for energy. GC actions generally oppose but sometimes synergize with those of insulin. For example, GCs and insulin have opposite actions on blood glucose levels, as well as on appetite, gluconeogenesis, glucose transport, protein synthesis, muscle wastage, lipolysis, lipogenesis, and fat deposition in adipose tissue ; they synergize in stimulating hepatic glycogen deposition and lipogenesis , , Elevated GCs raise insulin concentrations; whether this is due to direct GC stimulation of secretion or is secondary to the metabolic actions of GCs is unclear , Sustained GC secretion causes sustained insulin secretion after a delay of a few hours.
Thus, in analyzing the actions of GCs, the concurrent effects of insulin must be taken into account. True GC effects are most readily demonstrated in the absence of insulin secretion e. This term is often used to describe how the secretion of these hormones, stimulated by the postprandial elevation of insulin levels , or by insulin administration in the diabetic patient, protects against hypoglycemia.
Insulin administration to a laboratory animal or normal human has long been used to stimulate an endocrine stress response or simulate the rise in insulin levels that follow a meal.
This reflects not only the convenience of the method, but the importance that the understanding and management of diabetes has in clinical endocrinology. However, an insulin surge and a sprint across the savanna are different stressors.
The latter, we believe, is the more logical setting to understand the evolution and physiological relevance of GC secretion during stress, although the former, which utilizes the same hormonal actions and metabolic pathways, also carries survival value.
However, under basal, nonstressed circumstances, GCs, catecholamines, GH, and glucagon interact with insulin in complex ways that justify the view that each class of hormones counterregulates the other at some point. The neurobiological actions of GCs were only briefly touched on in Ref. Since then, numerous studies have reported electrophysiological and neurochemical effects of GCs cf. Unfortunately, most of these findings are too reductive to be interpreted physiologically.
For example, consider that GCs modulate the effects of a neurotransmitter upon turnover of a second messenger in a particular brain region , or that GCs modulate the levels of mRNAs for a particular subtype of the N -methyl- d -aspartate receptor It is unlikely that information exists as to the time course and dose responsiveness of effects such as these, the effect of the rapid stress-responsive hormones on these endpoints, and the preparative value of any such actions.
For this reason, we have chosen three topics among the neurobiological and behavioral effects of GCs. They are interpretable in the context of adapting to stress, and there is information as to the effects of the early wave of stress-responsive hormones on these endpoints, plus dose-response information regarding GC actions. Cerebral glucose transport and utilization. Stress increases local cerebral glucose utilization within seconds , an effect mediated by sympathetic activation.
It is probably not due to catecholamines directly acting upon glucose transport mechanisms in neurons or glia, since catecholamines do not readily pass the blood-brain barrier. Instead, sympathetic arousal stimulates cardiovascular tone and increases cerebral blood flow. GCs are well known for inhibiting glucose transport in various peripheral tissues This phenomenon appears to extend to the brain. In vivo , GCs inhibit local cerebral glucose utilization throughout the brain — and inhibit glucose transport in neurons, glia, and possibly endothelial cells in vitro , The effect requires stress levels of GCs a minimum of n m and is GR-mediated.
The mechanisms underlying the inhibition are understood. Over the course of minutes to hours, GCs cause the translocation of glucose transporters from the cell surface to inactive intracellular storage sites — In addition, over the course of hours to days, GCs also decrease the level of mRNA for the glucose transporter These findings yield a consistent categorization when the criteria are applied.
Insofar as GCs do the opposite of catecholamines, by the criterion of conformity GC actions are suppressive. GCs are also suppressive by the criterion of time course in that they reverse the stimulation of glucose utilization occurring in the early seconds of the stress response.
Adrenalectomy increases glucose utilization throughout the brain , suggesting a suppressive action by the subtraction criterion. Appetite and feeding. Stress suppresses feeding in less than 1 h, even in food-deprived animals This effect is probably mediated by CRH; the peptide is a potent anorexic agent, and CRH antagonists block the anorexic effects of stress These CRH actions reflect a neurotransmitter role, as the effect occurs in hypophysectomized animals, or after intracerebroventricular injection of CRH In contrast, GCs stimulate appetite over days in rats.
Adrenalectomy decreases feeding and food-seeking behavior , which is reversed by GC administration. Appetite normally peaks at the time of the circadian cycle when GC concentrations peak, and this peak can be shifted with GC treatment These GC actions appear to center in the paraventricular nucleus of the hypothalamus, where crystalline implants of GCs also stimulate feeding , GCs stimulate appetite monotonically over the entire dose range in various species, including humans.
There are two complications in reaching this conclusion. First, while basal concentrations of GCs stimulate appetite , stress concentrations decrease appetite, a finding that changes the interpretation of this section , This inhibition was subsequently shown to be due to the high concentrations of GCs stimulating a burst of insulin secretion. The inhibitory effects of insulin upon appetite more than offset the stimulating GC effects; in the absence of GC-induced insulin secretion in streptozotocin diabetic rats , GCs stimulate appetite over the entire dose range Second, aldosterone, or GCs at concentrations that only occupy the MR, stimulate consumption of both carbohydrates and fats, whereas GR-specific agonists stimulate only carbohydrate consumption However, despite low and high concentrations of GCs stimulating appetite in different ways, GCs nonetheless stimulate feeding in a monotonic manner over their entire dose range.
Thus, by the criteria of conformity and of time course, GC actions suppress these facets of the stress response. The criterion of subtraction leads to this categorization as well as the adrenalectomy data just noted.
In considering the criterion of homeostasis, we can perceive no way in which the relatively slow stimulation of appetite by GCs could help during a stressor such as a sprint across a savanna. In contrast, the earlier responses, which are then inhibited by GCs, are readily viewed in that manner. Feeding, a costly process that provides energy relatively slowly, is obviously expendable during a stressful crisis.
Thus, this criterion suggests that GC actions suppress and aid the recovery from the anorectic facet of the stress response. In addition, to the extent that GCs stimulate appetite to the point that metabolic stores are ultimately greater than before the onset of the stressor [a pattern often seen ], there are preparative features to this GC effect, equipping the organism for the metabolic costs of a subsequent stressor.
Thus, by stimulating appetite and feeding, GC effects are mostly suppressive, with some preparative features as well. The fact that GCs have these effects over their entire dose range, plus the seeming involvement of both MRs and GRs, suggest that basal and stress levels of GCs tend to suppress this facet of the stress response. Moreover, insofar as feeding is preparatory for the energy expenditure of the next sprint across a savanna, there are preparative elements to these GC actions as well.
Memory formation. Acute stressors enhance memory formation, a phenomenon familiar to many in the form of vividly remembering where they were when some tragic historical news was announced As a more controlled demonstration of this phenomenon, volunteers were read one of two stories, equivalent in length and complexity and virtually identical in their beginning and end, but differing dramatically in the emotionally stressful content of the middle of the story the first story being fairly neutral in content, and the second describing a disturbing accident.
Memory of the emotionally laden component, but not of the neutral components of the second story, was enhanced relative to the first The sympathetically mediated increase in cerebral perfusion rate and glucose delivery to the brain during the early phases of the stress response probably plays a role in the memory enhancement. As evidence, peripheral or ventricular infusion of glucose in the ranges achieved during stress enhance memory formation — , commensurate with the metabolic costs of neuronal plasticity during learning.
Other mechanisms for the catecholamine involvement in this phenomenon have been advanced The effects of GCs upon memory are complex and are centered in the hippocampus, a brain region central to learning and memory that possesses high levels of MR and GR. Basal levels of GCs enhance forms of synaptic plasticity thought to be underpinnings of learning — These effects are mediated by MRs — Moreover, basal levels of GCs, acting via MRs, enhance hippocampal excitability in general — This is probably accomplished by shortening and shallowing the hyperpolarized refractory period of hippocampal neurons after an action potential As would be expected from these findings, adrenalectomy disrupts memory processes in animals, and occupancy of MRs with GCs restores function , while MR antagonists disrupt cognition , In contrast, stress levels of GCs, working via the GR, have opposite effects.
Over the course of hours, GCs disrupt those same forms of synaptic plasticity and blunt general hippocampal excitability by prolonged hyperpolarizations — , — These effects can be shown in hippocampal slices in vitro , suggesting direct intrinsic effects on these neurons.
Insofar as stress levels of GCs inhibit glucose transport and utilization see above , this should be an extrinsic, metabolic mechanism for disrupting memory formation as well [given the importance of glucose availability to memory ]. Prolonged exposure to stress levels of GCs atrophy hippocampal neuronal processes and, ultimately, cause neuron loss as well although the relevance of these very gradual effects to the prototypical scenario of the sprint across the savanna is minimal.
These GC effects have been relatively well documented in rodents and primates [emerging over the course of weeks and months, respectively ], and hints have emerged for a similar phenomenon in the human [emerging over the course of years ]. As would be expected, sustained exposure to elevated GC concentrations disrupts memory.
This has been long recognized in patients prescribed high-dose corticosteroids for sustained periods and has been demonstrated as well in cross-sectional and longitudinal neuropsychological studies of such patients Moreover, administration of GR agonists to healthy volunteers disrupts memory within a few days , The application of the criteria produces clear conclusions. The criterion of conformity suggests that basal levels of GCs are permissive, in that they enhance memory as do catecholamines.
In contrast, by that criterion stress levels of GCs are suppressive. A similar dichotomy emerges when applying the criterion of time course. The same conclusion is reached in considering the careful adrenalectomy studies in which there was a distinction between replacement with low levels of GCs or with MR-specific agonists in which adrenalectomy-induced memory problems are reversed , and replacement with high GC levels or GR-specific agonists [in which memory problems are worsened ].
The criterion of homeostasis is readily applied to some components of GC actions. It seems apparent that sharpening memory consolidation and retrieval is a valuable response to a stressor, in that it aids the recall of behaviors that worked previously, as well as the consolidation of memories meant to avoid this stressor in the future.
In that regard, the enhancement of memory processes during the early stages of responding to a stressor can be viewed as logical and salutary. The value, if any, of disrupting memory with more sustained stressors, is unclear to us. Thus, the criteria suggest that basal GC levels at the onset of a stressor permissively help mediate the cognitive stress response, whereas the subsequent stress-induced rise in GC concentrations suppresses the cognitive response.
The neurobiological and behavioral effects of GCs during stress discussed above can all be categorized as having suppressive elements. In the case of glucose utilization and transport, stress-induced GC concentrations suppress the earlier stress response, while both basal and stress-induced concentrations suppress appetite.
The review of this literature also suggests that GCs might have some preparative actions in the realm of appetite. Other aspects of GC neuroendocrinology might be categorized differently. For example, GCs can have rapid effects over the course of seconds to minutes on behavior in birds and reptiles 7 , 8 , These actions which are probably mediated by membrane-bound receptors include inhibition of sexual behavior, and stimulation of escape behavior, and have been interpreted as helping to mediate behavioral features of the stress response , The review 1 did not consider the effects of GCs upon reproduction.
Nevertheless, the wealth, consistency, and physiological and pathophysiological relevance of the data in this area lead us to include the topic now. The onset of a stressor initiates inhibition of reproductive physiology and behavior. This involves a decline in portal GnRH concentrations and pituitary release of gonadotropins within minutes Fig. Moreover, there is rapid loss of erections in response to an acute stressor in males and a decline in sexual proceptivity and receptivity in both sexes.
The first wave of hormonal mediators of the stress response are central to this reproductive suppression. CRH inhibits reproductive physiology and behavior , , and administration of CRH antagonists partially reverses stress-induced suppression of LH release The effect on the pituitary is secondary to inhibition of GnRH release, since intracerebroventricular rather than peripheral administration of CRH or its antagonists is effective — , CRH does not directly blunt pituitary responsiveness to GnRH , and CRH can directly inhibit hypothalamic release of GnRH in vitro Opiate release during stress is also reproductively suppressive and, like CRH, involves inhibition of hypothalamic GnRH release — The opiate inhibition of GnRH appears to be the proximal mechanism by which CRH exerts its antireproductive actions , Finally, the sympathetic nervous system has antireproductive properties.
For example, sympathetic activation blocks the parasympathetically mediated initiation of erections The effects of GCs in this realm are well understood.
GCs potently disrupt reproductive physiology through a number of mechanisms. These patterns occur in both in vivo and in vitro systems and in rodents, humans, and other primates. These studies have mostly used concentrations of GCs in the stress range.
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