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Chronic Stress-Induced Hippocampal Vulnerability: The Glucocorticoid Vulnerability Hypothesis
Abstract
The hippocampus, a limbic structure important in learning and memory, is particularly sensitive to chronic stress and to glucocorticoids. While glucocorticoids are essential for an effective stress response, their oversecretion was originally hypothesized to contribute to age-related hippocampal degeneration. However, conflicting findings were reported on whether prolonged exposure to elevated glucocorticoids endangered the hippocampus and whether the primate hippocampus even responded to glucocorticoids as the rodent hippocampus did. This review discusses the seemingly inconsistent findings about the effects of elevated and prolonged glucocorticoids on hippocampal health and proposes that a chronic stress history, which includes repeated elevation of glucocorticoids, may make the hippocampus vulnerable to potential injury. Studies are described to show that chronic stress or prolonged exposure to glucocorticoids can compromise the hippocampus by producing dendritic retraction, a reversible form of plasticity that includes dendritic restructuring without irreversible cell death. Conditions that produce dendritic retraction are hypothesized to make the hippocampus vulnerable to neurotoxic or metabolic challenges. Of particular interest is the finding that the hippocampus can recover from dendritic retraction without any noticeable cell loss. When conditions surrounding dendritic retraction are present, the potential for harm is increased because dendritic retraction may persist for weeks, months or even years, thereby broadening the window of time during which the hippocampus is vulnerable to harm, called the 'glucocorticoid vulnerability hypothesis'. The relevance of these findings is discussed with regard to conditions exhibiting parallels in hippocampal plasticity, including Cushing's disease, major depressive disorder (MDD), and post-traumatic stress disorder (PTSD).
... These steroid hormones-primarily cortisol in humans, and corticosterone (CORT) in rodents-go on to regulate a host of systems involved in the stress response (Sapolsky et al., 2000). While basal levels of GCs are necessary for maintaining normal homeostasis (Herman et al., 2016), chronically high levels of circulating GCs have been associated with disrupted energy production (Sapolsky, 1986) and increased disease susceptibility (Conrad, 2008;Shimba and Ikuta, 2020;10.3389/fnmol.2023.1115993 Frontiers in Molecular Neuroscience 02 frontiersin.org ...
... The observations described herein demonstrate that the consumption of exogenous CORT by nursing dams can influence the neurobiology of the offspring, including by altering the GCR protein content of three glucocorticoid-sensitive brain regions. Chronic overactivation of the HPA axis is known to have a dampening effect on the negative feedback loop that limits glucocorticoid secretion (Conrad, 2008;Godoy et al., 2018). This regulatory loop involves brain-resident GCR and in the present study, maternal CORT exposure caused a downward trend in brain GCR levels that was statistically significant in the hippocampus of offspring of both sexes. ...
... This regulatory loop involves brain-resident GCR and in the present study, maternal CORT exposure caused a downward trend in brain GCR levels that was statistically significant in the hippocampus of offspring of both sexes. This finding is consistent with past literature on the negative regulatory effect of GCs on hippocampal GCR (Conrad, 2008). This phenomenon is hypothesized to be a protective adaptation as GCs can increase the risk of glutamate excitotoxicity in the hippocampus (Stein-Behrens et al., 1994;Treccani et al., 2014). ...
Aberrant activation of the stress-response system in early life can alter neurodevelopment and cause long-term neurological changes. Activation of the hypothalamic-pituitary-adrenal axis releases glucocorticoids into the bloodstream, to help the organism adapt to the stressful stimulus. Elevated glucocorticoid levels can promote the accumulation of reactive oxygen species, and the brain is highly susceptible to oxidative stress. The essential trace element selenium is obtained through diet, is used to synthesize antioxidant selenoproteins, and can mitigate glucocorticoid-mediated oxidative damage. Glucocorticoids can impair antioxidant enzymes in the brain, and could potentially influence selenoprotein expression. We hypothesized that exposure to high levels of glucocorticoids would disrupt selenoprotein expression in the developing brain. C57 wild-type dams of recently birthed litters were fed either a moderate (0.25 ppm) or high (1 ppm) selenium diet and administered corticosterone (75 μg/ ml) via drinking water during postnatal days 1 to 15, after which the brains of the offspring were collected for western blot analysis. Glutathione peroxidase 1 and 4 levels were increased by maternal corticosterone exposure within the prefrontal cortex, hippocampus, and hypothalamus of offspring. Additionally, levels of the glucocorticoid receptor were decreased in the hippocampus and selenoprotein W was elevated in the hypothalamus by corticosterone. Maternal consumption of a high selenium diet independently decreased glucocorticoid receptor levels in the hippocampus of offspring of both sexes, as well as in the prefrontal cortex of female offspring. This study demonstrates that early life exposure to excess glucocorticoid levels can alter selenoprotein levels in the developing brain.
... [73] Finally, GC neuro-endangerment refers to the ability of GCs to endanger neurons [74] where exposure to GCs of an inadequate degree or duration to induce neurotoxicity or atrophy may still impact the neurons through hindering their ability to survive subsequent insults. [75] In addition to these effects, more recent research has also highlighted the role of chronic stress in inhibiting adult neurogenesis. [76] While this begins as self-correcting and reversible, there comes a point when hypersecretion of cortisol induces irreversible damage. ...
... Increased stress levels during early childhood can affect both PFC and subcortical functioning, for example in the hippocampus (e.g., Hanson et al., 2015;Teicher et al. 2003). A high density of glucocorticoid receptors in these brain regions makes them vulnerable to elevated cortisol exposure and, therefore, to stress (Conrad, 2008;McEwen & Morrison, 2013). Apart from stress transmission through caregivers, direct stress exposure can affect infant cognition as well (e.g., Cowell et al., 2015). ...
Exposure to chronic stress is associated with habitual learning in adults. We studied the origins of this association by examining the link between stressful life events and infant cognitive flexibility. The final sample consisted of N = 72 fifteen-month-old infants and their mothers. Mothers completed a survey on pre- and postnatal negative life events. To assess chronic stress physiologically, infant and maternal hair cortisol concentrations were determined for cortisol accumulation during the past 3 months. Each infant participated in two cognitive tasks in the laboratory. An instrumental learning task tested infants' ability to disengage from a habituated action when this action became ineffective (Seehagen et al., 2015). An age-adequate version of the A-not-B task tested infants' ability to find a toy at location B after repeatedly finding it at location A. Correlations between cortisol concentrations and postnatal negative life events (number, perceived impact) did not yield significance. Infant and maternal hair cortisol concentrations were not correlated. Infants' ability to shift to a new action in either task, controlled for acute stress, correlated neither with pre- and postnatal negative life events nor with cortisol concentrations. Taken together, these results indicate that the potential link between long-term stress exposure and cognitive flexibility might not be present in samples with low levels of psychosocial stress.
... Additionally, a chronic model of unpredictable stress led to a large volumetric shrinkage of the mPFC, as it includes all subregions, and additionally disrupted the PrL LTP acquired from highfrequency stimulation of the ventral hippocampus CA1 [197]. Excess of glucocorticoid is supposed to underlie the stress effects, at least partially, on synaptic disconnections [198]. Therefore, it is noteworthy that the brain changes triggered by corticosteroid treatment resemble those described previously for stressed animals [199]. ...
Since the brain was found to be somehow flexible, plastic, researchers worldwide have been trying to comprehend its fundamentals to better understand the brain itself, make predictions, disentangle the neurobiology of brain diseases, and finally propose up-to-date treatments. Neuroplasticity is simple as a concept, but extremely complex when it comes to its mechanisms. This review aims to bring to light an aspect about neuroplasticity that is often not given enough attention as it should, the fact that the brain’s ability to change would include its ability to disconnect synapses. So, neuronal shrinkage, decrease in spine density or dendritic complexity should be included within the concept of neuroplasticity as part of its mechanisms, not as an impairment of it. To that end, we extensively describe a variety of studies involving topics such as neurodevelopment, aging, stress, memory and homeostatic plasticity to highlight how the weakening and disconnection of synapses organically permeate the brain in so many ways as a good practice of its intrinsic physiology. Therefore, we propose to break down neuroplasticity into two sub-concepts, “upward neuroplasticity” for changes related to synaptic construction and “downward neuroplasticity” for changes related to synaptic deconstruction. With these sub-concepts, neuroplasticity could be better understood from a bigger landscape as a vector in which both directions could be taken for the brain to flexibly adapt to certain demands. Such a paradigm shift would allow a better understanding of the concept of neuroplasticity to avoid any data interpretation bias, once it makes clear that there is no morality with regard to the organic and physiological changes that involve dynamic biological systems as seen in the brain.
... The hippocampus is well known for its role in cognition [51,52], most importantly in learning and memory [53]. As it was aforementioned, due to the high concentration of glucocorticoid receptors in the hippocampus, it is considered the area of the brain most targeted by adrenal hormones [54,55]. Several studies have shown the withdrawal of these hormones causes degeneration of different neuronal cell populations in the hippocampus. ...
The development of animal models to study cell death in the brain is a delicate task. One of the models, that was discovered in the late eighties, is the induction of neurodegeneration through glucocorticoid withdrawal by adrenalectomy in albino rats. Such a model is one of the few noninvasive models for studying neurodegeneration. In the present study, using stereological technique and ultrastructural examination, we aimed to investigate the impact of short-term adrenalectomy (2 weeks) on different hippocampal neuronal populations in Wistar rats. In addition, the underlying mechanism(s) of degeneration in these neurons were investigated by measuring the levels of insulin-like growth factor-1 (IGF-1) and β-nerve growth factor (β-NGF). Moreover, we examined whether the biochemical and histological changes in the hippocampus, after short-term adrenalectomy, have an impact on the cognitive behavior of Wistar rats. Stereological counting in the hippocampus revealed significant neuronal deaths in the dentate gyrus and CA4/CA3, but not in the CA2 and CA1 areas, 7 and 14 days post adrenalectomy. The ultrastructural examinations revealed degenerated and degenerating neurons in the dentate, as well as CA4, and CA3 areas, over the course of 3, 7 and 14 days. The levels of IGF-1 were significantly decreased in the hippocampus of ADX rats 24 h post adrenalectomy, and lasted over the course of two weeks. However, β-NGF was not affected in rats. Using a passive avoidance task, we found a cognitive deficit in the ADX compared to the SHAM operated rats over time (3, 7, and 14 days). In conclusion, both granule and pyramidal cells were degenerated in the hippocampus following short-term adrenalectomy. The early depletion of IGF-1 might play a role in hippocampal neuronal degeneration. Consequently, the loss of the hippocampal neurons after adrenalectomy leads to cognitive deficits.
... This was seen parallel to rapid antidepressant behavioral response 24h after Ket administration (Li et al., 2010). Chronic-stress, corticosterone treatment and stress-related illnesses like depression lead to dendritic atrophy and reduction in number, length of the same in neuronal population of limbic brain regions like the prefrontal cortex and hippocampus (Christian et al., 2011, Conrad, 2008, Sapolsky et al., 1986. Expanding human and animal studies throughout last decade have indicated towards alterations in specific signaling pathways in neurons, which undergo remodeling and adaptive changes during the progression of pathophysiology of depression (Duman and Voleti, 2012). ...
Major depressive disorder (MDD) is the most disorienting psychiatric disorder, causing a huge social and economic burden globally. Conventional treatment with classical antidepressants targeting the monoaminergic system have provided very limited efficacy in pacifying depression symptoms. Rapid-acting antidepressant Ketamine (Ket) has emerged as a novel therapeutic agent applicable in MDD and treatment resistant depression, over the recent decade. Antidepressant effects of Ket is attributed to its ability to block Glun2B subunits of NMDARs at inhibitory neurons, leading to bursting of glutamatergic transmission and subsequent AMPAR activation. However, unwanted side-effects and abuse potential of Ket cannot be ignored. Since 2016, numerous reports of antidepressive properties of major Ket metabolite Hydroxynorketamine (HNK) have emerged. Similar to Ket, HNK increased AMPAR activation and successfully mitigated depressive symptoms in rodent models of depression, but in an NMDAR-independent manner. Interestingly, HNK displayed no dissociative side-effects commonly seen with Ket administration, making it a promising candidate in antidepressive research. However, evidences of molecular and cellular signaling cascades important for HNK mediated effects on synaptic function remain ambiguous. Here, using mature cortical cultures, we demonstrate bidirectional and differential regulation of network-activity driven SV recycling upon HNK treatment. Using live antibody-uptake studies, we show that short-term HNK treatment leads to an acute weakening of exo-/endocytic cycle dependent presynaptic activity at both excitatory and inhibitory synapses. This is followed by a surprising delayed increase of the same, specifically in excitatory synapses. This exclusive biphasic effect on presynaptic efficacy involve HNK-mediated regulation of TRP and is dependent on the functional presence α7nAchRs, unlike its parent compound Ket. Using immunocytochemistry and quantitative immunoblotting, we have also shown that HNK induces ERK activation and regulates nuclear activity of its downstream target CREB, which are important in HNK mediated regulation of neuronal plasticity. Further, we reveal that HNK and Ket depict similar temporal regulation of activity-dependent genes like Arc and BDNF, which have been deemed of importance in antidepressant research. Additionally, we show modulation of nuclear translocation of transcriptional co-repressor CtBP1, which in some measure might regulate the temporal expression of HNK induced activity-dependent genes. Altogether, this study reveals converging and diverging effects of HNK and Ket on regulation of SV recycling and cellular signaling cascades, which would be important for future mechanistic understanding and comparison of antidepressant effects elicited by these drugs.
... For example, repeated exposure to stressors during puberty can result in the sensitization of the HPA axis and the overproduction of GC [83,84]. The overproduction of GC could then damage key brain regions (i.e., hippocampus, amygdala, PFC) responsible for the regulation of the HPA axis [51,85,86]. Dysregulation of the HPA axis could then result in the chronic overproduction of GC which could increase susceptibility to mental illness associated with chronic stress (i.e., depression, anxiety, and substance abuse) [87][88][89]. ...
Puberty is a critical period of development marked by the maturation of the central nervous system, immune system, and hypothalamic–pituitary–adrenal axis. Due to the maturation of these fundamental systems, this is a period of development that is particularly sensitive to stressors, increasing susceptibility to neurodevelopmental and neurodegenerative disorders later in life. The gut microbiome plays a critical role in the regulation of stress and immune responses, and gut dysbiosis has been implicated in the development of neurodevelopmental and neurodegenerative disorders. The purpose of this review is to summarize the current knowledge about puberty, neurodegeneration, and the gut microbiome. We also examine the consequences of pubertal exposure to stress and gut dysbiosis on the development of neurodevelopmental and neurodegenerative disorders. Understanding how alterations to the gut microbiome, particularly during critical periods of development (i.e., puberty), influence the pathogenesis of these disorders may allow for the development of therapeutic strategies to prevent them.
Social isolation stress (SIS) is associated with affective disorders (i.e., anxiety and depression) in adults. In a preclinical study, we aimed to investigate the effects of resveratrol (RV) on the mood swings of rats exposed to SIS. Animals were randomized into six different groups, including control: healthy animals received normal saline (NS) as a vehicle; SIS + NS: SIS animals received NS; SIS + FL: SIS animals received fluoxetine (10 mg/kg/i.p.); SIS + RV20, SIS + RV40, and SIS + RV80: SIS animals received RV (20, 40, and 80 mg/kg/i.p). SIS was induced for 4 weeks, then animals were treated with NS, FL, and RV for 4 weeks. Rats were evaluated by the behavioral tests, including the elevated plus-maze, tail suspension test, the open field test, and forced-swimming test, for mood alterations and nuclear factor kappa B (NF-κB) levels, along with NLRP3, apoptosis-associated speck-like (ASC), and proCaspase-1 were determined in the hippocampus. Behavioral tests confirmed that exposing the animals to SIS caused anxiety and depression. The highest concentrations of NLRP3, proCaspase-1, ASC, and NF-κB, were confirmed in the SIS + NS group. Compared to FL, RV showed antidepressant potential according to the behavioral tests. In particular, the administration of RV (20, 40, and 80 mg/kg) revered the NF-κB/NLRP3 axis cascade in rats exposed to chronic SIS. Our findings revealed that RV attenuated anxiety and depression of SIS-exposed rats via regulation of NF-κB/NLRP3 signaling pathways. RV can be used as a potential anxiolytic agent and antidepressant.
Exposure to different types of stress is one of the significant risk factors in the emergence of clinically diagnosable depression. Studies are considerably less correlating the effect of stress on glial cell astrocytes, cognitive functions and behavioral analysis. The present study was aimed to. correlate the effect of chronic unpredictable stress on astrocytes in the hippocampus, cognitive functions and behavioral analysis. Adult Wistar albino rats were divided into Control group and stressed group (n=6 in each group). The rat were exposed to chronic unpredictable stressors for 15 consecutive days. On 15th day, the cognitive functions and the behavioral analysis was done. The animals were anesthetized and hippocampus was dissected and the astrocyte count was done using immunostaining method. The astrocyte count significantly (p<0.0001) decreased in the hippocampal tissue in the stressed group of rats. Moreover the decrease in the astrocytes was well associated with the significant decrease in the cognitive functions (p<0.0001) and behavioral analysis(p<0.0001). The current study focuses attention towards the strategies mitigating stress-induced cognitive dysfunction and altered behavioral responses associating astrocyte count targeting hippocampus. Reconsolidating pre-stress glial structure might prove therapeutically effective.
Stress is a well-known risk factor to develop a functional neurological disorder, a frequent neuropsychiatric medical condition in which patients experience a variety of disabling neurological symptoms. Only little is known about biological stress regulation, and how it interacts with predisposing biological and psychosocial risk factors. Dysregulation of the hypothalamic-pituitary-adrenal axis in patients with functional neurological disorders has been postulated but its relationship to preceding psychological trauma and brain anatomical changes remains to be elucidated. We set out to study the hypothalamic-pituitary-adrenal axis analysing the cortisol awakening response and diurnal baseline cortisol in 86 patients with mixed functional neurological symptoms compared to 76 healthy controls. We then examined the association between cortisol regulation and the severity and duration of traumatic life events. Finally, we analysed volumetric brain alterations in brain regions particularly sensitive to psychosocial stress, acting on the assumption of the neurotoxic effect of prolonged cortisol exposure. Overall, patients had a significantly flatter cortisol awakening response (P < 0.001) and reported longer (P = 0.01) and more severe (P < 0.001) emotional neglect as compared to healthy controls. Moreover, volumes of the bilateral amygdala and hippocampus were found to be reduced in patients. Using a partial least squares correlation, we found that in patients, emotional neglect plays a role in the multivariate pattern between trauma history and hypothalamic-pituitary-adrenal axis dysfunction, whilst cortisol did not relate to reduced brain volumes. This suggests that psychological stress acts as a precipitating psychosocial risk factor, whereas a reduced brain volume rather represents a biological predisposing trait marker for the disorder. Contrarily, an inverse relationship between brain volume and cortisol was found in healthy controls, representing a potential neurotoxic effect of cortisol. These findings support the theory of reduced subcortical volumes representing a predisposing trait factor in functional neurological disorders, rather than a state effect of the illness. In summary, this study supports a stress-diathesis model for functional neurological disorders and showed an association between different attributes of trauma history and abnormalities in hypothalamus-pituitary-adrenal axis function. Moreover, we suggest that reduced hippocampal- and amygdalar volumes represent a biological ‘trait marker’ for functional neurological disorder patients, which might contribute to a reduced resilience to stress.
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.
Posttraumatic stress disorder (PTSD) is a psychiatric condition that is directly precipitated by an event that threatens a person's life or physical integrity and that invokes a response of fear, helplessness, or horror. In recent years it has become clear that only a proportion of those exposed to fear-producing events develop or sustain PTSD. Thus, it seems that an important challenge is to elucidate aberrations in the normal fear response that might precipitate trauma-related psychiatric disorder. This paper summarizes the findings from recent studies that examined the acute and longer term biological response to traumatic stress in people appearing to the emergency room immediately following trauma exposure. In the aggregate, these studies have demonstrated increased heart rate and lower cortisol levels at the time of the traumatic event in those who have PTSD at a follow-up time compared to those who do not. In contrast, certain features associated with PTSD, such as intrusive symptoms and exaggerated startle responses, are only manifest weeks after the trauma. The findings suggest that the development of PTSD may be facilitated by an atypical biological response in the immediate aftermath of a traumatic event, which in turn leads to a maladaptive psychological state.
This review examines the central actions exerted by corticosteroids that are mediated by mineralocorticoid receptors (MRs or Type 1) and glucocorticoid receptocs (GRs or Type 2) in the brain. The leitmotiv is that these MR- and GR-mediated effects of the steroid hormones are of critical importance for homeostatic control. MRs have aldosterone (ALDO)-selective properties in some nerve cells and apparent corticosterone (B)-selective properties in others, notably the limbic neurons. Compartmentalization of the MR subtypes hinges on activity of 11β-hydroxysteroid dehydrogenase and corticosteroid-binding globulin. B also binds to GRs, but with 10-fold lower affinity. GR density is high in brain regions involved in organization of the stress response. GR-mediated corticosteroid effects inhibit stress-induced pituitary proopiomelanocortin and hypothalamic corticotropin-releasing hormone and vasopressin synthesis, but facilitate activation and sensitization of ascending aminergic neurons. In hippocampal CA1 neurons, co-localized MRs and GRs coordinately and differentially mediate corticosteroid control of ion regulation and transmitter responsiveness. MRs are involved in maintenance of excitability, while GRs suppress excitability, which is transiently raised by excitatory transmitters. At the neuroendocrine level, B sets the threshold for the stress response system via binding to MRs. Blockade of MRs enhances basal and stress-induced hypothalamo-pituitary-adrenal (HPA) activity. Stress- and circadian-induced episodic occupancy by B of GRs in hippocampus attenuates MR-mediated limbic inhibition. In hypothalamus, B blocks via binding to GRs the communication of the HPA axis. At the behavioral level, the ALDO-selective MRs mediate specific effects on salt hunger and functions associated with sodium homeostasis such as central cardiovascular control. Limbic MRs seem primarily concerned with B effects on information handling and the organization of behavioral strategies. GRs mediate steroid effects on fear- and food-motivated behavior and information storage. GR-mediated effects on behavior may persist for weeks in adulthood and appear permanent during development. High glucocorticoids decrease hippocampal GR and increase MR capacity, while mineralocorticoids down-regulate both receptor types. Animals with an increased relative amount of limbic MRs over GRs show reduced emotional and adrenocortical reactivity and a decreased ability to organize behavior with the help of external stimuli. Deviations of an idiosyncratic MR/GR balance are proposed to alter individual-specific susceptibility to stress and © 1991 Raven Press perhaps to stress-related brain diseases. The findings place Selye's "pendulum hypothesis" on mineralocorticoid and glucocorticoid action in the perspective of co-localized MRs and GRs mediating coordinate and differential effects of B on regulation of cellular homeostasis and behavioral adaptation.
The hypothalamic-pituitary-adrenal (HPA) axis, which ultimately controls the secretion of glucocorticoids from the adrenal cortex, is simply one arm of a central CRH system that appears to be responsible for coordinated behavioral, neuroendocrine, autonomic, and immune responses to alterations in homeostasis. There are marked circadian rhythms in the HPA axis, well integrated with other circadian activity to optimize the daily release of CRH and AVP, and its primary function is to stimulate steroidogenesis by the adrenal cortex. In addition, the HPA axis is responsive to stimuli (stressors) that threaten homeostasis, either psychologically or physically. Responses to acute stressors are essential for life, and they turn on and off rapidly. Chronic stressors appear to change the response characteristics in the HPA axis, possibly through recruiting central neural pathways that normally contribute in only a minor fashion to the acute stress response. During chronic stress, both the CRH- and the glucocorticoid-regulatory components of the HPA axis serve to inhibit activity in other, energy-expending hormonal systems of the body, thus conserving energy stores for immediate use.