Adolescent development,hypothalamic-pituitary-adrenal function,and programming of adult learning and memory

Chronic exposure to stress is known to affect learning and memory in adults through the release of glucocorticoid hormones by the hypothalamic-pituitary-adrenal (HPA) axis. In adults, glucocorticoids alter synaptic structure and function in brain regions that express high levels of glucocorticoid receptors and that mediate goal-directed behaviour and learning and memory. In contrast to relatively transient effects of stress on cognitive function in adulthood, exposure to high levels of glucocorticoids in early life can produce enduring changes through substantial remodeling of the developing nervous system. Adolescence is another time of significant brain development and maturation of the HPA axis, thereby providing another opportunity for glucocorticoids to exert programming effects on neurocircuitry involved in learning and memory. These topics are reviewed, as is the emerging research evidence in rodent models highlighting that adolescence may be a period of increased vulnerability compared to adulthood in which exposure to high levels of glucocorticoids results in enduring changes in adult cognitive function.     

The hypothalamic-pituitary-adrenocortical system: Hormonal brain-gut interaction and gastroprotection

The hypothalamic-pituitary-adrenocortical system is a hormonal component of brain-gut axis. There are two opposite points of view regarding the influence of stress-induced activation of hypothalamic-pituitary-adrenocortical system on the stomach. According to the widely held view, glucocorticoids released during stress are ulcerogenic hormones and, therefore, stress-induced activation of hypothalamic-pituitary-adrenocortical system is harmful. The results of our investigations are, however, opposite to this traditional view. To estimate the action of glucocorticoids released during stress on the gastric mucosa, the effects of glucocorticoid deficiency or occupation of glucocorticoid receptors by the antagonist RU-38486 on the formation of stress-induced gastric erosions were estimated in rats. The reduction of stress-induced corticosterone release (induced by various experimental approaches) markedly potentiated a gastric erosion formation caused by stress and acute corticosterone replacement, mimicking stress-induced corticosterone response, prevented this erosion-potentiating effect. The administration of RU-38486 also caused a significant increase of vulnerability of gastric mucosa to stress action. Thus, an acute stress-induced increase of glucocorticoids has a gastroprotective action against stress-induced gastric injury. We also showed that various ulcerogenic stimuli, similar to stress, induce an increase in glucocorticoid production that in turn helps the gastric mucosa to resist against a harmful action of ulcerogenic stimuli. Gastroprotective action of glucocorticoids may be mediated by multiple actions, including maintenance of glucose homeostasis, gastric mucosal blood flow, mucus production and attenuation of enhanced gastric motility and microvascular permeability. For maintenance of gastric mucosal integrity glucocorticoids may cooperate with prostaglandins. In conclusion, these findings indicate that activation of hypothalamic-pituitary-adrenocortical system could be considered as a significant gastroprotective component of brain-gut axis.     

Prenatal stress: consequences of glucocorticoids on hippocampal development and function

Prenatally stressed offspring exhibit a variety of physiological and behavioral alterations. This paper highlights those alterations associated with prenatal stress-induced elevations in glucocorticoid secretion. Three major alterations are identified that may be produced by glucocorticoid-induced actions on the developing hippocampus. Changes include reductions in steroid receptors that bind endogenous glucocorticoids, enhanced secretion of stress hormones and increased reactivity or emotionality in stressful situations. Some of these alterations may be ameliorated by early postnatal environmental manipulations such as adoption and handling procedures. These latter results suggest that prenatal stress-induced effects of glucocorticoids extend into the early postnatal period to produce long-term hippocampal and behavioral alterations. Support for this hypothesis is based on studies demonstrating that the hippocampus undergoes considerable maturational changes during the early postnatal period such as establishing the regional distribution of corticosteroid receptor densities and development of hippocampal dentate gyrus cells as well as cholinergic systems. Hippocampal corticosteroid receptors are involved in the regulation of glucocorticoid negative feedback and hippocampal dentate gyrus and cholinergic development are influenced by endogenous glucocorticoids and are implicated in the development of defensive or stress-induced behavior. The developing hippocampus appears especially vulnerable to alterations induced by prenatal stress-induced elevations in glucocorticoids that continue to produce their effects throughout the early postnatal period.     

Systems mediating acute glucocorticoid effects on memory consolidation and retrieval

It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. This article reviews recent findings from this laboratory on the acute effects of glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors (GRs) enhances memory consolidation in a dose-dependent manner. Glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala (BLA) and interactions of the BLA with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of glucocorticoids or following infusions of GR agonists into the hippocampus. Although the BLA does not appear to be a site of glucocorticoid action in influencing memory retrieval, an intact BLA is required for enabling glucocorticoid effects on memory retrieval. The BLA appears to be a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.     

The exercise-glucocorticoid paradox: How exercise is beneficial to cognition,mood, and the brain while increasing glucocorticoid levels

Exercise is known to have beneficial effects on cognition, mood, and the brain. However, exercise also activates the hypothalamic–pituitary–adrenal axis and increases levels of the glucocorticoid cortisol (CORT). CORT, also known as the “stress hormone,” is considered a mediator between chronic stress and depression and to link various cognitive deficits. Here, we review the evidence that shows that while both chronic stress and exercise elevate basal CORT levels leading to increased secretion of CORT, the former is detrimental to cognition/memory, mood/stress coping, and brain plasticity, while the latter is beneficial. We propose three preliminary answers to the exercise-CORT paradox. Importantly, the elevated CORT, through glucocorticoid receptors, functions to elevate dopamine in the medial prefrontal cortex under chronic exercise but not chronic stress, and the medial prefrontal dopamine is essential for active coping. Future inquiries may provide further insights to promote our understanding of this paradox.     

The therapeutic use of glucocorticoid hormones in the perinatal period: potential neurological hazards

The expanding perinatal use of glucocorticoids entails potentially hazardous effects of these hormones on nervous system development. Neonatal animal experimentation with pharmacological doses of glucocorticoids has revealed immediate effects on brain cell division, differentiation, myelination, and electrophysiological reactions. In addition, delayed (latent) effects include changes in control of circadian periodicity, altered biogenic amine levels, altered response to stress, and changes in ultimate behavior. Thus perinatal hormone therapy during critical periods of brain development is capable of exerting irreversible immediate effects on brain cell division and differentiation, resulting in latent or long-term physiological and behavioral effects.     

Hypophysectomy increases vasoactive intestinal peptide-stimulated cyclic AMP generation in the hippocampus of the rat

In investigating the feedback effects of circulating hormones on the brain, we showed previously that adrenalectomy (ADX) increases vasoactive intestinal peptide (VIP)-stimulated cAMP generation in slices from rat hippocampus, a brain structure with high levels of glucocorticoid receptors. This effect is reversed by replacement with glucocorticoids such as dexamethasone (DEX) and corticosterone (CORT). Here we report that, like ADX, hypophysectomy (HYPOX) also elevates VIP-stimulated cAMP generation, compared with sham-operated controls. Moreover, like glucocorticoid replacement, administration of ACTH to HYPOX rats causes a decrease in cAMP stimulation by VIP. Furthermore, ACTH had no effect when given to HYPOX + ADX rats, indicating that the effects of ACTH require the presence of adrenal steroid secretion. However, we find that ACTH may have a permissive role in this glucocorticoid effect because, in the absence of the pituitary, DEX treatment does not decrease VIP-stimulated cAMP levels in the hippocampus. In addition, hippocampal beta-adrenergic-stimulated cAMP accumulation was not suppressed by DEX treatment of HYPOX rats, which again is different from the effect of DEX treatment on ADX animals. These results are discussed in terms of possible synergism between pituitary hormones and steroid hormones in exerting feedback actions on brain function.     

Circadian and ultradian glucocorticoid rhythmicity: Implications for the effects of glucocorticoids on neural stem cells and adult hippocampal neurogenesis

Psychosocial stress, and within the neuroendocrine reaction to stress specifically the glucocorticoid hormones, are well-characterized inhibitors of neural stem/progenitor cell proliferation in the adult hippocampus, resulting in a marked reduction in the production of new neurons in this brain area relevant for learning and memory. However, the mechanisms by which stress, and particularly glucocorticoids, inhibit neural stem/progenitor cell proliferation remain unclear and under debate.Here we review the literature on the topic and discuss the evidence for direct and indirect effects of glucocorticoids on neural stem/progenitor cell proliferation and adult neurogenesis. Further, we discuss the hypothesis that glucocorticoid rhythmicity and oscillations originating from the activity of the hypothalamus-pituitary-adrenal axis, may be crucial for the regulation of neural stem/progenitor cells in the hippocampus, as well as the implications of this hypothesis for pathophysiological conditions in which glucocorticoid oscillations are affected.     

Glucocorticoids and the regulation of memory in health and disease

Over the last decades considerable evidence has accumulated indicating that glucocorticoids – stress hormones released from the adrenal cortex – are crucially involved in the regulation of memory. Specifically, glucocorticoids have been shown to enhance memory consolidation of emotionally arousing experiences, but impair memory retrieval and working memory during emotionally arousing test situations. Furthermore, growing evidence indicates that these different glucocorticoid effects all depend on emotional arousal-induced activation of noradrenergic transmission within the basolateral complex of the amygdala (BLA) and on interactions of the BLA with other brain regions, such as the hippocampus and neocortical regions. Here we review findings from both animal and human experiments and present an integrated perspective of how these opposite glucocorticoid effects might act together to serve adaptive processing of emotionally significant information. Furthermore, as intense emotional memories also play a crucial role in the pathogenesis and symptomatology of anxiety disorders, such as posttraumatic stress disorder (PTSD) or phobias, we discuss to what extent the basic findings on glucocorticoid effects on emotional memory might have implications for the understanding and treatment of these clinical conditions. In this context, we review data suggesting that the administration of glucocorticoids might ameliorate chronic anxiety by reducing retrieval of aversive memories and enhancing fear extinction.     

Interaction between glucocorticoid hormones,stress and psychostimulant drugs

In this review we summarize data obtained from animal studies showing that glucocorticoid hormones have a facilitatory role on behavioural responses to psychostimulant drugs such as locomotor activity, self-administration and relapse. These behavioural effects of glucocorticoids involve an action on the meso-accumbens dopamine system, one of the major systems mediating the addictive properties of drugs of abuse. The effects of glucocorticoids in the nucleus accumbens are site-specific; these hormones modify dopamine transmission in only the shell of this nucleus without modifying it in the core. Studies with corticosteroid receptor antagonists suggest that the dopaminergic effects of these hormones depend mostly on glucocorticoid, not on mineralocorticoid receptors. These data suggest that an increase in glucocorticoid hormones, through an action on mesolimbic dopamine neurons, could increase vulnerability to drug abuse. We also discuss the implications of this finding with respect to the physiological role of glucocorticoids. It is proposed that an increase in glucocorticoids, by activating the reward pathway, could counteract the aversive effects of stress. During chronic stress, repeated increases in glucocorticoids and dopamine would result in sensitization of the reward system. This sensitized state, which can persist after the end of the stress, would render the subject more responsive to drugs of abuse and consequently more vulnerable to the development of addiction.     

Region-specific control of microglia by adenosine A2A receptors: uncoupling anxiety and associated cognitive deficits in female rats

Epidemiologic studies have provided compelling evidence that prenatal stress, through excessive maternal glucocorticoids exposure, is associated with psychiatric disorders later in life. We have recently reported that anxiety associated with prenatal exposure to dexamethasone (DEX, a synthetic glucocorticoid) correlates with a gender-specific remodeling of microglia in the medial prefrontal cortex (mPFC), a core brain region in anxiety-related disorders. Gender differences in microglia morphology, the higher prevalence of anxiety in women and the negative impact of anxiety in cognition, led us to specifically evaluate cognitive behavior and associated circuits (namely mPFC-dorsal hippocampus, dHIP), as well as microglia morphology in female rats prenatally exposed to dexamethasone (in utero DEX, iuDEX). We report that iuDEX impaired recognition memory and deteriorated neuronal synchronization between mPFC and dHIP. These functional deficits are paralleled by microglia hyper-ramification in the dHIP and decreased ramification in the mPFC, showing a heterogeneous remodeling of microglia morphology, both postnatally and at adulthood in different brain regions, that differently affect mood and cognition. The chronic blockade of adenosine A_2A receptors (A_2AR), which are core regulators of microglia morphology and physiology, ameliorated the cognitive deficits, but not the anxiety-like behavior. Notably, A_2AR blockade rectified both microglia morphology in the dHIP and the lack of mPFC-dHIP synchronization, further heralding their role in cognitive function.     

Evidence that metyrapone can act as a stressor: effect on pituitary-adrenal hormones,plasma glucose and brain c-fos induction

Metyrapone, a 11-beta steroid hydroxylase inhibitor that blocks stress-induced glucocorticoid release, is extensively used to study the physiological and behavioural roles of glucocorticoids. However, there is circumstantial evidence suggesting that metyrapone could act as a pharmacological stressor. Thus, the effects of various doses of metyrapone on two well-characterized stress markers (ACTH and glucose) were studied in male rats. Metyrapone administration, while exerting a modest effect on plasma corticosterone levels, dose-dependently increased plasma ACTH and glucose levels. Using the highest doses previously tested (200 mg/kg) we further observed, as evaluated by fos-like immunoreactivity (FLI), a strong activation of a wide range of brain areas, including the parvocellular region of the hypothalamic paraventricular nucleus (PVNp), the origin of the main ACTH secretagogues. Metyrapone-induced FLI was observed in neocortical and allocortical areas, in several limbic, thalamic and hypothalamic nuclei and, to a lesser extent, in the brainstem. In a final experiment, a dose-response study of metyrapone-induced FLI was carried out focusing on selected brain areas. The study revealed that the paraventricular thalamic nucleus and central amygdala were the areas most sensitive to metyrapone as they responded even to the lowest dose of the drug. Most areas, among them the PVNp, only showed enhanced FLI with the two highest doses, i.e. when it was associated with ACTH and glucose responses. These data suggest that some of the effects of metyrapone could be due to its stressful properties rather than its ability to inhibit glucocorticoid synthesis. The exact mechanisms involved remain to be established.     

The stress-induced response of the septo-hippocampal cholinergic system. A vectorial outcome of psychoneuroendocrinological interactions

Considerable data have emerged which strongly indicate that the septohippocampal cholinergic system is involved in the adaptive response to stress. Neurotransmitter regulatory mechanisms in cholinergic synaptic terminals of this part of the limbic system undergo adaptive changes in response to stress and recover slowly after stress. The initial stress-induced response is characterized by activation of hippocampal cholinergic terminals within minutes, as indicated by a rapid and transient elevation in high affinity choline uptake and increased newly synthesized acetylcholine release. The response of this cholinergic system to stress is influenced by both neuronal and hormonal stimuli. Among the several neuronal systems converging in the septum, terminals of the dopaminergic mesolimbic system have been found to be selectively involved in the early response to stress. Pharmacological interference with dopaminergic neurotransmission, with agonist and antagonist treatments, revealed that changes in the tonic inhibitory influence of septal dopaminergic terminals can modulate the response of hippocampal cholinergic terminals to stress. A similar activation of hippocampal cholinergic terminals as after short-term stress was observed after treatments with a large dose of either adrenocorticotropic hormone or corticosterone. Furthermore, glucocorticoids and not adrenocorticotropic hormone can directly enhance acetylcholine release, but only from excited terminals. This indicates that stress-induced activation of the septo-hippocampal system may occur secondary to, but not directly by, increased levels of pituitary-adrenocortical hormones. Yet, it is possible that under stressful conditions the increased glucocorticoid levels may modulate the activity of the stimulated hippocampal cholinergic terminals. Together the findings support the notion that the stress-induced response of the septo-hippocampal cholinergic system represents an integrated output of converging neuronal and hormonal stimuli which convey signals of stress to this limbic brain region.     

Modulation of microglia and CD8(+) T cell activation during the development of stress-induced herpes simplex virus type-1 encephalitis

The central nervous system (CNS) has been shown to be vulnerable to a variety of insults in animals exposed to glucocorticoids. For example, psychological stress, a known inducer of glucocorticoid production, enhances the susceptibility of mice to herpes simplex virus type-1 (HSV-1) infection and results in the development of HSV-1 encephalitis (HSE). To determine the immune mechanisms by which stress promotes the development of HSE, we examined the role of the glucocorticoid receptor (GR) and the N-methyl-d-aspartate (NMDA) receptor in the development of HSE. Our findings demonstrate that blockade of either the GR or the NMDA receptor enhances survival following HSV-1 infection in stressed mice to levels similar to non-stressed mice. Subsequent studies determined the effect of GR and NMDA receptor blockade on immune function by specifically examining both microglia and CD8(+) T cell activation. Stress inhibited the expression of MHC class I by microglia and other brain-derived antigen presenting cells (CD45(hi)) independent of either the glucocorticoid receptor or the NMDA receptor, suggesting that stress-induced suppression of MHC class I expression in the brain does not affect survival during HSE. Blockade of the NMDA receptor, however, diminished HSV-1-induced increases in class I expression by CD45(hi) cells, suggesting that blockade of the NMDA receptor may limit CNS inflammation. Also, while CD8(+) T cell activation and function in the brain were not affected by stress, the number of CD8(+) T cells in the superficial cervical lymph nodes (SCLN) was decreased in stressed mice via GR-mediated mechanisms. These findings indicate that stress-induced hypocellularity is mediated by the GR while NMDA receptor activation is responsible for enhancing CNS inflammation. The combined effects of GR-mediated hypocellularity of the SCLN and NMDA receptor-mediated CNS inflammation during stress promote the development of HSE.     

Steroid effects on brain functions: an example of the action of glucocorticoids on central dopaminergic and neurotensinergic systems.

It is now clearly established that steroid hormones released from peripheral endocrine glands may, through specific receptors in the brain, directly regulate brain function. These effects may be rapid or involve long-term modifications at the genomic level. Concerning the glucocorticoids, their receptors are found in most neuronal cells, an observation which can be related to their widespread effects on neuronal metabolism. Furthermore, glucocorticoids are often related to stress. We have previously demonstrated that neonatal handling of the rat prevented excessive endocrine response to stress. In adults, this action appeared to protect the animal from potential damaging effects of glucocorticoids and from related impairment of cognitive functions. The effects of glucocorticoids are thought to involve an interaction of several central neurotransmitter systems. One such neurotransmitter is neurotensin, a neuropeptide which was reported to be closely related to central dopaminergic system regulation. This paper presents a rapid overview of the central effects of glucocorticoids and possible evidence for the interrelationship between these steroids, dopamine and neurotensin systems in the regulation of the hypothalamo-pituitary-adrenal axis. It provides a new way to approach stress responses and to develop new substances that may become potential drugs in the treatment of some psychiatric disorders.     

Stress hormones and human memory function across the lifespan

In this paper, we summarize the data obtained in our laboratory showing the effects of glucocorticoids on human cognitive function in older adults, young adults and children. We first present data obtained in the aged human population which showed that long-term exposure to high endogenous levels of glucocorticoids is associated with both memory impairments and a 14% smaller volume of the hippocampus. We then report on studies showing that in older adults with moderate levels of glucocorticoids, memory performance can be acutely modulated by pharmacological manipulations of glucocorticoids. In young adults, we present data obtained in our laboratory showing that cognitive processing sustained by the frontal lobes is also sensitive to acute increases of glucocorticoids. We also summarize studies showing that just as in older adults, memory performance in young adults can be acutely modulated by pharmacological manipulations of glucocorticoids. We then present a study in which we showed a differential involvement of adrenergic and glucocorticoid hormones for short- and long-term memory of neutral and emotional information. In the last section of the paper, we present data obtained in a population of young children and teenagers from low and high socioeconomic status (SES), where we showed that children from low SES present significantly higher levels of basal cortisol when compared to children from high SES. We then present new data obtained in this population showing that children and teenagers from low and high SES do not process the plausibility of positive and negative attributes in the same way. Children from low SES tended to process positive and negative attributes on a more negative note than children from high SES, and this type of processing was significantly related to basal cortisol at age 10, 12 and 14. Altogether, the results of these studies show that both bottom-up (effects of glucocorticoids on cognitive function), and top-down (effects of cognitive processing on glucocorticoid secretion) effects exist in the human population.     

Modulation of motor function by stress: a novel concept of the effects of stress and corticosterone on behavior

Stress and stress hormones affect a variety of behaviors and cognitive abilities. The influences of stress and glucocorticoids on motor function, however, have not been characterized although the presence of glucocorticoid receptors in the motor system has been documented. Here we demonstrate that stress and the stress hormone corticosterone influence motor system function in rats. Groups of adult female Long-Evans rats underwent either a daily stress-inducing procedure (immobilization or swimming in cold water) or oral corticosterone treatment. While these treatments continued, animals were tested in skilled reaching and skilled walking tasks for a period of 2 weeks. Both acute (day 1) and chronic (day 14) stress and corticosterone treatment reduced skilled movement accuracy in reaching and walking and increased performance speed. Furthermore, both chronic stress and chronic corticosterone treatment altered skilled movement patterns in the reaching task. These findings indicate that stress modulates motor system function and that these effects are partially mediated by glucocorticoids. To examine whether stress-induced changes might also derive from enhanced emotionality, rats were treated with the benzodiazepine diazepam. Based on an inverted U-shaped dose-response relationship, a moderate dose of diazepam significantly improved reaching success while at the same time reducing corticosterone levels. Thus, stress-associated emotional responses such as anxiety might account for diminished movement accuracy. These results suggest that stress affects the motor system both directly via hormonal changes and indirectly via changes in emotionality. These findings are discussed with respect to the role of stress in motor system function and movement disorders.