E. Ronald de Kloet

Selective corticosteroid antagonists modulate specific aspects of spatial orientation learning

Receptors for mineralocorticoids (MRs) and glucocorticoids (GRs) display a high concentration and distinct distribution in the hippocampus. The effects of corticosteroids on behavior mediated by central MRs and GRs were assessed in rats. Spatial navigation is considered to be a sensitive measure for hippocampal functioning. Removal of circulating corticosteroids (via adrenalectomy) impaired spatial learning. In intact rats, blockade of central MRs and GRs by intracerebroventricular injection of selective MR and GR antagonists influenced different aspects of spatial learning. The analysis of the behavioral pattern revealed that treatment with the MR antagonist altered search-escape strategies in the water maze. The injection of the GR antagonist after training resulted in increased latencies to find the platform, which reflects the disturbed consolidation of spatial information. Corticosteroids affect in a differential and coordinated manner behavioral strategies and storage of spatial information.

Maternal Care and Hippocampal Plasticity: Evidence for Experience-Dependent Structural Plasticity, Altered Synaptic Functioning, and Differential Responsiveness to Glucocorticoids and Stress

Maternal licking and grooming (LG) in infancy influences stress responsiveness and cognitive performance in the offspring. We examined the effects of variation in the frequency of pup LG on morphological, electrophysiological, and behavioral aspects of hippocampal synaptic plasticity under basal and stress-like conditions. We found shorter dendritic branch length and lower spine density in CA1 cells from the adult offspring of low compared with high LG offspring. We also observed dramatic effects on long-term potentiation (LTP) depending on corticosterone treatment. Low LG offspring, in contrast to those of high LG mothers, displayed significantly impaired LTP under basal conditions but surprisingly a significantly enhanced LTP in response to high corticosterone in vitro. This enhanced plasticity under conditions that mimic those of a stressful event was apparent in vivo. Adult low LG offspring displayed enhanced memory relative to high LG offspring when tested in a hippocampal-dependent, contextual fear-conditioning paradigm. Hippocampal levels of glucocorticoid and mineralocorticoid receptors were reduced in low compared with high LG offspring. Such effects, as well as the differences in dendritic morphology, likely contribute to LTP differences under resting conditions, as well as to the maternal effects on synaptic plasticity and behavior in response to elevated corticosterone levels. These results suggest that maternal effects may modulate optimal cognitive functioning in environments varying in demand in later life, with offspring of high and low LG mothers showing enhanced learning under contexts of low and high stress, respectively.

Control of neuronal excitability by corticosteroid hormones

The rat adrenal hormone corticosterone can cross the blood-brain barrier and bind to two intracellular receptor populations in the brain--the mineralocorticoid and glucocorticoid receptors. Recent studies have revealed that the corticosteroid hormones are able to restore changes in neuronal membrane properties induced by current or neurotransmitters, probably through a genomic action. In general, mineralocorticoid receptors mediate steroid actions that enhance cellular excitability, whereas activated glucocorticoid receptors can suppress temporarily raised neuronal activity. The steroid-mediated control of excitability and the implications for information processing in the brain are reviewed in this article.

The coming out of the brain mineralocorticoid receptor

Corticosteroids - secreted after stress - have profound effects on brain and behavior. These effects are mediated by mineralocorticoid and glucocorticoid receptors, which are abundantly expressed in limbic neurons. The role of mineralocorticoid receptors in higher brain functions has never been well understood. Here we argue that the recently discovered low-affinity membrane version of the mineralocorticoid receptor contributes to the initial phase of the stress reaction; this is complemented by the glucocorticoid receptor which terminates the stress response. This concept may explain why human carriers of a mineralocorticoid receptor gene variant display enhanced neuroendocrine and autonomic responsiveness to a psychological stressor.

Effect of oxytocin and vasopressin on memory consolidation: sites of action and catecholaminergic correlates after local microinjection into limbic-midbrain structures

The effects of local postlearning microinjections of arginine-vasopressin (AVP) and oxytocin (OXT) on one-trial learning passive avoidance behavior and the influence of AVP on alpha-MPT-induced disappearance of norepinephrine (NE) and dopamine (DA) in discrete brain regions have been studied in the rat. OXT injected bilaterally in the hippocampal dentate gyrus (25-25 pg) or in the midbrain dorsal raphe nucleus (50 pg) significantly attenuated passive avoidance behavior. Facilitation of passive avoidance behavior was observed when the peptide was injected into the dorsal septal nucleus. AVP facilitated passive avoidance behavior when administered into the hippocampal dentate gyrus, dorsal raphe nucleus or dorsal septal nucleus. Injection of either neuropeptides into the central amygdaloid nucleus appeared to be ineffective. One week after the behavioral experiments a repeated injection of AVP into the hippocampal dentate gyrus increased the disappearance of NE in the dentate gyrus and in the nucleus ruber. An injection into the dorsal septal nuclei decreased the NE disappearance in the dorsal septal nucleus itself and increased it in the nucleus ruber. Injection in the dorsal raphe nucleus led to an increase in the disappearance of DA in the locus coeruleus and in the nucleus ruber. It is concluded that memory consolidation can be oppositely influenced by local application of minute amounts of either OXT or AVP into certain limbic-midbrain structures, suggesting an involvement of these brain regions in the memory effects of these peptides. Modulation of catecholamine turnover in specific brain areas after AVP administration may be related to this behavioral effect.

Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone.

Previously, we showed that corticosterone regulates BDNF mRNA levels in the hippocampus. In the present study, we have investigated the time course and dose-dependency of this effect at both the mRNA and the protein level. Corticosterone was administered in doses of 30 and 1000 microgram/kg b.w. subcutaneously to adrenalectomized animals. At 3, 6, 12 and 24 h after administration BDNF and trkB mRNA levels in hippocampal subfields were measured by in situ hybridization. Our results show a dose-dependent decrease in BDNF mRNA in dentate gyrus and CA1 at 3 h. After the high dose, this decrease was 70% and 40% respectively. In addition, ELISA was performed to study if this downregulation is also detectable at the protein level. Hippocampal tissue was used from adrenalectomized animals which had received 1000 microgram/kg b.w. corticosterone 4 and 6 h before decapitation. At both time points, a decrease in BDNF protein was observed; 17% at 4 h and 14% at 6 h after corticosterone, as compared to the vehicle injected controls. TrkB mRNA levels were not affected by corticosterone. However, between 6 and 24 h after treatment, increases in trkB mRNA were observed. In conclusion, we have found a transient, dose-dependent decrease in BDNF mRNA and protein in the hippocampus, which may underly changes in neuronal plasticity in the hippocampus after short-term changes in corticosterone concentrations.

Stress, genes and the mechanism of programming the brain for later life

Adverse conditions during early life are a risk factor for stress-related diseases such as depression and post-traumatic stress disorder (PTSD). How this long-term effect of early adversity occurs is not known, although evidence accumulates that the action of stress hormones is an important determinant. In rodents after a variety of experiences, even minor ones, during postnatal life permanent changes in emotional and neuroendocrine reactivity have been observed. Also stressful events occurring prenatally and even the pre-implantation hormonal conditions can have permanent consequences. Here we will focus on evidence obtained from (i) the blastocyst implantation during conditions of ovarian hyperstimulation, which is commonly used in the generation of transgenic mice; (ii) the stress system activity in the newborn under various conditions of maternal care; (iii) the long-term consequences of maternal separation procedures. The results clearly demonstrate that early experiences trigger immediate changes in the stress system that may permanently alter brain and behaviour.

Stress, glucocorticoids and development

Publisher Summary This chapter provides an overview of the current understanding of the dynamics of the hypothalamuspituitary-adrenal (HPA) system in the adult rat. The chapter particularly emphasizes on the role of glucocorticoid receptors in this process. In the adult organism, glucocorticoids (GCs) serve a wide variety of regulatory and permissive functions, aimed basically at controlling the organisms responses to stress, and at regulating circadian-driven activities. The principal GC synthesized by the rat adrenal cortex is corticosterone (CORT). CORT levels display a pronounced circadian rhythmicity: they are highest immediately preceding the animals active period, and lowest at the end of this period. During development, however, GCs have also been shown to produce, in experimental animals, permanent effects on growth and differentiation of a number of systems, including the central nervous system. In rats, for example, high doses of GCs administered neonatally cause a decrease in mitosis and myelination, as well as altered neural morphogenesis. In addition, the chapter also reviews some of the relevant human literature and considers the implications of animal studies for the field of human functional teratology.

Hormones and the Stressed Brain

Abstract: The stress system orchestrates brain and body responses to the environment. Cortisol (in humans) or corticosterone (in rodents) are important mediators of the stress system. Their action—in concert—is crucial for individual differences in coping with other individuals, which in turn depend on genetic‐ and experience‐related factors. The actions exerted by cortisol and corticosterone have an enormous diversity. They include the regulation of rapid molecular aggregations, membrane processes, and gene transcription. In the latter transcriptional regulation, the corticosteroid hormones have two modes of operation. One mode is mediated by high‐affinity mineralocorticoid receptors (MRs), which control gene networks underlying stabilization of neuronal activity as determinant for the sensitivity to trigger immediate responses to stress organized by corticotrophin‐releasing hormone (CRH)‐1 receptor. Whereas disturbance of homeostasis is prevented by MR‐mediated processes, its recovery is facilitated via the low‐affinity glucocorticoid receptors (GRs) that require stress levels of cortisol. GRs promote in coordination with CRH‐2 receptors and the parasympathetic system behavioral adaptation and enhances storage of energy and information in preparation for future events. The balance in the two stress system modes is thought to be essential for cell homeostasis, mental performance, and health. Imbalance induced by genetic modification or stressors changes specific neural signaling pathways underlying cognition and emotion. This yin‐yang concept in stress regulation is fundamental for genomic strategies to understand the mechanistic underpinning of corticosteroid‐induced stress‐related disorders such as severe forms of depression.

Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse

BACKGROUND High coincidence of childhood abuse, major depressive disorder (MDD), and posttraumatic stress disorder (PTSD) has been reported in patients with borderline personality disorder (BPD). Animals exposed to early trauma show increased stress-induced hypothalamic-pituitary-adrenal (HPA) axis activity due to an enhanced corticotropin-releasing hormone (CRH) drive and glucocorticoid feedback resistance. In humans, PTSD and MDD are associated with decreased and increased resistance to glucocorticoid feedback, respectively, which might reflect persistent changes in neuroendocrine sequelae following childhood abuse. METHODS We investigated the relationship between childhood abuse and HPA axis function using a combined dexamethasone/CRH (DEX/CRH) test in 39 BPD patients with (n = 24) and without (n = 15) sustained childhood abuse and comorbid PTSD (n = 12) or MDD (n = 11) and 11 healthy control subjects. RESULTS Chronically abused BPD patients had a significantly enhanced corticotropin (ACTH) and cortisol response to the DEX/CRH challenge compared with nonabused subjects. Comorbid PTSD significantly attenuated the ACTH response. CONCLUSIONS Hyperresponsiveness of the HPA axis in chronically abused BPD subjects might be due to the enhanced central drive to pituitary ACTH release. Sustained childhood abuse rather than BPD, MDD, or PTSD pathology accounts for this effect. Possibly due to an enhanced efficacy of HPA suppression by dexamethasone, PTSD attenuates the ACTH response to DEX/CRH.