Henk Karst

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.

Chronic stress : Implications for neuronal morphology, function and neurogenesis

In normal life, organisms are repeatedly exposed to brief periods of stress, most of which can be controlled and adequately dealt with. The presently available data indicate that such brief periods of stress have little influence on the shape of neurons or adult neurogenesis, yet change the physiological function of cells in two time-domains. Shortly after stress excitability in limbic areas is rapidly enhanced, but also in brainstem neurons which produce catecholamines; collectively, during this phase the stress hormones promote focused attention, alertness, vigilance and the initial steps in encoding of information linked to the event. Later on, when the hormone concentrations are back to their pre-stress level, gene-mediated actions by corticosteroids reverse and normalize the enhanced excitability, an adaptive response meant to curtail defense reactions against stressors and to enable further storage of relevant information. When stress is experienced repetitively in an uncontrollable and unpredictable manner, a cascade of processes in brain is started which eventually leads to profound, region-specific alterations in dendrite and spine morphology, to suppression of adult neurogenesis and to inappropriate functional responses to a brief stress exposure including a sensitized activation phase and inadequate normalization of brain activity. Although various compounds can effectively prevent these cellular changes by chronic stress, the exact mechanism by which the effects are accomplished is poorly understood. One of the challenges for future research is to link the cellular changes seen in animal models for chronic stress to behavioral effects and to understand the risks they can impose on humans for the precipitation of stress-related disorders.

Metaplasticity of amygdalar responses to the stress hormone corticosterone

High levels of corticosteroids (as circulate after stress) quickly and reversibly enhance hippocampal glutamatergic transmission via nongenomic actions requiring mineralocorticoid receptors. Subsequently, the hormone slowly and long-lastingly normalizes hippocampal cell function, through nuclear glucocorticoid receptors. Here we describe a rapid mineralocorticoid receptor-dependent enhancement of glutamatergic transmission in basolateral amygdala neurons. Contrary to the hippocampus, this rapid enhancement is long-lasting, potentially allowing an extended window for encoding of emotional aspects during stressful events. Importantly, the long-lasting change in state of amygdala neurons greatly affects the responsiveness to subsequent surges of corticosterone, revealing a quick suppression of glutamatergic transmission, which requires the glucocorticoid receptor. Responses of basolateral amygdala neurons to the stress hormone corticosterone can thus switch from excitatory to inhibitory, depending on the recent stress history of the organism.

Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus

It has become increasingly clear that the increase in corticosteroid levels, e.g. after a brief stressor induce molecular and cellular changes in brain, including the hippocampal formation. These effects eventually result in behavioral adaptation. Prolonged exposure to stress, though, may lead to mal-adaptation and even be a risk factor for diseases like major depression in genetically predisposed individuals. We conducted a series of experiments where changes in brain function were examined after 3 weeks of unpredictable stress. After unpredictable stress, inhibitory input to neurons involved in the hypothalamus-pituitary-adrenal (HPA) axis regulation was suppressed, which may dysregulate the axis and lead to overexposure of the brain to glucocorticoids. Furthermore, glutamate transmission in the dentate gyrus (DG) was enhanced, possibly through transcriptional regulation of receptor subunits. Combined with enhanced calcium channel expression this could increase vulnerability to cell death. Neurogenesis and apoptosis in the dentate were diminished. Synaptic plasticity was suppressed both in the dentate and CA1 area. Collectively, these effects may give rise to deficits in memory formation. Finally, we observed reduced responses to serotonin in the CA1 area, which could contribute to the onset of symptoms of depression in predisposed individuals. All of these endpoints provide potential targets for novel treatment strategies of stress-related brain disorders.

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

Brain cells are continuously exposed to corticosteroid hormones, although the levels vary (e.g., after stress). Corticosteroids alter neural activity via two receptor types, mineralocorticoid (MR) and glucocorticoid receptors (GR). These receptors regulate gene transcription but also, as we now know, act nongenomically. Via nongenomic pathways, MRs enhance and GRs suppress neural activity. In the hypothalamus, inhibitory GR effects contribute to negative feedback regulation of the stress axis. Nongenomic MR actions are also important extrahypothalamically and help organisms to immediately select an appropriate response strategy. Via genomic mechanisms, corticosteroid actions in the basolateral amygdala and ventral-most part of the cornu ammonis 1 hippocampal area are generally excitatory, providing an extended window for encoding of emotional aspects of a stressful event. GRs in hippocampal and prefrontal pyramidal cells increase surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and strengthen glutamatergic signaling through pathways partly overlapping with those involved in long-term potentiation. This raises the threshold for subsequent induction of synaptic potentiation and promotes long-term depression. Synapses activated during stress are thus presumably strengthened but protected against excitatory inputs reaching the cells later. This restores higher cognitive control and promotes, for example, consolidation of stress-related contextual information. When an organism experiences stress early in life or repeatedly in adulthood, the ability to induce synaptic potentiation is strongly reduced and the likelihood to induce depression enhanced, even under rest. Treatment with antiglucocorticoids can ameliorate cellular effects after chronic stress and thus provide an interesting lead for treatment of stress-related disorders.

Corticosteroid actions in hippocampus require DNA binding of glucocorticoid receptor homodimers

Glucocorticoids are secreted from the adrenal gland in very high amounts after stress. In the brain, these stress hormones potently modulate ionic currents, monoaminergic transmission, synaptic plasticity and cellular viability, most notably in the hippocampus where corticosteroid receptors are highly enriched. Here we show that at least some of these actions require DNA binding of glucocorticoid receptor (GR) homodimers.

Rapid changes in hippocampal CA1 pyramidal cell function via pre- as well as postsynaptic membrane mineralocorticoid receptors.

Corticosterone (100 nm) rapidly increases the frequency of miniature excitatory postsynaptic currents in mouse CA1 pyramidal neurons via membrane‐located mineralocorticoid receptors (MRs). We now show that a presynaptic ERK1/2 signalling pathway mediates the nongenomic effect, as it was blocked by the MEK inhibitors U0126 (10 µm) and PD098059 (40 µm) and occluded in H‐RasG12V‐mutant mice with constitutive activation of the ERK1/2 presynaptic pathway. Notably, the increase in mEPSC frequency was not mediated by retrograde signalling through endocannabinoids or nitric oxide, supporting presynaptic localization of the signalling pathway. Unexpectedly, corticosterone was also found to have a direct postsynaptic effect, rapidly decreasing the peak amplitude of IA currents. This effect takes place via postsynaptic membrane MRs coupled to a G protein‐mediated pathway, as the effect of corticosterone on IA was effectively blocked by 0.5 mm GDP‐β‐S administered via the recording pipette into the postsynaptic cell. Taken together, these results indicate that membrane MRs mediate rapid, nongenomic effects via pre‐ as well as postsynaptic pathways. Through these dual pathways, high corticosterone concentrations such as occur after stress could contribute to enhanced CA1 pyramidal excitability.

Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling.

The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brains response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor α.

Corticosteroid receptor-dependent modulation of calcium currents in rat hippocampal CA1 neurons

Pyramidal CA1 neurons in the rat hippocampus contain mineralocorticoid (MRs) and glucocorticoid receptors (GRs) for corticosterone, which, in activated form, act as transcription factors of the genome. The relative MR and GR occupation changes throughout the day, with predominant MR occupation under rest in the morning and additional GR occupation in the evening and after stress. We examined the effect of MR and GR activation on Ca currents in hippocampal slices from adrenalectomized (ADX) rats under whole-cell voltage-clamp conditions. In slices from ADX rats, where MRs and GRs are unoccupied, Ca currents (particularly in the low-voltage range) were larger than in neurons from the sham-operated controls; these effects became apparent with a delay of > or = 3 days after ADX. Selective occupation of MRs in tissue from ADX rats greatly (by 70%) and persistently (up to 3 h) reduced transient but also sustained Ca conductances. Voltage dependency and kinetic properties of the currents were not affected. Occupation of GRs as well as MRs by corticosterone (30 nM) resulted in relatively large Ca currents, comparable to those recorded in tissue from mildly stressed sham-operated control animals. Interestingly, exclusive occupation of GRs with 30 nM RU 28362 was not sufficient to induce large Ca currents. The data suggest that the changes in MR and GR occupation throughout the day, related to circadian and stress-induced corticosterone release, are linked to marked alterations in Ca currents, with small Ca currents in the morning and large currents in the evening or after stress.(ABSTRACT TRUNCATED AT 250 WORDS)

Glucocorticoids alter calcium conductances and calcium channel subunit expression in basolateral amygdala neurons

Glucocorticoid hormones, which are released in high amounts after stress, enter the brain where they bind to intracellular receptors that are abundant in limbic areas, in particular the hippocampus and amygdala nuclei. Behavioural studies indicate that glucocorticoids modulate learning and memory processes via receptors in the hippocampus and amygdala. So far, the effects of glucocorticoids on amygdala neurons have not been investigated at the cellular and molecular level. We report here that in vitro application of glucocorticoids for 20 min increases 1–4 h later the amplitude of sustained, high‐voltage‐activated calcium currents in principal neurons of the basolateral amygdala. In contrast, the transient, low‐voltage‐activated currents were decreased. We examined whether these functional changes in calcium conductance were accompanied by transcriptional regulation of calcium channel subunits. Analysis of the RNA – collected after recording and then linearly amplified – revealed that glucocorticoid‐mediated increases in sustained calcium currents are associated with a parallel shift in the relative expression of the α1 subunit constituting the pore of the sustained, high‐voltage‐activated (L‐type) calcium channel. These data indicate that glucocorticoids, probably by selectively targeting genes encoding calcium channel subunits, largely alter the calcium influx into basolateral amygdala neurons. These actions could modify amygdala network function and thus contribute to the behavioural effects exerted by the stress hormones via the basolateral amygdala.