Biomedical subjects

Marian Joëls

Publications and source records attributed to Marian Joëls.

At least 19 recordsLinked to original sources

PubMed2007

Brief RU 38486 treatment normalizes the effects of chronic stress on calcium currents in rat hippocampal CA1 neurons.

Chronic stress alters many properties in rat brain, like serotonin responsiveness and dendritic morphology. In the present study, we examined (i) whether unpredictable stress during 21 days affects calcium (Ca) currents of CA1 pyramidal neurons recorded on day 22; and (ii) if so, whether this change is normalized by treatment with the glucocorticoid receptor-antagonist RU 38486 during days 18-21. At 3 weeks of unpredictable stress increased the amplitude of the peak and sustained calcium current components, determined in hippocampal slices prepared from animals under rest (ie, with low corticosterone levels). The increased Ca-current amplitude was associated with an enhanced cell capacitance; current density was not significantly affected by chronic stress. In slices from stressed rats that received RU 38486, no stress-induced enhancement of calcium current amplitude was seen, while RU 38486 by itself did not alter calcium currents in handled controls. We confirmed earlier observations that brief in vitro treatment with 100 nM corticosterone, thus substantially activating the low-affinity glucocorticoid receptors, increases Ca-current amplitude recorded 1-4 h later in slices from naïve rats. However, Ca-current amplitude was not affected by corticosterone applied to slices from handled controls and currents were even decreased by corticosterone given to slices from chronically stressed rats, suggesting that corticosterone effects depend on the history of the animal. In conclusion, the data indicate that chronic stress, RU 38486 treatment as well as acute rises in corticosterone level strongly modulate calcium influx into CA1 neurons. This could have consequences for the viability of these neurons.

Animals↗

PubMed2006

Glucocorticoids specifically enhance L-type calcium current amplitude and affect calcium channel subunit expression in the mouse hippocampus.

Previous studies have shown that corticosterone enhances whole cell calcium currents in CA1 pyramidal neurons, through a pathway involving binding of glucocorticoid receptor homodimers to the DNA. We examined whether glucocorticoids show selectivity for L- over N-type of calcium currents. Moreover, we addressed the putative gene targets that eventually lead to the enhanced calcium currents. Electrophysiological recordings were performed in nucleated patches that allow excellent voltage control. Calcium currents in these patches almost exclusively involve N- and L-type channels. We found that L- but not N-type calcium currents were largely enhanced after treatment with a high dose of corticosterone sufficient to activate glucocorticoid receptors. Voltage dependency and kinetic properties of the currents were unaffected by the hormone. Nonstationary noise analysis suggests that the increased current is not caused by a larger unitary conductance, but rather to a doubling of the number of functional channels. Quantitative real-time PCR revealed that transcripts of the Ca(v)1 subunits encoding for the N- or L-type calcium channels are not upregulated in the mouse CA1 area; instead, a strong, direct, and consistent upregulation of the beta4 subunit was observed. This indicates that the corticosteroid-induced increase in number of L-type calcium channels is not caused by a simple transcriptional regulation of the pore-forming subunit of the channels.

Animals↗

PubMed2006

No effect of prolonged corticosterone over-exposure on NCAM, SGK1, and RGS4 mRNA expression in rat hippocampus.

Prolonged over-exposure of rats to corticosterone attenuates 5-HT(1A)-receptor-mediated responses in hippocampal CA1 cells through an unknown mechanism, not involving downregulation of 5-HT(1A) receptor expression. We here tested if corticosterone changes 5-HT(1A) receptor function indirectly, by altering hippocampal mRNA expression of NCAM, SGK1, or RGS4, which all modulate 5-HT(1A) receptor function. We found that the expression of none of these candidates was affected by corticosterone treatment.

Animals↗

PubMed2006

Corticosteroid effects in the brain: U-shape it.

The existence of U-shaped dose dependencies has been known for a long time. With regard to corticosteroid action in brain cells, a dual receptor system that works in opposing directions can explain the occurrence of a U-shaped dose dependency. However, recent evidence indicates that many cell- and tissue-specific factors (e.g. the local availability of corticosterone, the expression of receptor variants and the cellular content of other proteins and molecules) also determine the effectiveness of the hormone. This could result in dose dependencies with a different shape, despite the local presence of two receptor types.

Adrenal Cortex Hormones↗

PubMed2006

Timing is essential for rapid effects of corticosterone on synaptic potentiation in the mouse hippocampus.

Stress facilitates memory formation, but only when the stressor is closely linked to the learning context. These effects are, at least in part, mediated by corticosteroid hormones. Here we demonstrate that corticosterone rapidly facilitates synaptic potentiation in the mouse hippocampal CA1 area when high levels of the hormone and high-frequency stimulation coincide in time, but not when corticosterone is given either before or after repetitive stimulation. This effect could not be blocked by antagonists of the mineralocorticoid receptor and glucocorticoid receptor (spironolactone and RU 38486, respectively). These data provide a biological substrate for the important behavioral observation that stress and corticosteroid hormones can facilitate learning and memory processes.

Analysis of Variance↗

PubMed2006

Learning under stress: how does it work?

The effects of stress on learning and memory are not always clear: both facilitating and impairing influences are described in the literature. Here we propose a unifying theory, which states that stress will only facilitate learning and memory processes: (i) when stress is experienced in the context and around the time of the event that needs to be remembered, and (ii) when the hormones and transmitters released in response to stress exert their actions on the same circuits as those activated by the situation, that is, when convergence in time and space takes place. The mechanism of action of stress hormones, particularly corticosteroids, can explain how stress within the context of a learning experience induces focused attention and improves memory of relevant information.

Animals↗

PubMed2006

Effect of brief corticosterone administration on SGK1 and RGS4 mRNA expression in rat hippocampus.

Acute stress and corticosterone enhance 5-HT1A receptor-mediated responses in rat hippocampal CA1 cells within 1-2 h, through a process involving transcriptional regulation of unknown genes. Earlier studies showed that regulation of the 5-HT1A receptor gene cannot explain the functional effects. We here tested the hypothesis that corticosterone targets genes encoding RGS4 or SGK1, which can both affect the 5-HT1A receptor associated Kir channel, thus affecting 5-HT1A receptor function. To this end, the effect of a single corticosterone injection on hippocampal expression of RGS4 and SGK1 mRNAs, measured by in situ hybridization, was studied. Expression of RGS4 or SGK1 mRNA was not affected by the corticosterone injection, neither in the CA1 area nor in other hippocampal subregions. Strikingly, SGK1 mRNA expression was strongly up-regulated in the corpus callosum. We reject, however, the hypothesis that the effect of corticosterone on 5-HT1A responsiveness is mediated via altered RGS4 or SGK1 mRNA expression.

Animals↗

PubMed2005

Mineralocorticoid receptors are indispensable for nongenomic modulation of hippocampal glutamate transmission by corticosterone.

The adrenal hormone corticosterone transcriptionally regulates responsive genes in the rodent hippocampus through nuclear mineralocorticoid and glucocorticoid receptors. Via this genomic pathway the hormone alters properties of hippocampal cells slowly and for a prolonged period. Here we report that corticosterone also rapidly and reversibly changes hippocampal signaling. Stress levels of the hormone enhance the frequency of miniature excitatory postsynaptic potentials in CA1 pyramidal neurons and reduce paired-pulse facilitation, pointing to a hormone-dependent enhancement of glutamate-release probability. The rapid effect by corticosterone is accomplished through a nongenomic pathway involving membrane-located receptors. Unexpectedly, the rapid effect critically depends on the classical mineralocorticoid receptor, as evidenced by the effectiveness of agonists, antagonists, and brain-specific inactivation of the mineralocorticoid but not the glucocorticoid receptor gene. Rapid actions by corticosterone would allow the brain to change its function within minutes after stress-induced elevations of corticosteroid levels, in addition to responding later through gene-mediated signaling pathways.

Adrenal Cortex Hormones↗

PubMed2005

Corticosterone slowly enhances miniature excitatory postsynaptic current amplitude in mice CA1 hippocampal cells.

Corticosteroid hormones are released in high amounts after stress and bind to intracellular receptors in the brain, which in activated form function as transcription factors. We here tested the effect of a high dose of corticosterone on AMPA-receptor-mediated transmission in the CA1 hippocampal area, which is enriched in corticosteroid receptors. To focus on slow gene-mediated effects of the hormone, excitatory postsynaptic currents were measured at least 1 h after a brief application of 100 nM corticosterone to slices from adrenally intact adult mice. The amplitude but not frequency of miniature postsynaptic excitatory currents was found to be significantly enhanced. These effects were mimicked by 100 nM RU 28362, a selective agonist for intracellular glucocorticoid receptors. Evoked AMPA responses at the single cell were significantly enhanced when measured 2-4 h after application of 100 nM corticosterone, but not at earlier moments nor with a longer delay. In summary, the present results show that activation of hippocampal glucocorticoid receptors induces a slow enhancement of AMPA-receptor-mediated responses, at the single-cell level.

Adaptation, Physiological↗

PubMed2005

Corticosterone shifts different forms of synaptic potentiation in opposite directions.

Calcium entering the cell via different routes, e.g.,N-methyl-D-aspartate (NMDA) receptors or voltage-dependent calcium channels (VDCCs), plays a pivotal role in hippocampal synaptic potentiation. Since corticosteroid hormones have been reported to enhance calcium influx through VDCCs, one may predict that these hormones facilitate hippocampal synaptic efficacy. Surprisingly, though, stress and corticosteroids have so far been found to reduce synaptic potentiation. Here, we addressed this apparent paradox and examined synaptic potentiation in the CA1 area of hippocampal slices from mice with low basal corticosterone levels 1--4 h after a brief in vitro administration of corticosterone. Nifedipine and APV were used to isolate NMDA receptor-mediated and VDCC-mediated long-term potentiations (LTPs), respectively. We report that corticosterone facilitates synaptic potentiation that depends on activation of VDCCs while impairing synaptic plasticity that is mediated by NMDA receptor activation. The glucocorticoid-receptor (GR) antagonist RU 38486 blocked both the effects of corticosterone. These results indicate that the net effect of corticosteroid hormones on synaptic plasticity is determined by the balance between different types of potentiation, a balance that may be region specific and depends on the experimental conditions. We speculate that these opposite effects on synaptic efficacy are involved in the bidirectional modulation of cognitive performance by corticosteroid hormones.

Animals↗

PubMed2005

Stress and the brain: from adaptation to disease.

In response to stress, the brain activates several neuropeptide-secreting systems. This eventually leads to the release of adrenal corticosteroid hormones, which subsequently feed back on the brain and bind to two types of nuclear receptor that act as transcriptional regulators. By targeting many genes, corticosteroids function in a binary fashion, and serve as a master switch in the control of neuronal and network responses that underlie behavioural adaptation. In genetically predisposed individuals, an imbalance in this binary control mechanism can introduce a bias towards stress-related brain disease after adverse experiences. New candidate susceptibility genes that serve as markers for the prediction of vulnerable phenotypes are now being identified.

Adaptation, Physiological↗

PubMed2005

GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress.

Parvocellular neurons in the hypothalamic paraventricular nucleus receive hormonal inputs mediated by corticosterone as well as neuronal inputs, prominent among which is a GABAergic inhibitory projection. In the present study we examined the functional properties of this GABAergic innervation when corticosteroid levels fluctuate. Frequency, amplitude and kinetic properties of miniature inhibitory postsynaptic potentials (mIPSCs), mediated by gamma amino butyric acid (GABA) were studied with whole cell recording in parvocellular neurons. Injection of a high dose of corticosterone in vivo suppressed the frequency but did not change the amplitude and kinetic properties of mIPSCs recorded 1-5 h later in vitro. Similar effects were observed after restraint stress. The corticosteroid actions do not require involvement of extrahypothalamic brain regions, because in vitro administration of 100 nM corticosterone (20 min) directly to a hypothalamic slice also suppressed the frequency of mIPSCs recorded several hours later. Corticosterone administration to hypothalamic slices from restraint rats did not result in stronger reduction of mIPSC frequency than either treatment alone, pointing to a common underlying mechanism. Paired pulse response inhibition was reduced by corticosterone, suggesting that the hormone decreases the release probability of GABA-containing vesicles. Unlike neurosteroids, corticosterone induced no rapid effects on mIPSC properties. These results indicate that increases in glucocorticoid level due to stress can slowly but persistently inhibit the GABAergic tone on parvocellular hypothalamic neurons via a hitherto unknown local mechanism independent of limbic projections.

2-Amino-5-phosphonovalerate↗

PubMed2005

Chronic stress in the adult dentate gyrus reduces cell proliferation near the vasculature and VEGF and Flk-1 protein expression.

Recent evidence has shown that cell proliferation in the adult hippocampal dentate gyrus occurs in tight clusters located near the vasculature. Also, changes in neurogenesis often appear parallel to changes in angiogenesis. Moreover, both these processes share similar modulating factors, like vascular endothelial growth factor (VEGF) and its receptor Flk-1. In an earlier study we found that chronic stress decreased new cell proliferation in the adult dentate gyrus. We here questioned whether these effects of chronic stress are mediated through the vasculature and whether they involve an angiogenic-signaling pathway. We therefore measured the surface area covered by the vasculature, the proportion of vascular-associated newborn cells, and analysed VEGF and Flk-1 protein expression in the hippocampus of a control, chronically stressed and recovery group of rats. Our results show that 32% of the proliferating cells in the rat hippocampus is vascular associated. Chronic stress affected this population of newborn cells to a significantly larger extent than the non-associated cells. Interestingly, after 3 weeks of recovery, the decreased proliferation not associated with the vasculature was more effectively restored than vascular-associated proportion of proliferating cells. VEGF protein was expressed in high densities in GFAP-positive astrocytes located in the hilus, with VEGF-positive end feet extending into and often contacting the granule cells. After chronic stress, both VEGF and Flk-1 protein levels were significantly decreased in the granular cell layer, and again recovered after 3 weeks. This demonstrates that changes in angiogenic factors are implicated in the decreased adult proliferation found after chronic stress.

Animals↗

PubMed2004

Effect of early life stress on serotonin responses in the hippocampus of young adult rats.

In this study, we investigated the effects of early life stress on several aspects of serotonin (5-HT) transmission in hippocampus, later on in life. Three-day-old rats were subjected to 24-hour maternal deprivation or control treatment. Maternal deprivation is known to activate the hypothalamo-pituitary-adrenal axis, resulting in increased corticosterone levels at a time-point in life when the axis is particularly insensitive to most stressful stimuli. When these animals had matured to 3 months of age, functional responses to 5-HT as well as 5-HT1A-receptor mRNA expression were examined. Also, indices for hypothalamo-pituitary-adrenal function were studied in the adult state, including hippocampal mRNA expression for the mineralocorticoid and the glucocorticoid receptor. Resting membrane potential of CA1 pyramidal neurons was significantly depolarized in animals earlier subjected to maternal deprivation compared to the controls. Despite this depolarized resting potential, hyperpolarizing responses induced by 5-HT in CA1 pyramidal neurons from deprived compared to non-deprived rats were attenuated. This attenuation in 5-HT response was not accompanied by changes in mRNA expression of the 5-HT1A-receptor. Maternal deprivation was not found to change any of the neuroendocrine parameters investigated once animals had matured. We conclude that maternal deprivation can alter specific aspects of hippocampal 5-HT transmission later on in life, possibly by post-translational modification of the 5-HT1A-receptor or changes in the 5-HT1A-receptor signal transduction pathway.

Animals↗

PubMed2004

Prominent decline of newborn cell proliferation, differentiation, and apoptosis in the aging dentate gyrus, in absence of an age-related hypothalamus-pituitary-adrenal axis activation.

Neurogenesis and apoptosis in the hippocampal dentate gyrus (DG) occur during development and adulthood. However, little is known about how these two processes relate to each other during aging. In this study, we examined apoptosis, proliferation, migration, and survival of newborn cells in the young (2 weeks), young-adult (6 weeks), middle-aged (12 months), and old (24 months) rat DG. We also measured dentate volume and cell numbers, along with basal corticosterone and stress response parameters. We show that new cell proliferation and apoptosis slow down profoundly over this time period. Moreover, migration and differentiation into a neuronal or glial phenotype was strongly reduced from 6 weeks of age onwards; it was hardly present in middle-aged and old rats as confirmed by confocal analysis. Surprisingly, we found no correlation between cell birth and corticosterone levels or stress response parameters in any age group.

Aging↗

PubMed2004

Suppressed proliferation and apoptotic changes in the rat dentate gyrus after acute and chronic stress are reversible.

Acute stress suppresses new cell birth in the hippocampus in several species. Relatively little is known, however, on how chronic stress affects the turnover, i.e. proliferation and apoptosis, of the rat dentate gyrus (DG) cells, and whether the stress effects are lasting. We investigated how 3 weeks of chronic unpredictable stress would influence the structural dynamic plasticity of the rat DG, and studied newborn cell proliferation, survival, apoptosis, volume and cell number in 10-week-old animals. To study lasting effects, another group of animals was allowed to recover for 3 weeks. Based on two independent parameters, bromodeoxyuridine (BrdU) and Ki-67 immunocytochemistry, our results show that both chronic and acute stress decrease new cell proliferation rate. The reduced proliferation after acute stress normalized within 24 h. Interestingly, chronically stressed animals showed recovery after 3 weeks, albeit with still fewer proliferating cells than controls. Apoptosis, by contrast, increased after acute but decreased after chronic stress. These results demonstrate that, although chronic stress suppresses proliferation and apoptosis, 3 weeks of recovery again normalized most of these alterations. This may have important implications for our understanding of the reversibility of stress-related hippocampal volume changes, such as occur, for example, in depression.

Acute Disease↗

PubMed2004

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.

Animals↗

PubMed2004

Chronic stress attenuates GABAergic inhibition and alters gene expression of parvocellular neurons in rat hypothalamus.

Chronic stress causes disinhibition of the hypothalamus-pituitary-adrenal axis. Consequently, the brain is overexposed to glucocorticoids which in humans may precipitate stress-related disorders, e.g. depression. The hypothalamus-pituitary-adrenal activity is strongly regulated by GABAergic input to parvocellular neurons in the hypothalamic paraventricular nucleus. We here report a reduced frequency of miniature inhibitory postsynaptic currents (mIPSCs) in parvocellular neurons of rats exposed to 3 weeks of unpredictable stress. The mIPSC amplitude and kinetic properties were unchanged, pointing to a presynaptic change caused by chronic stress. Because paired-pulse inhibition was unaffected by chronic stress, the number of functional GABAergic synaptic contacts rather than the release probability seems to be reduced after chronic stress. Linearly amplified RNA from postsynaptic cells was hybridized with multiple cDNA clones of interest, including most GABA(A) receptor subunits. In agreement with the electrophysiological observations, relative expression of the prevalent GABA(A)alpha1, alpha3, gamma1 and gamma2 receptor subunits, which largely contribute to the recorded responses, was not altered after chronic stress. However, expression of the extra-synaptic GABA(A)alpha5 subunit, earlier linked to depression in humans, and of the delta receptor subunit were found to be significantly changed. In conclusion, chronic stress leads to presynaptic functional alterations in GABAergic input to the paraventricular nucleus which could contribute to the observed disinhibition of the hypothalamus-pituitary-adrenal axis; additionally other aspects of GABAergic transmission may also be changed due to transcriptional regulation of specific receptor subunits in the parvocellular neurons.

6-Cyano-7-nitroquinoxaline-2,3-dione↗