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.␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor ͉ CA1 hippocampus ͉ glucocorticoid receptor knockout ͉ miniature excitatory postsynaptic current ͉ mineralocorticoid receptor knockout

Cerebral organoids are 3D stem cell-derived models that can be utilized to study the human brain. The current consensus is that cerebral organoids consist of cells derived from the neuroectodermal lineage. This limits their value and applicability, as mesodermal-derived microglia are important players in neural development and disease. Remarkably, here we show that microglia can innately develop within a cerebral organoid model and display their characteristic ramified morphology. The transcriptome and response to inflammatory stimulation of these organoid-grown microglia closely mimic the transcriptome and response of adult microglia acutely isolated from post mortem human brain tissue. In addition, organoid-grown microglia mediate phagocytosis and synaptic material is detected inside them. In all, our study characterizes a microglia-containing organoid model that represents a valuable tool for studying the interplay between microglia, macroglia, and neurons in human brain development and disease.

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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.basolateral amygdala | glucocorticoid receptor | glutamate | miniature excitatory postsynaptic current | mineralocorticoid receptor S hortly after stress, corticosteroid hormones are released in high amounts from the adrenal glands, enter the brain, and predominantly bind to intracellular glucocorticoid receptors (GRs), e.g., in the hippocampal CA1 area (1, 2). Neurons in this area also highly express intracellular mineralocorticoid receptors (MRs), but because of their high affinity these receptor are already largely occupied even under rest. Both receptor types act as transcription factors, altering the expression of responsive genes (3). In this way corticosterone (the prevailing hormone in rodents) changes cellular excitability in the CA1 area, starting 1-2 h after an elevation in corticosteroid level and lasting up to at least several hours (4). Overall, MRs serve to maintain glutamatergic transmission and viability in the CA1 area, whereas GRs cause a delayed suppression of synaptic transmission and plasticity, presumably normalizing stress-dependent rises in activity (4). Thus, the two receptor types exert a slow genomic yinyang control over hippocampal excitability.Recently, though, we demonstrated that, in the CA1 area, corticosterone also quickly and reversibly enhances the frequency of miniature excitatory postsynaptic currents (mEPSCs), each of which reflects the spontaneous release of a glutamate-containing vesicle (5). This nongenomic effect critically depends on the presence of MRs thought to reside in the presynaptic terminal membrane, and involves activation of the ERK1/2 pathway (6). The apparent affinity of this membrane-located MR is 10-fold lower than that of the intracellular MR, allowing it to play a prominent role in the behavioral stress response (7). It is thought that corticosterone via membrane MRs (in close interaction with other stress mediators such as noradrenaline and CRH) quickly raises hippocampal excitability, to be normalized 1-2 h later thr...

In response to a stressful encounter, the brain activates a comprehensive stress system that engages the organism in an adaptive response to the threatening situation. This stress system acts on multiple peripheral tissues and feeds back to the brain; one of its key players is the family of corticosteroid hormones. Corticosteroids affect brain functioning through both delayed, genomic and rapid, non-genomic mechanisms. The latter mode of action has long been known, but it is only in recent years that the physiological basis in the brain is beginning to be unravelled. We now know that corticosteroids exert rapid, non-genomic effects on the excitability and activation of neurons in (amongst others) the hypothalamus, hippocampus, amygdala and prefrontal cortex. In addition, corticosteroids affect cognition, adaptive behaviour and neuroendocrine output within minutes. Knowledge on the identity of the receptors and secondary pathways mediating the non-genomic effects of corticosteroids on a cellular level is accumulating. Interestingly, in many cases, an essential role for the 'classical' mineralocorticoid and glucocorticoid receptors in a novel membrane-associated mechanism is found. Here, we systematically review the recent literature on non-genomic actions of corticosteroids on neuronal activity and functioning in selected limbic brain targets. Further, we discuss the relevance of these permissive effects for cognition and neuroendocrine control, and the integration of this novel mode of action into the complex balanced pattern of stress effects in the brain.

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