Ratna Angela Sarabdjitsingh

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.

Ultradian corticosterone pulses balance glutamatergic transmission and synaptic plasticity

Significance A pulse of the adrenal hormone corticosterone (CORT) changes hippocampal glutamate transmission for many hours. CORT is normally released in hourly pulses, with a steeply rising amplitude just before awakening. How organisms can be prepared for imminent danger if the first high-amplitude pulse of CORT would lastingly change glutamate transmission—thus potentially deadlocking the system—has remained an enigma. We show that exposure of hippocampal cells to a second high-amplitude CORT pulse completely normalizes all aspects of glutamate transmission (including synaptic plasticity), thus lifting the potential deadlock caused by a first pulse. This ensures that the system remains fully responsive to any stressful event that requires encoding of information, an important principle that promotes survival of individuals. The rodent adrenal hormone corticosterone (CORT) reaches the brain in hourly ultradian pulses, with a steep rise in amplitude before awakening. The impact of a single CORT pulse on glutamatergic transmission is well documented, but it remains poorly understood how consecutive pulses impact on glutamate receptor trafficking and synaptic plasticity. By using high-resolution imaging and electrophysiological approaches, we report that a single pulse of CORT to hippocampal networks causes synaptic enrichment of glutamate receptors and increased responses to spontaneously released glutamatergic vesicles, collectively abrogating the ability to subsequently induce synaptic long-term potentiation. Strikingly, a second pulse of CORT one hour after the first—mimicking ultradian pulses—completely normalizes all aspects of glutamate transmission investigated, restoring the plastic range of the synapse. The effect of the second pulse is precisely timed and depends on a nongenomic glucocorticoid receptor-dependent pathway. This normalizing effect through a sequence of CORT pulses—as seen around awakening—may ensure that hippocampal glutamatergic synapses remain fully responsive and able to encode new stress-related information when daily activities start.

Stress-Induced Enhancement of Mouse Amygdalar Synaptic Plasticity Depends on Glucocorticoid and ß-Adrenergic Activity

Background Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA) which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP) as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. Principal Findings Exposure to 20 min of restraint stress (compared to control treatment) prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles) prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. Conclusions Acute stress changes BLA electrical properties such that subsequent LTP induction is facilitated. Both β-adrenergic and glucocorticoid receptors are involved in the development of these changes. Mineralocorticoid receptors are important for the maintenance of LTP in the BLA, irrespective of stress-induced changes in the circuit. The prolonged changes in BLA network function after stress may contribute to effective memory formation of emotional and stressful events.

Transient Prepubertal Mifepristone Treatment Normalizes Deficits in Contextual Memory and Neuronal Activity of Adult Male Rats Exposed to Maternal Deprivation

Abstract Early life adversity is a well-known risk factor for behavioral dysfunction later in life, including the formation of contextual memory; it is also (transiently) accompanied by hyperactivity of the stress system. We tested whether mifepristone (MIF) treatment, which among other things blocks glucocorticoid receptors (GRs), during the prepubertal period [postnatal days (PND)26-PND28] normalizes memory deficits in adult male rats exposed to 24-h maternal deprivation (MD) at PND3. MD reduced body weight gain and increased basal corticosterone (CORT) levels during the PND26, but not in adulthood. In adulthood, contextual memory formation of MD compared to noMD (i.e., control) male rats was significantly impaired. This impairment was fully prevented by MIF treatment at PND26-PND28, whereas MIF by itself did not affect behavior. A second behavioral test, a rodent version of the Iowa Gambling Task (rIGT), revealed that flexible spatial learning rather than reward-based aspects of performance was impaired by MD; the deficit was prevented by MIF. Neuronal activity as tested by c-Fos staining in the latter task revealed changes in the right hippocampal-dorsomedial striatal pathway, but not in prefrontal areas involved in reward learning. Follow-up electrophysiological recordings measuring spontaneous glutamate transmission showed reduced frequency of miniature postsynaptic excitatory currents in adult CA1 dorsal hippocampal and enhanced frequency in dorsomedial striatal neurons from MD versus noMD rats, which was not seen in MIF-treated rats. We conclude that transient prepubertal MIF treatment normalizes hippocampus-striatal-dependent contextual memory/spatial learning deficits in male rats exposed to early life adversity, possibly by normalizing glutamatergic transmission.

Rapid corticosteroid actions on synaptic plasticity in the mouse basolateral amygdala: relevance of recent stress history and β-adrenergic signaling.

The rodent stress hormone corticosterone rapidly enhances long-term potentiation in the CA1 hippocampal area, but leads to a suppression when acting in a more delayed fashion. Both actions are thought to contribute to stress effects on emotional memory. Emotional memory formation also involves the basolateral amygdala, an important target area for corticosteroid actions. We here (1) investigated the rapid effects of corticosterone on amygdalar synaptic potentiation, (2) determined to what extent these effects depend on the mouses recent stress history or (3) on prior β-adrenoceptor activation; earlier studies at the single cell level showed that especially a recent history of stress changes the responsiveness of basolateral amygdala neurons to corticosterone. We report that, unlike the hippocampus, stress enhances amygdalar synaptic potentiation in a slow manner. In vitro exposure to 100 nM corticosterone quickly decreases synaptic potentiation, and causes only transient potentiation in tissue from stressed mice. This transient type of potentiation is also seen when β-adrenoceptors are blocked during stress and this is further exacerbated by subsequent in vitro administered corticosterone. We conclude that stress and corticosterone change synaptic potentiation in the basolateral amygdala in a manner opposite to that seen in the hippocampus and that renewed exposure to corticosterone only allows induction of non-persistent forms of synaptic potentiation.

The stressed brain of humans and rodents

After stress, the brain is exposed to waves of stress mediators, including corticosterone (in rodents) and cortisol (in humans). Corticosteroid hormones affect neuronal physiology in two time‐domains: rapid, non‐genomic actions primarily via mineralocorticoid receptors; and delayed genomic effects via glucocorticoid receptors. In parallel, cognitive processing is affected by stress hormones. Directly after stress, emotional behaviour involving the amygdala is strongly facilitated with cognitively a strong emphasis on the “now” and “self,” at the cost of higher cognitive processing. This enables the organism to quickly and adequately respond to the situation at hand. Several hours later, emotional circuits are dampened while functions related to the prefrontal cortex and hippocampus are promoted. This allows the individual to rationalize the stressful event and place it in the right context, which is beneficial in the long run. The brains response to stress depends on an individuals genetic background in interaction with life events. Studies in rodents point to the possibility to prevent or reverse long‐term consequences of early life adversity on cognitive processing, by normalizing the balance between the two receptor types for corticosteroid hormones at a critical moment just before the onset of puberty.

Effects of early life stress on biochemical indicators of the dopaminergic system: A 3 level meta-analysis of rodent studies

&NA; Adverse early life events are a well‐established risk factor for the precipitation of behavioral disorders characterized by anomalies in the dopaminergic system, such as schizophrenia and addiction. The correlation between early life conditions and the dopaminergic system has been causally investigated in more than 90 rodent publications. Here, we tested the validity of the hypothesis that early life stress (ELS) alters dopamine signaling by performing an extensive 3‐level mixed effect meta‐analysis. We included several ELS models and biochemical indicators of the dopaminergic system in a variety of brain areas, for a total of 1009 comparisons. Contrary to our expectations, only a few comparisons displayed a significant effect. Specifically, the striatal area was the most vulnerable, displaying decreased dopamine precursor and increased metabolites after ELS. To make all data openly accessible, we created MaDEapp (https://osf.io/w25m4/), a tool to explore data of the meta‐analysis with the intent to guide future (pre)clinical research and allow power calculations. All in all, ELS induces a few yet robust changes on biochemical indicators of the dopaminergic system.

Rapid and Slow Effects of Corticosteroid Hormones on Hippocampal Activity

Hippocampal cells are continuously exposed to varying concentrations of corticosteroid hormones. These hormones can alter hippocampal activity by binding to mineralocorticoid receptor (MR) or glucocorticoid receptor (GR). Via nongenomic pathways, MRs generally enhance hippocampal excitability. The rapid nongenomic MR actions are important shortly after stress exposure and may help organisms selecting an appropriate response strategy. At the same time, slower genomic actions are started which several hours later, via GRs (among other factors), increase surface expression of AMPA receptors in hippocampal cells and strengthen glutamatergic signaling through pathways partly overlapping with long-term potentiation. This raises the threshold for subsequent induction of synaptic potentiation. Simultaneously, steady transfer of excitatory information is dampened. Synapses activated during stress are thus presumably strengthened and protected against excitatory inputs reaching the cells at a later time-point. This might facilitate consolidation of stress-related information. Thus, coordinated MR-mediated and GR-mediated actions on hippocampal neurons can promote behavioral adaptation.

3.07 – Corticosteroid Actions on Electrical Activity in the Limbic Brain

Corticosteroid hormones easily enter the brain and bind to receptors that translocate to the nucleus, where they regulate transcription of responsive genes. It has become evident that corticosteroid receptors can also mediate rapid nongenomic actions. Within the brain corticosterone binds with high affinity to mineralocorticoid receptors (MRs) that have a restricted distribution. Glucocorticoid receptors (GRs), which are much more widespread, display a 10-fold lower affinity. Principal cells in many limbic structures contain GRs as well as MRs. Electrophysiological studies over the past decades have addressed the role of these two receptor types in information transfer through limbic areas, most notably the hippocampus, amygdala, and prefrontal cortex. The current view is that intracellular MRs serve to maintain steady electrical activity and optimal viability in neurons under nonstress conditions. Following stress exposure, rapid nongenomic effects primarily via MRs are thought to enhance excitability, in concert with other stress hormones. This is thought to promote the appraisal of stressful situations and the selection of an adequate strategy. At the same time, GRs are activated which several hours later – through delayed genomic pathways – restore excitability, preserve earlier encoded information, and allow contextualization and rationalization of the event. While brief activation of MRs and GRs in the context of a stressful situation leads to adaptive responses, the pleiotropic hormone effects can become a vulnerability factor when GRs are repeatedly activated such as during chronic stress.