Marian Joëls

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.

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.

Cognitive dysfunction in psychiatric disorders: characteristics, causes and the quest for improved therapy

Studies of psychiatric disorders have traditionally focused on emotional symptoms such as depression, anxiety and hallucinations. However, poorly controlled cognitive deficits are equally prominent and severely compromise quality of life, including social and professional integration. Consequently, intensive efforts are being made to characterize the cellular and cerebral circuits underpinning cognitive function, define the nature and causes of cognitive impairment in psychiatric disorders and identify more effective treatments. Successful development will depend on rigorous validation in animal models as well as in patients, including measures of real-world cognitive functioning. This article critically discusses these issues, highlighting the challenges and opportunities for improving cognition in individuals suffering from psychiatric disorders.

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

In this review we have argued that corticosteroid hormones represent an endocrine signal that can influence neuronal communication. The steroids bind to intracellular receptors in the brain, resulting in slow effects that involve gene transcription, but they may also evoke rapid effects via membrane receptors. The signal carried by the corticosteroids is therefore divergent with respect to the dimension of space and time. Within the rat brain, at least two intracellular receptor subtypes, i.e. MRs and GRs, bind corticosterone. The affinity, density and localization of the MRs is different from the GRs, although the actual properties may vary somewhat depending on the condition of the animal. In general, due to the difference in affinity, low corticosteroid levels result in a predominant MR occupation, while higher steroid levels additionally occupy GRs. Recent studies indicate that predominant MR occupation is important for the maintenance of ongoing transmission in certain brain regions and for neuroprotection. By contrast, additional GR occupation (for a limited period of time) results in an attenuation of local excitability; yet, prolonged exposure to high steroid levels may become an endangering condition for neurons. Since predominant MR occupation on the one hand and additional GR occupation on the other hand induce different cellular actions, the ratio of MR/GR occupation is an important factor determining the net effect of corticosteroid hormones in the brain. How coordinated MR- and GR-mediated effects control neuronal communication under various physiological and pathological conditions will be a challenge for future research.

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.

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.

STEROID HORMONES AND EXCITABILITY IN THE MAMMALIAN BRAIN

Adrenocortical and gonadal steroid hormones can pass the blood-brain barrier and bind to intracellular receptors in the brain. In addition to steroid hormones binding to intracellular steroid receptors, metabolites of these steroids and steroid hormones produced in the brain (neurosteroids) are thought to bind to membrane recognition sites. Actions mediated by the intracellular receptors are generally delayed in onset and are of prolonged duration, whereas the hormones binding to membrane recognition sites induce fast effects. Both fast and delayed actions by steroid hormones potentially alter the electrical properties of neuronal membranes and thus the firing patterns of neurons carrying receptors for the hormones. We here review the fast and delayed actions by steroid hormones on single cell electrical properties in the mammalian nervous system. In general, fast effects by corticosteroids-presumably mediated by membrane receptors-induce inhibitory effects on cellular firing, although regional differences seem to exist. Delayed effects by corticosteroid hormones via mineralocorticoid receptors serve to maintain or enhance fast transmission in the brain, while modulatory inputs are suppressed. By contrast, corticosteroids acting through glucocorticoid receptors suppress transmission carried by amino acids, particularly when the activity is elevated in comparison to resting level; modulatory inputs are enhanced. Prolonged activation of glucocorticoid receptors can implicate the integrity of neuronal circuits by allowing considerable influx of calcium ions during depolarization. Of the gonadal hormones, estradiol mainly exerts excitatory actions, in both a rapid and a delayed mode. Progesterone on the other hand is predominantly inhibitory, usually with a short delay in onset. The effect of androgens on neuronal excitability has not yet been studied in great detail. Finally, neurosteroids and A-ring reduced steroids in general induce rapid effects on firing patterns, probably by acting on ligand gated ion channels. The diverse actions of steroid hormones on single cell activity have consequences for the excitability in local circuits in which these cells participate. This is illustrated in this review for two processes that depend on circuit rather than single cell function, i.e., long term potentiation and epilepsy. The diverging character of steroid hormones with regard to the time frame, space, and nature of their effects is also reflected in the functional processes that are linked to the activity of the networks responding to steroids. In this way steroid hormones add an essentially new aspect to the regulation of functional processes in the brain, during physiological conditions but also when networks are implicated during diseases and disorders. Future research on steroid modulation of cellular excitability will gain considerably from attempts to either link the changed excitability to the underlying molecular events or study the effects on cellular activity in close connection with behavioral functions.

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.

Point mutation in the mouse glucocorticoid receptor preventing DNA binding impairs spatial memory

Activation of central glucocorticoid receptors caused by the stress that is associated with a learning task facilitates storage of the acquired information. The molecular mechanism underlying this phenomenon is entirely unknown. Glucocorticoid receptors can influence transcription both through DNA binding-dependent and -independent mechanisms. To assess the importance of these two modes of action for spatial memory, we here used male mutant mice in which homodimerization and DNA binding of the glucocorticoid receptor is largely prevented (GRdim/dim) while protein–protein interactions still can take place. These mice showed a selective impairment of spatial memory in the water maze. Locomotion and anxiety-related parameters measured in an open field and a light/dark preference task were comparable for mutant and control mice. Mutant mice released more corticosterone than control mice under basal resting conditions and in response to swimming, which could have influenced memory processes of the mice. However, mimicking the task-related increase in corticosterone by supplementary injection of corticosterone (250 μg/kg, i.p.) in adrenalectomized mice, resulting in equal plasma corticosterone concentrations in both genotypes, improved spatial memory of control mice but had no effect on mutant mice. These findings suggest that task-related facilitating effects of corticosterone on spatial memory indeed depend on DNA binding of the glucocorticoid receptor rather than on protein–protein interactions of the receptor with other transcription factors. Although it cannot be excluded that both processes are involved in a coordinated way, interrupting the DNA-binding capacity of the receptor is sufficient to induce impairment.