Corticosteroid effects on cellular physiology of limbic cells

Abstract

After stress, circulating levels of stress hormones such as corticosterone are markedly increased. This will have an impact on the neurophysiology of limbic neurons that highly express corticosteroid receptors. Over the past decades several principles about the neurophysiological impact of corticosterone have emerged. First, corticosterone can quickly raise the excitability of hippocampal CA1 neurons shortly after stress exposure, via a nongenomic pathway involving mineralocorticoid receptors presumably located in the pre- as well as postsynaptic membrane. At the same time, gene-mediated actions via the glucocorticoid receptor are started which some hours later will result in enhanced calcium influx and impaired ability to induce long-term potentiation. These delayed actions are interpreted as a means to slowly normalize hippocampal activity and preserve information encoded early on after stress. Second, the full spectrum of neurophysiological actions by corticosterone is accomplished in interaction with other stress mediators, like noradrenaline. Third, these effects in the CA1 hippocampal region cannot be generalized to other brain regions such as the basolateral amygdala or paraventricular nucleus: There seems to be a highly differentiated response, which could serve to facilitate neuroendocrine/cognitive processing of some aspects of stress-related information, but attenuate other aspects. Finally, the time- and region-specific corticosteroid actions strongly depend on the individual's life history.

Introduction

When an organism is exposed to a stressful situation (or stressor, i.e. any change in the environment of potential threat) information from brain areas involved in the perception and evaluation of the situation funnels through the hypothalamus and from there leads to the activation of the rapidly acting sympatho-adrenomedullar system and the slower hypothalamo-pituitary-adrenal system (McGaugh, 2004, De Kloet et al., 2005, McEwen, 2007). As a result adrenal release of noradrenaline and corticosterone (in rodents; cortisol in humans) respectively is increased. These hormones have many peripheral effects, aiming to supply sufficient energy to face the challenge and suppress all functions that are not relevant under potentially threatening conditions. The brain is also a major target of these stress hormones. Via direct as well as indirect pathways, noradrenaline levels are raised in many brain areas, including important limbic regions such as the hippocampus and amygdala nuclei, shortly after exposure to a stressor (McGaugh, 2004). Slightly later corticosterone also enters the brain, reaching in principle all cells but acting only at those sites enriched with corticosteroid receptors.

Two types of receptors have been distinguished in brain through which corticosterone exerts its effects: The mineralocorticoid (MR) and glucocorticoid receptor (GR) (Reul and de Kloet, 1985). Both types belong to the family of nuclear receptors which bind to response elements in the DNA, thus modulating the activity of responsive genes (Lu et al., 2006). Considering this gene-mediated mechanism of action it is expected that cellular effects of corticosterone in brain will develop slowly and are long-lasting. The MR has a high affinity for the endogenous ligand, so that even low levels of corticosterone – such as circulate between ultradian pulses of the hormone (Young et al., 2004) – are sufficient to substantially bind to and activate the receptor (Fig. 1). MRs are enriched in a limited number of limbic regions, with particularly high expression in the hippocampal subfields and the lateral septum (De Kloet et al., 2005). By contrast, GRs are more ubiquitous and display a lower affinity for corticosterone. Consequently, these receptors are only partially occupied under rest but become gradually activated when hormone levels rise, e.g. during an ultradian pulse or after stress. The difference in affinity is particularly relevant for neurons that co-express the two corticosteroid receptor types, such as pyramidal neurons in the CA1 hippocampal region and granule neurons in the dentate gyrus. For many years it was thought that stress-induced changes in the neurophysiology of these cells are mediated via the low-affinity GRs rather than the MRs. Recently, however, it has become evident that stress-induced rises in corticosterone level can also activate MRs located in the membrane which transduce rapid nongenomic effects (Joëls et al., 2008; see Fig. 1).

In this review, we will highlight several principles that have become evident from recent work by us and other investigators. First, (as mentioned above), corticosteroids change the neurophysiology of hippocampal neurons not just in a delayed manner, but also more rapidly, thus encompassing a wide span of time. Second, it is evident that corticosterone acts in concert and interaction with other stress mediators, e.g. noradrenaline. Third, actions of corticosterone strongly depend on the local network properties and cellular context, so that effects observed in a particular hippocampal subfield cannot be simply extrapolated to other limbic areas. And finally, a stress-induced surge in corticosteroid level does not always affect a given cell type (e.g. a CA1 pyramidal neuron) in the same way: The effect strongly depends on the life history of the organism. In the following sections we will elaborate each of these issues. The final section will address the major challenges that are still ahead in this field of research.