ReviewGlucocorticoid regulation of diverse cognitive functions in normal and pathological emotional states
Introduction
Cortisol (corticosterone in rats) is a glucocorticoid hormone secreted by the adrenal gland into the bloodstream, and acts on numerous areas of the body. In some regions of the brain glucocorticoids have well-known inhibitory effects [1], [2], [3], such as restraint of the hypothalamic-pituitary–adrenal (HPA) axis and suppression of hippocampal glucose metabolism and blood flow [4], [5]. It also appears that glucocorticoids increase activation in some other areas of the brain, such as the amygdala [2], [6], [7], suggesting site-specific effects of glucocorticoid activation that have implications for behavioral and cognitive functions subserved by these brain regions. This review highlights the accumulating evidence that glucocorticoid dysfunction may contribute to the pathology of mood disorders through activation in extrahypothalamic regions.
Distribution of mineralocorticoid (MR) and glucocorticoid (GR) receptors have been described in the primate amygdala, hippocampus, medial prefrontal and orbitofrontal cortical areas [8], [9]. These same regions putatively underlie perception, memory and experience of emotional events. Cortisol serves a wide range of physiological, behavioral and cognitive functions and can be elevated in a number of contexts that may or may not be ‘stressful’ in the aversive sense of the term, such as territoriality, attachment behaviors, food intake, predatory behaviors, focused attention, social presentation, sustained effort and effortful thought (see Fig. 1) [10], [11], [12]. Therefore, it might be more accurate with regard to its influence on some brain regions to describe cortisol's effects in terms of ‘readiness to behave’ or as part of cognitive appraisal mechanisms. It is possible that the effects of cortisol on neurotransmitters and neuropeptides within various functional circuits can influence perception, attention and memory for environmental events.
In recent years, cortisol has been characterized as a ‘stress hormone,’ and elevated cortisol levels are sometimes considered synonymous with stress in certain areas of Ref. [13]. Indeed, cortisol is elevated in individuals under duress in order to allow physiological and cognitive response to stressful situations [14]. However, the characterization of cortisol as a ‘stress hormone’ is only partly accurate. Elevated peripheral cortisol levels are not necessarily an indicator of stress; subgroups of healthy individuals can have elevated basal cortisol concentrations [15], [16], as can individuals with certain physical and psychiatric conditions [17], [18], [19]. Cortisol may differentially affect certain neurotransmitters and brain areas in both psychiatrically healthy individuals and patients with various mood disorders, and these effects may be distinct in healthy versus ill populations. The disparate effects of glucocorticoids on the various brain regions have potential relevance to understanding normal behavioral adaptation and the cognitive mechanisms underlying them, and may also have relevance to the pathophysiology of mood disorders. This paper overviews the interactions of glucocorticoids with neurophysiological, endocrine, behavioral and cognitive functioning, and discusses implications of these findings for mood disordered populations.
Regulation of glucose and mineral availability are necessary to sustain life. Glucocorticoids regulate glucose metabolism, while mineralocorticoids regulate sodium metabolism. In the brain endogenous cortisol acts on both MRs and GRs within various functional systems, with MRs displaying higher affinity for cortisol than GRs such that at basal conditions glucocorticoids primarily bind to MRs, and GRs become occupied when glucocorticoid levels increase [20]. Species differences in the distribution of MRs and GRs are prominent; receptor distribution tends to be limited to specific brain areas in lower animals [9] but are distributed widely throughout the primate brain [8], [21], [22], [23]. Additionally, the primate hippocampus expresses fewer GRs than the rat hippocampus, and also expresses high levels of MRs [8].
At the cellular level cortisol exerts genomic actions through translation of mRNAs, and these genomic effects are important for the production of various neurotransmitters and neuropeptides [24]. A single GR gene has been identified in humans [25]. GR expression is regulated by a number of transcription factors through many unique binding sites (as many as fifteen) [25], which may allow the differential regulation of GR protein expression under varying conditions. Although these genomic effects are relatively slow, rapid steroid effects that could not be accounted for through genomic actions also exist, which presumably are effective when fast cognitive appraisals of the environment are needed [26], [27], [28], [29], [30]. Fast (msec) membrane effects of cortisol may be the result of rapid modulation of membrane-associated receptor proteins [31]. The functional roles of cortisol's membrane actions are less clear but some evidence indicates a link to rapid changes in monoamine levels [32].
Cortisol is part of a fundamental system engaged in a wide range of regulatory functions within various anatomical sites. Fig. 1 illustrates that, within the brain, cortisol apparently participates in the regulation of various neuropeptide systems such as corticotropin-releasing hormone (CRH) [2], [33] and neuropeptide Y [12], and neurotransmitter systems such as serotonin [34], norepinephrine [35], dopamine [36], acetylcholine [37], and glutamate [38]. The effects on these systems influence psychological states that inform the animal of needs for preserving physiological homeostasis [39]. Through interactions with these neurochemical systems, glucocorticoids exert a wide range of effects on basic appetitive behaviors such as hunger, thirst, and drug intake. Finally, glucocorticoids may also influence the production of emotional and social behaviors such as attachment, temperament and mood.
The physiological, cognitive and behavioral effects of cortisol appear to act in a curvilinear, or ‘inverted U-shaped,’ fashion on many physiological and cognitive systems, in which moderate levels are optimal while extremely low or high concentrations each have distinct adverse behavioral or cognitive outcomes [28], [40]. For example, when cortisol levels are extremely low or high the central state of hunger is reduced, while modestly elevated levels can induce the central state of hunger [12], [41]. The central states influenced by the actions of cortisol on functional systems increases the likelihood of performing certain behaviors in suitable environments [12].
The interactions of the glucocorticoid and dopamine systems illustrate the diverse effects of glucocorticoids on neurotransmitter systems. Glucocorticoids can influence dopamine activity in the brain, and both glucocorticoids and dopamine appear to work in concert across various functional systems. Modest glucocorticoid elevations can have facillitory effects on appetetive systems, in part through influencing dopaminergic neurons [42], [43], [44]. Rats will exert modest effort (via bar press) in order to self-administer corticosterone, suggesting that glucocorticoid effects may be intrinsically motivating [45]. Some healthy human subjects initially report feelings of euphoria following cortisol and dexamethasone injections, similar to receiving a dose of adrenaline [46], [47], and glucocorticoids can induce euphoria and hypomania during chronic treatment [46], [48], [49]. A small subset of people report mood elevation or ‘giddiness’ after 5-day prednisone treatment [50].
The cortisol elevation in animals during search and subsequent reward suggests that glucocorticoids are likely acting on a number of experiential aspects, which encompass arousal, orientation in the environment, and memory for previous sources of reward [51], [52]. Rats that are ‘high responders’ in drug self-administration paradigms tend to have higher levels of endogenous glucocorticoids than those that are ‘low responders’, despite a high rate of variability between animals [53]; adrenelectomy reduces the rates of drug self-administration [54]. Glucocorticoids may alter dopamine transmission in specific sites, potentially generating these behavioral effects of drug administration [53] because of dopamine's role in signaling the salience for and learning of rewarding objects [55], [56]. In rats who are ‘high responders’ glucocorticoids apparently increase dopamine synthesis in the nucleus accumbens, where dopamine release plays a role in modulating both reward-related learning and psychomotor activity [57]. In adrenaliectomized rats, extracellular dopamine is decreased in the shell of the nucleus accumbens [42]. Also, in the medial prefrontal cortex, chronic corticosterone administration can increase dopamine turnover, as demonstrated by homovanillic acid levels [58].
Section snippets
Arousal, attention and cortisol
Subjective reports and behavioral observations of arousal and energy levels correlate with cortisol measures in humans, providing support for cortisol's role in sustaining and facilitating cognitive functions. Administration of glucocorticoids generally leads to increased subjective arousal in humans [47], [59]. Cortisol release is inhibited during sleep [60] and increased in the morning hours [12]. The normal elevation of morning cortisol concentrations in children and adults suggests a ‘wake
Cortisol, fear and anxiety
During states related to fear or anxiety, glucocorticoids are generally elevated [105], and if an animal is already fearful, glucocorticoid administration can lead to increased response to and memory of the experience of fear, as measured by increases in freezing behavior [68], [69]. For example, freezing responses to conditioned stimuli were potentiated by high-dose corticosterone treatments in rats [69]. Cortisol is important for sustained fear-related responses, for efficient cognitive
Conclusions
Glucocorticoids participate in sustaining circadian energy levels in mammals. They facilitate cognition and behavior pertaining to fear and anxiety responses by initiating changes in various functional brain systems that underlie cognitive mechanisms. These effects are produced via interactions with classical neurotransmitter and neuropeptide systems. Cortisol is necessary to sustain behavior and plays a protective role, but has deleterious effects on physiology and cognition during chronic
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