Glucocorticoid receptor signaling in the brain and its involvement in cognitive function

Abstract

The hypothalamic–pituitary–adrenal axis regulates the secretion of glucocorticoids in response to environmental challenges. In the brain, a nuclear receptor transcription factor, the glucocorticoid receptor, is an important component of the hypothalamic–pituitary–adrenal axis’s negative feedback loop and plays a key role in regulating cognitive equilibrium and neuroplasticity. The glucocorticoid receptor influences cognitive processes, including glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor–mediated pathways, through a combination of genomic and non-genomic mechanisms. Protein interactions within the central nervous system can alter the expression and activity of the glucocorticoid receptor, thereby affecting the hypothalamic–pituitary–adrenal axis and stress-related cognitive functions. An appropriate level of glucocorticoid receptor expression can improve cognitive function, while excessive glucocorticoid receptors or long-term exposure to glucocorticoids may lead to cognitive impairment. Patients with cognitive impairment–associated diseases, such as Alzheimer’s disease, aging, depression, Parkinson’s disease, Huntington’s disease, stroke, and addiction, often present with dysregulation of the hypothalamic–pituitary–adrenal axis and glucocorticoid receptor expression. This review provides a comprehensive overview of the functions of the glucocorticoid receptor in the hypothalamic–pituitary–adrenal axis and cognitive activities. It emphasizes that appropriate glucocorticoid receptor signaling facilitates learning and memory, while its dysregulation can lead to cognitive impairment. This provides clues about how glucocorticoid receptor signaling can be targeted to overcome cognitive disability-related disorders.

Introduction

The intricate interplay between stress and cognition is a fundamental aspect of neuroendocrine regulation and has implications for a variety of brain functions, particularly learning and memory (Schwabe et al., 2022; Brosens et al., 2024). At the core of this relationship lies the hypothalamic–pituitary–adrenal (HPA) axis, a critical pathway through which the body adapts to and copes with environmental challenges. Glucocorticoids (GCs), the end products of HPA-axis activation, have long been recognized to have pervasive effects on bodily systems, including their regulatory role in cognitive processes (Joëls, 2018; De Alcubierre et al., 2023; Qiao et al., 2023). The GC receptor (GR) is a nuclear receptor transcription factor that serves as the primary mediator of GC actions in the brain. GR, which is instrumental in the negative feedback mechanism of the HPA axis, plays a key role in modulating cognitive equilibrium and neuroplasticity (Gulyaeva, 2023). The non-genomic and genomic mechanisms of GR are vital for shaping cognitive neural processes such as glutamate neurotransmission, calcium signaling, and the activation of brain-derived neurotrophic factor (BDNF)–mediated pathways (Musazzi et al., 2010; Chen et al., 2012b; Joëls and Karst, 2012). However, the link between GR signaling and cognitive function is not one-dimensional (Finsterwald and Alberini, 2014). While appropriate stress and GC levels can facilitate cognitive activity by activating GR, chronic stress and sustained high levels of GCs can lead to cognitive impairment. Conditions such as Alzheimer’s disease (AD), depression, Parkinson’s disease (PD), Huntington’s disease (HD), stroke, and addiction, which are often linked to cognitive deficits, are frequently accompanied by dysregulation of the HPA axis and GR function (Aziz et al., 2009; Aguilera, 2011; Du and Pang, 2015; Lupien et al., 2018; Zhang et al., 2023).

In this review, we aim to provide a comprehensive overview of our current understanding of GR’s role in the modulation of cognitive function (Figure 1). We will explore the mechanisms by which GR influences cognitive processes and discuss the consequences of GR dysregulation in the context of various cognitive-impairment-related neurological disorders. By examining the interplay between GR signaling and cognitive function, we hope to shed light on potential therapeutic targets for the treatment of cognitive disabilities associated with stress-related disorders.

Figure 1.

Timeline of studies exploring the role of the glucocorticoid receptor in cognitive function.

This timeline figure was created by www.figdraw.com based on studies (Munck and Brinck-Johnsen, 1968; Payvar et al., 1983; Hollenberg et al., 1985; Denis et al., 1988; Munck and Náray-Fejes-Tóth, 1992; Takahashi et al., 2002; Karst and Joëls, 2005; Nikzad et al., 2011; Chen et al., 2012b; Lee et al., 2012; Park et al., 2015; Vyas et al., 2016; Canet et al., 2020; Kim et al., 2024). AD: Alzheimer’s disease; BDNF: brain-derived neurotrophic factor; CORT: corticosterone; DBD: DNA-binding domain; GC: glucocorticoid; GR: glucocorticoid receptor; GRE: glucocorticoid response element; Hsp90: heat-shock protein 90; LBD: ligand-binding domain; LTP: long-term potentiation; NMDA: N-methyl-D-aspartic acid; NTD: N-terminal transactivation domain; PD: Parkinson’s disease.

Retrieval Strategy

For this review, we conducted an online search of the PubMed database to identify pertinent literature published up to March 1, 2024. The search was not restricted by study type. Combinations of the following keywords were used to maximize the specificity and sensitivity of our search strategy: “stress,” “hypothalamic-pituitary-adrenal axis,” “glucocorticoid,” “glucocorticoid receptor,” “cognitive function,” “glutamate transmission,” “calcium signaling,” “brain-derived neurotrophic factor,” “huntingtin-associated protein 1,” “Abelson helper integration site 1,” “FK506-binding protein 51,” “histone deacetylase-1,” “FK506-binding protein 52,” “histone deacetylase-2,” “cyclic guanosine monophosphate,” “cGMP,” “Alzheimer’s disease,” “aging,” “Huntington’s disease,” “depression,” “Parkinson’s disease,” “addiction,” and “neuroinflammation.” After removing duplicates from the retrieved studies, an initial screening was performed based on the title and abstract of each article, followed by a full-text assessment to select literature highly consistent with the subject matter.

Hypothalamic–Pituitary–Adrenal Axis

The HPA axis consists of the hypothalamic paraventricular nucleus (PVN), the anterior pituitary gland, and the adrenal cortex (Smith and Vale, 2006). When the body encounters a psychological or physiological stressor, corticotropin-releasing hormone (CRH), produced by the hypothalamic neurons of the PVN, enters the bloodstream and prompts the anterior pituitary to secrete adrenocorticotropic hormone (ACTH). ACTH subsequently reaches the adrenal cortex through the circulatory system. Upon binding to its receptor, ACTH triggers the activation of adenylyl cyclase, initiating the intracellular synthesis of cyclic adenosine monophosphate (cAMP). The subsequent rise in cAMP levels catalyzes the activation of protein kinase A, which in turn initiates the phosphorylation of the cAMP response element-binding protein (CREB). This phosphorylation event is instrumental in facilitating the expression of steroidogenic acute regulatory protein, leading to the transport of cholesterol to the mitochondria, where the synthesis of GCs is achieved (Cruz-Topete et al., 2020). Intracellular concentrations of GCs are modulated by the metabolic activities of two 11β-hydroxysteroid dehydrogenase isozymes (11β-HSDs): 11β-HSD1 and 11β-HSD2. Specifically, cortisol is converted into its inactive metabolite, cortisone, by the high-affinity dehydrogenase activity of 11β-HSD2. Conversely, cortisone is converted back to active cortisol by 11β-HSD1, which serves as the primary reductase in most cells (Chapman et al., 2013). Cortisol is the primary GC in humans and other primates, whereas corticosterone (CORT) fulfills the role in rodents (Smith and Vale, 2006; Wong et al., 2012). The HPA axis maintains homeostasis through a self-regulating feedback loop in which GCs inhibit the synthesis and secretion of CRH in the hypothalamus and ACTH in the pituitary. The secretion of GCs follows a natural circadian pattern and is additionally elicited by stress (Hadad et al., 2020). Under normal conditions, the HPA axis operates on a discernible circadian schedule, with hormone release peaking in sync with the active period of the day–night cycle. In humans, GC levels typically hit their zenith around 8:00 AM, then experience a steady decrease throughout the day, hitting their nadir around midnight. However, in response to stress, GC concentrations in the blood surge to their highest levels approximately 15–30 minutes post–stressor exposure and then recede to their pre-stress levels within a span of 60–90 minutes (De Kloet et al., 1998).

GCs exert a profound influence on a diverse range of tissues and organs throughout the body. In the brain, they modulate the HPA axis and neuronal activity through two distinct nuclear receptors: GR (encoded by Nr3c1) and the mineralocorticoid receptor (MR, encoded by Nr3c2) (De Kloet et al., 1998; Ulrich-Lai and Herman, 2009). GRs are prevalent across the brain, with notably high levels in the hippocampus, prefrontal cortex, PVN, and amygdala. In contrast, MRs are chiefly confined to limbic system regions such as the frontal cortex, hippocampus, and amygdala (Reul and de Kloet, 1985; Ahima et al., 1991; Herman, 1993). GCs exhibit an approximately 10 times greater affinity for MR than GR. With GC levels at basal, MRs are substantially occupied, governing the baseline GC secretion that aligns with the circadian rhythm. Conversely, GRs, with their lower affinity for GCs, become more engaged during the circadian peak and are especially active when GC levels increase due to stress (Reul and de Kloet, 1985; De Kloet and Reul, 1987; Bradbury et al., 1991; ter Heegde et al., 2015). GR activation is essential for the brain’s negative-feedback stress responses. By binding GCs in the hippocampus, PVN, and anterior pituitary, it curbs CRH release, moderating the HPA axis (De Kloet et al., 1998; de Kloet et al., 1999, 2005). Additionally, this activation is involved in energy mobilization and enhances learning and memory formation. In general, MRs mediate the early stages of stress responses by facilitating swift neural circuit adjustments. When the stress proceeds and circulating GCs rise, the activated GRs serve to inhibit the initial defense mechanism, preventing it from turning into a destructive process (McEwen et al., 2015; de Kloet et al., 2019; Xiong et al., 2021). The genomic impact of GR on neuronal function typically begins around 3 hours post-GC exposure and persists for several hours (Joëls and de Kloet, 1992; Henckens et al., 2011). GRs enhance the encoding and retention of memories, equipping the brain to handle similar challenges more effectively in the future (Herman et al., 2003; de Kloet et al., 2019; Xiong et al., 2021).

Brain regions associated with cognitive and emotional processes are connected to the effects of GCs, which can affect neuronal activity, synaptic flexibility, and the retrieval and solidification of memories (Joëls et al., 2013; de Kloet et al., 2018; Holloway and Lerner, 2024). The effective control of the stress response is essential, as dysregulation of the HPA axis is correlated with the various physiological and psychological disorders that are accompanied by impaired cognition and emotion (Wingenfeld and Wolf, 2015). Cushing’s syndrome (CS), also referred to as chronic endogenous hypercortisolism, serves as a pertinent example. This endocrine disorder arises from the adrenal gland’s sustained, autonomous overproduction of cortisol (Pivonello et al., 2016). A primary characteristic of CS is the disruption of the GC feedback mechanism (Feelders and Hofland, 2013). Other clinical features of CS include cognitive impairments, notably in memory and attention, along with mood disturbances such as depression and anxiety (Pivonello et al., 2016). The neurocognitive deficits that are characteristic of CS are significantly linked to GC-induced alterations within the hippocampus, encompassing anatomical, functional, and biochemical changes (Patil et al., 2007). In a randomized, controlled clinical trial focused on the ultradian GC rhythm’s impact on the modulation of mood and resting-state brain networks, the biosynthesis of endogenous GCs was pharmacologically inhibited, and plasma cortisol levels were restored through hydrocortisone replacement under different protocols. The results suggested that, under non-stressful conditions, the ultradian cortisol rhythmic pattern may affect cognitive psychophysiology, offering insights into the neuropsychological effects of cortisol fluctuations (Kalafatakis et al., 2021). This could help clinicians refine GC-replacement strategies, especially post-CS surgery.

Glucocorticoid Receptor

The human GR (hGR) gene NR3C1 is situated on the q31.3 region of chromosome 5 and is composed of nine exons (Vandevyver et al., 2014). The first exon houses the 5′-untranslated region, which modulates GR expression in a tissue-specific manner. The subsequent 2–9 exons encode the functional receptor, which is structured into three main domains: the N-terminal domain, the DNA-binding domain (DBD), and the ligand-binding domain (LBD) (Schaaf and Cidlowski, 2002; Kadmiel and Cidlowski, 2013). Alternative splicing of the NR3C1 gene results in several human GR isoforms: GRα, GRβ, GRγ, GR-A, and GR-P (Moalli et al., 1993; Bamberger et al., 1995; Vandevyver et al., 2014). Among the various isoforms, GRα and GRβ, which are highly homologous, have garnered significant interest. Conservation between the two isoforms’ sequences ends at the 727^th amino acid, with divergence introduced in their C-terminal exon 9 (Hollenberg et al., 1985; Oakley and Cidlowski, 2011). GRα, the primary GR, is found in nearly all cells, spans 777 amino acids, and possesses a molecular weight of 97 kDa. It serves as a typical ligand-activated transcription factor (Lewis-Tuffin and Cidlowski, 2006). GRβ, with a shorter LBD, consists of 742 amino acids and is unable to conventionally bind to GC (Hollenberg et al., 1985; Oakley et al., 1999). GRβ was shown to exert a dominant negative impact on GRα’s transcriptional activity (He et al., 2015).

GRα is widely recognized for its role in mediating most of the physiological effects of GCs. Its N-terminal domain encompasses a ligand-independent activation function 1 domain, crucial for GR’s transcriptional regulation and a key participant in the recruitment of essential transcriptional coregulators, including Brahma-related gene 1, CREB-binding protein and its paralog p300, as well as p300/CREB-binding-protein-associated factor (Fadel et al., 2023). Activation of the function 1 domain involves critical phosphorylation sites at serine residues S203, S211, and S226, which are functionally important for GRα activity (Wang et al., 2002). The phosphorylation of GRα serves as an indicator of its activation by ligand binding and is necessary for the receptor’s nuclear translocation and subsequent transcriptional regulation (Ismaili and Garabedian, 2004). The highly conserved DBD features two zinc-finger motifs that enable GRα to bind to GC-response elements (GREs), the specific DNA sequences located in the promoter regions of GC-targeted genes. The C-terminal LBD contains a ligand-dependent activation function (activation function 2), along with a hydrophobic pocket for GC-binding. This domain is pivotal for the activation of GRα upon ligand binding, encompassing processes such as ligand and chaperone interaction, receptor dimerization, and the recruitment of coregulators (Weikum et al., 2017). The DBD and LBD are connected by a hinge region that facilitates receptor dimerization and GR transcriptional activity. GRα also features two nuclear localization signals, one at the junction of the DBD/hinge region and another in the LBD. These nuclear localization signals play pivotal roles in directing GRα to the nucleus (Nicolaides et al., 2010; Figure 2).

Figure 2.

Structure of the glucocorticoid receptor protein.

The GR is composed of a NTD, a central DBD, a hinge region and a C-terminal LBD. The NTD domain encompasses a ligand-independent AF-1 domain. The DBD features two zinc-finger motifs that bind GREs. The C-terminal LBD contains AF-2 along with a hydrophobic pocket for GC-binding. GR features two NLS, one at the junction of the DBD/hinge region and another in the LBD. Created by Figdraw (www.figdraw.com). AF-1/2: Activation function-1/2; COOH: carboxyl terminal; DBD: DNA-binding domain; GR: glucocorticoid receptor; GRE: glucocorticoid response element; LBD: ligand-binding domain; NLS: nuclear localization signal; NH: amino-terminal; NTD: N-terminal transactivation domain.

Without a ligand, inactive GRα in the cytoplasm resides within a multiprotein complex that includes the heat-shock proteins Hsp90 and Hsp70, the co-chaperone p23, and immunophilins from the FK506-binding protein family, namely FKBP51 and FKBP52 (Pratt and Toft, 1997). Upon binding to GCs, GR undergoes structural alterations and becomes hyperphosphorylated, which results in the exposure of nuclear localization signals and the migration of the GRα/ligand complex into the nucleus to exert genomic effects (Figure 3). Upon nuclear entry, the activated GR forms dimers that bind to GREs, promoting the transcription of specific target genes via a transactivation process (Schoneveld et al., 2004). The activated GR also interacts with two transcription factors, nuclear factor-κB and activator protein-1, and disrupts their binding to corresponding DNA sequences, thereby repressing gene expression via a negative regulatory mechanism called transrepression (Giguère et al., 1986; Hollenberg and Evans, 1988; Bamberger et al., 1996; Föcking et al., 2003). GR transrepression is also involved in the binding of negative GREs (Schoneveld et al., 2004). Following the transcriptional regulation of GC-responsive genes, GR detaches from the DNA, re-enters the cytoplasm, and may reassociate with Hsps to form a heterocomplex, or it can be targeted for degradation by the ubiquitin-proteasome pathway (Pratt et al., 2006; Nicolaides et al., 2010). In addition to activating genomic pathways, cytosolic and membrane-associated GR can initiate swift cellular responses through non-genomic mechanisms. These mechanisms involve cellular protein–protein interactions and allow for rapid signaling effects that are independent of transcriptional regulation (Croxtall et al., 2000; Bartholome et al., 2004).

Figure 3.

The role of the glucocorticoid receptor in the HPA axis and its genomic signaling.

Stress-induced activation of the HPA axis triggers the release of CRH from the hypothalamus and ACTH from the pituitary, ultimately promoting the synthesis and secretion of GC by the adrenal glands. GC binds to GR in the hippocampus and the paraventricular nucleus of the hypothalamus to inhibit the further release of CRH. Additionally, GC binds to GR in the pituitary to inhibit the release of ACTH. When GR in the cytoplasm binds to a ligand, it undergoes a conformational change and becomes hyperphosphorylated. It then separates from the chaperone protein complex, which includes Hsp90, Hsp70, p23, and FK506, and moves into the nucleus to exert genomic effects. Within the nucleus, GR can either promote or inhibit the transcription of target genes by binding to GREs or interacting with other transcription factors such as NF-κB and AP-1. GR then returns to the cytoplasm, where it can form complexes with Hsps or be targeted for degradation via the ubiquitin-proteasome pathway. Created by Figdraw (www.figdraw.com). ACTH: Adrenocorticotropic hormone; AP-1: activator protein-1; CRH: corticotropin-releasing hormone; FK506: FK506-binding proteins; GC: glucocorticoid; GR: glucocorticoid receptor; GRE: glucocorticoid response element; HIP: hippocampus; HPA axis: hypothalamic–pituitary–adrenal axis; Hsp70: heat-shock protein 70; Hsp90: heat-shock protein 90; HY: hypothalamus; MR: mineralocorticoid receptor; NF-κB: nuclear factor-κB; P: phosphorylation; p23: p23 protein; Ub: ubiquitin.

The widespread expression of GR in mammalian cells is accompanied by the cell-type-specific modulation of gene expression. For example, GR signaling exerts opposing effects on CRH transcription in distinct brain regions; it suppresses CRH in the PVN while augmenting it in the central amygdala (McNally and Akil, 2002; Bali et al., 2008; Kovács, 2013). These regional differences are likely to be due to the tissue-specific distribution of steroid receptor coactivators such as steroid receptor coactivator 1. The steroid receptor coactivator 1a isoform is particularly abundant in the PVN, while the central amygdala exhibits a higher concentration of the steroid receptor coactivator 1e isoform, corresponding to the divergent effects of CORT in these regions (Meijer et al., 2000). Furthermore, the phosphorylation of GR is responsible for its gene specificity and plays a pivotal role in transcriptional regulation (Chen et al., 2008). Intense training, for instance, has been demonstrated to selectively enhance phosphorylation at serine 232 on GR (pGRser232) in the CA1 region of the rat hippocampus, an effect not observed in the CA3 region and dentate gyrus (González-Franco et al., 2023). The pGRser232 in rats is homologous to serine 211 (pGRser211) in humans and is recognized to be a critical post-translational modification that augments GR’s transcriptional activity (Chen et al., 2008). The variations in responses across different hippocampal regions could be associated with the distinct immunoreactivity profiles of GR and the differential expression of 11β-HSD1. Specifically, the CA3 regions exhibit weaker GR immunoreactivity and higher 11β-HSD1 levels (Moisan et al., 1990; Morimoto et al., 1996), potentially explaining the region-specific effects of intense training on GR phosphorylation.

Glucocorticoid Receptor Signaling in Cognitive Function

Stress-induced GC secretion activates specific brain areas that have an abundance of GRs, including the hippocampus, amygdala, and prefrontal cortex, regions critical for cognitive and memory functions (Finsterwald and Alberini, 2014). Many studies have demonstrated that the influence of GCs on learning and memory is contingent upon a stressor’s duration and severity, in adherence to an inverted U-shaped dose-response pattern (Lupien et al., 2002, 2007; Calabrese, 2008). Moderate levels of GCs can enhance cognitive functions, whereas excessive GC levels or extended exposure to GC may result in detrimental effects (Tabassum and Frey, 2013; Naninck et al., 2015). Substantial data from both animal and human research demonstrate that, in addition to their impact on acquisition and consolidation processes, stress and GCs also affect memory retrieval (Kirschbaum et al., 1996; Luine et al., 1996; de Quervain et al., 1998, 2000; Cai et al., 2006; Dos Santos Corrêa et al., 2021; Buurstede et al., 2022; Cuccovia et al., 2022; Brosens et al., 2023; González-Franco et al., 2023; Pegueros-Maldonado et al., 2024). GCs, when administered following a training session, are recognized for their ability to bolster the consolidation of memories (Roozendaal, 2002). Interestingly, clinical trials have hinted at an alternative therapeutic potential for GCs, as the administration of GCs might offer relief to individuals suffering from established posttraumatic stress disorder and specific phobias (Aerni et al., 2004; Soravia et al., 2006). A further investigation led to the authors of the study proposing that CORT administration in rats immediately after training sessions of mild or moderate intensity have different regulatory effects on memory consolidation and time-dependent fear generalization, the latter of which involves the incorporation of new memories into the neocortex network by CORT (Bahtiyar et al., 2020; Dos Santos Corrêa et al., 2021). Consistent evidence shows GRs are of importance in cognition homeostasis and neuroplasticity (Joëls and de Kloet, 1992; Herman et al., 2003; Henckens et al., 2011; Gulyaeva, 2023), but GR saturation after treatment with high doses of GC attenuates cognitive function (McEwen and Sapolsky, 1995; Lupien et al., 2007). For instance, acute high concentrations of CORT and chronic stress disrupt long-term potentiation (LTP), widely recognized as being fundamental to learning and memory processes, by activating GR (Park et al., 2015). Notably, after exposure to mild stress, particularly when integrated into a learning process, GRs positively influence dendritic structure, synaptic plasticity, and memory consolidation (Roozendaal, 2000; de Kloet, 2022). The increase in dendritic spine density on pyramidal neurons in the CA1 and CA3 regions of the hippocampus induced by CORT is reversed by the GR antagonist RU486, thus GRs are implicated in the GC-mediated development of neuronal morphology (Komatsuzaki et al., 2012; Yoshiya et al., 2013; Gulyaeva, 2023). Hippocampal LTP, which is enhanced in animals with elevated GR, is markedly diminished in those with compromised GR expression (Calis et al., 2023). Moreover, activated GRs affect the consolidation of various forms of memories that are dependent on the hippocampus (Finsterwald and Alberini, 2014). Spatial memory was impaired in mice with the targeted disruption of GR and those with impairments in the DBD of GR (Oitzl et al., 1997, 2001). Additionally, inhibition of GRs with the antagonist RU38486 suppresses fear memory consolidation (Nikzad et al., 2011). Aging-related cognitive decline may be correlated with diminished GR signaling within the hippocampus, as manifested by a decreased capacity for nuclear translocation and the suboptimal DNA binding of GRs (Murphy et al., 2002; Mizoguchi et al., 2009; Lee et al., 2012).

An investigation utilizing Affymetrix GeneChips revealed a distinctive temporal pattern of gene expression changes following GR activation in rat hippocampal slices. It also provided evidence that genes regulated by GR are involved in the processes of neurotransmission and synaptic plasticity (Morsink et al., 2006). More and more studies are suggesting that genes targeted by GR, such as FKBP prolyl isomerase 5, synaptosomal-associated proteins, inositol 1,4,5-trisphosphate receptor type 1, activity-regulated cytoskeleton-associated protein, neurotrophic tyrosine receptor kinase 2, myelin basic protein, and LIM domain kinase 1, participate in signal transduction, neuronal structure, synaptic plasticity, and neurotransmitter metabolism (Morsink et al., 2006; Datson et al., 2008; Gray et al., 2014; McReynolds et al., 2014; Mahfouz et al., 2017; Gregory and Goudet, 2021; Buurstede et al., 2022). These data imply that the traditional, genomic-dependent pathway of GR activation is required for memory processes, neuroplasticity, and morphological alterations. Nonetheless, many effects of GR are facilitated through swift genomic-independent pathways (Prager and Johnson, 2009; Groeneweg et al., 2011). As an example, non-genomic actions of GRs trigger the endocannabinoid system in the amygdala and hippocampus, thereby influencing the HPA axis and cognitive functions (Di et al., 2003; Atsak et al., 2012). It has been shown that GR-regulated Ca²⁺ signaling and rapid glutamate release are partly dependent on non-genomic effects (Takahashi et al., 2002; Tasker et al., 2006; Groeneweg et al., 2011). In summary, cognitive functions within the brain are regulated by GRs via a combination of genomic and non-genomic mechanisms.

Glucocorticoid receptor and glutamate transmission

As the primary excitatory neurotransmitter in the central nervous system, glutamate is engaged in the regulation of the synaptic transmission that is very important in a broad spectrum of brain functions, including learning, memory, cognition, and development (Nisar et al., 2022; Li et al., 2023). The synaptic transmission that affects neuroplasticity is accomplished by glutamate and its receptors, such as α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) and N-methyl-D-aspartic acid (NMDA) receptors. The role of GRs in the regulation of the glutamatergic system includes both the mediation of rapid genomic-independent responses and the orchestration of sustained genomic effects (Finsterwald and Alberini, 2014).

GCs are capable of swiftly increasing the rate of glutamate release at presynaptic terminals in the prefrontal cortex and hippocampus via the immediate non-genomic mechanisms of both GRs and MRs (Karst and Joëls, 2005; Olijslagers et al., 2008; Musazzi et al., 2010). This mechanism leads to a prompt and reversible increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs), reflecting the postsynaptic neuron’s response to spontaneous glutamate release from presynaptic vesicles. However, the neuroendocrine cells of the PVN in hypothalamic slices stimulated with CORT and dexamethasone exhibited a decreased frequency of mEPSCs via the action of retrograde endocannabinoid signaling involving the type I cannabinoid receptor (Di et al., 2003; Nahar et al., 2015). The capacity to rapidly suppress excitatory glutamate transmission was diminished upon the conditional deletion of GRs (Nahar et al., 2015). These findings indicate that GRs have distinct influences on the rapid release of glutamate across different regions of the brain.

GR-mediated transcriptional activation is also necessary for glutamate neurotransmission. For instance, exposing hippocampal slices to 100 nM CORT for at least 1 hour led to a significant increase in the amplitude of mEPSCs induced via AMPA receptors in CA1 neurons, without affecting their frequency (Karst and Joëls, 2005). The delayed effect was mimicked by a highly selective GR-agonist, suggesting that the genomic mechanism of hippocampal GR clearly mediates the effect on the mEPSC amplitude (Karst and Joëls, 2005). Moreover, GR-mediated transcriptional regulation may have been crucial for the increased synaptic content and lateral diffusion of GluR2-containing AMPA receptors induced by CORT in cultured hippocampal neurons (Martin et al., 2009). In agreement with this, the enduring increase in glutamate transmission produced by acute stress in the prefrontal cortex via the activation of GR is closely related to elevated surface levels of postsynaptic NMDA and AMPA receptors, which directly affect prefrontal cortical circuits and thus working memory performance (Yuen et al., 2009).

Glucocorticoid receptor and calcium signaling

Calcium signaling plays a crucial role in numerous cellular processes, including neural transmission (Dhureja et al., 2023; Qu et al., 2023; Brockie et al., 2024). In hippocampal CA1 cells, synaptic efficacy is significantly influenced by an increase in postsynaptic calcium influx, which can occur through different pathways, such as NMDA receptors or voltage-dependent calcium channels (including L-, N-, R-, P/Q-, and T-type) (Joëls and Karst, 2012). The necessity of calcium influx through NMDA receptors for LTP induction is a widely recognized concept (Bliss and Collingridge, 1993). Yet, the initiation of LTP through high-frequency stimulation is linked to calcium entry via voltage-dependent calcium channels (Grover and Teyler, 1990). Research has revealed that the activity of certain calcium channels and the resultant currents are highly responsive to GC modulation.

An investigation demonstrated that immediate and short-term CORT exposure (within 20 minutes) resulted in an extended duration of NMDA receptor-triggered intracellular calcium ([Ca²⁺]_i) increase in the hippocampal neurons of rats (Takahashi et al., 2002). This impact remained unaffected by specific agonists and antagonists of cytosolic GRs, as well as by cycloheximide, a substance that inhibits the synthesis of proteins (Takahashi et al., 2002). Intriguingly, the effect of CORT conjugated with bovine serum albumin, which cannot cross cell membranes, has been noted to elicit an analogous response, suggesting that the swift action of CORT is attributed to a non-genomic mechanism involving GRs on the cell membrane surface (Takahashi et al., 2002). Consistently, the immunoreactivity of GRs was noted to be located at neuronal plasma membranes in the hypothalamus and hippocampus (Liposits and Bohn, 1993). The binding of CORT to GRs on the neuronal membrane can take place across various brain areas with a moderate level of affinity (Towle and Sze, 1983).

The genomic effects of GRs also contribute to the regulation of calcium signaling. Specially, brief, high-dose CORT exposure, sufficient to activate GRs, led to an enhancement in L-type calcium current amplitude within hippocampal dorsal CA1 pyramidal neurons, which was attributed to a doubling of the number of functional calcium channels (Chameau et al., 2007). The delayed effect, which occurred for over more than an hour, necessitates GR homodimer binding to DNA and subsequent alterations in transcription (Kerr et al., 1992; Karst et al., 2000). The Cavβ4 auxiliary subunits, recognized for their role in helping transport calcium channels to the plasma membrane, are potential candidates for regulation by GRs (Arikkath and Campbell, 2003; Dalton et al., 2005; Chameau et al., 2007). The upregulation of Cavβ4 subsequently augments the expression of L-type calcium channels at the membrane surface, thereby amplifying calcium currents. Notably, this phenomenon has been specifically observed in the dorsal CA1 region following CORT pulses and was not replicated in the dentate gyrus granule cells (van Gemert et al., 2009), underscoring the region-dependent influence of CORT. Although the transcriptional response to CORT is similar in neurons of both areas, the lack of effect in granule cells at the protein and functional levels indicates the importance of GR’s downstream signaling pathways and the cellular context in shaping CORT’s overall influence (van Gemert et al., 2009).

Glucocorticoid receptor and recruitment of brain-derived neurotrophic factor-mediated signaling pathways

BDNF, which is essential for neuronal survival, differentiation, and function, plays a key role in memory processes and associated physiological functions such as synaptic formation and plasticity (Mizuno et al., 2003; Minichiello, 2009; Gao et al., 2022; Zhao et al., 2024). BDNF signaling occurs mainly through tyrosine kinase receptor B (TrkB) (Soppet et al., 1991), which is located at both pre- and postsynaptic terminals, where it influences neurotransmitter release and modulates postsynaptic responses (Madara and Levine, 2008). The binding of BDNF to TrkB with high affinity triggers intracellular signaling cascades integral to memory and synaptic modulation. These pathways include mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), phospholipase C-γ, and phosphatidylinositol-3-kinase/protein kinase B (also known as Akt) (Park and Poo, 2013). The recruitment of the BDNF pathway by GRs is crucial for effective memory consolidation under controllable stress. However, excessive GC levels during prolonged stress can disrupt BDNF signaling (Finsterwald and Alberini, 2014).

Under favorable circumstances, GC secretion and GR activation trigger a molecular cascade of BDNF-TrkB signaling pathways. First, GRs modulate the expression of BDNF. Hippocampal BDNF levels were notably downregulated in GR-deficient mice but obviously upregulated in GR-overexpressed mice (Ridder et al., 2005). GRs are thought to manage the transcription of BDNF by altering the activity levels of CREB (Kassel and Herrlich, 2007). The stimulation of GRs leads to the positive regulation of tissue-plasminogen activator protein levels, facilitating the proteolytic maturation of pro-BDNF. An increased concentration of mature BDNF facilitates binding to TrkB receptors, thereby amplifying downstream signaling pathways (Revest et al., 2014). Second, GRs are associated with the post-translational mechanisms required for memory processes. GR inhibition within the hippocampus of rats was found to notably decrease phosphorylation events for TrkB, ERK1/2, phospholipase C-γ, and Akt, suggesting GRs have a role in initiating the BDNF-mediated signaling cascade (Chen et al., 2012a). GRs also control the phosphorylation of CREB, calcium calmodulin kinase IIα, and synapsin 1 (Chen et al., 2012a). The phosphorylation of TrkB and downstream signaling proteins depends on GR-mediated genomic and/or non-genomic effects (Jeanneteau et al., 2008; Chen et al., 2012a). In the context of fear conditioning triggered by GCs, the activation of hippocampal GRs induces MAPK phosphorylation, which subsequently triggers the transcription of the immediate-early gene early growth response 1 (Egr-1, also known as Zif268). The activation of Egr-1 then facilitates the upregulation and phosphorylation of synapsin Ia and Ib, proteins imperative for contextual memory consolidation (Revest et al., 2005, 2010). Third, GRs control the downstream signaling of BDNF/TrkB via epigenetic modification. GR activation in response to an array of physical and psychological stressors instigates the dual modification of histone H3 through phosphorylation and acetylation in dentate gyrus neurons, which aids in solidifying stress-related behavioral reactions (Bilang-Bleuel et al., 2005; Chandramohan et al., 2007, 2008; Gutièrrez-Mecinas et al., 2011). In particular, following an acute stressor, GCs acting through GRs to promptly amplify the activation of mitogen- and stress-activated kinase 1 and ETS domain protein 1 via the pERK1/2 pathway (Gutièrrez-Mecinas et al., 2011). The activation of mitogen- and stress-activated kinase 1 and ETS domain protein 1 leads to phosphorylation at serine-10 and acetylation at lysine-14 of histone H3, thereby enhancing the expression of immediate-early genes that are pivotal for neuronal plasticity, including c-Fos and Egr-1 (Gutièrrez-Mecinas et al., 2011). During this process, GR influences the ERK signaling pathway in a non-genomic manner, resulting in epigenetic changes and gene expression alterations in neurons of the dentate gyrus. These modifications have enduring impacts on the behavioral responses associated with stress (Gutièrrez-Mecinas et al., 2011; Figure 4).

Figure 4.

Glucocorticoid receptor signaling in cognitive function.

Stress activates the HPA axis, which triggers the release of GCs. Within the brain, GCs bind to and activate GRs at synapses in the hippocampus. GRs regulate the release of glutamate in presynaptic neurons and influence neuronal plasticity by affecting glutamate receptors, such as AMPAR and NMDAR, in postsynaptic neurons. The calcium influx through NMDARs or VDCCs, essential for the activation of postsynaptic neurons, is also modulated by GRs. The GR-mediated BDNF/TrkB signaling pathway and the phosphorylation of CaMKII control the phosphorylation of CREB. Moreover, the genomic effects of GR regulate the expression of factors such as FKBP5, SNAPs and ARC, which are involved in signal transduction, neuronal structure, and synaptic plasticity. Collectively, these processes have a profound impact on cognitive function. Created by Figdraw (www.figdraw.com). Akt: Protein kinase B; AMPAR: α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor; ARC: activity-regulated cytoskeleton-associated protein; BDNF: brain-derived neurotrophic factor; CaMKII: calcium-calmodulin dependent protein kinase II; CREB: cAMP response element-binding protein; ERK: extracellular signal-regulated kinase; FKBP5: FKBP prolyl isomerase 5; GC: glucocorticoid; Glu: glutamate; GR: glucocorticoid receptor; HPA: hypothalamic-pituitary-adrenal; NMDAR: N-methyl-D-aspartic acid receptor; PLC-γ: phospholipase C-γ; SNAPs: synaptosomal-associated proteins; TrkB: tyrosine kinase receptor B; VDCC: svoltage-dependent calcium channel.

Recent Advances in Understanding Proteins that Interact with Glucocorticoid Receptor

Protein–protein interactions within the neurons of the central nervous system are very important for neural activity. Many proteins in the nervous system interact with GR to influence its expression or intracellular activity, thereby regulating the HPA axis and stress-related cognitive and emotional activities (Table 1).

Table 1.

GR interacting protein

Gene/protein	Role	Mechanism of action	Reference
Hap1	Scaffold protein	Stabilizes GR levels	Chen et al., 2020
Ahi1	Protein linked to depression susceptibility	Stabilizes GR levels in cytoplasm and mitochondria	Wang et al., 2021, 2023
14-3-3 proteins	Eukaryotic regulatory proteins	Modulate GR transcriptional activity	Wakui et al., 1997; Kino et al., 2003; Kim et al., 2005; Galliher-Beckley et al., 2011; Hwang et al., 2018
FKBP51/FKBP52	Co-chaperones of Hsp90	FKBP51 inhibits GR signaling; FKBP52 promotes GR signaling	Denny et al., 2000; Galigniana et al., 2001; Riggs et al., 2003; Wochnik et al., 2005; Baischew et al., 2023; Noddings et al., 2023
HDAC1/HDAC2	Class I HDACs	Modulate GR-mediated gene transcription	Qiu et al., 2006; Luo et al., 2009; Wu et al., 2021
BAG-1	Regulatory co-chaperone protein	Attenuates GR nuclear translocation, inhibits transactivation by the GR, and mediates GR transport to mitochondria	Schmidt et al., 2003; Zhou et al., 2005; Luo et al., 2021
cGMP	Second messenger	Downregulates GR expression levels	Zhou et al., 2011

Ahi1: Abelson helper integration site 1; BAG-1: Bcl-2 associated athanogene-1; cGMP: cyclic guanosine monophosphate; FKBP51/FKBP52: FK506-binding protein 51/52; GR: glucocorticoid receptor; Hap1: huntingtin-associated protein 1; HDAC1/HDAC2: histone deacetylase-1/2; HDACs: histone deacetylases; Hsp90: heat shock protein 90.

Glucocorticoid receptor and huntingtin-associated protein 1

Huntingtin-associated protein 1 (Hap1) was initially discovered in a study using yeast two-hybrid assays to examine its interaction with the huntingtin protein, a molecule implicated in HD (Li and Li, 2012). Hap1 is predominantly found in the nervous system and contributes to a spectrum of physiological neuronal activities, such as the modulation of gene expression, the conveyance of vesicles, the reclamation of membrane receptors, and the transduction of signals (Zhao et al., 2022; Chen et al., 2023). Our research has demonstrated that the presence of Hap1 is concurrent and has an interactive relationship with GR in PVN neurons of the mouse hypothalamus (Chen et al., 2020). The genetic removal of Hap1 led to a reduction in the expression of GR in the mouse hypothalamus, as well as diminishing the half-life of GR in cultured cells (Chen et al., 2020). Moreover, Hap1 deficiency promoted the stress-induced reduction in hypothalamic GR (Chen et al., 2020). The results indicated that Hap1 enhances the stability of GR within neuronal cells, and a lack of Hap1 could potentially modify the GR-driven stress-response mechanism.

Glucocorticoid receptor and Abelson helper integration site 1

Abelson helper integration site 1 (Ahi1), which has been linked to depression susceptibility (Jiang et al., 2002), is critical for protein–protein interactions and signal transduction (Wang et al., 2021). The deficiency of Ahi1 causes depression-like behavior in mice (Xu et al., 2010). A study demonstrated that Ahi1 forms a complex with GR in the cytoplasm, mutually stabilizing their presence (Wang et al., 2021). Stress can diminish the interaction between GR and Ahi1, leading to a reduction in Ahi1 protein levels (Wang et al., 2021). The deficiency of Ahi1 results in the breakdown of GR in the cytoplasm and its subsequent ligand-dependent translocation to the nucleus, weakening the effectiveness of antidepressant drugs that depend on the level and activity of GR (Anacker et al., 2011; Thiagarajah et al., 2014; Wang et al., 2021). The evidence indicates that Ahi1 dysfunction impairs the GR-mediated stress response, resulting in depressive phenotypes and hyposensitivity to antidepressant treatment. Furthermore, Ahi1 in the mitochondria is known to engage with GR, and a deficiency in Ahi1 has been shown to influence the levels of mitochondrial GR (Wang et al., 2023). The GR located in the mitochondria attaches to the D-loop area of mitochondrial DNA, and it works in tandem with the mitochondrial transcription factor A to manage the quantity of mitochondrial DNA copies (Wang et al., 2023). Research indicates that a decrease in mitochondrial Ahi1/GR leads to higher mitochondrial DNA copy numbers and reduced ATP levels, both of which are linked to depression. Conversely, enhanced mitochondrial Ahi1/GR and ATP levels were observed in mice that engaged in regular physical activity and mitigated behaviors indicative of depression (Cai et al., 2015; Wang et al., 2023).

Glucocorticoid receptor and 14-3-3 proteins

The 14-3-3 proteins constitute a group of evolutionarily conserved 30-kilodalton acidic proteins found in the cells of all eukaryotic organisms. These proteins are capable of recognizing and binding to the phosphorylated serine or threonine residues on their target molecules, acting as central molecular nodes to regulate the subcellular localization, folding, degradation, and interactions of the proteins, and thereby influencing the intracellular signal transduction process (Giusto et al., 2021). They contain nine α-helical structures with a classic nuclear export signal within the ninth helix, facilitating the cytoplasmic distribution of 14-3-3/chaperone complexes (Kino et al., 2003). The 14-3-3 proteins are also associated with the development of various diseases, including PD (Giusto et al., 2021). GR has been found to interact with several isoforms of the 14-3-3 protein family, including 14-3-3β, 14-3-3γ, 14-3-3σ, 14-3-3η, and 14-3-3ζ/δ. Specifically, 14-3-3β and 14-3-3γ isoforms are known to enhance GR activity in a ligand-dependent fashion by binding to the complete GR molecule (Hwang et al., 2018). The 14-3-3σ isoform interacts through its COOH-terminal portion with the LBD of GR to suppress ligand-activated GR transcriptional activity by causing a shift in GR’s subcellular localization toward the cytoplasm (Kino et al., 2003). The 14-3-3η isoform interacts with the LBD domain of GR, thereby increasing GR’s transcriptional activity and its protein levels by obstructing the pathway of ubiquitin-mediated proteasomal degradation (Wakui et al., 1997; Kim et al., 2005). The linkages between GR and the 14-3-3ζ/δ variants are contingent upon the phosphorylation of GR at serine 134, a process that is driven by the p38-MAPK signaling cascade. This modification to GR affects its transcriptional efficacy prior to ligand engagement, thereby shaping the receptor’s activity (Galliher-Beckley et al., 2011).

Glucocorticoid receptor and FKBP51/FKBP52

FKBP51, which is encoded by the FKBP5 gene, and FKBP52, encoded by the FKBP4 gene, are both part of the immunophilin protein family. These proteins are characterized by their possession of a unique peptidyl-prolyl-(cis/trans)-isomerase activity sequence, which is essential for their function (Zgajnar et al., 2019). FKBP51 and FKBP52, immunophilins identifiable by their molecular weights of 51 and 52 kDa, are highly homologous proteins that act as essential co-chaperones with Hsp90 and significantly contribute to the GR-mediated stress response and the signaling of GCs (Pratt and Toft, 1997; Binder, 2009; Zgajnar et al., 2019). The peptidyl-prolyl-(cis/trans)-isomerase domains (also called FK1 domain) of FKBP51 and FKBP52 interact with the LBD of GR, affecting its conformational structure and ligand-binding capacity (Riggs et al., 2003; Baischew et al., 2023). FKBP51 was shown to suppress GR signaling, while FKBP52 has the opposite effect. A study demonstrated that the dynein/dynactin complex, crucial for transporting vesicles in a retrograde fashion to the nucleus, interacts with GR via its linkage to the peptidyl-prolyl-(cis/trans)-isomerase domain of FKBP52 (Galigniana et al., 2001). Upon binding to GCs, the GR complex, which includes Hsp90, FKBP52, and dynein, navigates the cytoplasm and enters the nucleus through nuclear pores (Galigniana et al., 2001). FKBP51 demonstrates weaker binding to the dynein motor protein compared to FKBP52, leading to the delayed nuclear import of GR when influenced by FKBP51 (Wochnik et al., 2005). The activated GR’s interaction with GREs induces the expression of FKBP51, which in turn inhibits GR function through a negative regulatory feedback mechanism (Zannas et al., 2016; Noddings et al., 2023). This inhibition involves the conversion between FKBP51 and FKBP52 within the receptor complex, along with alterations to the folding and conformation of GR (Zgajnar et al., 2019). Within neurons of the hippocampus, the inhibition of GR function requires the conjugation of FKBP51 with the small ubiquitin-like modifier, which is a type of reversible post-translational modification (Antunica-Noguerol et al., 2016). An elevated level of FKBP51 can diminish the binding affinity of GR for GCs, impede the movement of GR into the nucleus, and lead to the downregulation of GR-targeted gene expression (Denny et al., 2000). Therefore, the upregulation of FKBP51 activity contributes to elevated GC levels, abnormal HPA stress responses, and GC resistance, which are linked to the development of stress-related neurological and psychiatric disorders (Binder et al., 2004; Zgajnar et al., 2019; Malekpour et al., 2023).

Glucocorticoid receptor and histone deacetylase-1/2

The dynamic regulation of histone acetylation and deacetylation under stress is vital for learning and memory processes. The blocking of histone deacetylases (HDACs) has been demonstrated to ameliorate memory deficits in animals that present neurodegenerative disorders (Morris et al., 2013). HDAC1 and HDAC2 belong to class I HDACs and often coexist in multiprotein nuclear complexes (Yang and Seto, 2008). The HDAC1/2 contained in coregulator complexes are involved in activating GR-mediated gene transcription by interacting with GR (Qiu et al., 2006; Luo et al., 2009). Within a rodent neural cell lineage, GR was demonstrated to form inhibitory complexes with HDAC1 and methyl CPG-binding protein 2 at the CRH promoter to modulate the HPA axis’s reaction to stress (Sharma et al., 2013). HDAC2 colocalizes with GR in the neurons of the mouse hippocampus and cortex (Wu et al., 2021). A previous study has revealed that, in the prefrontal cortex of repeatedly stressed rats, activated GR binds to the GRE of HDAC2 promoter, which in turn causes an upregulation of HDAC2 expression (Wei et al., 2016). Inhibition or knock-down of HDAC2 prevents the stress-triggered reduction of glutamatergic transmission, an decrease in AMPA receptor expression, and the deterioration of recognition memory (Wei et al., 2016). Upregulation of HDAC2 levels in hippocampal neurons is also likely to be related to the cognitive impairment induced by chronic stress (Wu et al., 2021). Furthermore, chronic stress inhibits the phosphorylation of the phosphatidylinositol-3-kinase/Akt signaling pathway modulated by GR, and HDAC2 reduction reverses the effect (Wu et al., 2021).

Glucocorticoid receptor and Bcl-2-associated athanogene 1

Bcl-2-associated athanogene 1 (BAG-1) functions as a co-chaperone that is associated with GR and influences its trafficking and function (Cato and Mink, 2001). In cortical neuron cultures, the interaction between GR and BAG-1 could be controlled through variations in the dosage and duration of CORT exposure (Luo et al., 2021). BAG-1 adjusts the GR complex’s structure through competitive binding with other chaperones and lowers GR activity by hindering its nuclear entry and impeding its transcriptional capacity (Schmidt et al., 2003; Zhou et al., 2005; Grad and Picard, 2007). BAG-1 is crucial for GR transport to mitochondria. A study showed that, in rat cortical neurons, CORT applied for a short duration markedly boosted the assembly of the BAG-1/GR complex and the localization of GR at mitochondria. However, CORT exposure for 3 days resulted in reduced levels of mitochondrial GR and diminished the formation of the BAG-1/GR complex (Luo et al., 2021). Impaired GR levels in the mitochondria and the depression-like behaviors induced by chronic CORT treatment were rescued by BAG-1 overexpression (Luo et al., 2021).

Glucocorticoid receptor and cyclic guanosine monophosphate

Cyclic guanosine monophosphate (cGMP), an intracellular cyclic nucleotide that acts as a second messenger, is essential for the governance of cognitive activities such as memory and learning (Yanai and Endo, 2019). cGMP plays a crucial role in the AMPA and NMDA receptor signaling pathways, promoting synaptic plasticity and memory formation (Giesen et al., 2022). GR, which is associated with the regulation of the glutamatergic system, may interact with cGMP, although the nature of this interaction requires further elucidation. GCs have been shown to activate MR, leading to the upregulation of neuronal nitric oxide synthase in hippocampal neurons. The nitric oxide derived from neuronal nitric oxide synthase results in the downregulation of GR expression through both cGMP-dependent and -independent pathways (Zhou et al., 2011). This alteration results in the hyperactivation of the HPA axis, which is involved in the modulation of stress-related depressive behaviors (Zhou et al., 2011).

Glucocorticoid Receptor in Neurocognitive Disorders

As mentioned earlier, under adaptive circumstances, the secretion of GCs and activation of GRs favor cognitive activities such as memory consolidation and storage, while high levels of stress and/or GCs may lead to cognitive deficits. There is a causal relationship between enduring stress, heightened GC concentrations, and the emergence of the cognitive and emotional disturbances found in aging, depression, AD, and other neurological diseases (Aguilera, 2011; Vyas et al., 2016; Canet et al., 2018). High GC levels and cognitive impairments in these patients are closely associated with the dysregulation of HPA and GR, as not only does GR regulate the HPA axis via negative feedback but its signals also control numerous brain functions pertinent to memory and cognition. GR therefore appears to play a vital role in the development of these neurocognitive disorders.

Glucocorticoid receptor in Alzheimer’s disease

AD, recognized as the leading cause of dementia globally, is marked by impairments in an individual’s capacity to form and retain new memories, followed by a gradual deterioration in cognitive abilities along with behavioral and emotional alterations (Soria Lopez et al., 2019; Wang et al., 2024). The primary pathological indicators of AD encompass the accumulation of amyloid-beta plaques, the formation of neurofibrillary tangles, and the occurrence of synaptic dysfunction or degeneration, as well as overall neuronal loss (Jack et al., 2018; Zhang and Yan, 2023). An increasing body of research indicates that prolonged stress or stress-associated conditions may heighten the risk or accelerate the progression of AD (Canet et al., 2018; Wallensten et al., 2023). Disruption to the HPA axis is an early feature of AD, characterized by increased levels of circulating GCs and deficits in GR signaling, which result in aggravated neuropathology and accelerated cognitive deficits (Csernansky et al., 2006; Green et al., 2006). The DNA-binding sites of GR, GREs, are present in the promoters of amyloid precursor protein (APP) and β-site APP cleavage enzyme 1 (BACE), making it likely that GCs regulate transcription of the APP and BACE genes and thereby affect the production of amyloid-beta (Green et al., 2006). The dysregulation of the HPA axis in AD could diminish the negative feedback control of GC levels. The increase in circulating GCs is likely to potentiate pathology, leading to a positive-feedback loop through which pathology increases GC levels, which in turn fuel further pathological progression (Green et al., 2006; Pineau et al., 2016). Research indicates that disruption of the feedback suppression mechanism within the HPA axis is closely related to GR dysfunction, as specific GR regulators can reverse the buildup of amyloid-beta, restore standard GC levels, and ameliorate cognitive performance (Pineau et al., 2016; Canet et al., 2020). The functional GR density is believed to underlie the cognitive reserve in the brain, affecting the onset of AD (Notarianni, 2013). Disruption of GR phosphorylation (S134A/S267A) at BDNF-dependent sites (serines 134/267) in double-transgenic AD model mice expressing APP and mutated human presenilin 1 (APP/PS1) was reported to exacerbate the detrimental effects of this genotype on mortality, neuroplasticity, and cognition (Dromard et al., 2022). The early downregulation of GR was found in various hippocampal subregions of transgenic hAPPswe-ind mice overexpressing mutant human APP with the Swedish and Indiana familial AD mutations, which is consistent with the commencement of memory deterioration. This reduction was more pronounced in older mice with elevated GC levels in their plasma (Escribano et al., 2009). The normalization of GR levels may have beneficial effects on cognition by restoring physiological control of the HPA axis (Escribano et al., 2009).

Glucocorticoid receptor in aging

Aging is a degenerative physiological process influenced by genetic and environmental factors that leads to degraded cognitive function and increased susceptibility to age-related pathologies (Yang and Huang, 2022; Khademi et al., 2024). Aging is widely recognized as a major factor in the development of neurodegenerative disorders such as AD, HD, and PD (Gonzalez-Cano et al., 2024). It has been reported that aging affects the daily secretion of GC and the adrenal response to stress (Piazza et al., 2010). The HPA axis becomes overactive and plasma GC levels are highly variable during aging in animals and humans, leading to a loss of circadian rhythmicity (Aguilera, 2011). The hippocampus, which is highly susceptible to increased GCs, exhibits functional and structural changes. Abnormalities in hippocampal synaptic plasticity during aging have been observed, such as alterations in calcium homeostasis and kinase activity, as well as retrograde messenger activity during the early phases of LTP and the dysfunction of gene transcription during the later phases (Mullany and Lynch, 1997; Davis et al., 2000; Eckles-Smith et al., 2000). Aged humans with prolonged cortisol elevation show a notable decrease in hippocampal volume and impairments in learning and memory processes. Furthermore, there is a positive correlation between the extent of hippocampal atrophy and degree of GC elevation (Lupien et al., 1998; Hibberd et al., 2000). Excessive activity of the HPA axis during aging is intricately connected to the GR downregulation that accounts for a loss of HPA axis sensitivity to feedback inhibition, leading to further elevations in plasma GC and exacerbating the destructive process (Sapolsky et al., 1986; Seeman and Robbins, 1994). Age-related cognitive deficits are consistent with the impairments observed with GR deficiency (Oitzl et al., 1997). Studies have demonstrated that GR mRNA levels significantly diminish with age, particularly in the CA1 and CA3 regions of the hippocampus in the human brain, as determined by in situ hybridization (Tohgi et al., 1995). Compared with older rats with intact cognitive function, aged rats with memory deficits were found to have a more significant loss of GRs in the hippocampus (Issa et al., 1990). In aging rats, there have been documented observations of lessened ligand binding to GR, lowered GR nuclear translocation efficiency, and a weakening of GR’s DNA-binding capability within the hippocampus (Murphy et al., 2002; Mizoguchi et al., 2009; Lee et al., 2012). Moreover, GCs modulate the activity of 11β-HSD1 through GR (Low et al., 1994; Seckl, 2024). Studies have shown that levels of 11β-HSD1, crucial for controlling tissue levels of GCs, exhibit variable degrees of elevation in the hippocampus and cortex of aging rodents and humans (Holmes et al., 2010; Bini et al., 2020). Most notably, an intriguing inverse correlation was observed between hippocampal levels of 11β-HSD1 and cognitive performance in aged mice (Yau et al., 2001). Thus, the disruption of hippocampal GR signaling and related factors is the main cause of age-related HPA axis dysregulation and cognitive deterioration.

Glucocorticoid receptor in depression

Depression as a prevalent mental disorder that frequently accompanies cognitive decline (Otte et al., 2016). Stressful life events have been identified as high-risk factors for triggering depression. HPA axis dysfunction plays a significant role in the negative effects of life stress on brain structure and cognitive function, suggesting there is a relationship between stressful life events and the onset of depression (Ding and Dai, 2019). Clinical research has shown that many individuals with major depressive disorder exhibit heightened activity in the HPA axis, often characterized by elevated cortisol levels in their blood plasma (Zobel et al., 1999; Holsboer, 2000). HPA axis dysregulation in chronic or traumatic stress results in the increased or sustained release of GCs and a subsequent reduction in GC-mediated GR expression. These effects negatively impact a wide range of brain activities, such as neurogenesis, synaptic plasticity, hippocampal volume, memory and learning capabilities, emotional appraisal of events, and peripheral functions such as metabolism and immune system regulation (Murray et al., 2008; Pariante and Lightman, 2008; Teicher et al., 2012). Research in animal models and examinations of post-mortem brain tissue of individuals with mood disorders have consistently shown a decrease in GR levels within the limbic system (McGowan et al., 2009; Chiba et al., 2012). Reduced GR levels or dysfunctional GR is believed to contribute to the disruption of GC feedback mechanisms, which could account for the heightened HPA axis activity observed in individuals with depression. Research showed that GR-heterozygous mutant mice (GR^+/–) exhibited a depression-like phenotype and a disinhibited HPA axis, whereas GR-overexpressing mice had resistance to helpless behavior and improved HPA system feedback regulation (Ridder et al., 2005). Moreover, compromised GR signaling was evidenced to downregulate BDNF expression and interfere with its function (Ridder et al., 2005; Chiba et al., 2012), suggesting a link between GR and the neurotrophins underlying the pathogenesis of depressive disorders. Stress-induced GR downregulation also negatively affects the hippocampal neurogenesis associated with cognition and mood (Kim et al., 2024). Considering that impaired GR signaling is critical to the development of depression, the normalization of GR function after antidepressant treatment is an important predictor of long-term clinical outcomes (Pariante and Lightman, 2008).

Glucocorticoid receptor in Huntington’s disease

HD, a hereditary neurodegenerative disorder, is predominantly due to an elongated CAG repeat within the huntingtin (HTT) gene that leads to motor, cognitive, and psychiatric disturbances (Giralt et al., 2012; Petersén and Gabery, 2012). A spectrum of non-motor symptoms, encompassing psychological and cognitive alterations, is acknowledged to emerge in the early phases of HD (Duff et al., 2007; Petersén and Gabery, 2012). Stress is a significant non-genetic influence on the progression of HD. Disruptions in GC feedback regulation have been observed in HD patients as well as in genetically modified mouse models, suggesting that HPA axis dysregulation is a prominent early characteristic of the disease (Björkqvist et al., 2006; Aziz et al., 2009; Petersén and Gabery, 2012). The dysregulation of the HPA axis and the consequent increase in cortisol levels observed in HD appear to stem from compromised GR function (Aziz et al., 2009). R6/1 HD mice, which carry a fragment of exon 1 that expresses the mutated human HTT, showed heightened vulnerability to stress, which included a detrimental effect on cognitive function (Mo et al., 2013). A severe stressor throughout adulthood has been linked to various behavioral manifestations in R6/1 mice, including attenuated body weight gain, a deterioration in motor skills, cognitive decline characterized by memory loss, and a diminished capacity for experiencing pleasure (anhedonia) (Mo et al., 2014). GR has been found to influence the nuclear localization and aggregation of truncated mutant HTT, which is associated with HD pathogenesis. Consequently, impairments to GR function could worsen the pathological features of HD (Diamond et al., 2000). Post-mortem examinations of brains from HD patients have demonstrated a reduction in both the mRNA and protein levels of BDNF and its receptor TrkB (Ferrer et al., 2000; Ginés et al., 2006; Pandya et al., 2014). Certain drugs developed to treat HD have shown therapeutic benefits in animal models of the condition and act by upregulating the expression of BDNF, GR, and Akt/phosphatidylinositol-3-kinase pathways, which are recognized to foster neuronal plasticity and survival (Geva et al., 2016).

Glucocorticoid receptor in Parkinson’s disease

PD, ranking as the second most common cause of neurodegeneration, is marked by the accumulation of intracellular Lewy bodies primarily made up of misfolded α-synuclein. This results in the progressive loss of dopaminergic neurons, particularly in the substantia nigra pars compacta region (de Lau and Breteler, 2006; Davie, 2008). Cognitive impairment is a common non-motor symptom in PD (Iravani and Shoaib, 2024), and dopamine deficiency is believed to significantly contribute to the development of this cognitive decline (Iravani and Shoaib, 2024). The dorsolateral dopamine neurons in the substantia nigra pars compacta have been demonstrated to participate in cognitive processes, particularly those demanding the engagement of working memory (Matsumoto and Takada, 2013). Synaptic dysfunction is also known to occur in early PD (Phan et al., 2017). Furthermore, the aggregation of α-synuclein in the hippocampus impacts the synaptic transmission mediated by AMPA and NMDA receptors, as well as LTP, processes that underlie the fundamental neurophysiological mechanisms that support learning and memory (Diógenes et al., 2012). Similar to AD and HD, PD patients also exhibit disruptions in the HPA axis. Research has indicated that individuals with idiopathic PD tend to have significantly higher plasma cortisol levels, surpassing those found in healthy individuals (Hartmann et al., 1997; Charlett et al., 1998; Vyas and Maatouk, 2013). In PD, it is crucial to recognize that the diurnal pattern of cortisol release, especially the normally stationary nocturnal cortisol secretion mode, is disrupted, indicating that the circadian control of HPA in individuals with PD is altered (Hartmann et al., 1997). Stress can exacerbate or initiate the manifestations of PD (Smith et al., 2002). Dexamethasone administration has been observed to upregulate the expression of leucine-rich repeat kinase 2 and α-synuclein, both of which, when mutated, are associated with an increased risk of developing PD (Park et al., 2013). Research on GR in PD has shown there is a reduction in GR expression within the substantia nigra pars compacta (Ros-Bernal et al., 2011). A deficiency of GR due to the expression of antisense RNA in transgenic mice intensifies the harmful effects on dopaminergic neurons caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine which can induce experimental PD models (Morale et al., 2004). Hence, during the initial phase of PD, the interactions between stress-related GC-GR activity and motivational/cognitive-related dopaminergic neuronal circuits determines the progression of the disorder (Vyas et al., 2016).

Glucocorticoid receptor in stroke

Globally, stroke ranks as the second most frequent cause of mortality and is marked by the abrupt onset of neurological impairments. The disease commonly arises from various cerebrovascular etiologies (Hilkens et al., 2024). Cognitive impairment is a primary consequence of stroke, encompassing deficits in memory, attention, information processing, and executive functioning. These impairments often lead to diminished living standards and a heightened risk of dementia (Patel et al., 2002). The engagement of the HPA axis and subsequent GC signaling significantly influence the severity of neuronal damage, the degree of functional impairment, and the trajectory of recovery in stroke patients (Feibel et al., 1977). Additionally, stress and high levels of GCs are linked to increased morbidity and a poor prognosis for stroke patients (Feibel et al., 1977; Harmsen et al., 1990). Research indicated that mice subjected to chronic stress exhibited significantly larger ischemic lesion volumes following middle cerebral artery occlusion. However, this effect was attenuated through GR antagonists, implying that GC signaling was at least partially responsible for the observed enlargement of lesions (Balkaya et al., 2011). Furthermore, the absence of GR has been proven to induce an enhanced pro-inflammatory response and curtail BDNF/TrkB signaling in the mouse brain, resulting in an increase in infarct volume and exacerbating the neurobehavioral deficits caused by middle cerebral artery occlusion (Li et al., 2018). These data provide novel perspectives on the feasibility of targeting GR in potential therapeutic strategies for addressing clinical stroke.

Glucocorticoid receptor in addiction

Drug addiction, a persistent and recurrent neurological condition, is distinguished by an uncontrollable urge to pursue drugs and a lack of capacity to restrain drug consumption (Hyman et al., 2006). The process of addiction formation involves the direct impact of a drug’s chemical composition on the brain, which leads to notable alterations in neural structure and functionality, in turn fostering behavior such as the ongoing pursuit and intake of drugs, and concluding in the establishment of addictive behaviors (Hyman et al., 2006). A large amount of research has indicated that various cognitive functions are significantly impaired in drug users, e.g., situational memory, attention, working memory, and reward-based decision-making (Baldacchino et al., 2012; Potvin et al., 2014; Biernacki et al., 2016; Leung et al., 2017). Stress, along with altered HPA axis responses, contributes to the development of addiction (Sinha, 2001). The selective suppression of GR in the mouse brain was found to result in a marked decrease in voluntary cocaine consumption and the inhibition of cocaine-induced behavioral and molecular sensitization. Furthermore, the GR antagonist mifepristone can effectively reduce the drive for cocaine self-administration (Deroche-Gamonet et al., 2003). Interestingly, selectively removing GR from neurons expressing dopamine receptor 1a was reported to alleviate cocaine-seeking behavior (Ambroggi et al., 2009). These results highlight the significant function of GR in both the development and maintenance of cocaine addiction. A rat model of alcohol addiction was found to have observable disruptions in the HPA axis and variations in GC concentrations (Richardson et al., 2008). In rats with a dependency on alcohol, a reduction in GR mRNA levels was observed in brain regions associated with stress and reward during acute withdrawal. Conversely, during extended periods of alcohol abstinence, there is an increase in GR expression (Vendruscolo et al., 2012). The GR antagonist mifepristone, when given either throughout the body or specifically to the central amygdala (a key brain region associated with stress), not only prevented the development of compulsive-like drinking but also significantly reduced alcohol self-administration in alcohol-dependent rats (Vendruscolo et al., 2015). In alignment with these findings, the oral administration of the GR blocker mifepristone has been observed to reduce alcohol cravings in humans (Vendruscolo et al., 2015). Notably, injections of mifepristone into the amygdala have been shown to elevate GR Ser232 phosphorylation, a sign of GR nuclear translocation and transactivation, in alcohol-dependent rats, indicating that GR signaling in the amygdala plays a pivotal role in alcohol consumption and seeking behaviors (Vendruscolo et al., 2015).

Glucocorticoid receptor in neuroinflammation

Mounting research is underscoring the pivotal role of neuroinflammation in a spectrum of neurological conditions, such as AD, depression, HD, PD, and addiction, among others (Alam et al., 2016; Vandenbark et al., 2019; Kraeuter et al., 2020). A symptom prevalent across these conditions is cognitive impairment. Strikingly, these disorders exhibit the elevated generation and/or concentrations of peripheral and central inflammatory factors (Vyas et al., 2016). GR is instrumental in modulating neuroinflammatory responses and cognitive performance (Vandewalle et al., 2018; de Quervain et al., 2019). The anti-inflammatory and immunosuppressive properties of GCs are mediated through GR activation (De Nicola et al., 2020). However, under certain conditions, the typically anti-inflammatory actions of GCs can paradoxically shift to promote inflammatory processes (Munhoz et al., 2006; Cruz-Topete and Cidlowski, 2015; Duque Ede and Munhoz, 2016). GC-induced pro-inflammatory states are underpinned by pathological contexts that includes stress, neuroinflammation, neurodegeneration, and excitability (Duque Ede and Munhoz, 2016). Elevated GC levels, resulting from an overactive HPA axis and disrupted GR function, can cause adverse outcomes in the hippocampus by promoting inflammation (Munhoz et al., 2006; Sorrells et al., 2014; Kim et al., 2016). Pro-inflammatory cytokines and their associated signaling mechanisms, including p38 MAPK, nuclear factor-κB, and signal transducer and activator of transcription 5, may hinder the function of GRs, which influences HPA regulation (McKay and Cidlowski, 1999; Biola et al., 2001; Wang et al., 2004). A vicious cycle of neuronal inflammation and GR damage is facilitated by the pro-inflammatory and neurodegenerative effects of chronic GCs (Kim et al., 2016). Studies have shown that GR antagonists attenuate the progression of neuroinflammatory, excitatory, and apoptotic signaling pathways by interfering with GR inactivation (Meyer et al., 2018, 2020). In the Wobbler mouse model, which exhibits persistent inflammation with hypercortisolemia, treatment with a GR antagonist produced anti-inflammatory and anti-apoptotic effects, reestablished glutamatergic homeostasis, and reduced spinal motor neuron degeneration (Meyer et al., 2018).

Conclusion

The interplay between the HPA axis and cognitive function is a testament to the complexity of the brain’s response to stress. The GR, as a key node in this dynamic, holds a significant role in both the adaptive and maladaptive outcomes of stress on cognitive processes. The evidence presented in this review underscores the importance of GR signaling in the modulation of neurotransmission, synaptic plasticity, and neuroprotection, which are fundamental to learning, memory, and overall cognitive performance. Dysregulation of GR signaling, often observed in conditions such as AD, depression, PD, and addiction, contributes to the cognitive deficits associated with these disorders.

The findings discussed in this review point toward the potential of using GR-targeted therapies in the treatment and management of cognitive impairments. However, a nuanced understanding of the diverse and sometimes opposing effects of GR activation is necessary to harness its therapeutic potential without disrupting the essential functions of the HPA axis. It should be noted that GR signaling involves multiple pathways and interactions that may not be fully addressed in this review. For instance, the complex balance between the genomic and non-genomic effects of GR in different cell types and its impact on cognitive function is a sophisticated subject that may require more in-depth research. Considering GR’s extensive association with various cognitive disorder diseases, this review may not cover all related conditions. While this review touches upon the therapeutic potential of targeting GR signaling and discusses the role of GR modulators, further explorations with a separate focus may be necessary to delve into the details of how these findings could be applied in clinical settings and the challenges related to such applications.

In conclusion, GR stands as a critical modulator of cognitive function, with its signaling pathways offering promising avenues for intervention in stress-related neurocognitive disorders. Future research should continue to unravel the complex mechanisms of GR action in the brain to develop targeted and effective treatments that can restore cognitive function and improve quality of life for affected individuals.

Funding Statement

Funding: This work was supported by the National Natural Science Foundation of China, No. 82371444 (to YZ); the Natural Science Foundation of Hubei Province, No. 2022CFB216 (to XC); the Key Research Project of Ministry of Science and Technology of China, No. 2022ZD021160 (to YZ).

Data availability statement:

Not applicable.