Stress, glucocorticoid receptors, and adult neurogenesis: a balance between excitation and inhibition?
- 3.5k Downloads
Adult neurogenesis, the birth of new neurons in the mature brain, has attracted considerable attention in the last decade. One of the earliest identified and most profound factors that affect adult neurogenesis both positively and negatively is stress. Here, we review the complex interplay between stress and adult neurogenesis. In particular, we review the role of the glucocorticoid receptor, the main mediator of the stress response in the proliferation, differentiation, migration, and functional integration of newborn neurons in the hippocampus. We review a multitude of mechanisms regulating glucocorticoid receptor activity in relationship to adult neurogenesis. We postulate a novel concept in which the level of glucocorticoid receptor expression directly regulates the excitation-inhibition balance, which is key for proper neurogenesis. We furthermore argue that an excitation-inhibition dis-balance may underlie aberrant functional integration of newborn neurons that is associated with psychiatric and paroxysmal brain disorders.
KeywordsHippocampus Post-mitotic maturation Depression Neural stem cell Dentate gyrus MicroRNA DCX Glutamate
“In the adult centres, the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated.” These words from Ramon y Cajal in 1913  highlight what has been one of the central dogma’s in neuroscience for a long time: the birth of new neurons, i.e., neurogenesis, was restricted to prenatal and early postnatal development and that the adult mammalian brain was unable to produce new neurons. However, in the 1960s, Joseph Altman and colleagues showed first evidence for adult neurogenesis in the brain of rodents [2, 3, 4]. Although these data were received with skepticism by the scientific community, results were reproduced and revealed the neuronal phenotype derived from dividing cells in the hippocampus .
In the 1990s, pioneering studies by Weiss and colleagues identified stem cell-like cells from the adult brain that were able to differentiate into neurons and astrocytes . Important for the acceptance of the concept of adult neurogenesis has been the development of novel techniques and scientific methods. Cell division for example, can be marked using bromodeoxyuridine (BrdU) or [3H]thymidine. These molecules label and incorporate into DNA of dividing cells and can be visualized with electron and confocal microscopy . By varying the paradigm and the examination time points after injection, these techniques allow quantitative analysis of proliferation, differentiation, and survival. During the last decades, it also became clear that developing neurons express distinct markers during their maturation process . BrdU-labeled DNA in combination with immuno-histochemical analysis of the expression of these specific neuronal markers by confocal microscopy unambiguously revealed the existence of neurogenesis in the adult brain . For example, for immature newborn neurons, doublecortin (DCX) is regularly used, while for mature neurons the specific adult neuronal marker of nuclei NeuN is mostly used [10, 11, 12]. Analysis of adult born neurons can also be performed using retroviral genetic marking, since retroviruses exclusively enter the target cell during mitosis . Adult neurogenesis has been shown in the brain of different species of rodents [14, 15], primates , and even humans [17, 18]. Newborn neurons have been observed to integrate into neuronal hippocampal circuits and have been functionally associated with complex brain processes like cognition, emotion, and pattern separation.
The discovery of environmental factors regulating adult neurogenesis in a bi-directional manner has been of key importance for the acceptance of the concept . In particular, the finding that stress and adrenal steroid hormones down-regulate adult neurogenesis [14, 20] contributed significantly. As aberrant forms of stress and chronic elevation of adrenal hormones are also linked to the psychopathology of depression, possible involvement of adult neurogenesis in psychiatric diseases has been a topic of intense research. Nowadays, changing rates of adult neurogenesis have been linked to aging, environment, hormones, neurochemicals, and behavior as well as to numerous brain diseases ranging from depression to epilepsy.
Overthrowing a dogma always attracts attention. Therefore, an impressive number of papers have appeared in the last decade and as a consequence, numerous reviews have been published covering specific topics of adult neurogenesis such as general mechanisms and signaling cascades [13, 21], cognition and memory formation [22, 23, 24], evolution , olfaction  psychiatric diseases , paroxysmal disorders such as epilepsy [28, 29], and neurodegenerative disorders . Also, the concept of stress and its effect on adult neurogenesis have been reviewed extensively [31, 32, 33, 34, 35]. Therefore, we will only briefly review the general aspects of the stress system and the interplay between stress and adult neurogenesis in the hippocampus. More extensively, we will highlight novel findings on the function of the glucocorticoid receptor, the main mediator of the stress response, in neuronal progenitor cells and in adult neurogenesis. We will present a novel concept about the role of the glucocorticoid receptor in the positioning and functional integration of newborn neurons and we discuss how this concept may contribute to the chronification of paroxysmal brain diseases.
Neurogenesis in the adult hippocampus
The DG area consists of three layers: the molecular layer (ML), the granule cell layer (GCL), and the hilus or polymorphic layer (PL; see Fig. 1b). The GCL is densely packed and consists of a stack of roughly six granule cell bodies [2, 3, 37]. These cells have an elliptical cell body of about 10–18 μm, are tightly packed, and are not ensheathed by glia cells. Granule cells have a cone-shaped dendritic tree that projects into the ML. At the other site of the cell body, granule cells give rise to unmyelinated axons called mossy fibers. These fibers have large boutons, which not only connect to pyramidal cells of the CA3 but also contact mossy cells in the hilus [2, 3, 38]. The border between GCL and hilus is called the subgranular zone (SGZ) and inhabits neural stem cells (NSCs), which are the source of adult neurogenesis and generate excitatory granule cells [5, 36].
Neurogenesis in the adult DG can be divided into three main stages (see Fig. 1b) [7, 36]. The first stage is called the precursor cell stage and is characterized by cell division [6, 39]. The primary NSC in the DG is a radial glia (RG)-like astrocyte called the type 1 cell [9, 36]. Like RGs, these NSCs have long processes that project into the ML. The second phase is called the early postmitotic phase and is characterized by neuronal differentiation and migration of neuroblasts/immature neurons. Under the influence of GABA, they start to develop dendrites and axons towards, respectively, the ML and CA3 regions. At this stage, the dendrites lack any spines but receive functional GABAergic input [13, 21, 40]. Initially, GABA has an excitatory effect, which induces dendritic growth. When this excitatory signaling is blocked, immature neurons develop abnormally [22, 23, 24, 41].
The immature neurons/neuroblasts migrate radially into the DG. Doublecortin, a gene that is causally involved in migration of neuronal precursor cells and neuroblasts , is a major marker in this process (see Fig. 1b). The majority of newborn cells end up in the inner third layer of the DG, while 10–20 % reach the mid third layer and only a few cells ends up in the outer third layer [37, 40]. This non-proportional distribution may be explained by the fact that the majority of GCs, which inhabit the middle and outer third layers, are born during early postnatal development while the inner third layer is generated later during development .
The third stage is called the late postmitotic maturation stage, wherein surviving cells integrate into the local DG network and further mature into genuine granule cells [40, 44, 45, 46]. Although newborn cells lose the expression of immature markers around 4–5 weeks after cell birth, full maturity is reached around 60 days after cell birth . After the first weeks, newborn neurons continue to extend their dendritic and axonal processes and many new connections are formed with glutamatergic synapses from the EC and output to pyramidal cells in the CA3. Not only newborn GCs increase and reshape their synaptic connectivity. Due to their interaction with newborn GCs, mature GCs also change their connectivity. Spines from newborns’ GCs compete at entorhinal boutons with old synapses from mature GCs and—possibly due to local glutamate spillover at the synapse—will replace the old synaptic connection [47, 48, 49]. This pattern of competitive synaptic plasticity in the molecular layer also seems to be present in the hilus and CA3 region at the axonal end of newborn neurons. Although boutons actively connect to synapses already 17 days after cell division, the connections are fully mature 2 months post-cell division [47, 50].
The stress system, glucocorticoids, and glucocorticoid receptors
Stress is the response of an organism aiming to maintain a physiological balance called homeostasis. When homeostasis is challenged by a stressor, the organism responds by behavioral and physiological adaptations, resulting in coping and recovery. A stressor can be an environmental challenge, e.g., taking a test, or a physical challenge, e.g., a viral infection. Whatever the nature of the stressor, the body reacts in a stereotypical way . Firstly, neurohormones, in particular corticotropin-releasing hormone (CRH), are released in the hypothalamus that subsequently project to the pituitary . Secondly, activation of CRH receptor expressing neuro-endocrine cells in the pituitary leads to the subsequent release of adrenocorticotropic hormone (ACTH) into the blood circulation, which activates endocrine cells in the adrenal cortex. Thirdly, ACTH stimulates the release of adrenal glucocorticoid hormones, also called stress hormones, which are cortisol in man and corticosterone in rodents, here collectively referred to as CORT. This adrenal steroid hormone affects many organs in the body: it causes release of glucose in the blood circulation, it acts as a repressor of the immune system, and in the brain it facilitates information processing in limbic neuronal networks involved in emotion, cognition, and memory formation [for a review, see 31, 32]. CORT also functions as a feedback mechanism to the same brain structures in the hypothalamus that triggered its release, thereby stabilizing the hypothalamus–pituitary–adrenal (HPA) axis and preventing sensitive organs in the body from CORT overexposure. HPA axis activity is organized in a circadian rhythm with high levels in the morning, enabling individuals to cope with energy demands ahead of them. It is important to note that rapid HPA axis activation by acute stress and the subsequent turn-off of the HPA axis by the negative feedback response of CORT is healthy, as it helps an individual to cope with the stressor. However, dysregulation of the HPA axis by e.g., chronic stress may endanger the immune system, cardiovascular functions, the regulation of fear, cognition, and memory formation, and as such is associated with numerous diseases, in the brain in particularly with depression [33, 53].
Lipophilic CORT passes the blood–brain barrier easily and enters neuronal target cells by penetrating across the cell membrane. At the neuronal level, CORT controls the stress response through binding to two types of steroid receptors in the cytosol: the mineralocorticoid receptor (MR or NR3C2; ) and the glucocorticoid receptor (GR or NR3C1; [55, 56, 57]). These steroid receptors belong to a superfamily of ligand-inducible, highly conserved nuclear hormone receptors. Upon binding CORT, GR and MR translocate to the nucleus where they affect expression of specific sets of genes in two ways: (1) by binding to specific so-called glucocorticoid-response element DNA motifs located in promoter regions of target genes; a process called transactivation and (2) by protein–protein interaction with other transcription factors and co-factors, such as cAMP-response element binding (CREB) protein and CREB binding protein (CBP), thereby mainly inhibiting the activation of these transcription factors and as such is called transrepression (for review, see ). In addition, CORT evokes fast non-genomic neuronal responses by binding to membrane-bound GR and MR . As these membrane-bound receptors have not yet been identified in NPCs, they are outside the scope of this review.
The hippocampus, a brain area crucially involved in cognition and memory formation, expresses both MR and GR at high levels, and is therefore particularly sensitive for fluctuating levels of CORT. Moreover, as neuronal stem cells in the dentate gyrus of the hippocampus are located in the close vicinity of blood vessels , stress and stress-induced elevated CORT levels may target NPCs easily and may be very profound (environmental) factors affecting adult hippocampal neurogenesis.
The glucocorticoid receptor and adult neurogenesis
Besides serotonergic signaling, controllable versus non-controllable stress and acute versus chronic stress may also affect other transmitter systems. Relevant for adult neurogenesis particularly is the interaction with glutamatergic signaling, e.g., acute cortisol exposure may facilitate clustering of AMPA receptors , thereby facilitating the pro-plasticity activities of glutamate in the early and post-mitotic maturation phase. Another important group that interacts with stress and stress hormones is neurotrophins, like BDNF, VEGF, and IGF-1 and their Trks. Expression of these neurotrophins is not only regulated by stress and circulating stress hormones (see e.g., ) but also by an enriched environment, chronic stress, and by learning, and may be differentially regulated by controllable versus non-controllable stress . The interplay between the stress system on the one hand and neurotrophins and excitatory stimuli on the other may direct the outcome on the proliferation, maturation, and functional integration of newborn cells in the DG. The nature of the stress, e.g., acute versus chronic, and the background of an organism—aging, traumatic early life events, environmental enrichment—further determine the outcome on adult neurogenesis. For more in-depth reviews on this topic, we refer to recent excellent papers highlighting the complex interplay between stress, stress hormones, and adult neurogenesis [27, 34, 39, 88, 89, 90].
The glucocorticoid receptor
Corticosterone has profound effects on the excitation-inhibition balance within the hippocampus. This effect is not identical in all hippocampal sub areas. In both CA1 and CA3, high concentrations of corticosterone enhance LTP via short-term MR activation. After this acute effect, GR-mediated inhibition of the LTP normalizes the excitation-inhibition balance in these brain areas. However, within the dentate gyrus, the effect of corticosterone on the excitation-inhibition balance seems reversed. Despite the abundant expression of the GR within the DG, high concentrations of corticosterone do not suppress LTP in the long run but, in contrast to the CA1 and CA3, enhance LTP .
The MR and the GR are the main intracellular mediators of the stress response (for review, see [31, 32, 33]). In the DG, both receptors are abundantly expressed in all GCLs except in the SGZ. In neuronal precursor cells, MR expression is below detection levels and the GR is expressed in about 50 % of neuronal precursor cells, both in vivo [65, 92] as well as in primary neuronal precursor cell cultures . These data suggest that the GR (and not the MR) is the main mediator of direct stress-suppressive effects on cell proliferation. Indeed, pharmacological blockade of the GR prevents the negative effect of exogenous CORT administration on the proliferation of neuronal progenitor cells . The absence of both MR and GR expression in a subpopulation of neuronal progenitor cells opens up the possibility that the effect of stress hormones is indirect, likely via NMDA receptors. Activation of NMDA receptors inhibits and NMDAR blockade promotes cell proliferation in the dentate gyrus [95, 96, 97]. In addition, stress and CORT are known to stimulate glutamate release [85, 98]. Therefore, it may well be possible that the CORT-suppressive effects are mediated by glutamatergic signaling. Indeed, pharmacological blockade of NMDAR by MK801 prevents the inhibitory effect on cell proliferation by CORT administration , suggesting that glutamate-induced inhibition acts downstream of CORT signaling.
Overview of factors affecting glucocorticoid receptor activity and adult neurogenesis
GR-KO ↓ 
GR-KO ↓ 
miR-124 ↑ 
Ube3a = 
Ube3a ↓ 
Genes with GREs
CALD1 ↓ 
Npas4 ↓ 
GR ↓ 
GR = 
GR ↑ 
GR ↑ 
CORT injection ↓ 
Adrenal ectomy ↑ 
CORT injection ↓ 
CORT injection ↓ 
Adrenal ectomy ↑ 
Maternal care ↑ 
Maternal care ↑ 
Maternal care = 
Maternal deprivation ↓ 
Maternal deprivation ↓ 
Maternal care ↑ 
Maternal deprivation = 
Social housing ↑ 
Isolation ↓ 
Defeat ↑ 
Social housing ↑ 
Defeat ↓ 
Defeat ↓ 
Social avoidance ↑ 
Communal nesting ↑ 
Running ↑ 
Running ↑ 
Stressed = 
Running ↑ 
Running ↑ 
Acute ↑ 
Chronic ↑ 
Chronic ↓ 
Chronic = 
Chronic ↓ 
The altered morphology and mis-positioning of newborn granule cells with reduced GR expression raise the question about the consequences for hippocampal functioning. Contextual fear conditioning, a task that is often used to monitor functional consequences of altered adult neurogenesis [110, 111], showed impairment of contextual but not of cued freezing behavior in mice with reduced GR expression in newborn, 5-week-old granule cells . This behavioral finding is remarkable, as only a limited number of cells, approximately 20,000, are transduced by the lentivirus , which further underscores the importance of adult neurogenesis for proper hippocampal functioning.
The studies outlined above suggest that the level of GR expression is important for adequate adult neurogenesis and should be in a narrow window. Too low expression leads to ectopic integration of newborn granule cells and too high expression may block proliferation and differentiation of NPCs. In line with the importance of a narrow window for GR expression is the finding that a 30 % reduction of GR protein levels results in a 70 % reduction of the expression of glucocorticoid-induced leucine zipper (GILZ), a GR-responsive gene . Indeed, intensive research of the last decades has revealed a myriad of mechanisms all aiming at the regulation of GR activity (see Table 1). Alternative splicing of the GR gene results in at least three different GR isoforms. In addition, alternative translation initiation results in the formation of another eight different GR isoforms. Each of these GR isoforms is expressed in a cell-specific way and control the expression of a unique set of genes [127, 128]. As such, these GR isoforms may contribute to mechanisms underlying cell-specific responses to CORT. GR activity can also be modulated by GR phosphorylation . In human neuronal progenitor cells, GR responsiveness towards CORT also depends on GR phosphorylation by serum- and glucocorticoid-inducible kinase 1 phosphorylation, a target gene for activated GRs . A further complicating factor for the outcome of GR action is the interaction with other proteins, in particular co-activators and co-inhibitors that are expressed in a cell-specific manner in the brain (for review, see ). Relevant for adult neurogenesis is Ube3a, a co-activator of the GR, which is crucially involved in the Angelman syndrome . Lack of Ube3a expression not only leads to impaired cognition and decreased numbers of NeuN/BrdU-positive cells  but may also result in impaired GR signaling . CBP is another important cofactor and integration point, bridging CREB or zif68/egr1 activity with GR signaling [131, 135]. Together with the regulation of GR levels by neurogenesis-related microRNA-124  and the presence of specific retrograde transport mechanisms for the GR in neuronal progenitor cells such as DCL , the different mechanisms outlined above clearly indicate that GR expression and activity are under tight control in neuronal progenitor cells.
An important question that emerges is what type of (environmental) factors regulating adult neurogenesis also affect GR levels in neuronal progenitor cells (see Table 1). Interestingly, early life events, such as maternal separation and parental care, are known to reduce GR levels at adult age by epigenetic programming of the GR promoter [137, 138, 139, 140] and is also associated with impaired adult neurogenesis [141, 142]. Aging is associated with lower rates of hippocampal neurogenesis [143, 144, 145], impaired negative feedback of CORT on the HPA axis, and reduced levels of the GR [146, 147]. Chronic stress is another factor negatively affecting both GR levels and adult neurogenesis [61, 148, 149, 150]. It is unknown whether aging, early life events, and chronic stress directly affect GR levels, thereby impairing proliferation and differentiation of neuronal progenitor cells. It is likely, however, that these effects are indirect, as proliferation, differentiation, migration, and survival depend on neurotrophins and excitatory input, first by GABA input and later in development by glutamatergic input. In other words, different phases of adult neurogenesis require excitatory neuronal activity [for review, see 151]. Chronic stress not only reduces GR levels but also impairs glutamate release via BDNF  and reduces expression of other neurotrophins as well [86, 153]. Thus, it seems likely that environmental factors negatively affecting adult neurogenesis attenuate multiple excitatory and inhibitory signaling cascades through the GR.
The glucocorticoid receptor and the excitation-inhibition balance in neuronal progenitor cells
Proper proliferation and neuronal differentiation of neuronal progenitor cells require excitatory input. As outlined before, in early stages this is excitatory GABA  and later this is glutamate that act on AMPA receptors and NMDA receptors [158, 159]. Another group of molecules that stimulate neurogenesis are neurotrophins, such as BDNF and VEGF, which are induced and released by environmental enrichment and learning, thereby promoting neurogenesis. Neurotrophins bind to tyrosine kinase receptors (Trk), membrane-bound receptors that are necessary for adult neurogenesis . Activated AMPA receptors, NMDA receptors, and Trk receptors are all known to activate an intracellular signaling cascade that results in the activation of transcription factors that subsequently stimulate proliferation of neuronal precursor cells, their differentiation, and functional integration in hippocampal circuits (for review, see ). Examples of such transcription factors are Zif68/egr1  and CREB [163, 164, 165], which are key transcription factors in the development and survival of newborn granule cells. Activated GR may interact with these pathways either by binding directly to these transcription factors and/or by interaction with co-factors such as CBP  (for review, see ). The net result of this GR–CPB–CREB interaction is the decreased CREB activity. The emerging picture in this concept is that CORT and the activated GR dampen excitatory input in neuronal progenitor cells thereby preventing the neurogenesis process from overshoot. Reduction of GR levels, e.g., by miR-124 (see Fig. 5) in NPCs or removal of CORT by adrenalectomy will relief this functional brake on excitatory signaling leading to increased proliferation, differentiation and (aberrant) integration of newborn granule cells in hippocampal circuits. Extrapolation of this model may explain ectopic newborn granule cells in the hilus after seizures, which are characterized by excessive glutamate and neurotrophin release, in particular BDNF. Other paroxysmal disorders like migraine are often also explained by a disturbed excitation-inhibition balance  with high levels of cortical glutamate release, which may reach limbic structures during cortical spreading depression  and increases proliferative activity in the dentate gyrus . Reversely, chronic high levels of CORT and diminished neuronal activity, i.e., diminished glutamate signaling and neurotrophin release—often associated with psychiatric diseases like depression—may lead to reduced proliferation, differentiation and survival of newborn granule cells (see Fig. 4) [27, 34, 89]. However, it is presently unknown if this high CORT-low glutamate signaling will lead to diminished neuronal migration and functional integration of newborn granule cells mainly in the inner layer of the GCL.
During the last decade, tremendous progress has been made in understanding adult neurogenesis. The process of morphological changes of neuronal stem cells leading to mature excitatory granule cells, the synaptic connectivity, functional integration and, to a lesser extent, the functional implications for learning and cognition, has been described in considerable detail. Similarly, many genes that are orchestrating the different stages of adult neurogenesis have been identified and numerous intrinsic and extrinsic factors influencing the rate of proliferation and fate of resulting newborn granule cells have been documented. Strangely, despite the fact that stress and stress hormones were one of the earliest discovered factors that manipulate adult neurogenesis [14, 64], their action on neurogenesis is still not fully understood. Likely, this is due to the complexity of the stress system that is controlled by several brain areas and peripheral tissues, i.e., the HPA axis; to different physiological responses after acute stress versus chronic stress and as outlined above, to the complex control of the GR, the main mediator of the stress response in relation to adult neurogenesis. A number of issues remain to be resolved. For example, which GR isoforms are expressed in neuronal progenitor cells. Perhaps more importantly, can reduced GR levels, as observed after chronic stress, aging, and traumatic early life events, also be found in NPCs? Does epigenetic programming of the GR promoter by early life stress also take place in NPCs? If so, what will be the consequences for adult neurogenesis with respect to the positioning of newborn granule cells?
Both chronic stress, a dysfunctional HPA axis, and aberrant neurogenesis have been implicated in psychiatric diseases [27, 33]. A proper excitation-inhibition balance seems key for the control of both the stress system and adult neurogenesis. Both the MR and GR are important mediators for the stress response and interact with proteins that are activated by neuronal activity. Therefore, the question emerges: are these receptors suitable therapeutic targets for restoring excitation-inhibition balances in not only psychiatric diseases  but also in paroxysmal disorders like epilepsy ? With availability of numerous potent GR and MR antagonists and agonists, which have been developed by the pharmaceutical companies during the last 50 years, and modern genetic technologies like in vivo viral delivery of RNA-interference molecules, these questions can now be addressed.
We would like to thank Dr. Jan van Minnen for a critical evaluation of our manuscript. Erno Vreugdenhil and Dirk-Jan Saaltink were supported by grants from The Netherlands Technology Foundation (STW), the Applied Science Division of the Netherlands Scientific Organization, the Technology Program of the Netherlands Ministry of Economic affairs (LFA6332) and The Center for Medical System Biology, Leiden, The Netherlands.
- 1.Cajal Y, Ramón S (1928) Degeneration and regeneration of the nervous system. Oxford University Press, LondonGoogle Scholar
- 9.Encinas JM, Enikolopov G (2008) Identifying and Quantitating Neural Stem and Progenitor Cells in the Adult Brain. In: Methods in Cell Biology. Elsevier, pp 243–272Google Scholar
- 15.Cameron HA, Woolley CS, McEwen BS, Gould E (1993) Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. NSC 56:337–344Google Scholar
- 36.Kempermann G, Song H, Gage FH (2008) Neurogenesis in the hippocampus. In: Gage FH, Kempermann G, Song H (eds) Adult neurogenesis. Cold Spring Harbor Laboratory Press, New York, pp 159–174Google Scholar
- 64.Cameron HA, Gould E (1994) Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. NSC 61:203–209Google Scholar
- 71.Veena J, Srikumar BN, Raju TR, Shankaranarayana Rao BS (2009) Exposure to enriched environment restores the survival and differentiation of new born cells in the hippocampus and ameliorates depressive symptoms in chronically stressed rats. Neurosci Lett 455:178–182. doi: 10.1016/j.neulet.2009.03.059 PubMedGoogle Scholar
- 78.Maier SF, Watkins LR (1998) Stressor controllability, anxiety, and serotonin. Cogn Ther Res 22:595–613Google Scholar
- 79.Banasr M, Hery M, Printemps R, Daszuta A (2004) Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventricular zone. Neuropsychopharmacology 29:450–460. doi: 10.1038/sj.npp.1300320 PubMedGoogle Scholar
- 86.Schaaf MJ, de Kloet ER, Vreugdenhil E (2000) Corticosterone effects on BDNF expression in the hippocampus. Implications for memory formation. Stress (Amsterdam, Netherlands) 3:201–208Google Scholar
- 98.Abrahám I, Juhasz G, Kékesi KA, Kovács KJ (1998) Corticosterone peak is responsible for stress-induced elevation of glutamate in the hippocampus. Stress (Amsterdam, Netherlands) 2:171–181Google Scholar
- 99.Cameron HA, Tanapat P, Gould E (1998) Adrenal steroids and N-methyl-d-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. NSC 82:349–354Google Scholar
- 111.Kirby ED, Friedman AR, Covarrubias D et al (2011) Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons. Mol Psychiatry 17:10. doi: 10.1038/mp.2011.71
- 124.Sinclair D, Fullerton JM, Webster MJ, Shannon Weickert C (2012) Glucocorticoid receptor 1B and 1C mRNA transcript alterations in schizophrenia and bipolar disorder, and their possible regulation by GR gene variants. PLoS ONE 7:e31720. doi: 10.1371/journal.pone.0031720 PubMedCentralPubMedGoogle Scholar
- 152.Chiba S, Numakawa T, Ninomiya M et al (2012) Chronic restraint stress causes anxiety- and depression-like behaviors, downregulates glucocorticoid receptor expression, and attenuates glutamate release induced by brain-derived neurotrophic factor in the prefrontal cortex. Prog Neuropsychopharmacol Biol Psychiatry 39:112–119. doi: 10.1016/j.pnpbp.2012.05.018 PubMedGoogle Scholar
- 166.Conway-Campbell BL, George CL, Pooley JR et al (2011) The HSP90 molecular chaperone cycle regulates cyclical transcriptional dynamics of the glucocorticoid receptor and its coregulatory molecules CBP/p300 during ultradian ligand treatment. Mol Endocrinol 25:944–954. doi: 10.1210/me.2010-0073 PubMedCentralPubMedGoogle Scholar
Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.