Regulation of adult hippocampal neurogenesis by GR in newborn neurons

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Stress and neurogenesis in the mammalian central nervous system

The stress response in the brain

The body strives to maintain homeostasis, or optimal biological functioning1–3. In order to achieve this, it needs to have systems in place that respond to the ever-changing external and internal events or stimuli that it faces. External events can range from being physical (e.g. injury, heat stroke, starvation), to psychological, such as fear of threat. These psychological events, whether real or imagined, stimulate the stress response. Two of these responses are called the norepinephrine-sympathetic adrenomedullary system (NE-SAM) and the hypothalamic-pituitary-adrenocortical system (HPA). These two systems work together to increase (or redirect) energy resources, particularly critical when an organism is in survival mode (for review4,5).
When the brain perceives a stressor, this triggers the stress response (Figure 1; for review6). The hypothalamus activates the NE-SAM system- releasing epinephrine (adrenaline) and norepinephrine into the blood stream for fast reactions7. These are the immediate physiological changes that occur, such as an increase in heart rate, breathing, and metabolism, and a decrease in digestion and growth. The hypothalamus, also activated by the HPA system, releases, via a portal system, corticotrophin-releasing hormone or factor (CRH/F) and vasopressin onto the anterior pituitary to evoke the release of adrenocorticotropin (ACTH). ACTH then reacts with the adrenal glands to secrete glucocorticoids (i.e. cortisol in humans, corticosterone in rodents; hereafter referred to as cort) into the bloodstream5. These lipophilic hormones can then pass through the blood brain barrier and circulate throughout the brain, indirectly affecting DNA transcription. This cascade of events in the HPA axis can take approximately 20 minutes5, however, the effect on protein synthesis can be persisting8.
Under stress conditions, circadian rhythms are overridden, and corticosterone secretion is at its peak16,17. The effects this asserts can depend on things such as whether the stressor is acute, chronic, predictable, or controllable18. The HPA axis has a negative feedback loop, such that corticosterone can inhibit both the further production of ACTH and the secretion of CRF, all with the goal of stabilizing the response19. However, as many people have experienced, when this system is not balanced, it can lead to more serious conditions, anxiety-related disorders, depression, or even memory impairment20–22.
Whether under basal or stress conditions, corticosterone can indirectly affect transcription through two steroid receptors: the mineralocorticoid receptor (MR), and the glucocorticoid receptor (GR)4,23,24. The MR has a 10-fold higher affinity for binding corticosterone, and thus, is usually fully occupied under basal conditions25. The expression pattern of MRs is more dense in the hippocampus4,23, an area of the brain highly relevant for stress and memory26. When conditions are more stressful and thus corticosterone is at greater levels, it begins to occupy GRs16,5. These receptors are ubiquitously expressed throughout the brain, with higher expression density in the limbic regions, particularly the hippocampus4,23. Both MR and GR can be found in the cytosol and upon binding corticosterone, translocate into the nucleus where they can directly promote or inhibit transcription (Figure 3)4,27.
Figure 1. The HPA axis. When the brain perceives a threat, a coordinated cascade of events occurs in response. Neurons in the hypothalamus release CRH and arginine vasopressin (AVP), which induce the secretion of ACTH from the pituitary. ACTH then triggers the adrenal cortex to produce glucocorticoids known as corticosteroids (cort). Corticosterone can pass through the blood brain barrier and interact with two receptors, MR and GR. Activation of these receptors can trigger feedback loops that can inhibit further activity of the HPA axis and return the system to a homeostatic point. Photo credit9.
Under basal conditions, the HPA axis functions in a circadian rhythm on a 24-hour cycle3,4. This typically consists of lower corticosterone secretion as the animals go to sleep and greater secretion as the animals begin to wake up (Figure 2). Although this secretion is pulsatile, averages lie predictably along this rhythm10–14.
GR is comprised of an N-terminus region, followed by a DNA-binding domain (DBD), a hinge region, a ligand-binding domain (LBD), and a C-terminus (Figure 4)28–30. In the cytosol, GR is already bound to other chaperones inhibiting its DBD from being exposed31. When corticosterone binds to the LBD, GR changes its conformational structure, releasing previously bound chaperones, and allowing it to dimerize and pass into the nucleus32,33. Here it can directly affect transcription by binding onto DNA fragments known as glucocorticoid-response-elements (GRE), located upstream of a gene promoter (Figure 3)34. By binding to GREs, GR can promote or inhibit (negative GREs) transcription of RNA that codes for proteins. Alternatively, GR can bind to other nuclear transcription factors, sequestering their activity, and thus, indirectly promoting or inhibiting transcription. Without the actions of this steroid receptor, the animal could not survive, as we know from genetic mutations that GR gene inactivation is lethal at birth27.
Figure 2. Corticosterone secretion throughout day in freely moving rat. Corticosterone plasma is released in a circadian pattern that consists of ultradian (pulsatile) oscillations. During rodents’ night cycle (awake), corticosterone secretion is higher and as they enter their light cycle (sleep), levels begin to decline. Photo credit15.
Figure 3. The glucocorticoid receptor can regulate gene transcription. Due to their size and lipophilic nature, glucocorticoids (i.e. cort) can pass through the cell membrane. When they bind to GR, this induces a conformational change that releases GR from a complex with heat-shock proteins (hsp) allowing GR to translocate into the nucleus. Here, GR can affect transcription as a dimer bound to GREs, as well as a monomer, interfering with other factors (e.g. AP-1 and NF-kB). Photo credit25.
Although the focus of this research is on GR-mediated stress, there are other stress-related molecules that may play a role in the stress response, including dopamine, serotonin, BDNF, VEGF, glutamate, and NMDA35,36. Despite these other mediators of the stress response, we focused on corticosterone because of its robust effect on NPCs. While mature neurons are found to express both MR and GR, newborn neuronal cells only express GR (see Figure 5)37. Thus, it may not be surprising that high levels of circulating corticosterone, such as that caused by environmental stressors, affect the development of these cells.
Figure 4. Structural organization of glucocorticoid receptor. Schematic 1 dimensional (1D) amino acid sequence of nuclear receptors, such as GR. Sequence C represents the DBD (where receptor interacts with DNA) and sequence E represents the LBD (where hormone binds), both shown below as 3 dimensional (3D) structures.

Neurogenesis in the hippocampus

During brain development, neural stem cells, responding to both internal and external cues, multiply (proliferate), migrate, and mature (differentiate) into neurons (a process referred to as neurogenesis) or glia (referred to as gliogenesis) (for review38). Gliogenesis, more specifically, refers to astrocytes (astrogenesis) or oligodendrocytes (oligodendrogenesis). These mature cells are some of the main players that constitute the brain and contribute to its function. This developmental process goes through stages that become increasingly more restrictive in cell-type and self-renewal39. It culminates with the mature cell, neuron or glia, that is fully differentiated and no longer mitotic (Figure 5)40. Referred to broadly as neurogenesis (since most cells become neurons), this process occurs in the pre- or early post-natal stages of all vertebrate mammals41–46. Grandfather of neuroscience, Ramón y Cajal, established the long-held dogma that after this initial period, the brain no longer retained this regenerative capacity: “In the adult centres, the nerve paths are something fixed, ended, and immutable. Everything may die, nothing may be regenerated”47.
It was not until the 1960s, with more sophisticated tools and scientific methods, that it was discovered that neurogenesis takes place in the adult brain as well. Although the results were not widely accepted, Altman and colleagues (1965) first presented evidence of mammalian adult neurogenesis using autoradiography and light microscopy of general cytological stains48. This result was further supported by combining autoradiography and high-resolution electron microscopy to show evidence that adult-born cells with tritiated thymidine uptake, a marker of cell division, exhibited definite neuronal morphology49. Still, mammalian adult neurogenesis was not firmly established until the 1990s, when the use of more advanced techniques in cell culturing and immunohistochemistry provided evidence of adult neural progenitor cells that were multipotent in vitro50–52, and in vivo53–58. Now widely accepted, adult neurogenesis has been demonstrated across species, including bird59, tree shrew60, mouse61, rats49,53,62, monkeys63, and humans54,64,65. Not only did the discovery of this phenomenon overturn a long-held central dogma of neuroscience, but it also enlightened us to a new form of adult plasticity that could contribute to learning processes and be a potential source for treating damage to, disorders, or diseases of the brain.
There are two locations where adult neurogenesis is found to occur: the subventricular zone (SVZ) of the lateral ventricles, and the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG)62,66. Within the hippocampus, as cells proliferate, some daughter cells become NPCs which further mature into neurons (approximately 70-90%), or other glial cells (~10%)36,62,67–69. Typically, these maturing cells migrate into the granular cell layer, differentiate into granule neurons, and integrate into the circuitry by extending the appropriate projections to their CA3 target area70 and acquiring electrophysiological properties that make them indistinguishable from the adjacent, older neurons (Figure 5)71. Across species, the rate and degree of neurogenesis is varied. For example, rats have ~9000 newborn cells surviving after 1 week and ~70% of these cells are already neurons by 2 weeks; whereas mice have ~3000 newborn cells surviving after 1 week (although they have similar levels of newborn cells per area to rats at this time) and still, less than 50% have developed into mature neurons by the 4 week time point72. Nonetheless, in a matter of weeks depending on the species, adult NPCs can become functionally responsive neurons72,73. Although NPCs are restricted to two discrete brain regions and comprise less than 10% of the total DG neuronal population68, their long-term, regular self-renewal has remained a conserved mechanism across species. Understandably, this begs the question of what significant role they play in brain function.
Figure 5. Proposed development of newborn neurons in the dentate gyrus of the hippocampus. Neuronal development in the adult hippocampus can be readily identified in stages on the basis of morphology, proliferative ability, and expression of markers such as nestin, GFAP, DCX, calbindin and NeuN. Development begins from the putative stem cell (type-1 cell; stage 1) that has radial glia and astrocytic properties and potentially unlimited proliferative ability, although it is more quiescent. The next stages of neural development include transiently amplifying progenitor cells (type-2a, type-2b and type-3 cells; stages 2–4), which proliferate more rapidly, although with limited self-renewal, and lineage is more restricted. Note that type-2b cells were not found to express GR. The next stage marks the early post-mitotic period, where cells differentiate and migrate into the GCL. Finally, the last two postmitotic stages are characterized by NeuN expression and spine formation. This progresses until the cell is functionally integrated, extending its axons to the CA3 region, and is now a mature granule cell with large and complex synapses. Adapted from35,37,40,44,74.

Measuring neurogenesis

There are different methods of measuring neurogenesis. Four of these strategies involve labeling newborn cells through the use of exogenous markers, endogenous markers, retro-viral markers, or genetic techniques. Exogenous labeling of proliferative cells involves injecting a solution of either tritiated thymidine, or a thymidine analog called 5’-bromo-2’-deoxyuridane (BrdU), which incorporates itself during DNA replication by replacing the thymidine nucleoside75,76. Thus, when BrdU is present, any replicating cell in S-phase will take up this analog into its DNA structure and by using immunofluorescence, anti-BrdU antibody can identify them throughout their lifecycle. By thoughtfully planning the paradigm and temporal order of events, one can examine proliferation, survival, and differentiation of the cells. For example, differentiation can be qualitatively and quantitatively measured with anti-BrdU co-labeled with other cell markers if the timing between BrdU administration and tissue fixation provided enough time for the newborn cell to mature. These other cell markers can identify distinct or overlapping stages of development, such as nestin for progenitor cells, doublecortin (DCX) for immature neurons, or NeuN for mature neurons (Figure 5). By co-labeling with antibodies for distinct cell types, one can for track cell fate.
Another method of measuring neurogenesis involves immunofluorescence of endogenous markers of cell division such as Ki67 or proliferating cell nuclear antigen (PCNA)76,77. Ki67 is a protein that is naturally expressed during the S-phase of the cell division cycle78,79. PCNA is a protein that also naturally exists during cell division80. By immuno-labeling with antibodies against themselves, one can quantitatively and qualitatively measure proliferation. A drawback of this method, however, is that the cell is only identified while replicating, making survival or differentiation measures impossible. Still, it is a less-invasive and simpler way of examining proliferation at the time of death.
Labeling of adult neurogenesis is also possible using particular retroviruses. These retroviruses are a type of virus that only enters the cell when it is dividing. Thus, this method only targets proliferating cells. If the retrovirus is bound to a fluorescent protein, similar to the BrdU method, when the virus is present, any replicating cell will be infected and using immunofluorescence, it can be identified throughout its lifecycle44,71.
The last method mentioned includes genetic techniques such as Cre/lox recombination. Cre is a recombinase protein that can be inserted into the promoter region of any gene such that when the gene is being expressed, Cre will be active concomitantly81. When active, Cre locates and excises any DNA contained between (floxed by) head-to-tail loxP fragments. Then Cre recombines the genetic coding (minus the floxed DNA segment) and from that point onward, the cell’s genetic code is permanently altered, including its progeny82. Both Cre and loxP are genetic manipulations not occurring naturally in mammals. One way this technique can be used to label progenitor cells could be by using a mouse that has a gene with Cre in the promoter region of a proliferative cell marker (i.e. nestin) and a gene with loxP floxing a STOP codon preceding a yellow fluorescent protein (YFP). The Cre will remove the STOP codon, causing YFP to be visible only in nestin-expressing cells. This method, although more intricate, would label all nestin-expressing cells from birth. A more clever alternative technique is through the use of CreERT2, a form of Cre that is inducible at any selected time point83–85. This type of Cre is controlled by a mutated estrogen receptor (ERT2) that is only active when induced exogenously by an estrogen analog such as tamoxifen85,86. Unlike Cre, which becomes active as soon as nestin (for example) is expressed, CreERT2 becomes active when both tamoxifen is bound to its ERT2 and nestin is expressed. Thus, using this inducible CreERT2 genetic technique, proliferative cells can be labeled and tracked for proliferative, survival, and differentiation analyses84,87–89.

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Stress-induced regulation of neurogenesis

Both the stress response and neurogenesis appear to be well-conserved mechanisms that provide an organism with the ability to cope and perhaps more importantly, adapt to future occurrences74,90,91. It is not so surprising then that the hippocampus is the brain structure where the stress-sensitive limbic system and one of two neurogenic niches converge. The hippocampus is critically involved in both learning and memory, two plastic processes that necessitate the continuous need to receive, reorganize, relay, and readjust to new information26,92–94. The regenerating NPCs of the hippocampus are well situated to react to the environment as they are found predominantly in the direct vicinity of the vasculature95. This would allow for stress hormones circulating in the blood to quickly communicate with these regenerating cells. Thus, one of the first discovered and widely studied mediators of neurogenesis was stress96.
Neurogenesis is not only regulated by stress, but also other stimuli that are associated with elevated corticosterone, such as voluntary exercise, learning tasks, and enriched environments97–101. The effects of stress on neurogenesis can be during the proliferation, survival, or differentiation of the cell. The responses can vary depending on the type of stressor (i.e. restraint, predator smell, tail suspension) and the duration of its application (i.e. acute, chronic)102. Each stage of neurogenesis appears to be a plastic progression with the potential to be influenced by stress and corticosterone.

Stress and glucocorticoids affect cell proliferation

The first stage in neurogenesis is when the cell undergoes mitosis and multiplies itself. This proliferative stage can be sensitive to environmental stressors depending on the duration of the stress. The effect of acute and chronic stress has been studied in a variety of animals, including mouse, rat, tree shrew, and marmoset monkey, and is generally found to be inhibitory.
Many studies have found that acute stress causes decreases in proliferation7,103. Acute stress usually involves one instance or one day of a stressful paradigm. In one study, rats were exposed to odors from a fox, a natural predator, or nonthreatening stimuli (mint or orange). Only acute exposure to fox odor was found to decrease the number of newborn cells104. Additionally, rats underwent adrenalectomies to remove glucocorticoids from their system, and then were given low levels of corticosterone for maintaining normal functioning. When these rats were exposed to the odors now, there was no effect on proliferation, implying that the stress effect suppressing proliferation was driven by raised corticosterone levels104. Other researchers confirmed these results, finding predator odor caused inhibition of proliferation105,106. Decreased proliferation was also seen in acute exposure to a social defeat paradigm107, but not always significantly108. A psychosocial stress, also referred to as resident-intruder, was found to inhibit proliferation of NPCs60,109, as well as an acute duration of unpredictable stressors110, such as forced cold swim and cold immobilization. Similarly, after a day of inescapable shock, proliferation again was shown to be suppressed111. During early life, rat pups exposed to an adult male odor showed suppressed proliferation112. While all these studies refer to suppressed neurogenesis in the SGZ of the hippocampus, neurogenesis in the SVZ has also been examined but found to show no effect of acute stress on cell production111,113. This suggests that the effect of stress on proliferation is specific to the hippocampus and not due to the uptake or labeling of BrdU. The duration of the decreased proliferation may vary if experienced during the early postnatal stage or adulthood. In one study that looked at rat pups, they found that early life stress from maternal separation caused reduced proliferation rates that lasted into adulthood113 However, other groups found that acute stress effects on proliferation normalized within 24 hours, but these were performed on adult mice107,114.
Although many studies show acute stress induces inhibition of newborn neurons, there are several studies that do not confirm those results. There was no change found in proliferation in two studies of acute restraint on rats115,116. Likewise, acute stress from both psychosocial stress or a predator odor were not always found to suppress proliferation117,118, although these studies were criticized for administering BrdU shortly before the stressor, and thus were not a direct measure of proliferation change caused by the stressor36. Recently, Kaufer and colleagues (2013) found that acute immobilization stress increased proliferation119. In this study, researchers were sensitive to pre-handling procedures that prepared both experimental and control rodents for handling the day of the stress, which may have made a significant difference as well. Increased proliferation from acute stress is also found in female rodents110,120 and attributed to estradiol effects that are neurogenesis enhancing. In one of these studies, when female rats were exposed to predator odor, there was no change seen in proliferation, but after an ovariectomy and exogenous estradiol was added, there was an increase in cell birth120. Overall, it seems as though acute stress can regulate proliferation, although these effects are sensitive to the type of stressor experienced, the protocol of the paradigm, the age of the animal, the species being studied, and the time course in which proliferation was examined.
While acute stress effects on proliferation appear to be variable, chronic stress appears to be a strong inhibitor of proliferation. Chronic stress refers to any stressor experienced repeatedly over a course of a few days to several weeks. In a chronic unpredictable stress paradigm, that can include various stressors such as forced cold swim, cold immobilization, isolation, vibration, shaking, overcrowding, wet bedding, restraint, odors, altered light schedules, or strobe lighting, rodents were found to have significant reductions in the birth of new neurons110,121–124Chronic restraint for 6 hours per day for 2-3 weeks also induced inhibition of cell proliferation115,116. Likewise, reduced proliferation was found after chronic psychosocial stress125–127 as well as chronic shock exposure128, and repeated social defeat108. During early life, rat pups that had prolonged maternal deprivation were found to have significantly reduced basal proliferation rates as adults113.
These effects appear to last longer than those from acute stress. Chronic stress experienced during early life exhibits inhibited proliferation into adulthood113 while chronic stress experienced as an adult appears to recover from inhibited cell birth after 3 weeks114,123.
Whether acute or chronic, the question remains whether decreases in proliferation are due to a slowing or a pausing of the cell cycle, or if the cells are exiting the cell cycle or dying. This question was investigated and researchers found that when dexamethasone, a GR-specific synthetic glucocorticoid, was applied in vitro, it concomitantly reduced proliferation and increased p21 protein129. P21 is an enzyme involved in cell-cycle arrest by inhibiting progression from the G1 to the S phase in the cell cycle130. Similarly, increased p21 expression was found in NPCs131 as well as HT-22 cells exposed to dexamethasone132. In one study in vivo, while stress was found to downregulate newborn cell births, this correlated with an upregulation in p27Kip1, another enzyme of cell cycle arrest130. Although the pathway in which stress or glucocorticoids enacts its effects on cell proliferation is still unknown, particularly whether its effect is directly or indirectly through NPCs, these results suggest that the stress and GC-induced inhibition of proliferation is mediated by a slowing of the G1-S phase in a cell cycle, and not just due to cell cycle exit.

Stress and glucocorticoids affect cell survival

Although thousands of newborn neurons are born each day, approximately 50% of these cells die within 3 weeks68,78. This stage is referred to as survival, and this pruning process is also sensitive to environmental input133,134.
Results from measurements of cell apoptosis after an acute stressor are conflicting. Cell survival was measured at different time points post-BrdU uptake from rats exposed to an acute psychosocial stressor118. These time points assessed the immediate, short-term, and long-term survival of newborn neurons. The study found no change in survival rates immediately after BrdU administration, but did find a decrease in both the short-term and long-term survival rates118. Similarly, rats exposed to acute unpredictable stress had increased apoptosis in the hilus, SGZ, and granule cell layer (GCL) of the hippocampus110. The opposite effect, however, was seen in rats exposed to acute predator odor120. In this study, the acute stressor suppressed cell death in the DG, and thus survival rates were higher than controls120. In addition to decreased and increased survival rates from acute stressors, some studies find no change at all107,121, although these were performed with mice, suggesting that stress effects are more deleterious on particular species. The variability in the intensity, duration, and protocol of the stressor, along with differences in BrdU time course and measurement methods can perhaps account for the conflicting results found from stress on cell death.
Although most experiments are done with male rodents to control for the neurogenic enhancing effects of estrogen in females135, one study also tested cell survival rates in females exposed to the same predator odor as males were and found no change120. This emphasizes sex differences in stress-induced effects on neurogenesis, particularly since ovariectomized female rodents had vast cell death in the hippocampus that was ameliorated by exogenous estradiol hormone120. This could imply that any suppressive effect on survival induced by stress may be counteracted by the enhancing effect of estrogen.
The effects of chronic stress on cell survival appear to be clearer. Cell death was increased in the DG of adult rats after experiencing chronic stress paradigms such as psychosocial stress125, restraint stress115, and unpredictable variable stress110,136,137. One study that measured cell death determined that the effects were restricted to the GCL, and not seen in the hilus136. Interestingly, when a GR antagonist, mifeprisone, was administered for 4 days after the chronic unpredictable variable stress paradigm, cell survival increased137. This suggests that the suppressive effects on cell survival induced by chronic stress are mediated through the GR. These effects may be similar as well if stress is experienced in early life. Gould and colleagues examined rats that experienced prolonged maternal deprivation as pups and found that these pups also had lower survival rates for newborn neurons in adulthood113. This effect persisted for 1 week, however, dissipating after 3 weeks113. Studies on cell survival after chronic stress all seem to concur that stress, perhaps mediated through the GR, increase apoptosis of newborn NPCs.

Stress and glucocorticoids affect cell differentiation

In the rodent hippocampus, after NPCs proliferate and survive the pruning process, they begin to take on morphological, molecular, and functional characteristics of more mature cell types44. This process is referred to as differentiation and typically, 70-90% of these surviving cells become granule neurons68,69. Although most of the research on stress effects on neurogenesis point to the proliferation stage as the mediator of neurogenic changes, differentiation appears to also be sensitive to environmental input.
Unlike the proliferation stage, there are not many studies showing an effect of acute stress on cell fate. Adult rats subjected to acute restraint were found to have no significant differences in cell differentiation115. Similarly, rats exposed to an acute psychosocial stressor had no changes in percentage of BrdU-positive cells that co-labeled with mature neuronal markers118. Since there was an overall significant reduction in the number of neurons, but not in the percentage of newborn cells that differentiated into neurons, this would indicate that changes in neurogenesis from acute stressors probably derive from the initial changes seen on proliferation.
The effects of chronic stress on cell differentiation appear to vary from decreased neuronal fate or no change in cell fate. Both adult rats and 3-week-old mouse pups subjected to chronic restraint showed reduced neuronal differentiation115,138. Mice that experienced chronic social isolation displayed suppressed neuronal differentiation as well in both the GCL and SGZ, but not the hilus139. Likewise, exposure to a chronic shock paradigm reduced neural cell fate in rats128, although not always140. Chronic exposure to a psychosocial stressor showed suppressed neuronal differentiation in tree shrews127, but no effect in rats125. The effects on neuronal differentiation from chronic unpredictable stressors or chronic mild stressors, which can include cage tilting, wet bedding, predator sounds, empty cages with water on the bottom, reversal of the light/dark cycle, sporadic light changes, restraint, forced cold swim, water deprivation, pairing with a stressed littermate, or cage switching, were found to be nonsignificant in rats114,136, but significantly reduced in mice141,142. One study that looked at 7 weeks of chronic mild stress on mice, however, did not see this reduction as both stressed and control groups had 73% of BrdU positive cells co-labeling with NeuN143. One study examined a similar paradigm on three strains of mice and found a significant suppression of neuronal fate in both the males and females of all strains142. None of these studies found any shift in astrocytic cell fate; however, a recent study found that chronic restraint stress not only decreased neuronal differentiation in rats, but increased oligodendrogenesis144. In this study, not only stress induced this shift in cell fate from neurons to oligodendrocytes, but also lineage tracing of NPCs in vivo showed that after administering corticosterone, oligodendrocytic fate was increased, implying that this stress effect is a cort-mediated mechanism144. Overall, it appears that while acute stress does not change the fate of newborn cells, chronic stress can often reduce or alter the differentiation of newborn cells through elevated corticosterone.

Table of contents :

CHAPTER 1 Introduction 
1.1 Scope of thesis
1.2 Stress and neurogenesis in the mammalian central nervous system
1.3 The role of glucocorticoids in hippocampal neuroplasticity
1.4 The role of neurogenesis in hippocampal function
1.5 Functional significance of stress-induced changes to neurogenesis
CHAPTER 2 Regulation of adult hippocampal neurogenesis by GR in newborn neurons 
2.1 Abstract
2.2 Introduction
2.3 Results
2.4 Discussion
2.5 Materials and Methods
2.6 Figures and Legends
CHAPTER 3 Functional contributions of the glucocorticoid receptor in adult neurogenesis
3.1 Abstract
3.2 Introduction
3.3 Results
3.4 Discussion
3.5 Materials and Methods
3.6 Figures and Legends
CHAPTER 4 Introduction to general discussion
4.1 Introduction to general discussion
4.2 CreERT2-mediated GR gene inactivation in neural progenitor cells
4.3 Glucocorticoid receptor signaling in the neurogenic niche
4.4 GR signaling in adult-born granule cells: implications for stress-related brain disorders
4.5 Future directions
CHAPTER 5 References


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