Gonadal hormone modulation of neurogenesis in the dentate gyrus of adult male and female rodents

Gonadal hormones modulate neurogenesis in the dentate gyrus differentially in male and female adult rodents. Neurogenesis is comprised of at least two components: cell proliferation (the production of new cells) and cell survival (the number of new neurons that survive to maturity). Previous studies have found sex differences in the level of cell proliferation in the dentate gyrus only when comparing females in a high estrogen state to males. This review focuses on the effects of acute and chronic levels of estrogens or androgens on hippocampal neurogenesis in the adult male and female rodent. Evidence is also reviewed for the co-localization of androgen receptors and estrogen receptors (ER) with markers for cell proliferation or immature new cell survival. Briefly, evidence suggests that acute estradiol initially enhances and subsequently suppresses cell proliferation in the dentate gyrus of adult female rodents but may have limited effects in male rodents. Both the two known ER subtypes, ER and β upregulate hippocampal neurogenesis via cell proliferation. Intriguingly, repeated exposure to estradiol modulates hippocampal neurogenesis and cell death in adult female, but not male, rodents. However short-term estradiol treatment (5 days) in male meadow voles enhances new cell survival in the dentate gyrus but only when administered during the ‘axon extension’ phase. Furthermore, evidence is also reviewed showing a difference in response to acute and chronic estradiol treatment in older female rats compared to younger female rats. Recent findings from our laboratory indicate that testosterone and dihydrotestosterone upregulate hippocampal neurogenesis (via cell survival), but not cell proliferation, in adult male rodents. Effects of endogenous fluctuations in gonadal hormones on adult neurogenesis are observed across the seasons in meadow voles and during pregnancy and lactation in the rat dam. Pregnancy and motherhood differentially regulate adult hippocampal neurogenesis in the adult female rodent, with primiparous rats displaying lower levels of hippocampal cell proliferation and survival after parturition. Few studies have compared males and females but existing research suggests a sex difference in the hormonal regulation of hippocampal neurogenesis in the adult. Clearly more work is needed to elucidate the effects of gonadal hormones on neurogenesis in the dentate gyrus of both male and female rodents across the lifespan, especially if we are to use our knowledge of how adult neurogenesis is regulated to develop strategies to repair neuron loss in neurodegenerative diseases.     

Gonadal hormone modulation of hippocampal neurogenesis in the adult

Gonadal hormones modulate neurogenesis in the dentate gyrus (DG) of adult rodents in complex ways. Estradiol, the most potent estrogen, initially enhances and subsequently suppresses cell proliferation in the dentate gryus of adult female rodents. Much less is known about how estradiol modulates neurogenesis in the adult male rodent; however, recent evidence suggests that estradiol may have a moderate effect on cell proliferation but enhances cell survival in the DG of newly synthesized cells but only when estradiol is administered during a specific stage in the cell maturation cycle in the adult male rodent. Testosterone likely plays a role in adult neurogenesis, although there have been no direct studies to address this. However, pilot studies from our laboratory suggest that testosterone up-regulates cell survival but not cell proliferation in the DG of adult male rats. Progesterone appears to attenuate the estradiol-induced enhancement of cell proliferation. Neurosteroids such as allopregnalone decrease neurogenesis in adult rodents, while pregnancy and motherhood differentially regulate adult neurogenesis in the adult female rodent. Very few studies have investigated the effects of gonadal hormones on male rodents; however, studies have indicated that there is a gender difference in the response to hormone-regulated hippocampal neurogenesis in the adult. Clearly, more work needs to be done to elucidate the effects of gonadal hormones on neurogenesis in the DG of both male and female rodents.     

Decreased adult hippocampal neurogenesis in the PDAPP mouse model of Alzheimer's disease

Abnormal subgranular zone (SGZ) neurogenesis is proposed to contribute to Alzheimer's disease (AD)-related decreases in hippocampal function. Our goal was to examine hippocampal neurogenesis in the PDAPP mouse, a model of AD with age-dependent accumulation of amyloid-beta(42) (Abeta(42))-containing plaques that is well studied with regard to AD therapies. A secondary goal was to determine whether altered neurogenesis in the PDAPP mouse is associated with abnormal maturation or number of mature cells. A tertiary goal was to provide insight into why hippocampal neurogenesis appears to be increased in AD post-mortem tissue and decreased in most AD mouse models. We report an age-dependent decrease in SGZ proliferation in homozygous PDAPP mice. At 1 year of age, PDAPP mice also had new dentate gyrus granule neurons with abnormal maturation and fewer dying cells relative to control mice. In contrast to decreased SGZ cell birth, PDAPP mice had increased birth of immature neurons in the outer portion of the granule cell layer (oGCL), providing insight into why some studies link AD with increased neurogenesis. However, these ectopic oGCL cells were still rare compared with SGZ proliferating cells, emphasizing that the primary characteristic of PDAPP mice is decreased neurogenesis. The decrease in SGZ neurogenesis was not associated with an age-dependent loss of dentate granule neurons. The altered neurogenesis in the PDAPP mouse may contribute to the age-related cognitive deficits reported in this model of AD and may be a useful adjunct target for assessing the impact of AD therapies.     

Acute inflammation alters adult hippocampal neurogenesis in a multiple sclerosis mouse model

Neural precursor cells (NPCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) give rise to thousands of new cells every day, mainly hippocampal neurons, which are integrated into existing neuronal circuits. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of inflammation is somewhat controversial. The present study demonstrates that the inflammatory environment prevailing in the brain of experimental autoimmune encephalomyelitis (EAE) mice enhances the proliferation of NPCs in SGZ of the dorsal DG and alters the proportion between radial glial cells and newborn neuroblasts. The injection protocol of the cell cycle marker bromodeoxyuridine and the immunohistochemical techniques that were employed revealed that the proliferation of NPCs is increased approximately twofold in the SGZ of the dorsal DG of EAE mice, at the acute phase of the disease. However, although EAE animals exhibited significant higher percentage of newborn radial‐glia‐like NPCs, the mean percentage of newborn neuroblasts rather was decreased, indicating that the robust NPCs proliferation is not followed by a proportional production of newborn neurons. Significant positive correlations were detected between the number of proliferating cells in the SGZ and the clinical score or degree of brain inflammation of diseased animals. Finally, enhanced neuroproliferation in the acute phase of EAE was not found to trigger compensatory apoptotic mechanisms. The possible causes of altered neurogenesis observed in this study emphasize the need to understand more precisely the mechanisms regulating adult neurogenesis under both normal and pathological conditions. © 2013 Wiley Periodicals, Inc.     

Protection of hippocampal neurogenesis by TAT-Bcl-xL after cerebral ischemia in mice

Endogenous neurogenesis persists in the subgranular zone (SGZ) of the adult rodent brain. Cerebral ischemia stimulates endogenous neurogenesis involving proliferation, migration and differentiation of SGZ-derived neural precursor cells (NPC). However, the biological meaning of this phenomenon is limited by poor survival of NPC. In order to study the effects of an acute neuroprotective treatment on hippocampal endogenous neurogenesis after transient cerebral ischemia in mice, we applied a fusion protein consisting of the TAT domain of the HI virus with the anti-apoptotic Bcl-x_L. Intravenous injection of TAT-Bcl-x_L resulted in reduced hippocampal cell injury for up to 4 weeks after stroke as assessed by TUNEL and NeuN staining. This was in line with a TAT-Bcl-x_L-mediated reduced postischemic microglia activation. Analysis of endogenous hippocampal cell proliferation revealed an increased number of BrdU⁺ cells in the TAT-Bcl-x_L group 4 weeks after stroke compared to animals treated with saline and TAT-HA (negative control). Cell proliferation in non-ischemic sham operated animals was not affected by TAT-Bcl-x_L. Twenty-eight days after stroke co-expression of BrdU⁺ cells with the immature neuronal marker doublecortin was significantly increased in TAT-Bcl-x_L animals. Although TAT-Bcl-x_L treatment also resulted in an increased number of BrdU⁺ cells expressing the mature neuronal marker NeuN, the total amount of these cells was low. These data show that TAT-Bcl-x_L treatment yields both postischemic sustained hippocampal neuroprotection and increased survival of NPC rather than an induction of endogenous neurogenesis itself.     

Stress differentially regulates the effects of voluntary exercise on cell proliferation in the dentate gyrus of mice

It has been well-established that cell proliferation and neurogenesis in the adult mouse dentate gyrus (DG) can be regulated by voluntary exercise. Recent evidence has suggested that the effects of voluntary exercise can in turn be influenced by environmental factors that regulate the amount of stress an animal is exposed to. In this study, we use bromodeoxyuridine and proliferating cell nuclear antigen immunohistochemistry to show that voluntary exercise produces a significant increase in cell proliferation in the adult mouse DG in both isolated and socially housed mice. This effect on proliferation translates into an increase in neurogenesis and neuronal branching of new neurons in the mice that exercised. Although social condition did not regulate proliferation in young adult mice, an effect of social housing could be observed in mice exposed to acute restraint stress. Surprisingly, only exercising mice housed in isolated conditions showed an increase in cellular proliferation following restraint stress, whereas socially housed, exercising mice, failed to show a significant increase in proliferation. These findings indicate that social housing may increase the effects of any stressful episodes on hippocampal neurogenesis in the mouse DG.     

Decreased proliferation of hippocampal progenitor cells in APPswe/PS1dE9 transgenic mice

A recent hypothesis suggests that there is impaired hippocampal neurogenesis in Alzheimer's disease. Here we examined the proliferation, the first stage in neurogenesis, of hippocampal progenitor cells in amyloid precursor protein with Swedish mutation and presenilin-1 with deletion of exon 9 (APPswe/PS1dE9) transgenic mice. Compared with age-matched wild-type mice, transgenic mice at 5 months of age with low amyloid beta-peptide (Abeta) levels and subtle Abeta deposits showed normal proliferation of hippocampal progenitor cells; however, transgenic mice at 9 months of age with high Abeta levels and numerous Abeta deposits showed decreased proliferation of these cells. The number of proliferating cells in male transgenic mice was indistinguishable from that in female transgenic mice. These results indicate that neurogenesis is decreased with degrees of Abeta pathology, and that there is no gender difference in their proliferation in APPswe/PS1dE9 transgenic mice.     

Hippocampal neurogenesis increase with stereotypic behavior in mink (Neovison vison)

We investigated the hypothesis that performance of abnormal behavior is a stress response concurrent with reduced cell formation in the hippocampal region of the brain, using groups of adult female American mink with high occurrence of stereotypic behavior (STEREO, n=12), high occurrence of fur-chewing behavior (FURCHEW, n=12), or without abnormal behavior (CONTROL, n=12). Following repeated injections of Bromodeoxyuridine (BrdU) as a marker of dividing cells, animals were sacrificed and brain tissue fixated. After brain sectioning and a mink-adapted free-floating BrdU/NeuN doublestaining protocol, we counted the number of cells formed in the subgranular zone (SGZ) and the granular cell layer (GCL) of the dentate gyrus (DG) in the mink hippocampus. Results: (1) proliferation of cells in the SGZ and the GCL of the ventral hippocampal DG was demonstrated for the first time in adult mink, (2) with no significant difference between the experimental groups (CONTROL: 1509 (191.1); FURCHEW: 1377 (199.8); STEREO: 1968 (288.8); P=0.18), (3) however, with a positive correlation between the amount of stereotypic behavior performed and the number of new hippocampal cells formed (P=0.016). In conclusion, our results do not support that abnormal behavior in mink is concurrent with reduced hippocampal neurogenesis. On the contrary, cell proliferation increased with increasing performance of stereotypic behavior, being of an active/locomotory nature in mink.     

Selective serotonin depletion does not regulate hippocampal neurogenesis in the adult rat brain: differential effects of p-chlorophenylalanine and 5,7-dihydroxytryptamine

Serotonin is suggested to regulate adult hippocampal neurogenesis, and previous studies with serotonin depletion reported either a decrease or no change in adult hippocampal progenitor proliferation. We have addressed the effects of serotonin depletion on distinct aspects of adult hippocampal neurogenesis, namely the proliferation, survival and terminal differentiation of hippocampal progenitors. We used the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA) or the serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) to deplete serotonin levels. 5,7-DHT selectively decreased hippocampal serotonin levels, while PCPA resulted in a significant decline in both serotonin and norepinephrine levels. We observed a robust decline in the proliferation and survival of adult hippocampal progenitors following PCPA treatment. This was supported by a decrease in the number of doublecortin-positive cells in the neurogenic niche in the hippocampus. In striking contrast, 5,7-DHT did not alter the proliferation or survival of adult hippocampal progenitors and did not alter the number of doublecortin-positive cells. The terminal differentiation of adult hippocampal progenitors was not altered by either PCPA or 5,7-DHT treatment. An acute increase in serotonin levels also did not influence adult hippocampal progenitor proliferation. These results suggest that selective serotonin depletion or an acute induction in serotonin levels does not regulate adult hippocampal neurogenesis, whereas treatment with PCPA that induces a decline in both serotonin and norepinephrine levels results in a significant decrease in adult hippocampal neurogenesis. Our results highlight the need for future studies to examine the role of other monoamines in both the effects of stress and antidepressants on adult hippocampal neurogenesis.     

Injury-Induced Neurogenesis: Consideration of Resident Microglia as Supportive of Neural Progenitor Cells

The induction of neurogenesis in the adult subgranular zone (SGZ) by injury is often accompanied by changes in the extracellular environment that can have significant impacts on neural progenitor cells (NPCs). We examined the induction of neurogenesis in the SGZ at 72 h following an injection of the hippocampal toxicant, trimethyltin (TMT; 2 mg/kg, ip) inducing apoptosis in dentate granule neurons. BrdU+ incorporation during the active period of neuronal death indicated NPC proliferation and migration of newly generated cells into the granule cell layer (GCL). BrdU+ cells were transiently in contact with process bearing microglia within the inner SGZ layer. Contact with GFAP+ astrocyte processes occurred once cells were within the GCL. A small percentage of the BrdU+ cells within the SGZ region showed immunoreactivity for tumor necrosis factor (TNF) p75 receptor (TNFp75R). In mice deficient for TNFp75R, TMT injection produced an equivalent level of dentate granule cell death however; BrdU+ cells were localized at the SGZ as compared to the presence of cells within the GCL in the WT mice dosed with TMT. These data suggest that cells generated by NPCs in the SGZ induced with a focal lesion to the dentate granule neurons of adolescent mice maintain the capacity to utilize the neuroinflammation and microglia responses within their environment for migration into the GCL.     

Dynamic expression of TrkB receptor protein on proliferating and maturing cells in the adult mouse dentate gyrus

Brain-derived neurotrophic factor (BDNF) is implicated in the regulation of adult hippocampal neurogenesis, presumably via its primary receptor, TrkB. However, controversy exists about how BDNF affects neurogenesis (e.g., proliferation vs. survival/differentiation). This controversy arises, in part, due to the lack of information about whether and when TrkB is expressed on adult neural precursors in vivo. We utilized multiple methods to analyze proliferating and maturing cells in the adult mouse subgranular zone (SGZ) for TrkB protein. Using bromodeoxyuridine (BrdU) to "birthdate" cells, we found that the proportion of proliferating cells that were TrkB-immunoreactive (IR) was low and remained low for at least 1 week, but increased with further survival after BrdU labeling. Use of the nestin-GFP transgenic mouse and the immature neuron marker, doublecortin (Dcx), revealed that the likelihood of being TrkB-IR increased with presumed maturity of the cell type. Stem-like cells, which rarely divide, were likely to express TrkB protein. However, early progenitors (GFP+/Dcx-) and late progenitors (GFP+/Dcx+), both of which are still in the cell cycle, were unlikely to be TrkB-IR. Immature neuroblasts (GFP-/Dcx+) were more likely to express TrkB, especially as they presented a more mature morphology. Taken together, these findings emphasize that expression of TrkB protein is closely linked to progression toward neuronal maturity. This provides evidence that maturing, but not proliferating, cells in the adult mouse SGZ have the molecular machinery necessary to respond directly to BDNF. Furthermore, these findings lay critical groundwork for further exploration of the role of BDNF-TrkB signaling in regulation of adult hippocampal neurogenesis.     

Effects of steroid hormones on neurogenesis in the hippocampus of the adult female rodent during the estrous cycle, pregnancy, lactation and aging

Adult neurogenesis exists in most mammalian species, including humans, in two main areas: the subventricular zone (new cells migrate to the olfactory bulbs) and the dentate gyrus of the hippocampus. Many factors affect neurogenesis in the hippocampus and the subventricular zone, however the focus of this review will be on factors that affect hippocampal neurogenesis, particularly in females. Sex differences are often seen in levels of hippocampal neurogenesis, and these effects are due in part to differences in circulating levels of steroid hormones such as estradiol, progesterone, and corticosterone during the estrous cycle, in response to stress, with reproduction (including pregnancy and lactation), and aging. Depletion and administration of these same steroid hormones also has marked effects on hippocampal neurogenesis in the adult female, and these effects are dependent upon reproductive status and age. The present review will focus on current research investigating how hippocampal neurogenesis is altered in the adult female rodent across the lifespan.     

Nature and fate of proliferative cells in the hippocampal dentate gyrus during the life span of the rhesus monkey

The nature of proliferative cells in the subgranular zone (SGZ) of the hippocampal region and the fate of their progeny was analyzed by 3H-thymidine (3H-TdR) autoradiography combined with immunocytochemistry at the light and electron microscopic levels in 18 rhesus monkeys ranging in age from late gestation to 17 years. Our analysis indicates that, during the last quarter of gestation and the first 3 postnatal months, the SGZ produces both glial and neuronal cells. These 2 major classes of cells originate from the 2 precursor lines and, following their mitotic division, migrate to the granular layer. During the juvenile period (4-6 months of age), neuronal production tapers off and most postmitotic cells remaining within the SGZ differentiate into glial elements. In postpubertal animals (3 years and older), the 3H-TdR-labeled cells in the dentate gyrus belong to several non-neuronal classes. The largest group was immunoreactive to the glial fibrillary acidic protein (GFAP) at both the light and electron microscopic levels, indicating their astrocytic nature. The remaining 3H-TdR-labeled, GFAP-negative cells had ultra-structural characteristics of either microglia, oligodendroglia, or their progenitory stem cells. Therefore, there is a continuing addition and/or turnover of the glial cells in the dentate gyrus of sexually mature monkeys, but, in contrast to the massive neurogenesis reported in adult rodents, the production of new neurons could not be detected after puberty. The significance of a stable population of neurons in the hippocampal formation of mature primates is discussed in relation to its possible function in memory.     

The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain

Neurogenesis occurs in two regions of the adult brain, namely, the subventricular zone (SVZ) throughout the wall of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) in hippocampal formation. Adult neurogenesis requires several neurotrophic factors to sustain and regulate the proliferation and differentiation of the adult stem cell population. In the present review, we examine the cellular and functional aspects of a trophic system mediated by fibroblast growth factor-2 (FGF-2) and its receptors (FGFRs) related to neurogenesis in the SVZ and SGZ of the adult rat brain. In the SVZ, FGF-2 is expressed in GFAP-positive cells of SVZ but is not present in proliferating precursor cells, which instead express FGFR-1 and FGFR-2, but not FGFR-3 mRNA, although expressed in the SVZ, and FGFR-4. Therefore, it seems that in the SVZ FGF-2 may be released by GFAP-positive cells, different from the precursor cell lineage, and via volume transmission it reaches the proliferating precursor cells. FGFR-1 mRNA is also expressed in the SGZ and is localized in BrdU-labeled precursor cells, whereas FGFR-2 and FGFR-3 mRNA, although expressed in the SGZ, are not located within proliferating precursor cells. An aged-related decline of proliferating precursor cells in the SVZ and DG of old rats has been well documented, and there is the suggestion that in part it could be the consequence of alterations in growth factor expression levels. Thus, the old precursors may respond to growth factors, suggesting that during aging the basic components for neuronal precursor cell proliferation are retained and the capacity to increase neurogenesis after appropriate stimulation is still preserved. In conclusion, the trophic system mediated by FGF-2 and its receptors contributes to create an important micro-environmental niche that promotes neurogenesis in the adult and aged brain. This article is dedicated to the special issue Brain Plasticity: Aging and Neuropychiatric Disorders.     

Impaired basal and running-induced hippocampal neurogenesis coincides with reduced Akt signaling in adult R6/1 HD mice

Huntington's disease (HD) is a fatal neurodegenerative disorder affecting a range of cellular and molecular functions in the brain. Deficits in adult hippocampal neurogenesis (AHN) have been documented in the R6/1 mouse model of HD. Here we examined basal and running-induced neuronal precursor proliferation in adult female and male R6/1 HD mice. We further tested whether sequential delivery of voluntary running followed by environmental enrichment could synergistically enhance functional AHN in female R6/1 HD mice. R6/1 HD mice engaged in significantly reduced levels of voluntary running, with males showing a more severe deficit. Basal neural precursor proliferation in the hippocampal sub-granular zone remained unchanged between female and male R6/1 HD mice and neither sex significantly responded to running-induced proliferation. While discrete provision of running wheels and enriched environments doubled AHN in adult female R6/1 HD mice it did not reflect the significant 3-fold increase in female wildtypes. Nevertheless, triple-label c-Fos/BrdU/NeuN immunofluorescence and confocal microscopy provided evidence that the doubling of AHN in female R6/1 HD mice was functional. Intrinsic cellular dysfunction mediated by protein aggregates containing mutant huntingtin (mHtt) did not appear to coincide with AHN deficits. In the hippocampus of female R6/1 HD mice, proliferating precursors and 6 week old adult-generated neurons were devoid of mHtt immuno-reactive aggregates, as were endothelial, microglial and astroglial cells populating the neurogenic niche. Serum transforming growth factor-β concentrations remained unaltered in female R6/1 HD mice as did the hippocampal levels of proliferating microglia and glial fibrillarly acidic protein expression. Examining the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis showed no change in base-line serum GH between genotypes. However, despite a reduced distance, acute running increases serum GH in both female wildtype and R6/1 HD mice. Serum IGF-1 levels were increased in female R6/1 HD mice compared to wildtypes during daytime inactive period, while hippocampal levels of the IGF-1 receptor remained unchanged. Running induced Akt phosphorylation in the hippocampus of female wildtype mice, which was not reflected in R6/1 HD mice. Total Akt levels were decreased in the hippocampus of both control and running R6/1 HD mice. Our results show adult-generated hippocampal neurons in female R6/1 HD mice express c-Fos and that running and Akt signaling deficits may mediate reduced basal and running-induced AHN levels.     

Neurotransmitter regulation of adult neurogenesis: putative therapeutic targets

The evidence that new neuron addition takes place in the mammalian brain throughout adult life has dramatically altered our perspective of the potential for plasticity in the adult CNS. Although several recent reports suggest a latent neurogenic capacity in multiple brain regions, the two major neurogenic niches that retain the ability to generate substantial numbers of new neurons in adult life are the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) in the hippocampal formation. The discovery of adult neurogenesis has also unveiled a novel therapeutic target for the repair of damaged neuronal circuits. In this regard, understanding the endogenous mechanisms that regulate adult neurogenesis holds promise both for a deeper understanding of this form of structural plasticity, as well as the identification of pathways that can serve as therapeutic targets to manipulate adult neurogenesis. The purpose of the present review is to discuss the regulation of adult neurogenesis by neurotransmitters and to highlight the relevance of these endogenous regulators as targets to modulate adult neurogenesis in a clinical context.     

Toll‐like receptor 4 differentially regulates adult hippocampal neurogenesis in an age‐ and sex‐dependent manner

Toll‐like receptor 4 (TLR4) is primarily responsible for initiating an immune response following pathogen recognition. However, TLR4 is also expressed on neural progenitor cells and has been reported to regulate hippocampal neurogenesis as young male TLR4 knockout mice show increases in cell proliferation and doublecortin positive cells. Whether these effects occur in both sexes and are sustained with normal aging is currently unknown. The present study evaluated whether TLR4 deficiency alters adult hippocampal neurogenesis in young (3–4 months) and aged (18–20 months), male and female, TLR4 deficient (TLR4?/?; B6.B10ScN‐Tlr4lps‐del/JthJ) and wild type (WT) mice. Additionally, neurogenesis within the dorsal and the ventral hippocampal subdivisions was evaluated to determine if TLR4 has differential effects across the hippocampus. Bromodeoxyuridine (BrdU) was administered to quantify new cell survival as well as cell differentiation. Ki‐67 was measured to evaluate cell proliferation. Results show that young TLR4?/? females had higher rates of proliferation and neuronal differentiation in both the dorsal and ventral hippocampus relative to WT females. Young TLR4?/? males show elevated proliferation and neuronal differentiation mainly in the ventral hippocampus. While young TLR4?/? mice show enhanced neurogenesis compared to young WT mice, the increase was not apparent in the aged TLR4?/? mice. Both aged WT and TLR4?/? mice showed a decrease in proliferation, new cell survival, and neuronal differentiation compared to young WT and TLR4?/? mice. The data collectively indicate that TLR4 regulates hippocampal neurogenesis in young adults, but that these effects are region‐specific in males and that females show broader changes in neurogenesis throughout the hippocampus.     

Adult neurogenesis and the ischemic forebrain.

The recent identification of endogenous neural stem cells and persistent neuronal production in the adult brain suggests a previously unrecognized capacity for self-repair after brain injury. Neurogenesis not only continues in discrete regions of the adult mammalian brain, but new evidence also suggests that neural progenitors form new neurons that integrate into existing circuitry after certain forms of brain injury in the adult. Experimental stroke in adult rodents and primates increases neurogenesis in the persistent forebrain subventricular and hippocampal dentate gyrus germinative zones. Of greater relevance for regenerative potential, ischemic insults stimulate endogenous neural progenitors to migrate to areas of damage and form neurons in otherwise dormant forebrain regions, such as the neostriatum and hippocampal pyramidal cell layer, of the mature brain. This review summarizes the current understanding of adult neurogenesis and its regulation in vivo, and describes evidence for stroke-induced neurogenesis and neuronal replacement in the adult. Current strategies used to modify endogenous neurogenesis after ischemic brain injury also will be discussed, as well as future research directions with potential for achieving regeneration after stroke and other brain insults.