Morris water maze learning in two rat strains increases the expression of the polysialylated form of the neural cell adhesion molecule in the dentate gyrus but has no effect on hippocampal neurogenesis

In the current study, the authors investigated whether Morris water maze learning induces alterations in hippocampal neurogenesis or neural cell adhesion molecule (NCAM) polysialylation in the dentate gyrus. Two frequently used rat strains, Wistar and Sprague-Dawley, were trained in the spatial or the nonspatial version of the water maze. Both training paradigms did not have an effect on survival of newly formed cells that were labeled 7-9 days prior to the training or on progenitor proliferation in the subgranular zone. However, the granule cell layer of the spatially trained rats contained significantly more positive cells of the polysialylated form of the NCAM. These data demonstrate that Morris water maze learning causes plastic change in the dentate gyrus without affecting hippocampal neurogenesis.     

Nerve growth factor improves spatial learning and restores hippocampal cholinergic fibers in rats withdrawn from chronic treatment with ethanol

The cholinergic septohippocampal pathway has long been known to be important for learning and memory. Prolonged intake of ethanol causes enduring memory deficits, which are paralleled by partial depletion of hippocampal cholinergic afferents. We hypothesized that exogenous supply of nerve growth factor (NGF), known to serve as a trophic substance for septal cholinergic neurons, can revert the ethanol-induced changes in the septohippocampal cholinergic system. Adult rats were given a 20% ethanol solution as their only source of fluid for 6 months. During the first 4 weeks after the animals were withdrawn from ethanol, they were intraventricularly infused with either NGF or vehicle alone via implanted osmotic minipumps. The vehicle-infused withdrawn animals showed impaired performance on a spatial reference memory version of the Morris water maze task, both during the task acquisition and on the retention test. In contrast, NGF-treated withdrawn rats were able to learn the task as well as controls, and significantly outperformed the vehicle-infused withdrawn rats. The histological analysis revealed that, in the latter group, the length density of fibers immunoreactive to choline acetyltransferase was reduced relative to control values by approximately 25%, as measured in the dentate gyrus and regio superior of the hippocampal formation. However, in NGF-treated withdrawn rats, the length density of these fibers was identical to that of control rats. These data provide support to the notion that NGF is capable of ameliorating memory deficits and restoring septohippocampal cholinergic projections following chronic treatment with ethanol. Electronic Publication     

Working memory training decreases hippocampal neurogenesis

The relationship between adult hippocampal neurogenesis and cognition appears more complex than suggested by early reports. We aimed to determine if the duration and task demands of spatial memory training differentially affect hippocampal neurogenesis. Adult male rats were trained in the Morris water maze in a reference memory task for 4 days, or alternatively working memory for either 4 or 14 days. Four days of maze training did not impact neurogenesis regardless of whether reference or working memory paradigms were used. Interestingly, 2 weeks of working memory training using a hidden platform resulted in fewer newborn hippocampal neurons compared with controls that received either cue training or no maze exposure. Stress is a well-established negative regulator of hippocampal neurogenesis. We found that maze training in general, and a working memory task in particular, increased levels of circulating corticosterone after 4 days of training. Our study indicates that working memory training over a prolonged period of time reduces neurogenesis, and this reduction may partially be mediated by increased stress.     

Role of the cholinergic system in regulating survival of newborn neurons in the adult mouse dentate gyrus and olfactory bulb

Neurogenesis in the subgranular zone of the hippocampal dentate gyrus and olfactory bulbs continues into adulthood and has been implicated in the cognitive function of the adult brain. The basal forebrain cholinergic system has been suggested to play a role in regulating neurogenesis as well as learning and memory in these regions. Herein, we report that highly polysialylated neural cell adhesion molecule (PSA-NCAM)-positive immature cells as well as neuronal nuclei (NeuN)-positive mature neurons in the dentate gyrus and olfactory bulb express multiple acetylcholine receptor subunits and make contact with cholinergic fibers. To examine the function of acetylcholine in neurogenesis, we used donepezil (Aricept), a potent and selective acetylcholinesterase inhibitor that improves cognitive impairment in Alzheimer's disease. Intraperitoneal administrations of donepezil significantly enhanced the survival of newborn neurons, but not proliferation of neural progenitor cells in the subgranular zone or the subventricular zone of normal mice. Moreover, donepezil treatment reversed the chronic stress-induced decrease in neurogenesis. Taken together, these results suggest that activation of the cholinergic system promotes survival of newborn neurons in the adult dentate gyrus and olfactory bulb under both normal and stressed conditions.     

Forebrain acetylcholine regulates adult hippocampal neurogenesis and learning

Hippocampus-mediated learning enhances neurogenesis in the adult dentate gyrus (DG), and this process has been suggested to be involved in memory formation. The hippocampus receives abundant cholinergic innervation and acetylcholine (ACh) plays an important role in learning and Alzheimer's disease (AD) pathophysiology. Here, we show that a selective neurotoxic lesion of forebrain cholinergic input with 192 IgG-saporin reduces DG neurogenesis with a concurrent impairment in spatial memory. Conversely, systemic administration of the cholinergic agonist physostigmine increases DG neurogenesis. We find that changes of forebrain ACh levels primarily influence the proliferation and/or the short-term survival rather than the long-term survival or differentiation of the new neurons. We further demonstrate that these newly born cells express the muscarinic receptor subtypes M1 and M4. Our data provide evidence that forebrain ACh promotes neurogenesis, and suggest that the impaired cholinergic function in AD may in part contribute to deficits in learning and memory through reductions in the formation of new hippocampal neurons.     

Experimental approaches to age-related cognitive impairments

Rats exhibit morphological, biochemical, and metabolic changes in their brains, as well as cognitive deficits, with aging. Aged rats were found to be significantly impaired compared to young rats in a water maze task and test of motor coordination, and show reduced locomotor activity and exploration. Although aged rats did exhibit deficits as a group, not all aged rats were impaired. Additionally, the subgroup that was impaired on one task was not necessarily the subgroup that was impaired on another task. The cholinergic projection neurons in the basal forebrain region were significantly atrophied in the aged rodent. The degree of atrophy was highly correlated with the cognitive impairment exhibited on the Morris water maze task. Swollen choline acetyltransferase (ChAT)-positive "plaque-like" structures were observed in the neocortex of the aged but not the young rats. Declines in cholinergic activity in the brain has also been observed during aging. Biochemical measurements of ChAT in the basal forebrain region of aged rats revealed small but consistent decreases in ChAT activity compared to young rats. General metabolic activity, measured by the 2-deoxyglucose method, was also decreased in the hippocampal CA1 and CA3 fields, the dentate gyrus, the medial septal-diagonal band area, and the prefrontal cortex of aged rats. There was a significant correlation between the decrease in glucose utilization and deficits on the Morris water maze. Most aged rats exhibit pathological EEG patterns as reflected by frequent long-duration high voltage neocortical spindles (HVS) during immobility. Bilateral lesions of the nucleus basalis and scopolamine treatment increased the incidence of HVS, thereby mimicking changes in the aged brain. We attempted to ameliorate the cognitive deficits observed in subgroups or impaired rats by either: (1) implanting fetal cells of basal forebrain origin into the hippocampus, or (2) infusing nerve growth factor (NGF) chronically into the lateral ventricle. The grafts appeared to facilitate an improvement in the ability of the impaired aged rats to perform in the Morris water maze. This improved performance was reversed by injections of atropine at doses that did not affect the behavior of young animals that performed well in the same task. These results suggest that enhancement of the cholinergic system could have an effect on the performance of the impaired aged animals. The study of the effects of infusions of NGF clearly demonstrate that the ability of impaired aged rats to remember what they had previously learned was increased after NGF treatment.(ABSTRACT TRUNCATED AT 400 WORDS)     

Inhibitor of vascular endothelial growth factor receptor tyrosine kinase attenuates cellular proliferation and differentiation to mature neurons in the hippocampal dentate gyrus after transient forebrain ischemia in the adult rat

Neurogenesis in the adult hippocampal dentate gyrus is promoted by transient forebrain ischemia. The mechanism responsible for this ischemia-induced neurogenesis, however, remains to be determined. It has been suggested that there may be a close relationship between neurogenesis and the expression of vascular endothelial growth factor, an angiogenic factor. The purpose of the present study was to examine the relationship between vascular endothelial growth factor and cell proliferation in the dentate gyrus after transient forebrain ischemia. The mRNA expression of vascular endothelial growth factor was increased in the dentate gyrus on day 1 after ischemia. Immunohistochemical analysis on day 9 after ischemia, when a significant increase in cell proliferation was seen, showed that the cerebral vessel space in the subgranular zone of the dentate gyrus had not been affected by the ischemia. Neither were the vascular densities on days 1 and 3 after ischemia altered compared with those of non-operated naïve control rats. Furthermore, the distance from the center of the proliferative cells to the nearest cerebral vessel of ischemic rats was comparable to that of the sham-operated rats. We demonstrated that transient forebrain ischemia-induced cell proliferation and differentiation to mature neurons in the hippocampal dentate gyrus was attenuated by the i.c.v. administration of a vascular endothelial growth factor receptor tyrosine kinase inhibitor. These results suggest that vascular endothelial growth factor receptor at the early period of reperfusion may contribute to neurogenesis rather than to angiogenesis in the hippocampal dentate gyrus.     

Selective loss of hilar neurons and impairment of initial learning in rats after repeated administration of electroconvulsive shock seizures

Prolonged seizures induced by neurotoxins or intracranial electrical stimulation provoke death of hippocampal neurons, which results in conspicuous learning and memory deficits. We examined whether repeated brief seizures elicited by electroconvulsive shock (ECS) can also deteriorate hippocampal structure and function. Adult Wistar rats were administered six ECS seizures, the first five of which were 24 h apart, whilst the last two were spaced by a 2-h interval. Following a 2-month recovery period, the cognitive status of the animals was assessed using the water maze task. ECS-treated animals were incapable of learning the constant platform position version of this task during the first 4 days of training, but performed similarly to control rats throughout the rest of the acquisition period, on the probe trial, and on the variable platform position and visible platform tasks. The results of the morphological analysis showed that the total number of hippocampal pyramidal neurons and dentate gyrus granule cells were similar in control and ECS-treated rats. However, ECS treatment caused loss of approximately 17% of cells in the hilus of the dentate gyrus, which was accompanied by significant mossy fiber sprouting into the dentate inner molecular layer. In addition, we found that the ECS-induced decrease in the total number of hilar cells was not due to loss of inhibitory interneurons immunoreactive to somatostatin. These findings support the view that ECS-induced seizures can produce a number of morphological and functional changes in the rat hippocampal formation, which qualitatively resemble those previously described in other seizure models.     

Septo-temporal gradients of neurogenesis and activity in 13-month-old rats

Recent studies suggest that hippocampal function is partially dissociable along its septo-temporal axis: the septal hippocampus is more critical for spatial processing, while the temporal hippocampus may be more important for non-spatial-related behavior. In young adults, water maze training specifically activates new neurons in the temporal hippocampus, but it is unknown whether subregional differences are maintained in older animals, which have reduced neurogenesis levels. We therefore examined gradients of activity-related Fos expression and neurogenesis in 13-month-old rats and found that neurogenesis occurs relatively evenly throughout the dentate gyrus. Water maze experience significantly increased Fos expression in the suprapyramidal blade and Fos was highest in the septal pole of the dentate gyrus whether the animal learned a platform location, swam in the absence of a platform or remained in their cage. No Fos+ young neurons were found using typical markers of immature neurons. However, Fos expression in the subgranular zone, where adult-born neurons predominate, was disproportionally high in the temporal dentate gyrus. These findings indicate that adult-born neurons in the temporal hippocampus are preferentially activated compared with older neurons.     

Short-term behavioral and electrophysiological consequences of underwater trauma

In a previous work we found that a 30-s underwater trauma, following 8 days of training for a spatial memory task in the water maze, resulted in poor performance in the spatial memory task at both 1 h and 3 weeks after the trauma. Here we found that compared with naive animals and animals that were trained for the spatial learning task but were not traumatized, the traumatized rats showed impaired performance in a spatial learning task in the water maze 20 min after the trauma and a reduced level of dentate gyrus long-term potentiation (LTP) 40 min after high-frequency stimulation to the perforant path. We also found a positive correlation between the behavioral performance and hippocampal plasticity. The reduced ability to induce LTP suggests that the trauma-related behavioral impairment is mediated by hippocampal-dependent processes. The underwater trauma may provide an important and potentially powerful model for understanding the mechanisms underlying the relationship between stress, cognition, and learning.     

The role of adult hippocampal neurogenesis in reducing interference

Adult neurogenesis in the hippocampal dentate gyrus plays an important role in learning and memory. However, the precise contribution of the new neurons to hippocampal function remains controversial. Emerging evidence suggests that neurogenesis is important for pattern separation and for mitigating interference when similar items must be learned at different times. In the present study, we directly test this prediction using a recently developed olfactory memory task that has those specific features. In this task, rats learn two highly interfering lists of odor pairs, one after the other, in either the same or in different contexts. Consistent with our hypothesis, focal cranial irradiation, resulting in selective reduction of neurogenesis within the dentate gyrus, significantly impaired the ability to overcome interference during learning of the second list. The ability to learn a single odor list was unimpaired. We also show that irradiation had no effect on learning in a hippocampal-dependent spatial alternation task. Although both tasks involved learning interfering responses, the time course for learning the interfering items differed. Learning the interfering odor lists took place sequentially, over the course of several sessions, whereas learning the interfering spatial locations took place concurrently, within each session. Thus, the gradual addition of new neurons may have provided a pattern separation mechanism for the olfactory task but not for the maze task. These findings demonstrate a role for neurogenesis in resolving interference and they are consistent with models suggesting a critical role for neurogenesis in pattern separation.     

Chronic high corticosterone reduces neurogenesis in the dentate gyrus of adult male and female rats

Adult neurogenesis in the dentate gyrus of the hippocampus is altered with stress exposure and has been implicated in depression. High levels of corticosterone (CORT) suppress neurogenesis in the dentate gyrus of male rats. However both acute and chronic stress do not consistently reduce adult hippocampal neurogenesis in female rats. Therefore, this study was conducted to investigate the effect of different doses of corticosterone on hippocampal neurogenesis in male and female rats. Rats received 21 days of s.c. injections of either oil, 10 or 40 mg/kg CORT. Subjects were perfused 24 h after the last CORT injection and brains were analyzed for cell proliferation (Ki67-labeling) or immature neurons (doublecortin-labeling). Results show that in both males and females high CORT, but not low CORT, reduced both cell proliferation and the density of immature neurons in the dentate gyrus. Furthermore, high CORT males had reduced density in immature neurons in both the ventral and dorsal regions while high CORT females only showed the reduced density of immature neurons in the ventral hippocampus. The high dose of CORT disrupted the estrous cycle of females. Further, the low dose of CORT significantly reduced weight gain and increased basal CORT levels in males but not females, suggesting a greater vulnerability in males with the lower dose of CORT. Thus we find subtle sex differences in the response to chronic CORT on both body weight and on neurogenesis in the dorsal dentate gyrus that may play a role in understanding different vulnerabilities to stress-related neuropsychiatric disorders between the sexes.     

Reproductive experience alters hippocampal neurogenesis during the postpartum period in the dam

Pregnancy and the postpartum period are a time of maximal neural and behavioral plasticity. Recent work has shown that hippocampus-dependent learning and memory performance and hippocampus morphology are affected by motherhood and reproductive experience (number of times pregnant and given birth). Adult neurogenesis in the dentate gyrus of the hippocampus is influenced by steroid hormones such as estradiol and corticosterone, which fluctuate during pregnancy and the postpartum period. Thus, it is possible that hippocampal neurogenesis may be affected by motherhood and reproductive experience. The present study aimed to investigate the role of reproductive experience on hippocampal neurogenesis via cell proliferation and cell survival and to determine whether differences were due to the effect of pregnancy and/or pup-exposure alone. Four groups of female Sprague-Dawley rats were used; multiparous, primiparous, nulliparous, and nulliparous rats exposed to pups. All rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg) approximately 24 h after birth/pup-exposure with age-matched controls. Rats were perfused either 24 h (Expt. 1: Cell proliferation) or 21 days (Expt. 2: Cell survival) after BrdU injection. Results show there is a significant decrease in cell proliferation in the dentate gyrus of primiparous and multiparous rats during the early postpartum period, and a decrease in cell survival in the dentate gyrus during the postpartum in primiparous rats, regardless of pup-exposure, compared with all other groups. In addition, brief pup exposure to nulliparous rats significantly increased cell proliferation and cell death in the dentate gyrus, while 22 days of pup exposure to nulliparous rats (sensitized rats) resulted in increased cell survival and cell death in the dentate gyrus. Collectively these results indicate that reproductive experience significantly affects hippocampal neurogenesis and that these effects are not due to the effect of pregnancy or pup-exposure alone.     

Changes in the expression of Hes5 and Mash1 mRNA in the adult rat dentate gyrus after transient forebrain ischemia

Accumulating evidence indicates that neurogenesis in the adult brain occurs in restricted brain regions, including the hippocampal dentate gyrus and is promoted by ischemia. The mechanism responsible for ischemia-induced neurogenesis in the adult brain, however, remains unclear. Notch pathway plays a pivotal role in the regulation of the timing for differentiation and determination of the fate of neural progenitor cells in the developing nervous system. To elucidate the mechanism underlying ischemia-induced neurogenesis, we investigated changes in the expression of mRNAs of Hes5, which is a downstream target of Notch, and Mash1, a neurogenic basic helix-loop-helix factor, which is negatively regulated by Hes5, in the adult hippocampal dentate gyrus after transient forebrain ischemia. Transient forebrain ischemia was produced by four-vessel occlusion procedure in rats. The levels of Hes5 mRNA decreased on days 1 and 3 after the start of reperfusion and the decreased levels of the mRNA returned to the basal level by 5 days after ischemia. In contrast, the level of Mash1 mRNA increased on day 1 and then returned to the basal level by 3 days after ischemia. These results suggest that an inhibition of Notch activity and subsequent expression of neurogenic basic helix-loop-helix factors, including Mash1, may, at least in part, contribute to ischemia-induced neurogenesis in the adult dentate gyrus.     

Neonatal lesion of forebrain cholinergic neurons: further characterization of behavioral effects and permanency

Intraventricular injections of 192 IgG-saporin in the neonatal rat caused severe loss of basal forebrain cholinergic neurons and ectopic hippocampal ingrowths. These were evident at 24 months of age and thus, were lifelong consequences of the 192 IgG-saporin treatment. When tested as young adults on a novel water-escape radial arm maze, the rats with this lesion were slower to learn the task, committing significantly more working and reference memory errors before they achieved control level of performance. It is unlikely that this was a result of attentional impairment as the lesioned rats performed as vigilantly as controls in a five choice serial reaction time task. When tested in the Morris water maze at 22 months of age, they were slower at learning the hidden platform location. This contrasts with previous studies which have repeatedly shown that they normally acquire this task as young adults. It was concluded that this neonatal cholinergic lesion has modest but discernable effects on problem solving in young adulthood that are consistent with the reported effects of the lesion on cortical pyramidal neurons. The cognitive effects of the lesion may become more severe in aging, perhaps as a result of the added effects of aging on these neurons.     

Lack of effect of moderate Purkinje cell loss on working memory.

192 immunoglobulin G-saporin (192-sap) is an immunotoxin which targets the cholinergic basal forebrain after injection into either the ventricular system or the parenchyma of the rat brain. When injected by the i.c.v. route, 192-sap kills some cerebellar Purkinje cells in addition to its more extensive killing of the cholinergic basal forebrain. Behaviorally, i.c.v. injections of 192-sap result in impaired performance in a variety of experimental paradigms of learning and memory including a working memory task in the radial maze. The current study examined the contribution, if any, of immunotoxin-induced Purkinje cell loss to impaired performance in the radial maze. To meet this aim, we used i.c.v. injection of another immunotoxin, OX7-saporin (OX7-sap), at a dose that produced Purkinje cell loss of similar extent to that produced by i.c.v. 192-sap. We then compared these OX7-sap-injected rats with 192-sap-injected rats in a radial maze working memory task. We found a working memory impairment only in the 192-sap-injected rats.These data show that moderate Purkinje cell loss alone is insufficient to impair working memory. Furthermore, the data are consistent with the idea that the working memory deficit observed in 192-sap-injected animals is likely due to lesioning of the cholinergic basal forebrain.     

Neurogenesis in the adult dentate gyrus after cortical infarcts: effects of infarct location, N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment

Stimulation of cell proliferation and neurogenesis in the adult dentate gyrus has been observed after focal and global brain ischemia but only little is known about the underlying mechanisms. We here analyzed neurogenesis in the dentate gyrus after small cortical infarcts leaving the hippocampal formation and subcortical regions intact. Using the photothrombosis model in adult rats, focal ischemic infarcts were induced in different cortical areas (sensorimotor forelimb and hindlimb cortex) and proliferating cells were labeled at days 3-14 after infarct induction with bromodeoxyuridine. At 2, 4, and 10 weeks after ischemia, immunocytochemistry was performed with immature neuronal (doublecortin), mature neuronal (neuronal nuclei antigen) and glial (calcium-binding protein beta S100beta) markers. When compared with sham-operated controls, animals with infarcts in the forelimb as well as hindlimb cortex revealed an increase in survival of newborn progenitor cells at four and 10 weeks after the insult with predominance at the ipsilateral side. Triple immunofluorescence and confocal laser scanning microscopy revealed an increase in neurogenesis in all groups that was more pronounced 10 weeks after the infarct. Application of the N-methyl-D-aspartate (NMDA)-receptor antagonist MK-801 during lesion induction significantly enhanced neurogenesis in the dentate gyrus. An even stronger increase in newborn neurons was observed after anti-inflammatory treatment with indomethacine during the first 16 days of the experiment. The present study demonstrates that small cortical infarcts leaving subcortical structures intact increase neurogenesis in the dentate gyrus and that these processes can be stimulated by N-methyl-D-aspartate receptor blockade and anti-inflammatory treatment.     

Basal dendrites are present in newly born dentate granule cells of young but not aged pilocarpine-treated chronic epileptic rats

Epilepsy is known to influence hippocampal dentate granule cell (DGC) layer neurogenesis. In young adult rats, status epilepticus (SE) increases the number DGC newly borne cells and basal dendrites (BD), which persist at long-term. In contrast, little is known on whether these phenomena occur in elderly epileptic animals. In the present study, we compare DGC proliferation and the incidence of BD in young and aged pilocarpine-treated rats. Three epileptic groups were considered: Young animals given pilocarpine at 3 months of age. Aged animals treated with pilocarpine at 3 months of age that were sacrificed at 17–20 months. Aged animals that had pilocarpine and developed SE at 20 months, being sacrificed 2 months later. Nine days prior to sacrifice, animals underwent swimming sessions in the Morris water maze as a protocol for the development of hippocampal neurogenesis. We found a higher incidence of newly born DGC cells in young as compared to aged epileptic animals (P<0.001). This later group however, was not homogeneous. While a significant increase in DGC neurogenesis was observed when aged animals with long lasting epilepsy were compared to non-epileptic controls (P<0.01), this has not been recorded in aged animals that had epilepsy for only 2 months (P>0.05). When the number of DGC containing BD was considered, a significantly higher incidence was observed in young as compared to aged epileptic rats (P=0.001). Animals in this later group virtually lacked BD in newly formed dentate gyrus (DG) cells. Based on these results we conclude that plastic changes during epileptogenesis and the development of a pathological substrate in young animals is associated with DGC proliferation and the emergence of BD. As aging occurs, DGC neurogenesis can still be induced in rats with a long-term history of epilepsy but the emergence of BD is markedly reduced.     

Repeated estradiol administration alters different aspects of neurogenesis and cell death in the hippocampus of female, but not male, rats

Estradiol has been shown to have neuroprotective effects, and acute estradiol treatment enhances hippocampal neurogenesis in the female brain. However, little is known about the effects of repeated administration of estradiol on the female brain, or about the effects of estradiol on the male brain. Gonadectomized male and female adult rats were injected with 5-bromo-2-deoxyuridine (BrdU) (200 mg/kg), and then 24 h later were given subcutaneous injections of either estradiol benzoate (33 mug/kg) or vehicle daily for 15 days. On day 16, animals were perfused and the brains processed to examine cells expressing Ki-67 (cell proliferation), BrdU (cell survival), doublecortin (young neuron production), pyknotic morphology (cell death), activated caspase-3 (apoptosis), and Fluoro-Jade B (degenerating neurons) in the dentate gyrus. In female rats, repeated administration of estradiol decreased the survival of new neurons (independent of any effects on initial cell proliferation), slightly increased cell proliferation, and decreased overall cell death in the dentate gyrus. In male rats, repeated administration of estradiol had no significant effect on neurogenesis or cell death. We therefore demonstrate a clear sex difference in the response to estradiol of hippocampal neurogenesis and apoptosis in adult rats, with adult females being more responsive to the effects of estradiol than males.