Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

Dentate gyrus adult neurogenesis is implicated in the formation of hippocampal‐dependent contextual associations. However, the role of adult neurogenesis during reward‐based context‐dependent paradigms—such as conditioned place preference (CPP)—is understudied. Therefore, we used image‐guided, hippocampal‐targeted X‐ray irradiation (IG‐IR) and morphine CPP to explore whether dentate gyrus adult neurogenesis plays a role in reward memories created in adult C57BL/6J male mice. In addition, as adult neurogenesis appears to participate to a greater extent in retrieval and extinction of recent (<48 hr posttraining) versus remote (>1 week posttraining) memories, we specifically examined the role of adult neurogenesis in reward‐associated contextual memories probed at recent and remote timepoints. Six weeks post‐IG‐IR or Sham treatment, mice underwent morphine CPP. Using separate groups, retrieval of recent and remote reward memories was found to be similar between IG‐IR and Sham treatments. Interestingly, IG‐IR mice showed impaired extinction—or increased persistence—of the morphine‐associated reward memory when it was probed 24‐hr (recent) but not 3‐weeks (remote) postconditioning relative to Sham mice. Taken together, these data show that hippocampal‐directed irradiation and the associated decrease in dentate gyrus adult neurogenesis affect the persistence of recently—but not remotely—probed reward memory. These data indicate a novel role for adult neurogenesis in reward‐based memories and particularly the extinction rate of these memories. Consideration of this work may lead to better understanding of extinction‐based behavioral interventions for psychiatric conditions characterized by dysregulated reward processing.     

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin–thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU‐positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir‐containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU‐positive/NeuN‐positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir‐fed runner mice showed similar levels of neurogenesis as sedentary, normal‐fed controls. However, valganciclovir‐fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.     

Involvement of the dorsal hippocampus in expression and extinction of cocaine‐induced conditioned place preference

A key aspect of substance abuse is that drug taking often occurs in a specific context. As a consequence, exposure to drug‐associated contexts can trigger cravings and relapse, even after long periods of abstinence. Although many studies have demonstrated that the hippocampus is critical for developing and retrieving contextual and spatial memories, comparatively little is known about the role of the hippocampus in acquiring and inhibiting memories involving contexts and drugs of abuse. We examined the effects of hippocampal inactivation on expression of cocaine‐induced conditioned place preference (CPP) after initial acquisition or extinction of CPP in C57BL/6 mice. During acquisition of CPP, distinct tactile cues were paired with cocaine (20 mg kg^?1, intraperitoneal, CS+) and different tactile cues were paired with saline (CS?) on alternate days. Groups differed in whether the CS+ and CS? cues were presented in the same large space (one‐compartment procedure) or distinct small spaces (two‐compartment procedure), as previous findings demonstrate that a two‐compartment configuration facilitates acquisition and attenuates extinction of a cocaine‐induced CPP. Microinjection of the GABA_A agonist, muscimol, into the dorsal hippocampus impaired (1) retrieval of a place preference after acquisition, (2) extinction of a place preference, and (3) retrieval of extinction. These effects differed depending on the spatial configuration during acquisition or extinction, suggesting that the dorsal hippocampus may differentially modulate drug seeking during retrieval and extinction of CPP.     

Involvement of Brain‐Derived Neurotrophic Factor and Neurogenesis in Oestradiol Neuroprotection of the Hippocampus of Hypertensive Rats

The hippocampus of spontaneously hypertensive rats (SHR) and deoxycorticosterone (DOCA)‐salt hypertensive rats shows decreased cell proliferation and astrogliosis as well as a reduced number of hilar cells. These defects are corrected after administration of 17β‐oestradiol (E₂) for 2 weeks. The present work investigated whether E₂ treatment of SHR and of hypertensive DOCA‐salt male rats modulated the expression of brain‐derived neurotrophic factor (BDNF), a neurotrophin involved in hippocampal neurogenesis. The neurogenic response to E₂ was simultaneously determined by counting the number of doublecortin‐immunopositive immature neurones in the subgranular zone of the dentate gyrus. Both hypertensive models showed decreased expression of BDNF mRNA in the granular zone of the dentate gyrus, without changes in CA1 or CA3 pyramidal cell layers, decreased BDNF protein levels in whole hippocampal tissue, low density of doublecortin (DCX)‐positive immature neurones in the subgranule zone and decreased length of DCX+ neurites in the dentate gyrus. After s.c. implantation of a single E₂ pellet for 2 weeks, BDNF mRNA in the dentate gyrus, BDNF protein in whole hippocampus, DCX immunopositive cells and the length of DCX+ neurites were significantly raised in both SHR and DOCA‐salt‐treated rats. These results indicate that: (i) low BDNF expression and deficient neurogenesis distinguished the hippocampus of SHR and DOCA‐salt hypertensive rats and (ii) E₂ was able to normalise these biologically important functions in the hippocampus of hypertensive animals.     

Neurogenesis in the septal and temporal part of the adult rat dentate gyrus

Structural and functional dissociation between the septal and the temporal part of the dentate gyrus predispose for possible differentiations in the ongoing neurogenesis process of the adult hippocampus. In this study, BrdU‐dated subpopulations of the rat septal and temporal dentate gyrus (coexpressing GFAP, DCX, NeuN, calretinin, calbindin, S100, caspase‐3 or fractin) were quantified comparatively at 2, 5, 7, 14, 21, and 30 days after BrdU administration in order to examine the successive time‐frames of the neurogenesis process, the glial or neuronal commitment of newborn cells and the occurring apoptotic cell death. Newborn neurons' migration from the neurogenic subgranular zone to the inner granular cell layer and expression of glutamate NMDA and AMPA receptors were also studied. BrdU immunocytochemistry revealed comparatively higher numbers of BrdU⁺ cells in the septal part, but stereological analysis of newborn and total granule cells showed an identical ratio in the two parts, indicating an equivalent neurogenic ability, and a common topographical pattern along each part's longitudinal and transverse axis. Similarly, both parts exhibited extremely low levels of newborn glial and apoptotic cells. However, despite the initially equal division rate and pattern of the septal and temporal proliferating cells, their later proliferative profile diverged in the two parts. Dynamic differences in the differentiation, migration and maturation process of the two BrdU‐incorporating subpopulations of newborn neurons were also detected, along with differences in their survival pattern. Therefore, we propose that various factors, including developmental date birth, local DG microenvironment and distinct functionality of the two parts may be the critical regulators of the ongoing neurogenesis process, leading the septal part to a continuous, rapid, and less‐disciplined genesis rate, whereas the quiescent temporal microenvironment preserves a quite steady, less‐demanding neurogenesis process. © 2014 Wiley Periodicals, Inc.     

Retrieval of morphine‐associated context induces cFos in dentate gyrus neurons

Addiction has been proposed to emerge from associations between the drug and the reward‐associated contexts. This associative learning has a cellular correlate, as there are more cFos+ neurons in the hippocampal dentate gyrus (DG) after psychostimulant conditioned place preference (CPP) versus saline controls. However, it is unknown whether morphine CPP leads to a similar DG activation, or whether DG activation is due to locomotion, handling, pharmacological effects, or—as data from contextual fear learning suggests—exposure to the drug‐associated context. To explore this, we employed an unbiased, counterbalanced, and shortened CPP design that led to place preference and more DG cFos+ cells. Next, mice underwent morphine CPP but were then sequestered into the morphine‐paired (conditioned stimulus+ [CS+]) or saline‐paired (CS−) context on test day. Morphine‐paired mice sequestered to CS+ had ∼30% more DG cFos+ cells than saline‐paired mice. Furthermore, Bregma analysis revealed morphine‐paired mice had more cFos+ cells in CS+ compared to CS− controls. Notably, there was no significant difference in DG cFos+ cell number after handling alone or after receiving morphine in home cage. Thus, retrieval of morphine‐associated context is accompanied by activation of hippocampal DG granule cell neurons. © 2014 Wiley Periodicals, Inc.     

Chronic cocaine exposure impairs progenitor proliferation but spares survival and maturation of neural precursors in adult rat dentate gyrus

Recent observations indicate that drugs of abuse, including alcohol and opiates, impair adult neurogenesis in the hippocampus. We have studied in rats the impact of cocaine treatment (20 mg/kg, daily, i.p.) on cell proliferation, survival and maturation following short-term (8-day) and long-term (24-day) exposure. Using 5'-bromo-2-deoxyuridine (BrdU) and Ki-67 as mitotic markers at the end of the drug treatments, we found that both short- and long-term cocaine exposures significantly reduced cell proliferation in the dentate gyrus (DG) of the hippocampus. By labelling mitotic cells with BrdU pulses before or during the early stages of the drug treatment, we determined that long-term cocaine exposure did not affect the survival of newly generated cells. In register with this finding, cocaine chronic exposure did not increase the number of apoptotic cells labelled by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling). Using doublecortin (DCX) immunocytochemistry and electron microscopy, we next examined the effects of cocaine exposure on the maturation of the neural precursors and on synaptic output to CA3. DCX immunocytochemistry showed that immature hippocampal cells of rats exposed to cocaine displayed normal arborization patterns and similar degrees of colocalization with BrdU at two different developmental stages. Moreover, cocaine did not produce significant morphological alterations of the mossy fibre projection system to stratum lucidum in the CA3 area of the hippocampus. The results presented demonstrate that chronic cocaine exposure impairs proliferation dynamics in the DG without significantly altering either the survival and growth of immature cells or the structural features of terminal projections to CA3.     

NDRG2通过Hes1参与癫痫发作后海马齿状回的神经发生

目的 探讨N-Myc下游调节基因2(N-Myc downstream regulated gene 2,NDRG2)与癫痫发作后海马齿状回神经发生的关系。方法 C57BL/6小鼠20只,随机分为癫痫组和对照组,每组又分为癫痫造模后1和7 d两个时间点,每个时间点5只,通过蛋白免疫印迹检测癫痫后海马齿状回NDRG2蛋白相对表达水平和mRNA相对表达水平变化; 使用双皮质素(DCX)染色标记未成熟神经元,神经巢蛋白(Nestin)标记神经干细胞,神经核蛋白(NeuN)标记成熟神经元,观察NDRG2对海马齿状回神经干细胞增殖影响; 采用RT-PCR检测发状分裂相关增强子1(hairy and enhancer of split 1,Hes 1)、NDRG2 mRNA相对表达表达水平,并分析两者之间的相关性; 观察NDRG2参与癫痫发作后神经发生的可能机制。结果 癫痫组与对照组比较,DCX、Nestin、NeuN、Hes1、NDRG2蛋白相对表达水平在1和7 d这2个时间点有显著性增高,并随时间逐渐递增。结论 癫痫发作后海马NDRG2蛋白相对表达水平增高,与癫痫发作后海马齿状回的神经细胞增值时间具有一致性和相关性,NDRG2可能参与癫痫发作后海马齿状回的神经发生过程; 同时发现海马NDRG2表达增加和Hes1分子表达增加具有相关性,故推测NDRG2可能通过Hes1参与癫痫发作后海马齿状回的神经发生。     

Microglial VPAC1R mediates a novel mechanism of neuroimmune‐modulation of hippocampal precursor cells via IL‐4 release

Neurogenesis, the production of new neurons from neural stem/progenitor cells (NSPCs), occurs throughout adulthood in the dentate gyrus of the hippocampus, where it supports learning and memory. The innate and adaptive immune systems are increasingly recognized as important modulators of hippocampal neurogenesis under both physiological and pathological conditions. However, the mechanisms by which the immune system regulates hippocampal neurogenesis are incompletely understood. In particular, the role of microglia, the brains resident immune cell is complex, as they have been reported to both positively and negatively regulate neurogenesis. Interestingly, neuronal activity can also regulate the function of the immune system. Here, we show that depleting microglia from hippocampal cultures reduces NSPC survival and proliferation. Furthermore, addition of purified hippocampal microglia, or their conditioned media, is trophic and proliferative to NSPCs. VIP, a neuropeptide released by dentate gyrus interneurons, enhances the proliferative and pro‐neurogenic effect of microglia via the VPAC1 receptor. This VIP‐induced enhancement is mediated by IL‐4 release, which directly targets NSPCs. This demonstrates a potential neuro‐immuno‐neurogenic pathway, disruption of which may have significant implications in conditions where combined cognitive impairments, interneuron loss, and immune system activation occurs, such as temporal lobe epilepsy and Alzheimer's disease. GLIA 2014;62:1313–1327     

Dorsal, but not ventral, hippocampal lesions disrupt cocaine place conditioning

The environment in which cocaine is experienced becomes associated with the effects of the drug and can then elicit cocaine craving. This study examined whether the hippocampus is involved in such associations using the conditioned place preference model. Rats received bilateral lesions of the dorsal or ventral hippocampus and were then conditioned to associate a particular environment with cocaine. Following conditioning, rats with lesions of the dorsal, but not ventral, hippocampus failed to demonstrate conditioned place preference for the cocaine-associated environment. These findings suggest that the dorsal hippocampus plays a role in the association of environmental stimuli with the effects of cocaine and may have important implications for understanding craving elicited by cocaine-conditioned stimuli.     

Initial rewarding effects of cocaine and amphetamine assessed in a day using the single‐exposure place preference protocol

In rodents, only a single dose of cocaine or amphetamine is required to cause a marked increase in extracellular dopamine, induce hyperlocomotion and cause persistent plasticity changes within dopaminergic neurons of the ventral tegmental area (VTA). The initial drug experience is suggested to predict vulnerability of developing addiction, but only few studies have assessed the perception of reward accompanying this initial exposure. We recently presented an approach to assess the initial rewarding effects of cocaine in mice with a single‐exposure place preference (sePP) protocol, avoiding repeated drug injections. Here, we demonstrate a condensed version of the sePP, allowing assessment of initial subjective reward‐perception within a day. By using this protocol, we demonstrate that a single exposure to both cocaine and amphetamine is sufficient to induce place preference. Furthermore, we use chemogenetics ( Designer Receptors Exclusively Activated by Designer Drugs [DREADD]) to show that both inhibitory and stimulatory modulation of VTA DA signalling disrupts cocaine‐induced place preference in the condensed sePP. Our findings support the presence of initial reward‐perception of both cocaine and amphetamine, and the formation of drug‐context association. In addition, our data support that VTA DA signalling prior to drug exposure affects either reward‐perception or the time during which associations are formed, thereby preventing induction of cocaine‐induced place preference in the sePP. The easy and timesaving sePP protocol should form a critical basis for further deciphering the complex mechanisms underlying the progression from the initial drug experience to escalating drug intake and addiction.     

Deafferentation enhances neurogenesis in the young and middle aged hippocampus but not in the aged hippocampus

Increased neurogenesis in the dentate gyrus (DG) after brain insults such as excitotoxic lesions, seizures, or stroke is a well known phenomenon in the young hippocampus. This plasticity reflects an innate compensatory response of neural stem cells (NSCs) in the young hippocampus to preserve function or minimize damage after injury. However, injuries to the middle‐aged and aged hippocampi elicit either no or dampened neurogenesis response, which could be due to an altered plasticity of NSCs and/or the hippocampus with age. We examined whether the plasticity of NSCs to increase neurogenesis in response to a milder injury such as partial deafferentation is preserved during aging. We quantified DG neurogenesis in the hippocampus of young, middle‐aged, and aged F344 rats after partial deafferentation. A partial deafferentation of the left hippocampus without any apparent cell loss was induced via administration of Kainic acid (0.5 μg in 1.0 μl) into the right lateral ventricle of the brain. In this model, degeneration of CA3 pyramidal neurons and dentate hilar neurons in the right hippocampus results in loss of commissural axons which leads to partial deafferentation of the dendrites of dentate granule cells and CA1‐CA3 pyramidal neurons in the left hippocampus. Quantification of newly born cells that are added to the dentate granule cell layer at postdeafferentation days 4–15 using 5′‐bromodeoxyuridine (BrdU) labeling revealed greatly increased addition of newly born cells (～three fold increase) in the deafferented young and middle‐aged hippocampi but not in the deafferented aged hippocampus. Measurement of newly born neurons using doublecortin (DCX) immunostaining also revealed similar findings. Analyses using BrdU‐DCX dual immunofluorescence demonstrated no changes in neuronal fate‐choice decision of newly born cells after deafferentation, in comparison to the age‐matched naive hippocampus in all age groups. Thus, the plasticity of hippocampal NSCs to increase DG neurogenesis in response to a milder injury such as partial hippocampal deafferentation is preserved until middle age but lost at old age. © 2010 Wiley‐Liss, Inc.     

Selective Oestrogen Receptor Agonists Rescued Hippocampus Parameters in Male Spontaneously Hypertensive Rats

Spontaneously hypertensive rats (SHR) show pronounced hippocampus alterations, including low brain‐derived neurotrophic factor (BDNF) expression, reduced neurogenesis, astrogliosis and increased aromatase expression. These changes are reverted by treatment with 17β‐oestradiol. To determine which oestradiol receptor (ER) type is involved in these neuroprotective effects, we used agonists of the ERα [propylpyrazole triol (PPT)] and the ERβ [diarylpropionitrite (DPN)] given over 2 weeks to 4‐month‐old male SHR. Wistar Kyoto normotensive rats served as controls. Using immunocytochemistry, we determined glial fibrillary protein (GFAP)+ astrocytes in the CA1, CA3 and hilus of the dentate gyrus of the hippocampus, aromatase immunostaining in the hilus, and doublecortin (DCX)+ neuronal progenitors in the inner granular zone of the dentate gyrus. Brain‐derived neurotrophic factor mRNA was also measured in the hippocampus by the quantitative polymerase chain reaction. In SHR, PPT had no effect on blood pressure, decreased astrogliosis, slightly increased BDNF mRNA, had no effect on the number of DCX+ progenitors, and increased aromatase staining. Treatment with DPN decreased blood pressure, decreased astrogliosis, increased BDNF mRNA and DCX+ progenitors, and did not modify aromatase staining. We hypothesise that, although both receptor types may participate in the previously reported beneficial effects of 17β‐oestradiol in SHR, receptor activation with DPN may preferentially facilitate BDNF mRNA expression and neurogenesis. The results of the present study may help in the design of ER‐based neuroprotection for the encephalopathy of hypertension.     

Repetitive noxious neonatal stimuli increases dentate gyrus cell proliferation and hippocampal brain‐derived neurotrophic factor levels

Neonatal noxious stimulation has been proposed to model pain triggered by diagnostic/therapeutic invasive procedures in premature infants. Previous studies have shown that hippocampal neurogenesis rate and the behavioral repertoire of adult rats may be altered by neonatal noxious stimuli. The purpose of this study was to evaluate whether noxious stimulation during neonatal period alters the nociceptive response and dentate gyrus neurogenesis when compared to rats subjected to a single noxious stimulus in late infancy. Plasma corticosterone and hippocampal brain‐derived neurotrophic factor (BDNF) levels were measured. Neurogenesis in the dentate gyrus was evaluated in adolescent rats (postnatal day 40; P40) exposed twice to intra‐plantar injections of Complete Freund's adjuvant (CFA) on P1 and P21 (group P1P21) or P8 and P21 (P8P21) or exposed once on P21 (pubertal). On P21, one subset of animals received 5‐bromo‐2′‐deoxyuridine (BrdU) and was euthanized on P40 for identification of proliferating cells in the dentate gyrus. Another subset was sampled for thermal response or plasma corticosterone measurement and hippocampal BDNF levels. Proliferative cell rate in dentate gyrus was the highest in all re‐exposed groups (P < 0.001), except for P8 females (P8P21F), revealing also a sex difference, where P8P21 males showed higher rate than females (P < 0.001). Stimulated groups took longer than CTL animals to lick the paws (P < 0.001), regardless of the age when the noxious stimulus was applied. Re‐exposed groups had lower corticosterone plasma level (P1P21 M and F, P8P21M) than controls. On the contrary, hippocampal BDNF was increased in males from both re‐exposed groups. These results show that infant noxious stimulation in neonatally previously stimulated rats is related to high proliferation in the DG and this association seems to be modified by the animal's sex. The new generated dentate granule cells in the hippocampus may have a role in the long‐term behavioral responses to neonatal nociceptive stimulation. Noxious stimulation in the neonatal period results in sex‐dependent neurogenic response. © 2013 Wiley Periodicals, Inc.     

Roles of astrocytes and microglia in seizure‐induced aberrant neurogenesis in the hippocampus of adult rats

Recent evidence showed that epileptic seizures increase hippocampal neurogenesis in the adult rat, but prolonged seizures result in the aberrant hippocampal neurogenesis that often leads to a recurrent excitatory circuitry and thus contributes to epileptogenesis. However, the mechanism underlying the aberrant neurogenesis after prolonged seizures remains largely unclear. In this study, we examined the role of activated astrocytes and microglia in the aberrant hippocampal neurogenesis induced by status epilepticus. Using a lithium‐pilocarpine model to mimic human temporal lobe epilepsy, we found that status epilepticus induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures. Then, we injected fluorocitrate stereotaxicly into the dentate hilus to inhibit astrocytic metabolism and found that fluorocitrate failed to prevent the seizure‐induced formation of ectopic hilar basal dendrites but instead promoted the degeneration of dentate granule cells after seizures. In contrast, a selective inhibitor of microglia activation, minocycline, inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus. Furthermore, with stereotaxic injection of lipopolysaccharide into the intact dentate hilus to activate local microglia, we found that lipopolysaccharide promoted the development of ectopic hilar basal dendrites in the hippocampus. These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons and that minocycline could be a potential drug to impede seizure‐induced aberrant migration of newborn neurons. © 2009 Wiley‐Liss, Inc.     

Chronic temporal lobe epilepsy is associated with severely declined dentate neurogenesis in the adult hippocampus

While it is clear that acute hippocampal injury or status epilepticus increases the production of new neurons in the adult dentate gyrus (DG), the effects of chronic epilepsy on dentate neurogenesis are unknown. We hypothesize that epileptogenic changes and spontaneous recurrent motor seizures (SRMS) that ensue after hippocampal injury or status epilepticus considerably decrease dentate neurogenesis. We addressed this issue by quantifying the number of cells that are positive for doublecortin (DCX, a marker of new neurons) in the DG of adult F344 rats at 16 days and 5 months after an intracerebroventricular kainic acid (ICV KA) administration or after graded intraperitoneal KA (IP KA) injections, models of temporal lobe epilepsy (TLE). At early post-KA administration, the injured hippocampus exhibited increased dentate neurogenesis in both models. Conversely, at 5 months post-KA administration, the chronically epileptic hippocampus demonstrated severely declined neurogenesis, which was associated with considerable SRMS in both KA models. Additionally, stem/progenitor cell proliferation factors, FGF-2 and IGF-1, were decreased in the chronically epileptic hippocampus. Interestingly, the overall decrease in neurogenesis and the extent of SRMS were greater in rats receiving IP KA than rats receiving ICV KA, suggesting that the extent of neurogenesis during chronic TLE exhibits an inverse relationship with SRMS. These results provide novel evidence that chronic TLE is associated with extremely declined dentate neurogenesis. As fraction of newly born neurons become GABA-ergic interneurons, declined neurogenesis may contribute to the increased seizure-susceptibility of the DG in chronic TLE. Likewise, the hippocampal-dependent learning and memory deficits observed in chronic TLE could be linked at least partially to the declined neurogenesis.     

Could hippocampal neurogenesis be a future drug target for treating temporal lobe epilepsy?

The dentate gyrus, a region of the hippocampal formation, displays the highest level of plasticity in the brain and exhibits neurogenesis all through life. Dentate neurogenesis, believed to be essential for learning and memory function, responds to physiological stimuli as well as pathological situations. The role of dentate neurogenesis in the pathophysiology of temporal lobe epilepsy (TLE) has received increased attention lately because of its disparate response in the early and chronic stages of the disease. Acute seizures or status epilepticus immensely enhance dentate neurogenesis and lead to an aberrant migration of newly born neurons into the dentate hilus and the formation of epileptogenic circuitry in the injured hippocampus. Conversely, spontaneous recurrent seizures that arise during chronic TLE are associated with dramatically reduced dentate neurogenesis. In this review, we discuss the potential significance of enhanced but abnormal neurogenesis taking place shortly after brain injury or the status epilepticus towards the development of chronic epilepsy, and prospective implications of dramatically waned dentate neurogenesis occurring during chronic epilepsy for learning and memory function and depression in TLE. Furthermore, we confer whether hippocampal neurogenesis is a possible drug target for preventing TLE after brain injury or the status epilepticus, and for easing learning and memory impairments during chronic epileptic conditions. Additionally, we discuss some possible drugs and approaches that need to be evaluated in future in animal models of TLE to further understand the role of neurogenesis in the pathogenesis of TLE and whether modulation of neurogenesis is useful for treating TLE.     

Differential neurogenesis in the adult rat dentate gyrus: an identifiable zone that consistently lacks neurogenesis

The dentate gyrus continues to produce new neurons in adult rodents. The possibility of differential regulation of neurogenesis within regions of the dentate gyrus is largely unexplored, despite several other aspects of this phenomenon being well characterized in a large number of studies. In this report, we describe an area located at the anterior pole of the dentate gyrus that consistently lacks neurogenesis. This neurogenically quiescent zone invariably lacks expression of the neuroblast marker doublecortin (DCX), bromodeoxyuridine and Ki-67, though DCX expression can be elicited in response to a combined paradigm of environmental enrichment and wheel running. We propose that this region may provide a valuable model system to discern the factors that regulate the process of neurogenesis.     

Adult‐born hippocampal neurons promote cognitive flexibility in mice

The hippocampus is involved in segregating memories, an ability that utilizes the neural process of pattern separation and allows for cognitive flexibility. We evaluated a proposed role for adult hippocampal neurogenesis in cognitive flexibility using variants of the active place avoidance task and two independent methods of ablating adult‐born neurons, focal X‐irradiation of the hippocampus, and genetic ablation of glial fibrillary acidic protein positive neural progenitor cells, in mice. We found that ablation of adult neurogenesis did not impair the ability to learn the initial location of a shock zone. However, when conflict was introduced by switching the location of the shock zone to the opposite side of the room, irradiated and transgenic mice entered the new shock zone location significantly more than their respective controls. This impairment was associated with increased upregulation of the immediate early gene Arc in the dorsal dentate gyrus, suggesting a role for adult neurogenesis in modulating network excitability and/or synaptic plasticity. Additional experiments revealed that irradiated mice were also impaired in learning to avoid a rotating shock zone when it was added to an initially learned stationary shock zone, but were unimpaired in learning the identical simultaneous task variant if it was their initial experience with place avoidance. Impaired avoidance could not be attributed to a deficit in extinction or an inability to learn a new shock zone location in a different environment. Together these results demonstrate that adult neurogenesis contributes to cognitive flexibility when it requires changing a learned response to a stimulus‐evoked memory. © 2012 Wiley Periodicals, Inc.