Chronic restraint stress in adolescence differentially influences hypothalamic‐pituitary‐adrenal axis function and adult hippocampal neurogenesis in male and female rats

Previous studies have shown a relationship between adversity in adolescence and health outcomes in adulthood in a sex‐specific manner. Adolescence is characterized by major changes in stress‐responsive regions of the brain, including the hippocampus, the site of ongoing neurogenesis throughout the lifespan. Prepubertal male and female rats exhibit different acute reactions to chronic stress compared to adults, but less is known about whether these stress‐induced changes persist into adulthood. Therefore, in this study, we investigated the effects of chronic, intermittent stress during adolescence on basal corticosterone levels, dentate gyrus (DG) volume, and neurogenesis in the hippocampus of adult male and female Sprague‐Dawley rats. Adolescent male and female rats were either restrained for 1 h every other day for 3 weeks from postnatal days (PDs) 30–52 at unpredictable times or left undisturbed. All rats received a single injection of bromodeoxyuridine (BrdU; 200 mg/kg) in adulthood on PD70 and were perfused 3 weeks later. Brains were processed for Ki67 (endogenous marker of cell proliferation) and BrdU (to estimate effects on cell survival). In addition, blood samples were taken during the restraint stress period and in adulthood. Results show that males and females exhibit different corticosterone responses to chronic stress during adolescence and that only adult female rats exposed to stress during adolescence show higher basal corticosterone levels compared to nonstressed controls. Furthermore, stressed females showed a reduced number of proliferating and surviving cells in the DG in adulthood compared to nonstressed same‐sex controls. The majority of BrdU‐labeled cells were co‐labeled with NeuN, an endogenous marker of mature neurons, indicating that neurogenesis was decreased in the DG of adult female rats that had undergone chronic restraint stress in adolescence. Although male rats were more responsive to the chronic stress as adolescents showing higher corticosterone levels and reduced body weight, as adults they showed a slight increase in cellsurvival and no effect of adolescent stress on basal corticosterone levels. These results suggest that stress during adolescence can have effects on hypothalamic‐pituitary‐adrenal axis function and hippocampus plasticity in adulthood, particularly in female rats. ©2010 Wiley‐Liss,Inc.     

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.     

Differential effects of adolescent and adult‐initiated exercise on cognition and hippocampal neurogenesis

Adolescence is a critical period for postnatal brain maturation and thus a time when environmental influences may affect cognitive processes in later life. Exercise during adulthood has been shown to increase hippocampal neurogenesis and enhance cognition. However, the impact of exercise initiated in adolescence on the brain and behavior in adulthood is not fully understood. The aim of this study was to compare the impact of voluntary exercise that is initiated during adolescence or early adulthood on cognitive performance in hippocampal‐dependent and ‐independent processes using both object‐based and touchscreen operant paradigms. Adult (8 week) and adolescent (4 week) male Sprague–Dawley rats had access to a running wheel (exercise) or were left undisturbed (sedentary control) for 4 weeks prior to behavioral testing and for the duration of the experiment. Results from touchscreen‐based tasks showed that reversal learning was enhanced by both adult and adolescent‐initiated exercise, while only exercise that began in adolescence induced a subtle but transient increase in performance on a location discrimination task. Spontaneous alternation in the Y‐maze was impaired following adolescent onset exercise, while object memory was unaffected by either adult or adolescent‐initiated exercise. Adolescent‐initiated exercise increased the number of hippocampal DCX cells, an indicator of neurogenesis. It also promoted the complexity of neurites on DCX cells, a key process for synaptic integration, to a greater degree than adult‐initiated exercise. Together the data here show that exercise during the adolescent period compared to adulthood differentially affects cognitive processes and the development of new hippocampal neurons in later life.     

Sex and strategy use matters for pattern separation,adult neurogenesis,and immediate early gene expression in the hippocampus

Adult neurogenesis in the dentate gyrus (DG) plays a crucial role for pattern separation, and there are sex differences in the regulation of neurogenesis. Although sex differences, favoring males, in spatial navigation have been reported, it is not known whether there are sex differences in pattern separation. The current study was designed to determine whether there are sex differences in the ability for separating similar or distinct patterns, learning strategy choice, adult neurogenesis, and immediate early gene (IEG) expression in the DG in response to pattern separation training. Male and female Sprague‐Dawley rats received a single injection of the DNA synthesis marker, bromodeoxyuridine (BrdU), and were tested for the ability of separating spatial patterns in a spatial pattern separation version of delayed nonmatching to place task using the eight‐arm radial arm maze. Twenty‐seven days following BrdU injection, rats received a probe trial to determine whether they were idiothetic or spatial strategy users. We found that male spatial strategy users outperformed female spatial strategy users only when separating similar, but not distinct, patterns. Furthermore, male spatial strategy users had greater neurogenesis in response to pattern separation training than all other groups. Interestingly, neurogenesis was positively correlated with performance on similar pattern trials during pattern separation in female spatial strategy users but negatively correlated with performance in male idiothetic strategy users. These results suggest that the survival of new neurons may play an important positive role for pattern separation of similar patterns in females. Furthermore, we found sex and strategy differences in IEG expression in the CA1 and CA3 regions in response to pattern separation. These findings emphasize the importance of studying biological sex on hippocampal function and neural plasticity. © 2015 Wiley Periodicals, Inc.     

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.     

Age‐dependent role for Ras‐GRF1 in the late stages of adult neurogenesis in the dentate gyrus

The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover, the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RAS‐GRF1 (GRF1), a calcium‐dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis. We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (～2 months of age), when wild‐type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2‐month‐old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age‐dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts. © 2013 Wiley Periodicals, Inc.     

Gender and strain influence on neurogenesis in dentate gyrus of young rats.

To investigate whether rat hippocampal neurogenesis varies with strain and gender, the authors examined proliferating progenitor cells and their progeny in young male and female Sprague-Dawley (SD) and spontaneously hypertensive rats (SHR) using the thymidine analog bromodeoxyuridine (BrdU) combined with immunohistochemistry for the neuronal marker Calbindin D28k and glial fibrillary acidic protein. Rats were given 7 consecutive daily BrdU injections and were killed 1 day or 4 weeks later to allow for discrimination between proliferation and cell survival. Stereologic analysis of the numbers of BrdU-immunoreactive cells in the dentate gyrus revealed both a strain difference with significantly higher cell proliferation and net neurogenesis in SHR than in SD and a gender difference with males from both strains producing significantly more cells than their female counterparts. Whereas the number of progenitors four weeks after BrdU injections was still significantly greater in male than in female SHRs, resulting in a greater net neurogenesis in the male, the number of BrdU-immunoreactive cells did not differ between male and female SD rats, suggesting a greater survival of newly generated cells in the dentate gyrus in female than in male SD rats. No sex or strain difference was observed in the relative ratio of neurogenesis and gliogenesis.     

Chronic early life stress alters developmental and adult neurogenesis and impairs cognitive function in mice

Early life stress (ES) increases vulnerability to psychopathology and impairs cognition in adulthood. These ES‐induced deficits are associated with lasting changes in hippocampal plasticity. Detailed information on the neurobiological basis, the onset, and progression of such changes and their sex‐specificity is currently lacking but is required to tailor specific intervention strategies. Here, we use a chronic ES mouse model based on limited nesting and bedding material from postnatal day (P) 2–9 to investigate; (1) if ES leads to impairments in hippocampus‐dependent cognitive function in adulthood and (2) if these alterations are paralleled by changes in developmental and/or adult hippocampal neurogenesis. ES increased developmental neurogenesis (proliferation and differentiation) in the dentate gyrus (DG) at P9, and the number of immature (NeurD1⁺) cells migrating postnatally from the secondary dentate matrix, indicating prompt changes in DG structure in both sexes. ES lastingly reduced DG volume and the long‐term survival of developmentally born neurons in both sexes at P150. In adult male mice only, ES reduced survival of adult‐born neurons (BrdU/NeuN⁺ cells), while proliferation (Ki67⁺) and differentiation (DCX⁺) were unaffected. These changes correlated with impaired performance in all learning and memory tasks used here. In contrast, in female mice, despite early alterations in developmental neurogenesis, no lasting changes were present in adult neurogenesis after ES and the cognitive impairments were less prominent and only apparent in some cognitive tasks. We further show that, although neurogenesis and cognition correlate positively, only the hippocampus‐dependent functions depend on changes in neurogenesis, whereas cognitive functions that are not exclusively hippocampus‐dependent do not. This study indicates that chronic ES has lasting consequences on hippocampal structure and function in mice and suggests that male mice are more susceptible to ES than females. Unraveling the mechanisms that underlie the persistent ES‐induced effects may have clinical implications for treatments to counteract ES‐induced deficits. © 2014 Wiley Periodicals, Inc.     

Sexual experience restores age‐related decline in adult neurogenesis and hippocampal function

Aging is associated with compromised hippocampal function and reduced adult neurogenesis in the dentate gyrus. As new neurons have been linked to hippocampal functions, such as cognition, age‐related decline in new neuron formation may contribute to impaired hippocampal function. We investigated whether a rewarding experience known to stimulate neurogenesis in young adult rats, namely sexual experience, would restore new neuron production and hippocampal function in middle‐aged rats. Sexual experience enhanced the number of newly generated neurons in the dentate gyrus with both single and repeated exposures in middle‐aged rats. Following continuous long‐term exposure to sexual experience, cognitive function was improved. However, when a prolonged withdrawal period was introduced between the final mating experience and behavioral testing, the improvements in cognitive function were lost despite the presence of more new neurons. Taken together, these results suggest that repeated sexual experience can stimulate adult neurogenesis and restore cognitive function in the middle‐aged rat as long as the experience persists throughout the testing period. The extent to which changes in adult neurogenesis underlie those in cognition remain unknown. © 2013 Wiley Periodicals, Inc.     

Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats

Increased dietary intake of choline early in life improves performance of adult rats on memory tasks and prevents their age-related memory decline. Because neurogenesis in the adult hippocampus also declines with age, we investigated whether prenatal choline availability affects hippocampal neurogenesis in adult Sprague-Dawley rats and modifies their neurogenic response to environmental stimulation. On embryonic days (ED) 12-17, pregnant rats ate a choline-supplemented (SUP-5 g/kg), choline sufficient (SFF-1.1 g/kg), or choline-free (DEF) semisynthetic diet. Adult offspring either remained in standard housing or were given 21 daily visits to explore a maze. On the last ten exploration days, all rats received daily injections of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg). The number of BrdU+ cells was significantly greater in the dentate gyrus in SUP rats compared to SFF or DEF rats. While maze experience increased the number of BrdU+ cells in SFF rats to the level seen in the SUP rats, this enriching experience did not alter cell proliferation in DEF rats. Similar patterns of cell proliferation were obtained with immunohistochemical staining for neuronal marker doublecortin, confirming that diet and exploration affected hippocampal neurogenesis. Moreover, hippocampal levels of the brain-derived neurotrophic factor (BDNF) were increased in SUP rats as compared to SFF and DEF animals. We conclude that prenatal choline intake has enduring effects on adult hippocampal neurogenesis, possibly via up-regulation of BDNF levels, and suggest that these alterations of neurogenesis may contribute to the mechanism of life-long changes in cognitive function governed by the availability of choline during gestation.     

Enhanced neurogenesis and possible synaptic reorganization in the piriform cortex of adult rat following kainic acid‐induced status epilepticus

Epileptic seizure has been reported to enhance adult neurogenesis and induce aberrant synaptic reorganization in the human dentate gyrus in the hippocampal formation. However, adult neurogenesis in the extrahippocampal regions has not been well studied. To investigate seizure‐enhanced neurogenesis in the extrahippocampal regions, we performed histological and immunohistochemical as well as western blot analyses on the cerebrum of Sprague–Dawley rats (n = 51, male, 7 weeks old, body weight 250–300 g) treated with intraperitoneal injection of kainic acid (KA, 10 mg/kg) to induce status epilepticus (SE) (n = 36) or normal saline solution (n = 15) followed by 5′‐bromo‐2‐deoxyuridine (BrdU) injection to label newborn cells. Even though severe neuronal damage was found in the piriform cortex of rats having SE, immunohistochemistry for double cortin (DCX) revealed an increase in the number of immature neurons in the piriform cortex. Double immunofluorescence staining demonstrated that DCX‐positive cells in the piriform cortex were positive for both BrdU and neuronal nuclear antigen. Immunohistochemistry and western blotting revealed increased expressions of synaptophysin and postsynaptic density protein 95 in the piriform cortex of rat having SE. These results suggested the enhanced neurogenesis and possible synaptic reorganization in the piriform cortex of the KA‐treated rat.     

Chronic repetitive transcranial magnetic stimulation increases hippocampal neurogenesis in rats

Aim: While the underlying therapeutic mechanisms of repetitive transcranial magnetic stimulation (rTMS) treatment for depression remain unclear, recent animal studies have suggested that hippocampal neurogenesis might be required for the effects of antidepressant treatments including antidepressant drugs and electroconvulsive therapy. The aim of this study was to examine chronic rTMS effects on hippocampal neurogenesis in rats. Methods: Using a 70‐mm figure‐of‐eight coil, the stimulating parameters were set to 25 Hz and 70% of the rTMS device's maximum power. For 14 consecutive days, bromodeoxyuridine (BrdU) and 1000 pulses of rTMS were administered daily. Cell proliferation in the dentate gyrus was examined with immunohistochemistry. Results: In the rTMS‐treated group, BrdU‐positive cells were significantly increased in the dentate gyrus. Conclusion: Our results suggest that hippocampal neurogenesis might be involved in the antidepressant effects of chronic rTMS.     

Cannabinoid effects on CB1 receptor density in the adolescent brain: An autoradiographic study using the synthetic cannabinoid HU210

The short‐ and long‐term behavioral effects of cannabinoids differ in adolescent and adult rodents. Few studies though have examined the underlying neurochemical changes that occur in the brain following adolescent cannabinoid exposure. In this study, we examined the effect of treatment with the synthetic cannabinoid, HU210, on CB1 receptor density in the brain and on body weight in adolescent male rats. Rats were treated daily with 25, 50, or 100 μg/kg HU210 for 4 or 14 days, or received a single dose of 100 μg/kg HU210 and sacrificed 24 h later. Receptor density was investigated using in vitro autoradiography with the CB1 receptor ligand [³H] CP55,940. In contrast to adult animals treated under the same paradigm in a previous study, adolescents continued on average, to gain weight over the course of the study. Weight gain was slowest in the 100 μg/kg group and improved dose dependently with controls gaining the most weight. Following the acute dose of HU210, a trend for a reduction in [³H] CP55,940 binding and a significant effect of treatment was observed. Statistically significant, dose‐dependent, region‐specific decreases in binding were observed in all brain regions examined following 4 and 14 days treatment. The pattern of CB1 receptor downregulation was similar to that observed in adults treated with cannabinoids in previous studies; however, its magnitude was smaller in adolescents. This reduced compensatory response may contribute to some acute behavioral effects, the pharmacological cross‐tolerance and the long‐lasting, adverse psychological consequences of cannabinoid exposure during adolescence. Synapse 64:845–854, 2010. © 2010 Wiley‐Liss, Inc.     

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.     

Long‐term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis

Neurogenesis is a well‐characterized phenomenon within the dentate gyrus (DG) of the adult hippocampus. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of chronic inflammation remains controversial. In this study the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis was used to investigate the long‐term effects of T cell–mediated central nervous system inflammation on hippocampal neurogenesis. 5‐Bromodeoxyuridine (BrdU)‐labeled subpopulations of hippocampal cells in EAE and control mice (coexpressing GFAP, doublecortin, NeuN, calretinin, and S100) were quantified at the recovery phase, 21 days after BrdU administration, to estimate alterations on the rate and differentiation pattern of the neurogenesis process. The core features of EAE mice DG are (i) elevated number of newborn (BrdU+) cells indicating vigorous proliferation, which in the long term subsided; (ii) enhanced migration of newborn cells into the granule cell layer; (iii) increased level of immature neuronal markers (including calretinin and doublecortin); (iv) trending decrease in the percentage of newborn mature neurons; and (v) augmented gliogenesis and differentiation of newborn neural precursor cells (NPCs) to mature astrocytes (BrdU+/S100+). Although the inflammatory environment in the brain of EAE mice enhances the proliferation of hippocampal NPCs, in the long term neurogenesis is progressively depleted, giving prominence to gliogenesis. The discrepancy between the high number of immature cells and the low number of mature newborn cells could be the result of a caused defect in the maturation pathway. © 2016 Wiley Periodicals, Inc.     

Early‐life stress diminishes the increase in neurogenesis after exercise in adult female mice

Exposure to early‐life stress (ES) has long‐lasting consequences for later cognition and hippocampal plasticity, including adult hippocampal neurogenesis (AHN), i.e., the generation of new neurons from stem/progenitor cells in the adult hippocampal dentate gyrus. We had previously demonstrated a sex‐specific vulnerability to ES exposure; female mice exposed to ES from P2‐P9 exhibited only very mild cognitive changes and no reductions in AHN as adult, whereas ES‐exposed male mice showed impaired cognition closely associated with reductions in AHN. Given the apparent resilience of AHN to ES in females, we here questioned whether ES has also altered the capacity to respond to positive stimuli for neurogenesis. We therefore investigated whether exercise, known for its strong pro‐neurogenic effects, can still stimulate AHN in adult female mice that had been earlier exposed to ES. We confirm a strong pro‐neurogenic effect of exercise in the dorsal hippocampus of 8‐month‐old control female mice, but this positive neurogenic response is less apparent in female ES mice. These data provide novel insights in the lasting consequences of ES on hippocampal plasticity in females and also indicate that ES might lastingly reduce the responsiveness of the hippocampal stem cell pool, to exercise, in female mice.     

Thyroid hormone regulates hippocampal neurogenesis in the adult rat brain

We have examined the influence of thyroid hormone on adult hippocampal neurogenesis, which encompasses the proliferation, survival and differentiation of dentate granule cell progenitors. Using bromodeoxyuridine (BrdU), we demonstrate that adult-onset hypothyroidism significantly decreases hippocampal neurogenesis. This decline is predominantly the consequence of a significant decrease in the survival and neuronal differentiation of BrdU-positive cells. Both the decreased survival and neuronal differentiation of hippocampal progenitors could be rescued by restored euthyroid status. Adult-onset hyperthyroidism did not influence hippocampal neurogenesis, suggesting that the effects of thyroid hormone may be optimally permissive at euthyroid levels. Our in vivo and in vitro results revealed that adult hippocampal progenitors express thyroid receptor isoforms. The in vitro studies demonstrate that adult hippocampal progenitors exhibit enhanced proliferation, survival and glial differentiation in response to thyroid hormone. These results support a role for thyroid hormone in the regulation of adult hippocampal neurogenesis and raise the possibility that altered neurogenesis may contribute to the cognitive and behavioral deficits associated with adult-onset hypothyroidism.     

Granule cell dispersion and aberrant neurogenesis in the adult hippocampus of an LIS1 mutant mouse

Human type 1 lissencephaly is a severe brain malformation associated with cognitive dysfunction and intractable epilepsy. Mutant mice with a heterozygous deletion of LIS1 show varying degrees of hippocampal abnormality and enhanced excitability. Whether a reduction of LIS1 function affects adult hippocampal neurogenesis, and if so, whether aberrant neurogenesis contributes to the generation of a disorganized hippocampus remain unknown. Previous reports indicate the presence of multiple pyramidal cell layers and granule cell dispersion in LIS1 mutant mice. Here we observed disruption of the subgranular zone and glial fibrillary acidic protein-immunoreactive radial astrocytes in the dentate gyrus of adult LIS1 mice. Using pulse-chase bromodeoxyuridine (BrdU) labeling combined with neuronal and glial antibody staining we provide evidence for ectopic adult neurogenesis in LIS1 mice. A gradually decreased survival rate for these newborn granule cells was also demonstrated in LIS1 mice 7 days after BrdU injection. This reduced survival rate was associated with impaired neuronal differentiation 28 days after BrdU administration. Thus, LIS1 haploinsufficiency can lead to abnormal cell proliferation, migration and differentiation in the adult dentate gyrus.     

Chemosensory cues affect amygdaloid neurogenesis and alter behaviors in the socially monogamous prairie vole

The current study examined the effects of pheromonal exposure on adult neurogenesis and revealed the role of the olfactory pathways on adult neurogenesis and behavior in the socially monogamous prairie vole (Microtus ochrogaster). Subjects were injected with a cell proliferation marker [5‐bromo‐2′‐deoxyuridine (BrdU)] and then exposed to their own soiled bedding or bedding soiled by a same‐ or opposite‐sex conspecific. Exposure to opposite‐sex bedding increased BrdU labeling in the amygdala (AMY), but not the dentate gyrus (DG), of female, but not male, voles, indicating a sex‐, stimulus‐, and brain region‐specific effect. The removal of the main olfactory bulbs or lesioning of the vomeronasal organ (VNOX) in females reduced BrdU labeling in the AMY and DG, and inhibited the male bedding‐induced BrdU labeling in the AMY, revealing the importance of an intact olfactory pathway for amygdaloid neurogenesis. VNOX increased anxiety‐like behavior and altered social preference, but it did not affect social recognition memory in female voles. VNOX also reduced the percentage of BrdU‐labeled cells that co‐expressed the neuronal marker TuJ1 in the AMY, but not the DG. Together, our data indicate the importance of the olfactory pathway in mediating brain plasticity in the limbic system as well as its role in behavior.     

Developmental lead exposure impairs contextual fear conditioning and reduces adult hippocampal neurogenesis in the rat brain

The effects of developmental lead exposure on the emotional reactivity, contextual fear conditioning and neurogenesis in the dentate gyrus of 60-80 days-old rats were studied. Wistar rat pups were exposed to 0.2% lead acetate via their dams' drinking water from postnatal day (PND) 1 to PND 21 and directly via drinking water from weaning until PND 30. At PND 60 and 80 the level of anxiety and contextual fear conditioning were studied, respectively. At PND 80 all animals received injections of BrdU to determine the effects of Pb on the generation of new cells in the dentate gyrus of hippocampus and on their survival and differentiation patterns. The results of the present study demonstrate that developmental lead exposure induces persistent increase in the level of anxiety and inhibition of contextual fear conditioning. Developmental lead exposure reduced generation of new cells in the dentate gyrus and altered the pattern of differentiation of BrdU-positive cells into mature neurons. A lower proportion of BrdU-positive cells co-expressed with the marker for mature neurons, calbindin. In contrast, the proportions of young not fully differentiated neurons and proportions of astroglial cells, generated from newly born cells, were increased in lead-exposed animals. Our results demonstrate that developmental lead exposure induces persistent inhibition of neurogenesis and alters the pattern of differentiation of newly born cells in the dentate gyrus of rat hippocampus, which could, at least partly, contribute to behavioral and cognitive impairments observed in adulthood.