scholarly journals Androgens Increase Survival of Adult-Born Neurons in the Dentate Gyrus by an Androgen Receptor-Dependent Mechanism in Male Rats

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3294-3304 ◽  
Author(s):  
D. K. Hamson ◽  
S. R. Wainwright ◽  
J. R. Taylor ◽  
B. A. Jones ◽  
N. V. Watson ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Male Rats ◽  
Male Rat ◽  
Testicular Feminization ◽  
Wild Type ◽  
Adult Born Neurons

Gonadal steroids are potent regulators of adult neurogenesis. We previously reported that androgens, such as testosterone (T) and dihydrotestosterone (DHT), but not estradiol, increased the survival of new neurons in the dentate gyrus of the male rat. These results suggest androgens regulate hippocampal neurogenesis via the androgen receptor (AR). To test this supposition, we examined the role of ARs in hippocampal neurogenesis using 2 different approaches. In experiment 1, we examined neurogenesis in male rats insensitive to androgens due to a naturally occurring mutation in the gene encoding the AR (termed testicular feminization mutation) compared with wild-type males. In experiment 2, we injected the AR antagonist, flutamide, into castrated male rats and compared neurogenesis levels in the dentate gyrus of DHT and oil-treated controls. In experiment 1, chronic T increased hippocampal neurogenesis in wild-type males but not in androgen-insensitive testicular feminization mutation males. In experiment 2, DHT increased hippocampal neurogenesis via cell survival, an effect that was blocked by concurrent treatment with flutamide. DHT, however, did not affect cell proliferation. Interestingly, cells expressing doublecortin, a marker of immature neurons, did not colabel with ARs in the dentate gyrus, but ARs were robustly expressed in other regions of the hippocampus. Together these studies provide complementary evidence that androgens regulate adult neurogenesis in the hippocampus via the AR but at a site other than the dentate gyrus. Understanding where in the brain androgens act to increase the survival of new neurons in the adult brain may have implications for neurodegenerative disorders.

Evaluating the functional state of adult-born neurons in the adult dentate gyrus of the hippocampus: from birth to functional integration

2015 ◽  
Vol 26 (3) ◽  
Author(s):  
Andrea Aguilar-Arredondo ◽  
Clorinda Arias ◽  
Angélica Zepeda
Keyword(s):  
Dentate Gyrus ◽  
Functional State ◽  
Functional Integration ◽  
Critical Time ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Maturation Stage ◽  
Methodological Approaches ◽  
Adult Born Neurons ◽  
Newborn Neurons

AbstractHippocampal neurogenesis occurs in the adult brain in various species, including humans. A compelling question that arose when neurogenesis was accepted to occur in the adult dentate gyrus (DG) is whether new neurons become functionally relevant over time, which is key for interpreting their potential contributions to synaptic circuitry. The functional state of adult-born neurons has been evaluated using various methodological approaches, which have, in turn, yielded seemingly conflicting results regarding the timing of maturation and functional integration. Here, we review the contributions of different methodological approaches to addressing the maturation process of adult-born neurons and their functional state, discussing the contributions and limitations of each method. We aim to provide a framework for interpreting results based on the approaches currently used in neuroscience for evaluating functional integration. As shown by the experimental evidence, adult-born neurons are prone to respond from early stages, even when they are not yet fully integrated into circuits. The ongoing integration process for the newborn neurons is characterised by different features. However, they may contribute differently to the network depending on their maturation stage. When combined, the strategies used to date convey a comprehensive view of the functional development of newly born neurons while providing a framework for approaching the critical time at which new neurons become functionally integrated and influence brain function.

scholarly journals Sex Differences in Maturation and Attrition of Adult Neurogenesis in the Hippocampus

2019 ◽  
Author(s):  
Shunya Yagi ◽  
Jared E.J. Splinter ◽  
Daria Tai ◽  
Sarah Wong ◽  
Yanhua Wen ◽  
...  
Keyword(s):  
Sex Differences ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Female Rats ◽  
Sprague Dawley ◽  
Male And Female Rats ◽  
Maturation Rate ◽  
Adult Born Neurons

ABSTRACTSex differences exist in the regulation of adult neurogenesis in the hippocampus in response to hormones and cognitive training. Here we investigated the trajectory and maturation rate of adult-born neurons in the dentate gyrus (DG) of male and female rats. Sprague-Dawley rats were perfused two hours, 24 hours, one, two or three weeks after BrdU injection, a DNA synthesis marker that labels dividing progenitor cells and their progeny. Adult-born neurons (BrdU/NeuN-ir) matured faster in males compared to females. Males had a greater density of neural stem cells (Sox2-ir) in the dorsal, but not in the ventral, DG and had higher levels of cell proliferation (Ki67-ir) than non-proestrous females. However, males showed a greater reduction in neurogenesis between one and two weeks after mitosis, whereas females showed similar levels of neurogenesis throughout the weeks. The faster maturation and greater attrition of new neurons in males compared to females suggests greater potential for neurogenesis to respond to external stimuli in males and emphasizes the importance of studying sex on adult hippocampal neurogenesis.Significance StatementPreviously studies examining the characteristics of adult-born neurons in the dentate gyrus have used almost exclusively male subjects. Researchers have assumed the two sexes have a similar maturation and attrition of new neurons in the dentate gyrus of adults. However, this study highlights notable sex differences in the attrition, maturation rate and potential of neurogenesis in the adult hippocampus that has significant implications for the field of neuroplasticity. These findings are important in understanding the relevance of sex differences in the regulation of neurogenesis in the hippocampus in response to stimuli or experience and may have consequences for our understanding of diseases that involve neurodegeneration of the hippocampus, particularly those that involve sex differences, such as Alzheimer’s disease and depression.

scholarly journals Intact memory for local and distal cues in male and female rats that lack adult neurogenesis

2018 ◽  
Author(s):  
Desiree R Seib ◽  
Erin Chahley ◽  
Oren Princz-Lebel ◽  
Jason S Snyder
Keyword(s):  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Granule Cells ◽  
Sensory Information ◽  
Female Rats ◽  
Male Rats ◽  
Separation Function ◽  
Male And Female ◽  
Male And Female Rats ◽  
Adult Born Neurons

ABSTRACTThe dentate gyrus is essential for remembering the fine details of experiences that comprise episodic memory. Dentate gyrus granule cells receive highly-processed sensory information and are hypothesized to perform a pattern separation function, whereby similar sensory inputs are transformed into orthogonal neural representations. Behaviorally, this is believed to enable distinct memory for highly interfering stimuli. Since the dentate gyrus is comprised of a large number of adult-born neurons, which have unique synaptic wiring and neurophysiological firing patterns, it has been proposed that neurogenesis may contribute to this process in unique ways. Some behavioral evidence exists to support this role, whereby neurogenesis-deficient rodents are impaired at discriminating the fine visuospatial details of experiences. However, the extent to which newborn neurons contribute to dentate gyrus-dependent learning tasks is unclear. Furthermore, since most studies of dentate gyrus function are conducted in male rats, little is known about how females perform in similar situations, and whether there might be sex differences in the function of adult neurogenesis. To address these issues, we examined spatial discrimination memory in transgenic male and female rats that lacked adult neurogenesis. The first task probed memory for the position of local objects in an open field, assessed by behavioral responses to novel object locations. The second task examined memory for distal environmental cues. All rats were able to successfully discriminate local and distal cue changes. Males and females also performed comparably, although females displayed higher levels of rearing and locomotion. Collectively, our results indicate that rats are capable of learning about local and distal cues in the absence of adult neurogenesis.

scholarly journals Adult neurogenesis in natural populations

2001 ◽  
Vol 79 (4) ◽  
pp. 297-302 ◽  
Author(s):  
R Boonstra ◽  
L Galea ◽  
S Matthews ◽  
J M Wojtowicz
Keyword(s):  
Adult Neurogenesis ◽  
Mammalian Species ◽  
Natural Populations ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Biologically Relevant ◽  
Evolutionarily Conserved ◽  
Functional Consequences ◽  
Song Production ◽  
And Function

The dogma that the adult brain produces no new neurons has been overturned, but the critics are still asking, so what? Is adult neurogenesis a biologically relevant phenomenon, or is it perhaps harmful because it disrupts the existing neuronal circuitry? Considering that the phenomenon is evolutionarily conserved in all mammalian species examined to date and that its relevance has been well documented in non-mammalian species, it seems self-evident that neurogenesis in adult mammals must have a role. In birds, it has been established that neurogenesis varies dramatically with seasonal changes in song production. In chickadees, the learning behaviour related to finding stored food is also correlated with seasonal adult neurogenesis. Such studies are still nonexistent in mammals, but the related evidence suggests that neurogenesis does vary seasonally in hamsters and shows sexual differences in meadow voles. To promote studies on natural populations asking fundamental questions of the purpose and function of neurogenesis, we organized a Workshop on "Hippocampal Neurogenesis in Natural Populations" in Toronto in May 2000. The Workshop highlighted recent discoveries in neurogenesis from the lab, and focused on its functional consequences. The consensus at the Workshop was that demonstration of a role for neurogenesis in natural behaviours will ultimately be essential if we are to understand the purpose and function of neurogenesis in humans.Key words: neurogenesis, hippocampus, dentate gyrus, learning, memory, wild population.

scholarly journals Metabolic tuning of inhibition regulates hippocampal neurogenesis in the adult brain

2020 ◽  
Vol 117 (41) ◽  
pp. 25818-25829
Author(s):  
Xinxing Wang ◽  
Hanxiao Liu ◽  
Johannes Morstein ◽  
Alexander J. E. Novak ◽  
Dirk Trauner ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Energy Homeostasis ◽  
Inhibitory Neuron ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Adult Hippocampal Neurogenesis ◽  
Neuron Activity ◽  
Adult Mice ◽  
Sphingosine 1 Phosphate ◽  
Underlying Mechanisms

Hippocampus-engaged behaviors stimulate neurogenesis in the adult dentate gyrus by largely unknown means. To explore the underlying mechanisms, we used tetrode recording to analyze neuronal activity in the dentate gyrus of freely moving adult mice during hippocampus-engaged contextual exploration. We found that exploration induced an overall sustained increase in inhibitory neuron activity that was concomitant with decreased excitatory neuron activity. A mathematical model based on energy homeostasis in the dentate gyrus showed that enhanced inhibition and decreased excitation resulted in a similar increase in neurogenesis to that observed experimentally. To mechanistically investigate this sustained inhibitory regulation, we performed metabolomic and lipidomic profiling of the hippocampus during exploration. We found sustainably increased signaling of sphingosine-1-phosphate, a bioactive metabolite, during exploration. Furthermore, we found that sphingosine-1-phosphate signaling through its receptor 2 increased interneuron activity and thus mediated exploration-induced neurogenesis. Taken together, our findings point to a behavior-metabolism circuit pathway through which experience regulates adult hippocampal neurogenesis.

scholarly journals The intellectual disability PAK3 R67C mutation impacts cognitive functions and adult hippocampal neurogenesis

2020 ◽  
Vol 29 (12) ◽  
pp. 1950-1968
Author(s):  
Charlotte Castillon ◽  
Laurine Gonzalez ◽  
Florence Domenichini ◽  
Sandrine Guyon ◽  
Kevin Da Silva ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Mouse Model ◽  
Spatial Memory ◽  
Adult Neurogenesis ◽  
Hippocampal Neurons ◽  
Memory Task ◽  
Clinical Signs ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Adult Born Neurons

Abstract The link between mutations associated with intellectual disability (ID) and the mechanisms underlying cognitive dysfunctions remains largely unknown. Here, we focused on PAK3, a serine/threonine kinase whose gene mutations cause X-linked ID. We generated a new mutant mouse model bearing the missense R67C mutation of the Pak3 gene (Pak3-R67C), known to cause moderate to severe ID in humans without other clinical signs and investigated hippocampal-dependent memory and adult hippocampal neurogenesis. Adult male Pak3-R67C mice exhibited selective impairments in long-term spatial memory and pattern separation function, suggestive of altered hippocampal neurogenesis. A delayed non-matching to place paradigm testing memory flexibility and proactive interference, reported here as being adult neurogenesis-dependent, revealed a hypersensitivity to high interference in Pak3-R67C mice. Analyzing adult hippocampal neurogenesis in Pak3-R67C mice reveals no alteration in the first steps of adult neurogenesis, but an accelerated death of a population of adult-born neurons during the critical period of 18–28 days after their birth. We then investigated the recruitment of hippocampal adult-born neurons after spatial memory recall. Post-recall activation of mature dentate granule cells in Pak3-R67C mice was unaffected, but a complete failure of activation of young DCX + newborn neurons was found, suggesting they were not recruited during the memory task. Decreased expression of the KCC2b chloride cotransporter and altered dendritic development indicate that young adult-born neurons are not fully functional in Pak3-R67C mice. We suggest that these defects in the dynamics and learning-associated recruitment of newborn hippocampal neurons may contribute to the selective cognitive deficits observed in this mouse model of ID.

scholarly journals Reactive, Adult Neurogenesis From Increased Neural Progenitor Cell Proliferation Following Alcohol Dependence in Female Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Natalie N. Nawarawong ◽  
K. Ryan Thompson ◽  
Steven P. Guerin ◽  
Chinchusha Anasooya Shaji ◽  
Hui Peng ◽  
...  
Keyword(s):  
Alcohol Dependence ◽  
Dentate Gyrus ◽  
Adult Neurogenesis ◽  
Progenitor Cell ◽  
Neural Progenitor Cell ◽  
Neural Progenitor ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Female Rats ◽  
Immature Neurons

Hippocampal neurodegeneration is a consequence of excessive alcohol drinking in alcohol use disorders (AUDs), however, recent studies suggest that females may be more susceptible to alcohol-induced brain damage. Adult hippocampal neurogenesis is now well accepted to contribute to hippocampal integrity and is known to be affected by alcohol in humans as well as in animal models of AUDs. In male rats, a reactive increase in adult hippocampal neurogenesis has been observed during abstinence from alcohol dependence, a phenomenon that may underlie recovery of hippocampal structure and function. It is unknown whether reactive neurogenesis occurs in females. Therefore, adult female rats were exposed to a 4-day binge model of alcohol dependence followed by 7 or 14 days of abstinence. Immunohistochemistry (IHC) was used to assess neural progenitor cell (NPC) proliferation (BrdU and Ki67), the percentage of increased NPC activation (Sox2+/Ki67+), the number of immature neurons (NeuroD1), and ectopic dentate gyrus granule cells (Prox1). On day seven of abstinence, ethanol-treated females showed a significant increase in BrdU+ and Ki67+ cells in the subgranular zone of the dentate gyrus (SGZ), as well as greater activation of NPCs (Sox2+/Ki67+) into active cycling. At day 14 of abstinence, there was a significant increase in the number of immature neurons (NeuroD1+) though no evidence of ectopic neurogenesis according to either NeuroD1 or Prox1 immunoreactivity. Altogether, these data suggest that alcohol dependence produces similar reactive increases in NPC proliferation and adult neurogenesis. Thus, reactive, adult neurogenesis may be a means of recovery for the hippocampus after alcohol dependence in females.

Quantification of the Uncertainties in Extrapolating From In Vitro Androgen Receptor Antagonism to In Vivo Hershberger Assay Endpoints and Adverse Reproductive Development in Male Rats

2020 ◽  
Vol 176 (2) ◽  
pp. 297-311
Author(s):  
Leon E Gray ◽  
Johnathan R Furr ◽  
Christy S Lambright ◽  
Nicola Evans ◽  
Phillip C Hartig ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Adverse Outcome ◽  
In Utero ◽  
Male Rats ◽  
Male Rat ◽  
Rat Offspring ◽  
Hershberger Assay ◽  
Key Events

Abstract Multiple molecular initiating events exist that disrupt male sexual differentiation in utero including androgen receptor (AR) antagonism and inhibition of synthesis, and metabolism of fetal testosterone. Disruption of androgen signaling by AR antagonists in utero reduces anogenital distance (AGD) and induces malformations in F1 male rat offspring. We are developing a quantitative network of adverse outcome pathways that includes multiple molecular initiating events and key events linking anti-AR activities to permanent reproductive abnormalities. Here, our objective was to determine how accurately the EC50s for AR antagonism in vitro or ED50s for reduced tissue growth in the Hershberger assay (HA) (key events in the adverse outcome pathway) predict the ED50s for reduced AGD in male rats exposed in utero to AR antagonists. This effort included in-house data and published studies from the last 60 years on AR antagonism in vitro and in vivo effects in the HA and on AGD after in utero exposure. In total, more than 250 studies were selected and included in the analysis with data from about 60 potentially antiandrogenic chemicals. The ability to predict ED50s for key events and adverse developmental effects from the in vitro EC50s displays considerable uncertainty with R2 values for HA and AGD of < 6%. In contrast, there is considerably less uncertainty in extrapolating from the ED50s in the HA to the ED50s for AGD (R2 value of about 85%). In summary, the current results suggest that the key events measured in the HA can be extrapolated with reasonable certainty to predict the ED50s for the adverse in utero effects of antiandrogenic chemicals on male rat offspring.

scholarly journals Sonic Hedgehog is expressed by hilar mossy cells and regulates cellular survival and neurogenesis in the adult hippocampus

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Luis E. Gonzalez-Reyes ◽  
Chia-Chu Chiang ◽  
Mingming Zhang ◽  
Joshua Johnson ◽  
Manuel Arrillaga-Tamez ◽  
...  
Keyword(s):  
Dentate Gyrus ◽  
Sonic Hedgehog ◽  
Hippocampal Neurons ◽  
Hippocampal Neurogenesis ◽  
Adult Brain ◽  
Cellular Survival ◽  
Mossy Cells ◽  
Cellular Source ◽  
Dynamic Source ◽  
Hilar Neurons

AbstractSonic hedgehog (Shh) is a multifunctional signaling protein governing pattern formation, proliferation and cell survival during embryogenesis. In the adult brain, Shh has neurotrophic function and is implicated in hippocampal neurogenesis but the cellular source of Shh in the hippocampus remains ill defined. Here, we utilize a gene expression tracer allele of Shh (Shh-nlacZ) which allowed the identification of a subpopulation of hilar neurons known as mossy cells (MCs) as a prominent and dynamic source of Shh within the dentate gyrus. AAV-Cre mediated ablation of Shh in the adult dentate gyrus led to a marked degeneration of MCs. Conversely, chemical stimulation of hippocampal neurons using the epileptogenic agent kainic acid (KA) increased the number of Shh+ MCs indicating that the expression of Shh by MCs confers a survival advantage during the response to excitotoxic insults. In addition, ablation of Shh in the adult dentate gyrus led to increased neural precursor cell proliferation and their migration into the subgranular cell layer demonstrating that MCs-generated Shh is a key modulator of hippocampal neurogenesis.

scholarly journals Physical Activity Ameliorates Impaired Hippocampal Neurogenesis in the Tg4-42 Mouse Model of Alzheimer’s Disease

ASN NEURO ◽  
2019 ◽  
Vol 11 ◽  
pp. 175909141989269 ◽  
Author(s):  
Anna-Lina Gerberding ◽  
Silvia Zampar ◽  
Martina Stazi ◽  
David Liebetanz ◽  
Oliver Wirths
Keyword(s):  
Physical Activity ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Dentate Gyrus ◽  
Structural Changes ◽  
Hippocampal Neurogenesis ◽  
Wild Type ◽  
Running Wheel ◽  
Model Of Alzheimer’S Disease

There is growing evidence from epidemiological studies that especially midlife physical activity might exert a positive influence on the risk and progression of Alzheimer’s disease. In this study, the Tg4-42 mouse model of Alzheimer’s disease has been utilized to assess the effect of different housing conditions on structural changes in the hippocampus. Focusing on the dentate gyrus, we demonstrate that 6-month-old Tg4-42 mice have a reduced number of newborn neurons in comparison to age-matched wild-type mice. Housing these mice for 4 months with either unlimited or intermittent access to a running wheel resulted in a significant rescue of dentate gyrus neurogenesis. Although neither dentate gyrus volume nor neuron number could be modified in this Alzheimer’s disease mouse model, unrestricted access to a running wheel significantly increased dentate gyrus volume and granule cell number in wild-type mice.

Sign in / Sign up

Export Citation Format

Share Document