The aPKC-CBP Pathway Regulates Adult Hippocampal Neurogenesis in an Age-Dependent Manner

AbstractAndrogens (testosterone and dihydrotestosterone) increase adult hippocampal neurogenesis by increasing new neuron survival in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in females and whether the effect is age-dependent. We investigated the effects of dihydrotestosterone, a potent androgen, on neurogenesis in adult and middle-aged males and females. Rats were gonadectomized and injected with the DNA synthesis marker, bromodeoxyuridine (BrdU). The following day rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell proliferation (Ki67) and new neuron survival (BrdU and BrdU/NeuN) in the hippocampus of male and female rats using immunohistochemistry. As expected, DHT increased new neuron survival in young males but surprisingly not in middle-aged male rats. In females, DHT did not significantly affect adult neurogenesis in young or middle age. Our results indicate that DHT regulates adult hippocampal neurogenesis in a sex- and age-dependent manner.

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Androgens Enhance Adult Hippocampal Neurogenesis in Males but Not Females in an Age-Dependent Manner

Endocrinology ◽

10.1210/en.2019-00114 ◽

2019 ◽

Vol 160 (9) ◽

pp. 2128-2136 ◽

Cited By ~ 10

Author(s):

Paula Duarte-Guterman ◽

Stephanie E Lieblich ◽

Steven R Wainwright ◽

Carmen Chow ◽

Jessica A Chaiton ◽

...

Keyword(s):

Middle Age ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Female Rats ◽

Male Rats ◽

Dependent Manner ◽

Middle Aged ◽

Male And Female ◽

Male And Female Rats ◽

Age Dependent

Abstract Androgens (testosterone and DHT) increase adult hippocampal neurogenesis by increasing survival of new neurons in male rats and mice via an androgen receptor pathway, but it is not known whether androgens regulate neurogenesis in female rats and whether the effect is age-dependent. We investigated the effects of DHT, a potent androgen, on neurogenesis in young adult and middle-aged male and female rats. Rats were gonadectomized and injected with the DNA synthesis marker bromodeoxyuridine (BrdU). The following day, rats began receiving daily injections of oil or DHT for 30 days. We evaluated cell proliferation (Ki67) and survival of new neurons (BrdU and BrdU/NeuN) in the hippocampus of male and female rats by using immunohistochemistry. As expected, DHT increased the number of BrdU+ cells in young males but surprisingly not in middle-aged males or in young and middle-aged females. In middle age, DHT increased the proportion of BrdU/NeuN cells, an effect driven by females. Androgen receptor expression also increased with aging in both female and male rats, which may contribute to a lack of DHT neurogenic effect in middle age. Our results indicate that DHT regulates adult hippocampal neurogenesis in a sex- and age-dependent manner.

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Short-term calorie restriction enhances adult hippocampal neurogenesis and remote fear memory in a Ghsr-dependent manner

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2015.09.023 ◽

2016 ◽

Vol 63 ◽

pp. 198-207 ◽

Cited By ~ 53

Author(s):

Amanda K.E. Hornsby ◽

Yushi T. Redhead ◽

Daniel J. Rees ◽

Michael S.G. Ratcliff ◽

Alex Reichenbach ◽

...

Keyword(s):

Calorie Restriction ◽

Fear Memory ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Dependent Manner ◽

Short Term

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Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms21010004 ◽

2019 ◽

Vol 21 (1) ◽

pp. 4 ◽

Cited By ~ 1

Author(s):

Haena Moon ◽

Seong Gak Jeon ◽

Jin-il Kim ◽

Hyeon soo Kim ◽

Sangho Lee ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Progression ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Dependent Manner ◽

Cell Cycle Regulators ◽

Proliferation Markers ◽

Cycle Progression ◽

Pharmacological Stimulation ◽

Stimulation Of

Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G0/G1 to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27KIP1 and p57KIP2 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27KIP1 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.

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