Adult neurogenesis in the orexin/ataxin-3 mouse
Introduction: The adult mammalian brain retains neural stem cells (NSCs) that continually generate new neurons within two restricted regions, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus (HC). This process is called adu...
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|Summary:||Introduction: The adult mammalian brain retains neural stem cells (NSCs) that continually generate new neurons within two restricted regions, the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus in the hippocampus (HC). This process is called adult neurogenesis. Controlled stimulation of endogenous neurogenesis might be an elegant way to treat neurodegenerative diseases. It is therefore important to understand the molecular signals, which govern the proliferation, migration, and differentiation of endogenous NSCs in the neurogenic niches. Regulatory mechanisms in the so-called neurogenic niches have already been shown by in vivo studies for various factors, including numerous neurotransmitters, and behavioral and environmental factors. However, our knowledge is still insufficient to exploit adult neurogenesis for controlled brain repair or for stimulation of its physiological function.
The sleep disorder narcolepsy is considered to be a neurodegenerative disease because there is a massive progressive loss of neurons containing the neuropeptide orexin. Consequently narcoleptic patients have very low cerebrospinal fluid levels of orexin. Narcolepsy is defined as a sleep-wake disorder with REM and non-REM sleep associated symptoms existing longer than 6 months, such as daytime sleepiness, cataplexy, fractionated sleep at night and automatic behaviors. The postulated pathophysiology of human narcolepsy is mimicked very closely in a transgenic mouse model called orexin/ataxin-3 mouse, in which orexin-containing neurons are ablated progressively by specific overexpression of a truncated cytotoxic ataxin-3 gene product under the orexin-promoter.
Aim: We aimed to study the possible role of the protein orexin in the regulation of adult neurogenesis in the orexin/ataxin-3 mouse.
Study design: Adult neurogenesis in the SGZ, SVZ and rostral migratory stream (RMS), where the cells migrate from the SVZ to the olfactory bulb (OB), was studied by immunohistology. For the evaluation of the stem cell proliferation in SVZ and SGZ and migration in the RMS, orexin/ataxin-3 mice (n = 8) and wild type (WT) mice (n = 8) received a single intraperitoneal injection of 100 mg BrdU (bromodeoxyuridine)/kg body weight 2 hour prior to sacrifice. For the analysis of differentiation and survival of newly built cells, BrdU was administered intraperitoneally on 5 consecutive days once per day to orexin/ataxin-3 mice (n = 8) and WT mice (n = 8) and they were sacrificed 30 days after the last injection.
Results: We found a significantly higher proliferation of stem/precursor cells in the orexin/ataxin-3 mice in both neurogenic regions, the SGZ and the SVZ. Also in the RMS, higher levels of newly built cells in the orexin/ataxin group were found, but these differences were not significant.
We were able to demonstrate a significantly higher survival of newly built cells in the granular zone, but not for the periglomerular zone of the OB in the orexin/ataxin group. A tendency for higher survival rates could be shown for the HC of the orexin/ataxin-3 mice (not significant).
By triple staining we could show that the proportion of newly born neurons relative to the total number of newly built cells in the HC was significantly higher with 90 % in the orexin-ataxin group compared to 83 % in the control group. In both the granular zone and the periglomerular zone of the OB, over 90 % of the total amount of new built cells differentiated into neurons in both groups. Also the rate of differentiation into a dopaminergic phenotype of the newly born neurons in the periglomerular zone of the OB was not significantly changed with 93 % in the orexin/ataxin-3 mice compared to 91 % in the WT mice.
Conclusion: In the absence of orexin in the adult mouse brain, the proliferation of adult neural stem/precursor cells was increased, the survival rate was significantly increased in the granular zone of the OB and a consistent not significant trend was seen in the HC. The proportion of newborn neurons among all newly born cells was higher in the HC, however, no significant differences in the differentiation of newly built cells could be found in the OB. Together, these observations lead to the assumption that orexin suppresses the proliferation of adult NSC, affects the survival rate in the OB negatively and hinders the differentiation of newly built cells into neurons in the HC.|
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