The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion
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Disruption in cholinergic signaling has been linked to many environmental and/or pathological conditions known to modify adult neurogenesis. The α7 nAChRs are in the family of cys-loop receptor channels which have been shown to be neuroprotective in adult neurons and are thought to be critical for survival and integration of immature neurons. However, in developing neurons, poor calcium buffering may cause α7 nAChR activation to be neurotoxic. To investigate whether the α7 nAChR regulates neurogenesis in the hippocampus, we used a combination of mouse genetics and imaging to quantify neural stem cell (NSC) densities located in the dentate gyrus of adult mice. In addition, we considered whether the loss of α7 nAChRs had functional consequences on a spatial discrimination task that is thought to rely on pattern separation mechanisms. We found that the loss of α7 nAChRs resulted in increased neurogenesis in male mice only, while female mice showed increased cell divisions and intermediate progenitors but no change in neurogenesis. Knocking out the α7 nAChR from nestin+ NSCs and their progeny showed signaling in these cells contributes to regulating neurogenesis. In addition, male, but not female, mice lacking α7 nAChRs performed significantly worse in the spatial discrimination task. This task was sexually dimorphic in wild-type mice, but not in the absence of α7 nAChRs. We conclude that α7 nAChRs regulate adult neurogenesis and impact spatial discrimination function in male, but not female mice, via a mechanism involving nestin+ NSCs and their progeny.
Keywordsα7 nicotinic acetylcholine receptors Adult neurogenesis Nestin Pattern separation Spatial discrimination Neural stem cells Sexually dimorphic
We would like to acknowledge Jesse Cushman for advice on behavior and analysis, and for kindly reviewing the article prior to publication, Patricia Lamb for creation and maintenance of mouse lines, and Charles J. Tucker for assistance with confocal microscopy.
This research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Science.
Compliance with ethical standards
All procedures were approved and performed in compliance with the NIEHS/NIH Humane Care and Use of Animals Protocols.
This article does not contain any studies with human participants performed by any of the authors. All procedures were approved and performed in compliance with the NIEHS/NIH Humane Care and Use of Animals Protocols.
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted. This article does not contain any studies with human participants performed by any of the authors. All procedures were approved and performed in compliance with the NIEHS/NIH Humane Care and Use of Animals Protocols.
Conflict of interest
The authors declare that they have no conflict of interest.
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