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Sustained Notch activation depletes adult neural stem cells and impairs cognitive function
Nur Azrah Fazera Mohd Ariffin1, Naoko Morimura1, Kenny Daun1,2
1Department of Integrative Physiology, Shiga University of Medical Science, Otsu, Japan.
Scientific Reports
|June 16, 2026
Summary
Sustained Notch activation in neural stem cells (NSCs) causes their depletion, leading to impaired brain function and memory deficits. This study reveals how overactive Notch signaling disrupts NSC maintenance and brain development.
Area of Science:
- Neuroscience
- Developmental Biology
- Cell Signaling
Background:
- Notch signaling is crucial for neural stem cell (NSC) maintenance and brain function.
- Dysregulation of Notch signaling can lead to aberrant neurodevelopment and cognitive impairments.
Purpose of the Study:
- To investigate the functional consequences of sustained Notch activation in Nestin-lineage cells.
- To elucidate the impact of Notch signaling on NSC self-renewal, differentiation, and behavior.
Main Methods:
- Generation of a spatiotemporally controlled, tetracycline-inducible transgenic mouse model (Nestin-CreER, ROSA26-rtTA, TRE-loxP-DsRed2-loxP-c-Myc-NICD).
- Analysis of NSC pool dynamics, neuronal differentiation, and behavioral outcomes in response to NICD overexpression.
Main Results:
- Sustained NICD overexpression promoted rapid cell division, driving NSCs to terminally differentiate and deplete NSC pools in the SEZ and hippocampal DG.
- Despite NSC depletion, SEZ showed increased newborn neurons in the olfactory bulb, which did not improve function.
- Mice exhibited significant impairments in spatial memory, emotional memory, and social discrimination.
Conclusions:
- Sustained Notch activation in Nestin-lineage cells leads to NSC pool exhaustion and the integration of non-functional neurons.
- This imbalance in NSC maintenance alters both olfactory and hippocampal-dependent behaviors, highlighting the critical role of regulated Notch signaling in brain function.
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