Age-dependent Cognitive Impairment and Inducible Expansion of Neural Stem Cells
Final Report Abstract
The Project was based on the observation that overexpression of the positive regulators of cell cycle Cdk4/cyclinD1 (4D for brevity) trigger the expansion of mammalian neural stem cells (NSC). In turn, this allowed us to genetically increase adult neurogenesis in the mouse brain. The Project aimed to capitalize on these findings and, in particular, investigate whether i) 4D could compensate the age-related decline in neurogenesis naturally occurring in the mammalian brain and, if so, ii) if increasing neurogenesis was sufficient to rescue certain aspects of age-related cognitive decline. Two approaches were proposed to address the first question. First, 4D was overexpressed in mice already old, i.e. after neurogenesis had long reached its minimum and, thus, attempting to acutely rescue its levels. Alternatively, second, 4D was chronically overexpressed starting at young age, i.e. when neurogenesis is still at high levels and mice subsequently aged for 1.5 year to assess whether increased neurogenesis would still persist in the old brain. Next, if either one of these two approaches were successful, we proposed to use the most effective to investigate potential positive effects in rescuing age-related cognitive decline. These two approaches were found to be equally successful showing that a 4D- triggered expansion of NSC acutely in old age or chronically over the course of life rescued the levels of neurogenesis compensating its natural decline (see data below). Hence, the next question as to whether or not increasing neurogenesis in the old brain rescued age-related cognitive impairments was investigated in both contexts. Also this aim was successfully reached by specifically looking at critical aspects of hippocampal learning, navigation and contextual memory. Going beyond what was originally proposed, these experiments combining manipulation of NSC, neurogenesis and behavioural analyses were performed while also measuring effects on hippocampal activity and physiological parameters underlying memory representation and consolidation. In fact, during the course of this project, we realized that assessing neural activation along the trisynaptic hippocampal circuitry and electrophysiological recordings in live mice was essential to gain a mechanistic understanding of the induced effects of newborn neurons in the computational performance of the hippocampus. In short, while the project involving life-long cellular and behavioural analyses over the course of life was challenging and time demanding, this project was entirely successful in all of its proposed approaches and goals and could also extend its original aims to new areas that, at the time, were not even considered. The study not only provides new mechanistic insights into the role of newborn neurons in hippocampal activity and function but it also provides the first evidence that specific age-related cognitive impairments can be rescued by a genetically-driven manipulation of the endogenous pool of NSC.
