What good is an old brain in a young body – a strategy for regenerating the neocortex

2013 Abstract on regenerating the neocortex

The neocortex is the seat of our highest cognitive functions. Neocortical projection neurons, the principle neurons of the become dysfunctional with age and can be lost due to neurodegeneration or insults such as stroke or trauma. The highly plastic nature of neocortical neuronal networks suggests that they could in theory withstand a slow turnover of neurons over time without significantly compromising function or memory. Therefore cell replacement may be a viable approach to rejuvenating the neocortex. We have recently shown that endogenous stem or precursor cells have little or no ability to replace projection neurons when they are lost in the adult neocortex (Diaz et al., April 2013, J. Neuroscience). Moreover, previous attempts at replacing these projection neurons using several types of transplanted neural stem or precursor cells have not provided viable strategies. One limitation of previous attempts is that the transplanted cells remained primarily in the transplant site or only migrated a short distance away from it. Therefore, to achieve the goal of functionally integrating new projection neurons throughout broad areas of the neocortex and to minimize the number of injection sites, a novel strategy is required that takes into account cell dispersion. Our goal is to develop an approach for introducing new, widely dispersed, projection neurons in the adult neocortex, providing a paradigm for testing whether they can functionally integrate. One way in which we are attempting to accomplish this is by using embryonic cells that are inherently migratory when transplanted into the adult mouse neocortex. However, because these particular migratory precursor cells generate interneurons rather than projection neurons, we engineer them with lentiviruses with which we can induce expression of transcription factors that will reprogram them to the desired fate once they have dispersed.

Video from 2012 talk

Journal of Neuroscience – Apoptosis of glutamatergic neurons fails to trigger a neurogenic response in the adult neocortex. (April 2013)


Adult neurogenesis is actively studied in part because of the potential to manipulate endogenous neural stem and progenitor cells for tissue repair. Although constitutive generation of neurons in the adult rodent olfactory bulb and hippocampal dentate gyrus is widely accepted and stroke-induced generation of striatal inhibitory neurons consistently observed, evidence supporting the generation of neurons in the neocortex after neuronal loss remains slim. Nevertheless, a few studies suggested that targeted apoptosis of neocortical glutamatergic neurons could trigger the generation of new ones in the adult brain. In light of such studies, we tested whether apoptosis of glutamatergic cortical neurons using two novel transgenic approaches in mice, an inducible Caspase-8 protein and an inducible diphtheria toxin gene, results in new neurons. After a thorough analysis, no new neurons were detected in the neocortex. Interestingly, an increase in the expression of the neuroblast marker DCX was observed in both models, in some cases in cells with morphologies previously associated with poststroke neuroblasts, but DCX(+) cells coexpressed the oligodendrocyte precursor marker Olig2, suggesting caution when using DCX as a marker for neuroblasts after injury. Given that the adult neocortex lacks an innate potential to regenerate lost glutamatergic neurons, future strategies should concentrate on manipulating the differentiation potential of endogenous or exogenous precursor cells.

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