Induction of neurogenesis in the neocortex of adult mice

Abstract

Neurogenesis normally only occurs in limited areas of the adult mammalian brain--the hippocampus, olfactory bulb and epithelium, and at low levels in some regions of macaque cortex. Here we show that endogenous neural precursors can be induced in situ to differentiate into mature neurons, in regions of adult mammalian neocortex that do not normally undergo any neurogenesis. This differentiation occurs in a layer- and region-specific manner, and the neurons can re-form appropriate corticothalamic connections. We induced synchronous apoptotic degeneration of corticothalamic neurons in layer VI of anterior cortex of adult mice and examined the fates of dividing cells within cortex, using markers for DNA replication (5-bromodeoxyuridine; BrdU) and progressive neuronal differentiation. Newly made, BrdU-positive cells expressed NeuN, a mature neuronal marker, in regions of cortex undergoing targeted neuronal death and survived for at least 28 weeks. Subsets of BrdU+ precursors expressed Doublecortin, a protein found exclusively in migrating neurons, and Hu, an early neuronal marker. Retrograde labelling from thalamus demonstrated that BrdU+ neurons can form long-distance corticothalamic connections. Our results indicate that neuronal replacement therapies for neurodegenerative disease and CNS injury may be possible through manipulation of endogenous neural precursors in situ.

Doublecortin maintains bipolar shape and nuclear translocation during migration in the adult forebrain

“…The two primary zones of adult proliferation are the subgranular layer of the hippocampal dentate gyrus and the SVZ of the forebrain, although other zones are also thought to exist 51,52 . DCX has become a widely used marker for newly generated neuroblasts in proliferative zones in adult 14,31,53,54 .…”

Manipulation of Neural Precursors in situ Induction of Neurogenesis in the Neocortex of Adult Mice

“…Our own results demonstrate a complete absence of constitutively occurring neurogenesis in murine neocortex (Magavi et al 2000). However, two studies reported low level, constitutively-occurring neurogenesis in specific regions of the neocortex of adult primates (Gould et al 1999c) and in the visual cortex of adult rat (Kaplan 1981).…”

“…Many adult precursors are capable of migrating long distances, using both tangential and radial forms of migration (Lois and Alvarez-Buylla 1994;Doetsch and Alvarez-Buylla 1996;Luskin and Boone 1994). Endogenous adult neural precursors are also capable of extending axons significant distances through the adult brain (Magavi et al 2000;Barber 1982;Crews and Hunter 1994). In addition, in vitro and in vivo experiments have begun to elucidate the responses of endogenous precursors to both growth factors and behavioral manipulations, and are beginning to provide key information toward manipulation of their proliferation and differentiation.…”

“…We have applied this approach in several mammalian and avian CNS systems, effecting 50% to 99% degeneration (typically ‫ف‬ 70%) of the targeted populations (Scharff et al 2000;Magavi et al 2000;Macklis 1993;Sheen and Macklis 1995). In neocortex, we have produced selective degeneration of pyramidal neurons with callosal projections (laminae 2/3 and/or 5 neurons) or cortico-thalamic projections (Magavi et al 2000;Macklis 1993;Sheen and Macklis 1995;Madison and Macklis 1993).…”

“…In neocortex, we have produced selective degeneration of pyramidal neurons with callosal projections (laminae 2/3 and/or 5 neurons) or cortico-thalamic projections (Magavi et al 2000;Macklis 1993;Sheen and Macklis 1995;Madison and Macklis 1993). Targeted neurons die by apoptosis, via a cascade of characteristic apoptotic cellular events.…”