Neurogenesis of corticospinal motor neurons extending spinal projections in adult mice

Abstract

The adult mammalian CNS shows a very limited capacity to regenerate after injury. However, endogenous precursors, or stem cells, provide a potential source of new neurons in the adult brain. Here, we induce the birth of new corticospinal motor neurons (CSMN), the CNS neurons that die in motor neuron degenerative diseases, including amyotrophic lateral sclerosis, and that cause loss of motor function in spinal cord injury. We induced synchronous apoptotic degeneration of CSMN and examined the fates of newborn cells arising from endogenous precursors, using markers for DNA replication, neuroblast migration, and progressive neuronal differentiation, combined with retrograde labeling from the spinal cord. We observed neuroblasts entering the neocortex and progressively differentiating into mature pyramidal neurons in cortical layer V. We found 20 -30 new neurons per mm 3 in experimental mice vs. 0 in controls. A subset of these newborn neurons projected axons into the spinal cord and survived >56 weeks. These results demonstrate that endogenous precursors can differentiate into even highly complex long-projection CSMN in the adult mammalian brain and send new projections to spinal cord targets, suggesting that molecular manipulation of endogenous neural precursors in situ may offer future therapeutic possibilities for motor neuron degenerative disease and spinal cord injury. The identification of populations of neural precursors, or stem cells, in the adult mammalian CNS raises the possibility of future repair of neuronal loss from neurodegenerative diseases or neuronal damage from brain and spinal cord injuries resulting from trauma or stroke (1-5). In the adult brain, new neurons are continuously generated, but such neurogenesis is normally restricted to two evolutionarily primitive regions: the olfactory bulb, from precursors in the subventricular zone (SVZ) (6), and the hippocampal dentate gyrus (1, 7), from local precursors in the subgranular zone.A variety of factors, ranging from genetics (8) to environmental modifications, can modulate neurogenesis in these regions. Exercise (9), environmental enrichment (10), pregnancy (11), and even seizure activity (12, 13) promote neurogenesis, whereas depression (14) and aging (15) reduce it. Modulating the cellular and molecular factors that control adult neurogenesis could yield new approaches to replacing neurons lost to injury or disease.Recently, our laboratory and those of others have demonstrated that neurogenesis can be induced from endogenous precursors by manipulating the microenvironment in regions of the adult CNS that are normally nonneurogenic (16-21). Selective neuronal death due to targeted apoptosis or ischemia induces endogenous precursors to divide and differentiate into neurons in mammalian neocortical layer VI (16), hippocampal region CA1 (17), striatum (18,19), substantia nigra (20), and the high vocal center in songbirds (21). These neurons express neuron-specific proteins and adopt appropriate morphologies, and in some cases their recruitment cor...

Can endocrine disruptors influence neuroplasticity in the aging brain?

“…Here the data may be less plentiful and convincing, but Arlotta et al (2003) and Chen et al (2004) showed that neurogenesis may be induced in the adult mouse neocortex, an area in which it normally is not observed. They hold out the possibility that endogenous multipotent precursors in such areas might be manipulated in situ to replace lost or damaged neurons, even for neurodegenerative disorders such as motor neuron diseases.…”

The culture of neural stem cells

“…More recent work has focused on investigating whether endogenous NSCs can give rise to neurons that integrate and function within the CNS. Two important studies in particular provide strong support for the role of NSCs in endogenous CNS repair outside known neurogenic areas [Magavi et al, 2000;Chen et al, 2004]. It seems that the endogenous NSC pathway in adult is stimulated by insults, injury, and disease but fails to unleash a complete response.…”

New Interneurons in the Adult Neocortex: Small, Sparse, but Significant?

“…In adult rodents, studies have reported finding new neurons in the anterior neocortex (5;7;12), but others found no new neocortical neurons in enriched, electroconvulsive seizure-treated, or control conditions (13; 14). Several additional studies have reported finding new neurons in the neocortex only after ischemia or targeted neuronal death (15)(16)(17)(18). These contradictory findings are difficult to reconcile, because all of the studies of adult neurogenesis in the neocortex carried out within the past ten years have used essentially the same methods: injection and immunohistochemical detection of the S-phase marker bromodeoxyuridine (BrdU) to mark newly-born cells combined with immunohistochemistry for neuronal markers to determine whether the new cells are neurons.…”