Abstract
Neurogenesis in the adult brain is largely restricted to the subependymal zone (SVZ) of the lateral ventricle, olfactory bulb (OB) and the dentate subgranular zone, and survival of adult-born cells in the OB is influenced by factors including sensory experience. We examined, in mice, whether survival of adult-born cells is also regulated by the rate of precursor proliferation in the SVZ. Precursor proliferation was decreased by depleting the SVZ of dopamine after lesioning dopamine neurons in the substantia nigra compacta with 6-hydroxydopamine. Subsequently, we examined the effect of reduced SVZ proliferation on the generation, migration and survival of neuroblasts and mature adult-born cells in the SVZ, rostral migratory stream (RMS) and OB. Proliferating cells in the SVZ, measured by 5-bromo-2-deoxyuridine (BrdU) injected 2 hours prior to death or by immunoreactivity against Ki67, were reduced by 47% or 36%, respectively, 7 days after dopamine depletion, and by 29% or 31% 42 days after dopamine depletion, compared to sham-treated animals. Neuroblast generation in the SVZ and their migration along the RMS were not affected, neither 7 nor 42 days after the 6-hydroxydopamine injection, since the number of doublecortin-immunoreactive neuroblasts in the SVZ and RMS, as well as the number of neuronal nuclei-immunoreactive cells in the OB, were stable compared to control. However, survival analysis 15 days after 6-hydroxydopamine and 6 days after BrdU injections showed that the number of BrdU+ cells in the SVZ was 70% higher. Also, 42 days after 6-hydroxydopamine and 30 days after BrdU injections, we found an 82% increase in co-labeled BrdU+/γ-aminobutyric acid-immunoreactive cell bodies in the granular cell layer, while double-labeled BrdU+/tyrosine hydroxylase-immunoreactive cell bodies in the glomerular layer increased by 148%. We conclude that the number of OB interneurons following reduced SVZ proliferation is maintained through an increased survival of adult-born precursor cells, neuroblasts and interneurons.
Highlights
The mammalian nervous system arises from coordinated proliferation, differentiation and migration of precursor cells during embryonic and early postnatal development [1]
We performed stereological quantification to examine whether reduced SVZ proliferation altered: 1) the number of neuroblasts generated in the SVZ and rostral migratory stream (RMS); 2) the number of neuroblasts migrating through the RMS; 3) the number of interneurons present in the olfactory bulb (OB); and 4) the survival of newborn cells in the OB
We examined the influence of a reduced number of proliferating precursor cells in the adult SVZ on the generation of neuroblasts, their migration through the RMS and their survival in the OB
Summary
The mammalian nervous system arises from coordinated proliferation, differentiation and migration of precursor cells during embryonic and early postnatal development [1]. Most of these processes are completed by the perinatal period, neurogenesis continues throughout adulthood in the subventricular or subependymal zone (SVZ) of the lateral ventricle and olfactory bulb (OB) [2,3], as well as the subgranular zone of the hippocampal dentate gyrus [4,5]. When neuroblasts reach the OB, they migrate radially into the granular (GCL), periglomerular (GL) and external plexiform cell layers of the OB, and differentiate into local interneurons [3,6,7,8] (Fig. 1).
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