The generation, migration, and differentiation of olfactory neurons in the adult primate brain

Abstract

In adult rodents, neural progenitor cells in the subependymal (SZ) zone of the lateral cerebral ventricle generate neuroblasts that migrate in chains via the rostral migratory stream (RMS) into the olfactory bulb (OB), where they differentiate into interneurons. However, the existence of this neurogenic migratory system in other mammals has remained unknown. Here, we report the presence of a homologue of the rodent SZ͞RMS in the adult macaque monkey, a nonhuman Old World primate with a relatively smaller OB. Our results-obtained by using combined immunohistochemical detection of a marker for DNA replication (5-bromodeoxyuridine) and several cell type-specific markers-indicate that dividing cells in the adult monkey SZ generate neuroblasts that undergo restricted chain migration over an extended distance of more than 2 cm to the OB and differentiate into granule interneurons. These findings in a nonhuman primate extend and support the use of the SZ͞RMS as a model system for studying neural regenerative mechanisms in the human brain.T he generation of mammalian brain structures is restricted to developmental periods (1). However, investigations of neurogenesis in the rodent brain revealed two forebrain regions that continue producing new neurons well into adulthood: the hippocampal dentate gyrus (2-4) and the subventricular, or subependymal, zone (SZ) (5-7). Of these two regions, the SZ harbors the largest pool of dividing neuronal progenitor cells in the adult rodent brain (8,9). Progenitor cells in the SZ generate immature neurons that aggregate to form an extensive network of neuroblast chains along the lateral wall of the lateral cerebral ventricle (10, 11). These chains of neuroblasts coalesce anteriorly to form a highly restricted migratory route, designated as the rostral migratory stream (RMS), which extends from the anterior SZ into the olfactory bulb (OB). Unlike the radial glialguided migration used by young neurons during early brain development (12), neuroblasts undergoing ''chain migration'' in the adult SZ͞RMS migrate along one another via neurophilic interactions (11, 13). These chains are ensheathed by tubes of flanking astrocytes, which delineate the RMS. Neuroblasts migrate rostrally within the RMS to enter the OB, whereupon they differentiate into local interneurons (6,7,10,14).However, although the SZ͞RMS neurogenic migratory system often is presumed to be a generic feature of all adult mammalian brains (including humans), in fact, its existence has remained documented only in murine rodents. In these rodents, which have relatively large OBs and are predominantly nocturnal, this system is thought to play a role in odor discrimination (15). Consequently, the question has remained open of whether this olfactory stream is peculiar to macrosmatic rodents or also exists in microsmatic nonrodent species, particularly anthropoid primates (monkeys, apes, and humans). Compared with rodents, anthropoids have relatively small OBs with elongated olfactory peduncles and are largely diurnal (16). Moreover, ...

Adult Neurogenesis and the Ischemic Forebrain

“…Technical advances such as the use of bromodeoxyuridine (BrdU) and retroviral reporter mitotic labeling (e.g., Corotto et al, 1994;Lois and AlvarezBuylla, 1994;Gage et al, 1995;van Praag et al, 2002) have facilitated unambiguous identification of adult-generated cells in vivo as new neurons. Adult neurogenesis persists in every mammalian species examined to date, including human and nonhuman primates (Eriksson et al, 1998;Gould et al, 1998Gould et al, , 1999Kornack and Rakic, 2001;Pencea et al, 2001a;Bedard and Parent, 2004), in two forebrain regions: the dentate gyrus and subventricular zone (SVZ) (Figure 1). …”

“…In the human dentate gyrus, new DGCs continue to be generated even as late as the seventh or eighth decades of life (Eriksson et al, 1998). Neuronal production also appears to continue in the adult SVZ-olfactory bulb pathway of primates (Kornack and Rakic, 2001;Pencea et al, 2001a). The adult primate SVZ underlies the ventral and lateral walls of the lateral ventricle.…”

“…Reports of persistent neurogenesis in the rodent cortex date as far back as several decades ago (Altman, 1963;Kaplan, 1981), but more contemporary studies both in rodents and primates Kornack and Rakic, 2001;Bernier et al, 2002;Koketsu et al, 2003;Dayer et al, 2005) thus far have failed to reach a consensus on the issue. Additional reports of new neurons in the adult striatum (Bedard et al, 2002;Dayer et al, 2005), substantia nigra , and amygdala (Bernier et al, 2002) suggest that low-level neurogenesis in the adult mammalian brain might be a widespread phenomenon, but some of these Figure 1 Schematic parasagittal view of the adult rodent brain.…”

Transcription factor protein expression patterns by neural or neuronal progenitor cells of adult monkey subventricular zone

“…Although studied less extensively in adult primates, SVZa precursor cells were documented also at the primate level, in vitro (Pincus et al, 1998;Roy et al, 2000) and in vivo (Kornack and Rakic, 2001;Pencea et al, 2001). Cerebral ischemia increases the proliferation of the precursor cells residing in SVZa, in both focal (Jin et al, 2001;Zhang et al, 2001;Arvidsson et al, 2002;Parent et al, 2002) and global (Iwai et al, 2003) rodent models.…”

Olfactory system modulation of hippocampal cell death

“…Olfactory information travels from the olfactory bulb to olfactory cortical areas including the piriform cortex, and then directly to the entorhinal cortex which is the major afferent to the hippocampal dentate gyrus [11,16]. Two regions uniformly agreed to display continual neurogenesis through life are the olfactory bulb and the hippocampal dentate gyrus [1,2,15,18]. In both structures, survival of adult generated neurons is dependent on their being incorporated into an active circuit [4,9,18,23].…”