The subventricular zone remains mitotically active throughout life in rodents. Studies with tritiated thymidine, which is incorporated into the DNA of mitotic cells, have revealed that the rodent subventricular zone produces neuroblasts that migrate toward the olfactory bulb along the rostral migratory stream. A similar migratory stream has been documented in monkeys by using the thymidine analogue BrdUrd. The same approach showed that neurogenesis occurred in the dentate gyrus of adult primates, including humans. In the present study, experiments combining injections of BrdUrd and the dye 1,1-dioctadecyl-3,3,3,3-tetramethylindo-carbocyanine, with the immunostaining for molecular markers of neurogenesis (polysialylated neural cell adhesion molecule, ␤-tubulin-III, collapsin response mediator protein-4, neuronal nuclear protein) in New World (Saimiri sciureus) and Old World (Macaca fascicularis) monkeys have revealed that new neurons are produced in the amygdala, piriform cortex, and adjoining inferior temporal cortex in adult primates. These newborn neurons expressed the antiapoptotic protein Bcl-2 and formed a more-or-less continuous pathway that extended from the tip of the temporal ventricular horn to the deep portion of the temporal lobe. The production of newborn neurons in the amygdala, piriform cortex, and inferior temporal cortex seems to parallel the continuing addition of neurons in the olfactory bulb. These two concomitant phenomena may ensure structural stability and functional plasticity to the primate olfactory system and temporal lobe. N eurogenesis is known to occur throughout life in specific areas of the mammalian brain, principally the dentate gyrus of the hippocampus and the subventricular zone (SVZ) that lines the lateral ventricles (1, 2). Adult SVZ produces neuroblasts that migrate tangentially toward the olfactory bulb along the socalled rostral migratory stream (RMS) (3, 4). Tangential migration is rare in embryonic brain development, but more than 50% of neurons generated prenatally in rodents seem to migrate tangentially for a certain distance before their final radial implantation (5). Therefore, it can be expected that a majority of neurons produced in mature brain would follow a tangential route to reach implantation level. In any event, the fact that migrating chains have been observed along the entire lateral ventricle system (6, 7) raises the possibility of the existence of migratory streams other than the RMS. Indeed, evidence shows that new neurons are produced in various neocortical regions in monkeys (8), but these cells seem to be transient (9).The present investigation was designed to study newly generated neurons in the deep portion of the temporal lobe of adult monkeys by using the thymidine analogue BrdUrd, which is incorporated into DNA of mitotic cells, combined with immunostaining for highly reliable molecular markers of newborn neurons. Experimental ProceduresPreparation of the Animals and BrdUrd Injections. Nine adult (3-6 years of age) squirrel monkeys (Saimiri sci...

Although the mechanisms underlying the loss of neurons in Parkinson's disease are not well understood, impaired mitochondrial function and pathological protein aggregation are suspected as playing a major role. Why DA (dopamine) neurons and a select small subset of brain nuclei are particularly vulnerable to such ubiquitous cellular dysfunctions is presently one of the key unanswered questions in Parkinson's disease research. One intriguing hypothesis is that their heightened vulnerability is a consequence of their elevated bioenergetic requirements. Here, we show for the first time that vulnerable nigral DA neurons differ from less vulnerable DA neurons such as those of the VTA (ventral tegmental area) by having a higher basal rate of mitochondrial OXPHOS (oxidative phosphorylation), a smaller reserve capacity, a higher density of axonal mitochondria, an elevated level of basal oxidative stress, and a considerably more complex axonal arborization. Furthermore, we demonstrate that reducing axonal arborization by acting on axon guidance pathways with Semaphorin 7A reduces in parallel the basal rate of mitochondrial OXPHOS and the vulnerability of nigral DA neurons to the neurotoxic agents MPP(+) (1-methyl-4-phenylpyridinium) and rotenone. Blocking L-type calcium channels with isradipine was protective against MPP(+) but not rotenone. Our data provide the most direct demonstration to date in favor of the hypothesis that the heightened vulnerability of nigral DA neurons in Parkinson's disease is directly due to their particular bioenergetic and morphological characteristics.

SUMMARY Hedgehog (Hh) proteins regulate important developmental processes including cell proliferation and differentiation. While Patched acts as the main Hh receptor, in Drosophila, Hh signaling absolutely requires the additional Hh-binding proteins Ihog and Boi. Here we show that, unexpectedly, cerebellar granule neuron progenitors (CGNPs) lacking Boc and Cdon, the vertebrate orthologs of Ihog and Boi, still proliferate in response to Hh. This is because in their absence, Gas1, a Hh-binding protein not present in Drosophila, mediates Hh signaling. Consistently, only CGNPs lacking all three molecules Boc, Cdon, and Gas1 have a complete loss of Hh-dependent proliferation. In a complementary manner, we find that a mutated Hh ligand which binds Patched1 but neither Boc, Cdon, nor Gas1 cannot activate Hh signaling. Together, this demonstrates an absolute requirement for Boc, Cdon, and Gas1 in Hh signaling and reveals a distinct requirement for ligand-binding components that distinguishes the vertebrate and invertebrate Hh receptor systems.