Topographic differences in adult neurogenesis in the mouse hippocampus: a stereology-based study using endogenous markers.

The hippocampus plays a critical role in various cognitive and affective functions. Increasing evidence shows that these functions are topographically distributed along the dorsoventral (septotemporal) and transverse axes of the hippocampus. For instance, dorsal hippocampus is involved in spatial memory and learning whereas ventral hippocampus is related to emotion. Here, we examined the topographic differences (dorsal vs. ventral; suprapyramidal vs. infrapyramidal) in adult neurogenesis in the mouse hippocampus using endogenous markers. The optical disector was applied to estimate the numerical densities (NDs) of labeled cells in the granule cell layer. The NDs of radial glia-like progenitors labeled by brain lipid binding protein were significantly lower in the infrapyramidal blade of the ventral DG than in other subdivisions. The NDs of doublecortin-expressing cells presumed neural progenitors and immature granule cells were significantly higher in the suprapyramidal blade of the dorsal DG than in the other subdivisions. The NDs of calretinin-expressing cells presumed young granule cells at the postmitotic stage were significantly higher in the suprapyramidal blade than in the infrapyramidal blade in the dorsal DG. No significant regional differences were detected in the NDs of dividing cells identified by proliferating cell nuclear antigen. Taken together, these findings suggest that a larger pool of immature granule cells in dorsal hippocampus might be responsible for spatial learning and memory, whereas a smaller pool of radial glia-like progenitors in ventral hippocampus might be associated with the susceptibility to affective disorders. Cell number estimation using a 300-μm-thick hypothetical slice indicates that regional differences in immature cells might contribute to the formation of topographic gradients in mature granule cells in the adult hippocampus. Our data also emphasizes the importance of considering such differences when evaluating changes in adult neurogenesis in pathological conditions and following experimental procedures.

Jinno S 《-》

Decline in adult neurogenesis during aging follows a topographic pattern in the mouse hippocampus.

In the rodent brain, diverse functions are topographically distributed within the hippocampus. For instance, the dorsal (septal) hippocampus is involved in spatial memory, whereas the ventral (temporal) hippocampus is related to emotion and anxiety. Accumulating evidence shows that age-dependent decline in hippocampal neurogenesis is associated with impairments of these functions. However, little is known about whether the decline in dentate granule cell production during aging follows a topographic pattern. Here we quantitatively estimated specific populations of adult-born cells in young adult and middle-aged mice by using endogenous markers and determined whether age-dependent reductions in adult neurogenesis exhibited topographic differences. The numerical densities (NDs) of putative primary progenitors, intermediate neuronal progenitors, and neuronal lineages were higher in the dorsal dentate gyrus (DG) than in the ventral DG both in young adult and in middle-aged mice, but the ratios of the NDs in the dorsal DG to the NDs in the ventral DG noticeably increased with age. The age-related reductions in the numbers of these populations were larger in the ventral DG than in the dorsal DG. By contrast, the NDs of glial lineages were higher in the ventral DG than in the dorsal DG during life, and the numbers of glial lineages showed no significant age-related changes. Our findings suggest that neurogenesis, but not gliogenesis, wanes faster in the ventral hippocampus than in the dorsal hippocampus during aging. Such age-related topographic changes in hippocampal neurogenesis might be implicated in memory and affective impairments in older people.

Jinno S 《-》

Stereological estimation of numerical densities of glutamatergic principal neurons in the mouse hippocampus.

Recent studies have emphasized functional dissociations between dorsal and ventral hippocampus in learning, emotion, and affect. A rigorous quantitative analysis concerning lamellar cytoarchitecture would be important for promoting further research on the regional differentiation of the hippocampus. Here, we stereologically estimated the numerical densities (NDs) of glutamatergic principal neurons in the mouse hippocampus and encountered the significant differences along the dorsoventral axis. In the CA1 region, the NDs of CA1 pyramidal neurons were almost three times higher at the dorsal level (447.5 x 10(3)/mm(3)) than at the ventral level (180.5 x 10(3)/mm(3)); meanwhile, along the transverse axis, the NDs were significantly higher in the proximal portion than in the distal portion both at the dorsal and ventral levels. An EF-hand calcium-binding protein, calbindin D28K, was expressed in approximately 45% of CA1 pyramidal neurons both at the dorsal and ventral level. In the CA3 region, there were no significant differences in the NDs along the dorsoventral and transverse axes (dorsal, 165.2 x 10(3)/mm(3); ventral, 172.4 x 10(3)/mm(3)). In the dentate gyrus (DG), the NDs of granule cells were significantly higher at the dorsal level (916.7 x 10(3)/mm(3)) than at the ventral level (788.9 x 10(3)/mm(3)). The significant differences were observed only in the suprapyramidal blade, but not in the infrapyramidal blade. Then, we calculated the total neuron numbers contained in a 300-microm-thick hypothetical transverse slice of the hippocampus and found that the ratios of GABAergic to glutamatergic neuron numbers were two to three times higher in the ventral slice than in the dorsal slice. The ratios of numbers of eight GABAergic neuron subtypes to principal cells indicate structural dissociations in the neural network between dorsal and ventral slices. These findings provide an essential quantitative basis for elucidating mechanisms of distinct neural circuits underlying various hippocampal functions.

Jinno S ，Kosaka T 《-》

Glial fibrillary acidic protein-expressing neural progenitors give rise to immature neurons via early intermediate progenitors expressing both glial fibrillary acidic protein and neuronal markers in the adult hippocampus.

Adult neurogenesis occurs in the subgranular zone (SGZ) of the dentate gyrus, where primary neuronal progenitors that express glial fibrillary acidic protein (GFAP) develop into granule neurons. Here, we used transgenic mice with mouse GFAP promoter-controlled enhanced green fluorescent protein (mGFAP-EGFP Tg mice) to examine how astrocyte-like progenitors differentiate into neuron-committed progenitors. Bromodeoxyuridine (BrdU) analysis indicated that proliferating cells in the neurogenic SGZ transiently expressed EGFP and GFAP, and finally differentiated into cells positive for the neuronal marker, Hu (Hu+). Most proliferating EGFP+ cells showed expression of the stem cell marker, Sox2, and formed clusters of two to four cells containing GFAP+/EGFP+ and GFAP-/EGFP+ cells. No GFAP-/EGFP+ cells were detected in non-neurogenic regions, such as CA1 and CA3 of the pyramidal cell layer. Together with the assumption that exogeneous EGFP has a higher stability than that of endogenous GFAP in the degradation process, it is highly probable that the GFAP-/EGFP+ cells were daughter cells or immediate progeny derived from GFAP+/EGFP+ cells. The subpopulation of proliferating GFAP+/EGFP+ cells expressed proneural protein Mash1 and neuronal marker Hu, while the proliferating GFAP-/EGFP+ cells expressed additional immature neuronal markers, such as polysialic acid-neural cell adhesion molecule (PSA-NCAM) and doublecortin. Therefore, these results suggest that through a few cell divisions, GFAP+ progenitors give rise to neuronal progenitors via neuron-committed early intermediate progenitors that express both GFAP and Hu (and/or Mash1). The findings of the present study also indicated that mGFAP-EGFP Tg mice are useful animals for identifying the daughter cells or immediate progeny derived from GFAP+ neural progenitors.

Liu Y ，Namba T ，Liu J ，Suzuki R ，Shioda S ，Seki T ... -  《-》

Strain differences in neurogenesis and activation of new neurons in the dentate gyrus in response to spatial learning.

Adult neurogenesis continues throughout life in the mammalian hippocampus and evidence suggests that adult neurogenesis is involved in hippocampus-dependent learning and memory. Numerous studies have demonstrated that spatial learning enhances neurogenesis in the hippocampus but few studies have examined whether enhanced neurogenesis is related to enhanced activation of new neurons in response to spatial learning. Furthermore, the majority of these studies have utilized Sprague-Dawley (SD) rats. However, Long-Evans and Sprague-Dawley rats have been reported to have different learning abilities. In order to determine whether these strains exhibit a similar enhancement of neurogenesis and new neuronal activation in response to spatial learning we tested both strains in a hippocampus-dependent or hippocampus-independent version of the Morris water task (MWT) and then compared levels of neurogenesis and activation of these new cells in the hippocampus. Here we show that despite equivalent performance in the MWT, spatial learning produced a different effect on neurogenesis in each strain. Spatial learning increased cell survival and the number of immature neurons in SD rats compared to cage control and cue-trained rats. In Long-Evans (LE) rats however, spatial learning increased cell survival (BrdU-labeling) but did not increase the number of immature neurons (doublecortin-labeling). Furthermore, we report here an intriguing difference in the activation of new neurons (using the immediate early gene product zif268) in SD versus LE rats. In SD rats we show that spatial learning increases the percentage of doublecortin-labeled cells that are activated during a probe trial. Conversely, in LE rats spatial learning increased the activation of BrdU-labeled but not doublecortin-labeled cells. This interesting difference suggests that different ages or maturational stages of cells are recruited by spatial learning in the two strains. These findings may lead to a better understanding of how and why neurogenesis is regulated by spatial learning.

Epp JR ，Scott NA ，Galea LA 《-》