Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation

Abstract

These studies were designed to determine whether adult neurogenesis occurs in the dentate gyrus of the tree shrew, an animal phylogenetically between insectivores and primates, and to explore the possibility that this process is regulated by stressful experiences and NMDA receptor activation. We performed immunohistochemistry for cell-specific markers and the thymidine analog bromodeoxyuridine (BrdU), a marker of DNA synthesis that labels proliferating cells and their progeny, on the brains of adult tree shrews subjected to psychosocial stress or NMDA receptor antagonist treatment. Cells that incorporated BrdU in the dentate gyrus of adult tree shrews were primarily located in the subgranular zone, had morphological characteristics of granule neuron precursors, and appeared to divide within 24 hr after BrdU injection. Three weeks after BrdU injection, BrdU-labeled cells had neuronal morphology, expressed the neuronal marker neuron specific enolase, and were incorporated into the granule cell layer. Vimentin-immunoreactive radial glia were observed in the dentate gyrus with cell bodies in the subgranular zone and processes extending into the granule cell layer. Exposure to acute psychosocial stress resulted in a rapid decrease in the number of BrdU-labeled cells in the dentate gyrus. In contrast, blockade of NMDA receptors, with the NMDA receptor antagonist MK-801, resulted in an increase in the number of BrdU-labeled cells in the dentate gyrus. These results indicate that adult neurogenesis occurs in the tree shrew dentate gyrus and is regulated by a stressful experience and NMDA receptor activation. Furthermore, we suggest that these characteristics may be common to most mammalian species.

Fig. 1.

Template showing a coronal half-section of the tree shrew brain at level A 3.0 (see Tigges and Shantha, 1969), demonstrating that the number and distribution of BrdU-labeled cells (open circles) change with increased survival time after BrdU injection. Two hours after BrdU injection, most labeled cells are located in the sgz, on the border of the gcl and hilus. Twenty-four hours after BrdU injection, more than twice as many BrdU-labeled cells are observed in the dentate gyrus, predominantly in the sgz. By 3 weeks after BrdU injection, most BrdU-labeled cells are located in the gcl and express NSE (solid dots). cc, Corpus callosum; lv, lateral ventricle; 3V, third ventricle;h, hilus; CA1, CA1 region;CA3, CA3 region.

Fig. 2.

Template showing a coronal half-section of the tree shrew brain at level A 2.5 (see Tigges and Shantha, 1969), showing changes in the number and distribution of BrdU-labeled cells (open circles) with increased survival time after BrdU injection. Two hours after BrdU injection, most labeled cells are located in the sgz, between the gcl and hilus. Twenty-four hours after BrdU injection, more than two times as many BrdU-labeled cells are observed in the dentate gyrus, but their distribution remains similar to the 2 hr time point. Three weeks after BrdU injection, most BrdU-labeled cells are located in thegcl and are NSE-immunoreactive (solid dots). cc, Corpus callosum; lv, lateral ventricle; 3V, third ventricle;h, hilus; CA1, CA1 region;CA3, CA3 region.

Fig. 3.

Template showing a coronal half-section of the tree shrew brain at level A 2.0 (see Tigges and Shantha, 1969), indicating changes in the number and distribution of BrdU-labeled cells (open circles) with increased survival time after BrdU injection. Most BrdU-labeled cells are located in the sgz, between thegcl and hilus at the 2 and 24 hr time points. Three weeks after BrdU injection, most BrdU-labeled cells are located in thegcl and are NSE-immunoreactive (solid dots). cc, Corpus callosum; 3V, third ventricle; h, hilus; CA1, CA1 region; CA3, CA3 region.

Fig. 4.

Examples of cell types in the dentate gyrus of the adult tree shrew. A, BrdU-labeled cell (arrows) in the sgz of the dentate gyrus with morphological characteristics of granule cell precursor, i.e., round or oval medium-sized cell body. B, Cluster of BrdU-labeled cells (arrows) in the sgz of the dentate gyrus after MK-801 treatment. C, Vimentin-immunoreactive cell with radial glial morphology, i.e., irregular shaped cell body with radial process. The cell body is located on the border of the hilus and gcl, and the process extends through the gcl. g, Granule cell layer; h, hilus. Scale bar in B, 20 μm (applies to all frames).