Research paperSustained Arc expression in adult-generated granule cells
Introduction
The hippocampus is thought to encode a record of experience to support episodic memory formation and recall, and the dentate gyrus (DG) is thought to play a unique role in this regard. Namely, the DG is critical for pattern separation—transforming initially similar input from the perforant path in order to disambiguate memories that have many features in common [1]. Fitting with its unique role in memory, the DG has many remarkable features—the most studied of which is arguably adult neurogenesis. Although the precise role of the lifelong addition of these cells for memory remains debated [2], [3], a large body of literature shows that most manipulations that reduce the number or function of adult-generated granule cells also impair memory.
Another distinct feature of DG is the transcriptional response of granule cells to behavioral stimulation. When processing spatial stimuli, principle cells throughout the hippocampal formation immediately transcribe Arc, an immediate-early gene critical for both plasticity and lasting memory formation. Across most brain regions this transcriptional response is short lived (i.e., <1 h), but in the DG transcription proceeds in the absence of further behavioral stimulation for at least 8 h [4], [5]. With age, the rate of neurogenesis declines dramatically [6], as does the expression of Arc. The decline in Arc production, however, is time-dependent—the late-phase of Arc expression, occurring hours after behavior, shows the greatest reduction and is most predictive of individual memory performance [7], [8]. This pattern of results suggests that adult-generated granule cells may form a critical part of the sustained transcriptional response. It remains unknown, however, if adult-generated granule cells become capable of prolonged Arc expression as soon as they integrate into existing dentate networks. The current study addresses this issue.
Section snippets
Materials and methods
The study includes 42 adult male F344 rats (3–4 months of age on arrival, Harlan Laboratories, Indianapolis, IN). Animals were single-housed in standard shoebox cages with ad lib food and water on a 12:12 reverse light cycle. Upon arrival, animals were permitted to acclimatize to the facility for 7 days, followed by 7 days of handling. After the completion of this handling, rats were injected with BrdU (50 mg/kg) daily for 5 days, followed by a 4 week delay for cells incorporating BrdU to mature
Results and discussion
No significant difference is observed in the proportion of granule cells expressing BrdU across regions (F1,70 = 0.36; p = 0.55) or behavioral groups (F6,70 = 1.70; p = 0.14), consistent with previous reports (Fig. 2d).
A main effect of behavioral group (F6,140 = 10.71; p < 0.001) demonstrates granule cells across the DG respond to spatial exploration (Fig. 2e). However, a main effect of region (F1,140 = 24.58; p < 0.001) and a group by region interaction (F6,140 = 2.63; p < 0.05) were both observed, indicating
Conclusions
Several conclusions can be made from the current observations. Foremost, these data demonstrate that newborn granule cells are capable of prolonged Arc expression in response to a single behavioral experience. Moreover, the fact that sustained transcription is reliably seen at 4 weeks post-BrdU-injection shows that adult-generated cells participate in the sustained transcriptional response of the DG to behavioral stimuli as soon as they are functionally integrated into DG circuits.
Although the
Competing interests
The authors declare no competing financial interests regarding the publication of this paper.
Authors contributions
DFM designed the study. AM, EL, and DFM conducted the research, and analyzed the data. AM and DFM wrote the paper.
Acknowledgements
The research was supported by an operating grant (DFM) and student scholarship (AM) from the Natural Sciences and Engineering Research Council of Canada and an operating grant from the Ontario Mental Health Foundation (DFM).
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Current address: Neuroscience Program, University of Victoria, Victoria, BC V8W 2Y2, Canada.