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Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging

Molecular Psychiatry volume 28, pages 5337–5349 (2023)Cite this article

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Abstract

Adult neurogenesis is reduced during aging and impaired in disorders of stress, memory, and cognition though its normal function remains unclear. Moreover, a systems level understanding of how a small number of young hippocampal neurons could dramatically influence brain function is lacking. We examined whether adult neurogenesis sustains hippocampal connections cumulatively across the life span. Long-term suppression of neurogenesis as occurs during stress and aging resulted in an accelerated decline in hippocampal acetylcholine signaling and a slow and progressing emergence of profound working memory deficits. These deficits were accompanied by compensatory reorganization of cholinergic dentate gyrus inputs with increased cholinergic innervation to the ventral hippocampus and recruitment of ventrally projecting neurons by the dorsal projection. While increased cholinergic innervation was dysfunctional and corresponded to overall decreases in cholinergic levels and signaling, it could be recruited to correct the resulting memory dysfunction even in old animals. Our study demonstrates that hippocampal neurogenesis supports memory by maintaining the septohippocampal cholinergic circuit across the lifespan.  It also provides a systems level explanation for the progressive nature of memory deterioration during normal and pathological aging and indicates that the brain connectome is malleable by experience.

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Fig. 1: Increased cholinergic hilar inputs in mice living with diminished neurogenesis.
Fig. 2: Reorganization of cholinergic septotemporal projection after a prolonged reduction in adult neurogenesis.
Fig. 3: A working memory deficit emerges in mice after a prolonged reduction of adult neurogenesis.
Fig. 4: Hippocampal acetylcholine release declines over time in mice without neurogenesis.
Fig. 5: Circuit-specific recruitment and systemic boosting of ACh reverses working memory deficits in NG− mice.
Fig. 6: Structural and functional reorganization of the septohippocampal circuit in NG− mice.

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Acknowledgements

The authors thank Yulong Li for sharing AAV-GRAB-ACh3.0; Joshua Gordon and Steven Siegelbaum for critical reading of the manuscript; and members of the ADL and Gordon labs for helpful insights. GSK was supported by a Canadian Institutes of Health Research Postdoctoral Fellowship. This work was supported by MH115215, MH106809, NARSAD young investigator award, and Columbia University Irving Scholar and Translational Therapeutics Accelerator awards (AD), MH091427 (EDL), and NS085502 (LMS).

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Author notes

  1. These authors contributed equally: Greer S. Kirshenbaum, Chia-Yuan Chang, Maria Bompolaki.

Authors and Affiliations

  1. Department of Psychiatry, Columbia University, New York, NY, 10032, USA

    Greer S. Kirshenbaum, Chia-Yuan Chang, Maria Bompolaki, Victoria R. Bradford, Joseph Bell, Rebecca M. Shansky, Alexander Z. Harris, E. David Leonardo & Alex Dranovsky

  2. New York State Psychiatric Institute, New York, NY, 10032, USA

    Greer S. Kirshenbaum, Chia-Yuan Chang, Maria Bompolaki, Victoria R. Bradford, Joseph Bell, Rebecca M. Shansky, Alexander Z. Harris, E. David Leonardo & Alex Dranovsky

  3. Department of Psychology, National Taiwan University, Taipei, Taiwan

    Chia-Yuan Chang

  4. Zuckerman Mind Brain Behavior Institute, Columbia University, New York, NY, 10027, USA

    Stylianos Kosmidis

  5. Department of Psychology, Northeastern University, Boston, MA, 02115, USA

    Rebecca M. Shansky

  6. RIKEN Center for Brain Science, Saitama, Japan

    Javier Orlandi

  7. Department of Psychology, Binghamton University, Binghamton, NY, 13902, USA

    Lisa M. Savage

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Kirshenbaum, G.S., Chang, CY., Bompolaki, M. et al. Adult-born neurons maintain hippocampal cholinergic inputs and support working memory during aging. Mol Psychiatry 28, 5337–5349 (2023). https://doi.org/10.1038/s41380-023-02167-z

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