Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits.
The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the DG. Rejuvenation of the DG by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
Kathleen M
KM
McAvoy
Departments of Neuroscience and Psychiatry, Columbia University, New York, NY 10032, USA.
Kimberly N
KN
Scobie
Department of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
Stefan
S
Berger
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Craig
C
Russo
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
Nannan
N
Guo
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Pakanat
P
Decharatanachart
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA.
Hugo
H
Vega-Ramirez
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
Sam
S
Miake-Lye
Neuroscience Center, Massachusetts General Hospital, Boston, MA 02129, USA.
Michael
M
Whalen
Echelon Biosciences, Salt Lake City, UT 84108, USA.
Mark
M
Nelson
Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD) and University Hospital of Cologne, Joseph-Stelzmann-Straße 26, D-50931 Cologne, Germany.
Matteo
M
Bergami
Department of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, 68159 Mannheim, Germany.
Dusan
D
Bartsch
Departments of Neuroscience and Psychiatry, Columbia University, New York, NY 10032, USA.
Rene
R
Hen
Institute of Physiological Chemistry, University Medical Center Johannes Gutenberg University, 55128 Mainz, Germany.
Benedikt
B
Berninger
Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114 USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. Electronic address: asahay@mgh.harvard.edu.
Amar
A
Sahay
D053687:Adult Stem Cells / Q000166:cytology; D000375:Aging / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D049229:Dendritic Spines / Q000502:physiology; D018891:Dentate Gyrus / Q000378:metabolism / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008568:Memory / Q000502:physiology*; D051379:Mice; D009154:Mutation; D058953:Neural Stem Cells / Q000378:metabolism / Q000502:physiology; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000235:genetics
C489675:Klf9 protein, mouse; D051741:Kruppel-Like Transcription Factors; D009479:Neuropeptides; C484602:Rac1 protein, mouse; D020830:rac1 GTP-Binding Protein