Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer's disease

Ya-Dong Li; Yan-Jia Luo; Ling Xie; Dalton S Tart; Ryan N Sheehy; Libo Zhang; Leon G Coleman Jr; Xian Chen; Juan Song

doi:10.1016/j.stem.2023.02.006

Activation of hypothalamic-enhanced adult-born neurons restores cognitive and affective function in Alzheimer's disease

Cell Stem Cell. 2023 Apr 6;30(4):415-432.e6. doi: 10.1016/j.stem.2023.02.006.

Authors

Ya-Dong Li¹, Yan-Jia Luo¹, Ling Xie², Dalton S Tart³, Ryan N Sheehy⁴, Libo Zhang³, Leon G Coleman Jr⁵, Xian Chen², Juan Song⁶

Affiliations

¹ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Pharmacology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁵ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁶ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: juansong@email.unc.edu.

Abstract

Patients with Alzheimer's disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Whether AHN can be enhanced in impaired AD brain to restore cognitive and affective function remains elusive. Here, we report that patterned optogenetic stimulation of the hypothalamic supramammillary nucleus (SuM) enhances AHN in two distinct AD mouse models, 5×FAD and 3×Tg-AD. Strikingly, the chemogenetic activation of SuM-enhanced adult-born neurons (ABNs) rescues memory and emotion deficits in these AD mice. By contrast, SuM stimulation alone or activation of ABNs without SuM modification fails to restore behavioral deficits. Furthermore, quantitative phosphoproteomics analyses reveal activation of the canonical pathways related to synaptic plasticity and microglia phagocytosis of plaques following acute chemogenetic activation of SuM-enhanced (vs. control) ABNs. Our study establishes the activity-dependent contribution of SuM-enhanced ABNs in modulating AD-related deficits and informs signaling mechanisms mediated by the activation of SuM-enhanced ABNs.

Keywords: Alzheimer’s disease; adult hippocampal neurogenesis; adult-born neurons; affective function; cognition; memory; supramammillary nucleus.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Alzheimer Disease* / metabolism
Animals
Brain
Cognition
Disease Models, Animal
Hippocampus
Mice
Mice, Transgenic
Neurogenesis / physiology
Neurons / metabolism

Abstract

Publication types

MeSH terms

Grants and funding