Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity

Taylor Landry¹, Laura Perrault², David Melville³, Zhe Chen¹, Ya-Dong Li¹, Ping Dong¹, W Todd Farmer¹, Brent Asrican¹, Hannah Lee⁴, Libo Zhang³, Ryan N Sheehy⁵, Corina Damian⁵, Thomas Collins⁵, Nehemiah Stewart⁵, E S Anton⁴, 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 Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Curriculum, 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 Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁵ 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.
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.

PMID: 40939593
PMCID: PMC12435909 (available on 2026-09-11)
DOI: 10.1016/j.neuron.2025.08.016

Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity

Taylor Landry et al. Neuron. 2025.

. 2025 Sep 11:S0896-6273(25)00622-1.

doi: 10.1016/j.neuron.2025.08.016. Online ahead of print.

Authors

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 Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Neuroscience Curriculum, 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 Neuroscience Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Cell Biology and Physiology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
⁵ 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.
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.

PMID: 40939593
PMCID: PMC12435909 (available on 2026-09-11)
DOI: 10.1016/j.neuron.2025.08.016

Abstract

Metabolic disorders are closely linked to increased risk of cognitive decline, with Western-style high-fat diets (HFDs) emerging as key contributors. However, the underlying cellular and molecular mechanisms remain unclear. Here, we demonstrate that short-term HFD (stHFD) consumption disrupts memory processing by inducing hyperactivity in dentate gyrus (DG) cholecystokinin-expressing interneurons (CCK-INs). We identify DG CCK-INs as glucose-inhibited neurons that become hyperactive in response to stHFD-induced reductions in DG glucose availability, coinciding with increased phosphorylation of the glycolytic enzyme pyruvate kinase M2 (PKM2). Restoring glucose availability, reducing PKM2 expression, or inhibiting PKM2 activity normalizes CCK-IN activity and rescues memory deficits. Furthermore, interventions preventing CCK-IN hyperactivity or PKM2 phosphorylation protect against long-term cognitive impairments in a diet-induced obesity mouse model. These findings reveal a previously unrecognized mechanism by which dietary metabolic stress disrupts hippocampal function and highlight DG CCK-INs and PKM2 as promising therapeutic targets for preventing cognitive decline associated with metabolic disorders.

Keywords: CCK interneurons; PKM2; cognitive decline; dentate gyrus; glucose; high-fat diet; hippocampus; hyperactivity; learning and memory; metabolic disorders; obesity; phosphorylation of PKM2.

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Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity

Affiliations

Targeting glucose-inhibited hippocampal CCK interneurons prevents cognitive impairment in diet-induced obesity

Authors

Affiliations

Abstract

Conflict of interest statement

References

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases

Miscellaneous