Evidence map›Paper›PMID 40939593›Full record

ArticleNeuron2025

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

Taylor Landry, Laura Perrault, David Melville, Zhe Chen, Ya-Dong Li, Ping Dong, W Todd Farmer, Brent Asrican, Hannah Lee, Libo Zhang and 6 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuron, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

16 authors.

Taylor LandryDepartment 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.
Laura PerraultNeuroscience 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.
David MelvilleDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Zhe ChenDepartment 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.
Ya-Dong LiDepartment 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.
Ping DongDepartment 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.
W Todd FarmerDepartment 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.
Brent AsricanDepartment 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.
Hannah LeeNeuroscience 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.
Libo ZhangDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
Ryan N SheehyDepartment 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.
Corina DamianDepartment 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.
Thomas CollinsDepartment 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.
Nehemiah StewartDepartment 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.
E S AntonNeuroscience 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.
Juan SongDepartment 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.

Funding

UNC Neuroscience Center Research Cores: MicroscopyP30NS045892 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ZYLKA, MARK J. · 2003 to 2022
$11.5M
RESEARCH TRAINING IN THE NEUROSCIENCEST32NS007431 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Juan Song, Mark J. Zylka · 1997 to 2026
$10.0M
Preclinical CoreU54HD079124 · NICHD · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BELGER, AYSENIL · 2013 to 2019
$8.0M
DEFINING MECHANISMS OF PROGENITOR BALANCE AND NEURONAL CONNECTIVITYR35NS116859 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI EVA S ANTON · 2020 to 2026
$4.1M
Predoctoral Training in the Pharmacological SciencesT32GM135095 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Joseph Mauro Calabrese, Michael James Emanuele · 2020 to 2026
$3.6M
Role of Cholecystokinin in the Dentate GyrusR01NS121300 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SONG, JUAN · 2021 to 2025
$2.3M
Regulation and functional contribution of hypothalamic modified adult hippocampal neurogenesisR01MH132222 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SONG, JUAN · 2023 to 2025
$2.3M
Primary Cilia: A Novel Signaling Gateway To Neural Circuit ModulationRF1MH132710 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ANTON, EVA S, LICHTMAN, JEFF W · 2025 to 2025
$2.2M
Enhancing adult-born neurons to restore brain functions in Alzheimer's diseaseR01AG084207 · NIA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SONG, JUAN · 2023 to 2025
$2.1M
Glutamatergic neural circuit modulation for treating Alzheimer’s diseaseR01AG071000 · NIA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Juan Song · 2024 to 2026
$1.2M
Role of TRIM9 in regulating neurogenesis-associated hippocampal functionsR21NS104530 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SONG, JUAN · 2018 to 2019
$428k
NIA NIH HHS R01 AG071000NIA NIH HHS R01 AG084207NICHD NIH HHS U54 HD079124NIGMS NIH HHS T32 GM135095NIMH NIH HHS R01 MH132222NIMH NIH HHS RF1 MH132710NINDS NIH HHS P30 NS045892NINDS NIH HHS R01 NS121300NINDS NIH HHS R21 NS104530NINDS NIH HHS R35 NS116859NINDS NIH HHS T32 NS007431
6 · The paper itself

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.

Indexed as

CholecystokininCognitive DysfunctionDentate GyrusDiet, High-FatGlucoseHippocampusInterneuronsObesityAnimalsMaleMiceMice, Inbred C57BLPyruvate KinaseCholecystokininGlucosePkm protein, mousePyruvate KinaseCCK interneuronscognitive declinedentate gyrusglucosehigh-fat diethippocampushyperactivitylearning and memorymetabolic disordersobesityphosphorylation of PKM2PKM2

Identifiers

PMID40939593
PMCPMC12435909

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.