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GLP-1R activation alters performance in cognitive tasks in a sex-dependent manner

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Abstract

Rationale

The activation of the glucagon-like peptide-1 receptor (GLP-1R) has been purported to have antidepressant-like and cognitive-enhancing effects. Many people suffering from major depressive disorder (MDD) also experience deficits in cognition. While currently approved antidepressant pharmacotherapies can alleviate the mood symptoms in some patients, they do not treat the cognitive ones.

Objectives

We tested whether systemic administration of a GLP-1R agonist would alter location discrimination, a cognitive task that is diminished in humans with MDD.

Methods

Male and female laboratory mice (6–8 weeks old, N = 6–14/sex) were trained in a touchscreen operant task of location discrimination. Upon reaching baseline criterion, mice were administered vehicle or a GLP-1R agonist, Exendin-4, systemically prior to testing in probe trials of varying difficulty.

Results

Following GLP-1R activation, males showed modest yet non-significant performance in the location discrimination task. Females, however, showed enhanced performance during the most difficult probe tests following Exendin-4 administration.

Conclusions

GLP-1R activation appears to enhance overall performance in the location discrimination task and does so in a sex- and difficulty-dependent manner. These preliminary yet impactful data indicate that GLP-1R agonists may be useful as an adjunctive pharmacotherapy to treat cognitive deficits associated with MDD and/or multiple neurological disorders.

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Data availability

The authors confirm that the data supporting the findings of this study are available within the article as well as from the corresponding author upon reasonable request.

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Acknowledgments

We would like to thank Matt Croxall (Lafayette Instruments) for technical advice.

Funding

This work was supported by National Institutes of Health grant R03MH110749 (DLG), the Florida State University Council on Research & Creativity (DLG), and the Florida State University College of Medicine.

Author information

Author notes

  1. Gregg D. Stanwood and Devon L. Graham contributed equally to this project.

Authors and Affiliations

  1. Department of Biomedical Sciences and Center for Brain Repair, Florida State University College of Medicine, Tallahassee, FL, 32306, USA

    Taylor S. Trammell, Natalie L. Henderson, Haley S. Madkour, Gregg D. Stanwood & Devon L. Graham

Authors
  1. Taylor S. Trammell
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  2. Natalie L. Henderson
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  3. Haley S. Madkour
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  4. Gregg D. Stanwood
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  5. Devon L. Graham
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Contributions

The study was conceived and designed by DLG and GDS. TST, NLH, HSM, and DLG performed the experiments. Data analyses were performed by TST and DLG. Manuscript was written by DLG, and all authors read and approved the final manuscript.

Corresponding author

Correspondence to Devon L. Graham.

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The authors declare that they have no conflict of interest.

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All protocols were approved by the local Institutional Animal Care and Use Committee, and all studies were performed in accordance with the recommendations in the National Institutes of Health’s Guide for the Care and Use of Laboratory Animals.

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Trammell, T.S., Henderson, N.L., Madkour, H.S. et al. GLP-1R activation alters performance in cognitive tasks in a sex-dependent manner. Neurol Sci 42, 2911–2919 (2021). https://doi.org/10.1007/s10072-020-04910-8

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