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

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.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

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.

References

  1. 1.

    Dickson SL, Shirazi RH, Hansson C, Bergquist F, Nissbrandt H, Skibicka KP (2012) The glucagon-like peptide 1 (GLP-1) analogue, exendin-4, decreases the rewarding value of food: a new role for mesolimbic GLP-1 receptors. J Neurosci 32(14):4812–4820. https://doi.org/10.1523/JNEUROSCI.6326-11.2012

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Egecioglu E, Steensland P, Fredriksson I, Feltmann K, Engel JA, Jerlhag E (2013) The glucagon-like peptide 1 analogue Exendin-4 attenuates alcohol mediated behaviors in rodents. Psychoneuroendocrinology 38(8):1259–1270. https://doi.org/10.1016/j.psyneuen.2012.11.009

    CAS  Article  PubMed  Google Scholar 

  3. 3.

    Graham DL, Erreger K, Galli A, Stanwood GD (2013) GLP-1 analog attenuates cocaine reward. Mol Psychiatry 18(9):961–962. https://doi.org/10.1038/mp.2012.141

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Tweedie D, Rachmany L, Rubovitch V, Lehrmann E, Zhang Y, Becker KG, Perez E, Miller J, Hoffer BJ, Greig NH, Pick CG (2013) Exendin-4, a glucagon-like peptide-1 receptor agonist prevents mTBI-induced changes in hippocampus gene expression and memory deficits in mice. Exp Neurol 239:170–182. https://doi.org/10.1016/j.expneurol.2012.10.001

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN (2003) Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9(9):1173–1179. https://doi.org/10.1038/nm919

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Huang HJ, Chen YH, Liang KC, Jheng YS, Jhao JJ, Su MT, Lee-Chen GJ, Hsieh-Li HM (2012) Exendin-4 protected against cognitive dysfunction in hyperglycemic mice receiving an intrahippocampal lipopolysaccharide injection. PLoS One 7(7):e39656. https://doi.org/10.1371/journal.pone.0039656

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bhalla RK, Butters MA, Mulsant BH, Begley AE, Zmuda MD, Schoderbek B, Pollock BG, Reynolds CF 3rd, Becker JT (2006) Persistence of neuropsychologic deficits in the remitted state of late-life depression. Am J Geriatr Psychiatry 14(5):419–427. https://doi.org/10.1097/01.JGP.0000203130.45421.69

    Article  PubMed  Google Scholar 

  8. 8.

    Weitz ES, Hollon SD, Twisk J, van Straten A, Huibers MJ, David D, DeRubeis RJ, Dimidjian S, Dunlop BW, Cristea IA, Faramarzi M, Hegerl U, Jarrett RB, Kheirkhah F, Kennedy SH, Mergl R, Miranda J, Mohr DC, Rush AJ, Segal ZV, Siddique J, Simons AD, Vittengl JR, Cuijpers P (2015) Baseline depression severity as moderator of depression outcomes between cognitive behavioral therapy vs pharmacotherapy: an individual patient data meta-analysis. JAMA Psychiatry 72(11):1102–1109. https://doi.org/10.1001/jamapsychiatry.2015.1516

    Article  PubMed  Google Scholar 

  9. 9.

    McDermott LM, Ebmeier KP (2009) A meta-analysis of depression severity and cognitive function. J Affect Disord 119(1–3):1–8. https://doi.org/10.1016/j.jad.2009.04.022

    Article  PubMed  Google Scholar 

  10. 10.

    Shilyansky C, Williams LM, Gyurak A, Harris A, Usherwood T, Etkin A (2016) Effect of antidepressant treatment on cognitive impairments associated with depression: a randomised longitudinal study. Lancet Psychiatry 3(5):425–435. https://doi.org/10.1016/S2215-0366(16)00012-2

    Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Isacson R, Nielsen E, Dannaeus K, Bertilsson G, Patrone C, Zachrisson O, Wikstrom L (2011) The glucagon-like peptide 1 receptor agonist exendin-4 improves reference memory performance and decreases immobility in the forced swim test. Eur J Pharmacol 650(1):249–255. https://doi.org/10.1016/j.ejphar.2010.10.008

    CAS  Article  PubMed  Google Scholar 

  12. 12.

    Bertilsson G, Patrone C, Zachrisson O, Andersson A, Dannaeus K, Heidrich J, Kortesmaa J, Mercer A, Nielsen E, Ronnholm H, Wikstrom L (2008) Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res 86(2):326–338. https://doi.org/10.1002/jnr.21483

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Hunter K, Holscher C (2012) Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 13:33. https://doi.org/10.1186/1471-2202-13-33

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Moller C, Sommer W, Thorsell A, Rimondini R, Heilig M (2002) Anxiogenic-like action of centrally administered glucagon-like peptide-1 in a punished drinking test. Prog Neuro-Psychopharmacol Biol Psychiatry 26(1):119–122

    CAS  Article  Google Scholar 

  15. 15.

    Lupien SJ, McEwen BS, Gunnar MR, Heim C (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 10(6):434–445. https://doi.org/10.1038/nrn2639

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Chaves Filho AJM, Cunha NL, de Souza AG, Soares MV, Juca PM, de Queiroz T, Oliveira JVS, Valvassori SS, Barichello T, Quevedo J, de Lucena D, Macedo DS (2020) The GLP-1 receptor agonist liraglutide reverses mania-like alterations and memory deficits induced by D-amphetamine and augments lithium effects in mice: relevance for bipolar disorder. Prog Neuro-Psychopharmacol Biol Psychiatry 99:109872. https://doi.org/10.1016/j.pnpbp.2020.109872

    CAS  Article  Google Scholar 

  17. 17.

    Bierman EJ, Comijs HC, Jonker C, Beekman AT (2005) Effects of anxiety versus depression on cognition in later life. Am J Geriatr Psychiatry 13(8):686–693. https://doi.org/10.1176/appi.ajgp.13.8.686

    CAS  Article  PubMed  Google Scholar 

  18. 18.

    Greenberg DL, Rice HJ, Cooper JJ, Cabeza R, Rubin DC, Labar KS (2005) Co-activation of the amygdala, hippocampus and inferior frontal gyrus during autobiographical memory retrieval. Neuropsychologia 43(5):659–674. https://doi.org/10.1016/j.neuropsychologia.2004.09.002

    Article  PubMed  Google Scholar 

  19. 19.

    Clelland CD, Choi M, Romberg C, Clemenson GD Jr, Fragniere A, Tyers P, Jessberger S, Saksida LM, Barker RA, Gage FH, Bussey TJ (2009) A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science 325(5937):210–213. https://doi.org/10.1126/science.1173215

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Yassa MA, Stark CE (2011) Pattern separation in the hippocampus. Trends Neurosci 34(10):515–525. https://doi.org/10.1016/j.tins.2011.06.006

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Fujii T, Saito DN, Yanaka HT, Kosaka H, Okazawa H (2014) Depressive mood modulates the anterior lateral CA1 and DG/CA3 during a pattern separation task in cognitively intact individuals: a functional MRI study. Hippocampus 24(2):214–224. https://doi.org/10.1002/hipo.22216

    Article  PubMed  Google Scholar 

  22. 22.

    Graham DL, Durai HH, Trammell T, Noble BL, Mortlock DP, Galli A, Stanwood GD (2020) A novel mouse model of glucagon-like peptide-1 receptor expression: a look at the brain. J Comp Neurol 528:2445–2470. https://doi.org/10.1002/cne.24905

    CAS  Article  PubMed  Google Scholar 

  23. 23.

    Oomen CA, Hvoslef-Eide M, Heath CJ, Mar AC, Horner AE, Bussey TJ, Saksida LM (2013) The touchscreen operant platform for testing working memory and pattern separation in rats and mice. Nat Protoc 8(10):2006–2021. https://doi.org/10.1038/nprot.2013.124

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Rock PL, Roiser JP, Riedel WJ, Blackwell AD (2014) Cognitive impairment in depression: a systematic review and meta-analysis. Psychol Med 44(10):2029–2040. https://doi.org/10.1017/S0033291713002535

    CAS  Article  PubMed  Google Scholar 

  25. 25.

    Ledford H (2016) Drugmakers target depression’s cognitive fog. Nature 530(7588):17. https://doi.org/10.1038/530017a

    CAS  Article  PubMed  Google Scholar 

  26. 26.

    Yagi S, Galea LAM (2019) Sex differences in hippocampal cognition and neurogenesis. Neuropsychopharmacology 44(1):200–213. https://doi.org/10.1038/s41386-018-0208-4

    Article  PubMed  Google Scholar 

  27. 27.

    Jonasson Z (2005) Meta-analysis of sex differences in rodent models of learning and memory: a review of behavioral and biological data. Neurosci Biobehav Rev 28(8):811–825. https://doi.org/10.1016/j.neubiorev.2004.10.006

    Article  PubMed  Google Scholar 

  28. 28.

    Yagi S, Chow C, Lieblich SE, Galea LA (2016) Sex and strategy use matters for pattern separation, adult neurogenesis, and immediate early gene expression in the hippocampus. Hippocampus 26(1):87–101. https://doi.org/10.1002/hipo.22493

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Park J, Shin GI, Park YM, Kim IY, Jang DP (2017) Sex differences of cognitive load effects on object-location binding memory. Biomed Eng Lett 7(4):305–309. https://doi.org/10.1007/s13534-017-0038-z

    Article  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Tanapat P, Hastings NB, Reeves AJ, Gould E (1999) Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat. J Neurosci 19(14):5792–5801

    CAS  Article  Google Scholar 

  31. 31.

    Lagace DC, Fischer SJ, Eisch AJ (2007) Gender and endogenous levels of estradiol do not influence adult hippocampal neurogenesis in mice. Hippocampus 17(3):175–180. https://doi.org/10.1002/hipo.20265

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Tzeng WY, Chen LH, Cherng CG, Tsai YN, Yu L (2014) Sex differences and the modulating effects of gonadal hormones on basal and the stressor-decreased newly proliferative cells and neuroblasts in dentate gyrus. Psychoneuroendocrinology 42:24–37. https://doi.org/10.1016/j.psyneuen.2014.01.003

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Bangasser DA, Eck SR, Telenson AM, Salvatore M (2018) Sex differences in stress regulation of arousal and cognition. Physiol Behav 187:42–50. https://doi.org/10.1016/j.physbeh.2017.09.025

    CAS  Article  PubMed  Google Scholar 

  34. 34.

    Rajab E, Alqanbar B, Naiser MJ, Abdulla HA, Al-Momen MM, Kamal A (2014) Sex differences in learning and memory following short-term dietary restriction in the rat. Int J Dev Neurosci 36:74–80. https://doi.org/10.1016/j.ijdevneu.2014.05.011

    Article  PubMed  Google Scholar 

  35. 35.

    Erreger K, Davis AR, Poe AM, Greig NH, Stanwood GD, Galli A (2012) Exendin-4 decreases amphetamine-induced locomotor activity. Physiol Behav 106(4):574–578. https://doi.org/10.1016/j.physbeh.2012.03.014

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Knauf C, Cani PD, Ait-Belgnaoui A, Benani A, Dray C, Cabou C, Colom A, Uldry M, Rastrelli S, Sabatier E, Godet N, Waget A, Penicaud L, Valet P, Burcelin R (2008) Brain glucagon-like peptide 1 signaling controls the onset of high-fat diet-induced insulin resistance and reduces energy expenditure. Endocrinology 149(10):4768–4777. https://doi.org/10.1210/en.2008-0180

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Brown E, Cuthbertson DJ, Wilding JP (2018) Newer GLP-1 receptor agonists and obesity-diabetes. Peptides 100:61–67. https://doi.org/10.1016/j.peptides.2017.12.009

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    Hsu TM, Noble EE, Liu CM, Cortella AM, Konanur VR, Suarez AN, Reiner DJ, Hahn JD, Hayes MR, Kanoski SE (2017) A hippocampus to prefrontal cortex neural pathway inhibits food motivation through glucagon-like peptide-1 signaling. Mol Psychiatry 23:1555–1565. https://doi.org/10.1038/mp.2017.91

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Moser MB, Moser EI (1998) Functional differentiation in the hippocampus. Hippocampus 8(6):608–619. https://doi.org/10.1002/(SICI)1098-1063(1998)8:6<608::AID-HIPO3>3.0.CO;2-7

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Substance Abuse and Mental Health Services (2013) Results from the 2012 National Survey on Drug Use and Health: mental health findings. NSDUH Series H-47, HHS Publication No. (SMA) 13–4805. Rockville, MD

Download references

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

Affiliations

Authors

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.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval

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.

Informed consent

None

Consent to participate

N/A

Consent for publication

All authors have read and approved of the manuscript and its publication.

Code availability

N/A

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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 (2020). https://doi.org/10.1007/s10072-020-04910-8

Download citation

Keywords

  • GLP-1
  • Cognition
  • Location discrimination
  • Depression