Original Article | Published:

Hypervulnerability of the adolescent prefrontal cortex to nutritional stress via reelin deficiency

Molecular Psychiatry volume 22, pages 961971 (2017) | Download Citation

Subjects

Abstract

Overconsumption of high-fat diets (HFDs) can critically affect synaptic and cognitive functions within telencephalic structures such as the medial prefrontal cortex (mPFC). The underlying mechanisms, however, remain largely unknown. Here we show that adolescence is a sensitive period for the emergence of prefrontal cognitive deficits in response to HFD. We establish that the synaptic modulator reelin (RELN) is a critical mediator of this vulnerability because (1) periadolescent HFD (pHFD) selectively downregulates prefrontal RELN+ cells and (2) augmenting mPFC RELN levels using transgenesis or prefrontal pharmacology prevents the pHFD-induced prefrontal cognitive deficits. We further identify N-methyl-d-aspartate-dependent long-term depression (NMDA-LTD) at prefrontal excitatory synapses as a synaptic signature of this association because pHFD abolishes NMDA-LTD, a function that is restored by RELN overexpression. We believe this study provides the first mechanistic insight into the vulnerability of the adolescent mPFC towards nutritional stress, such as HFDs. Our findings have primary relevance to obese individuals who are at an increased risk of developing neurological cognitive comorbidities, and may extend to multiple neuropsychiatric and neurological disorders in which RELN deficiency is a common feature.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    . Epigenetic consequences of a changing human diet. Proc Nutr Soc 2013; 72: 363–371.

  2. 2.

    . Essential fatty acids in health and chronic disease. Am J Clin Nutr 1999; 70: 560S–569S.

  3. 3.

    , , . American Diet Quality: where it is, where it is heading, and what it could be. J Acad Nutr Diet 2016; 116: e1.

  4. 4.

    , . The 2015 US Dietary Guidelines: lifting the ban on total dietary fat. JAMA 2015; 313: 2421–2422.

  5. 5.

    , , . The utility of animal models to evaluate novel anti-obesity agents. Br J Pharmacol 2011; 164: 1248–1262.

  6. 6.

    , . The longer-term impacts of Western diet on human cognition and the brain. Appetite 2013; 63: 119–128.

  7. 7.

    , , . Modeling combined schizophrenia-related behavioral and metabolic phenotypes in rodents. Behav Brain Res 2015; 276: 130–142.

  8. 8.

    , . Dietary fat composition and dementia risk. Neurobiol Aging 2014; 35(Suppl 2): S59–S64.

  9. 9.

    , , , , , et al. Obesity weighs down memory through a mechanism involving the neuroepigenetic dysregulation of Sirt1. J Neurosci 2016; 36: 1324–1335.

  10. 10.

    , , , , , et al. Juvenile, but not adult exposure to high-fat diet impairs relational memory and hippocampal neurogenesis in mice. Hippocampus 2012; 22: 2095–2100.

  11. 11.

    , , , . Dietary-induced obesity disrupts trace fear conditioning and decreases hippocampal reelin expression. Brain Behav Immun 2015; 43: 68–75.

  12. 12.

    , , , , , et al. Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. Faseb J 2011; 25: 1088–1096.

  13. 13.

    , , , , , et al. A high-fat diet impairs cardiac high-energy phosphate metabolism and cognitive function in healthy human subjects. Am J Clin Nutr 2011; 93: 748–755.

  14. 14.

    , , , , , et al. Obesity diminishes synaptic markers, alters microglial morphology, and impairs cognitive function. Proc Natl Acad Sci USA 2015; 112: 15731–15736.

  15. 15.

    , , , . The effects of energy-rich diets on discrimination reversal learning and on BDNF in the hippocampus and prefrontal cortex of the rat. Behav Brain Res 2007; 182: 57–66.

  16. 16.

    , , , , , et al. Dynamic mapping of human cortical development during childhood through early adulthood. Proc Natl Acad Sci USA 2004; 101: 8174–8179.

  17. 17.

    . The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 2000; 24: 417–463.

  18. 18.

    . Critical period plasticity in local cortical circuits. Nat Rev Neurosci 2005; 6: 877–888.

  19. 19.

    . Trajectories of brain development: point of vulnerability or window of opportunity? Neurosci Biobehav Rev 2003; 27: 3–18.

  20. 20.

    , . The brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course. Neuron 2013; 79: 16–29.

  21. 21.

    , , , , . Impact of metabolic syndrome on cognition and brain: a selected review of the literature. Arterioscler Thromb Vasc Biol 2012; 32: 2060–2067.

  22. 22.

    , , . Self-reported learning difficulties and dietary intake in Norwegian adolescents. Scand J Public Health 2013; 41: 754–760.

  23. 23.

    , , , . Disinhibited eating in obese adolescents is associated with orbitofrontal volume reductions and executive dysfunction. Obesity (Silver Spring, MD) 2011; 19: 1382–1387.

  24. 24.

    , , , , , et al. Preliminary evidence for brain complications in obese adolescents with type 2 diabetes mellitus. Diabetologia 2010; 53: 2298–2306.

  25. 25.

    , , , , , et al. Prospective associations between dietary patterns and cognitive performance during adolescence. J Child Psychol Psychiatry 2014; 55: 1017–1024.

  26. 26.

    , , , , . Disrupted functional connectivity in adolescent obesity. NeuroImage Clin 2016; 12: 262–268.

  27. 27.

    , , , , , et al. Dietary recommendations for children and adolescents: a guide for practitioners. Pediatrics 2006; 117: 544–559.

  28. 28.

    , , , , , et al. Reelin modulates NMDA receptor activity in cortical neurons. J Neurosci 2005; 25: 8209–8216.

  29. 29.

    , , , , , . Reelin an extracellular matrix protein linked to early onset psychiatric diseases, drives postnatal development of the prefrontal cortex via GluN2B-NMDARs and the mTOR pathway. Mol Psychiatry 2014; 19: 417–426.

  30. 30.

    , , . Impairment of cognitive performance after reelin knockdown in the medial prefrontal cortex of pubertal or adult rats. Neurobiol Dis 2011; 44: 239–247.

  31. 31.

    , , , , , et al. Multivariate synaptic and behavioral profiling reveals new developmental endophenotypes in the prefrontal cortex. Sci Rep 2016; 6: 35504.

  32. 32.

    , , , , , . NMDA receptor surface trafficking and synaptic subunit composition are developmentally regulated by the extracellular matrix protein Reelin. J Neurosci 2007; 27: 10165–10175.

  33. 33.

    , , , , , et al. Modulation of synaptic plasticity and memory by Reelin involves differential splicing of the lipoprotein receptor Apoer2. Neuron 2005; 47: 567–579.

  34. 34.

    , , , , , . Cognitive disruption and altered hippocampus synaptic function in Reelin haploinsufficient mice. Neurobiol Learn Mem 2006; 85: 228–242.

  35. 35.

    , , , . Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus. J Neurosci 2006; 26: 12943–12955.

  36. 36.

    , , , , . Adult brain and behavioral pathological markers of prenatal immune challenge during early/middle and late fetal development in mice. Brain Behav Immun 2008; 22: 469–486.

  37. 37.

    , , , , , et al. Epigenetic modifications of GABAergic interneurons are associated with the schizophrenia-like phenotype induced by prenatal stress in mice. Neuropharmacology 2013; 68: 184–194.

  38. 38.

    , . Corticosterone treatment during adolescence induces down-regulation of reelin and NMDA receptor subunit GLUN2C expression only in male mice: implications for schizophrenia. Int J Neuropsychopharmacol 2014; 17: 1221–1232.

  39. 39.

    , , , , , et al. Reelin delays amyloid-beta fibril formation and rescues cognitive deficits in a model of Alzheimer’s disease. Nat Commun 2014; 5: 3443.

  40. 40.

    , , , , , et al. Reelin protects against amyloid β toxicity in vivo. Sci Signal 2015; 8: ra67.

  41. 41.

    , , , , , et al. Overexpression of Reelin prevents the manifestation of behavioral phenotypes related to schizophrenia and bipolar disorder. Neuropsychopharmacology 2011; 36: 2395–2405.

  42. 42.

    . Reelin, a Marker of Stress Resilience in Depression and Psychosis. Neuropsychopharmacology 2011; 36: 2371–2372.

  43. 43.

    , , , , , et al. Reelin regulates postnatal neurogenesis and enhances spine hypertrophy and long-term potentiation. J Neurosci 2010; 30: 4636–4649.

  44. 44.

    , . Maturation of excitatory synaptic transmission of the rat nucleus accumbens from juvenile to adult. J Neurophysiol 2009; 101: 2516–2527.

  45. 45.

    , , , , , . miR-200c regulates FGFR-dependent epithelial proliferation via Vldlr during submandibular gland branching morphogenesis. Development 2012; 139: 191–202.

  46. 46.

    , , , , , et al. Reelin supplementation recovers sensorimotor gating, synaptic plasticity and associative learning deficits in the heterozygous reeler mouse. J Psychopharmacol 2013; 27: 386–395.

  47. 47.

    . Regional and cellular fractionation of working memory. Proc Natl Acad Sci U S A 1996; 93: 13473–13480.

  48. 48.

    , . Behavioral flexibility in rats and mice: contributions of distinct frontocortical regions. Genes Brain Behav 2015; 14: 4–21.

  49. 49.

    , , , , , et al. Regional and cellular patterns of reelin mRNA expression in the forebrain of the developing and adult mouse. J Neurosci 1998; 18: 7779–7799.

  50. 50.

    , , , , , . Assessment of cognitive function in the heterozygous reeler mouse. Psychopharmacology (Berl) 2006; 189: 95–104.

  51. 51.

    , , , . Executive functions in the heterozygous reeler mouse model of schizophrenia. Behav Neurosci 2006; 120: 984–988.

  52. 52.

    , , . Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci 2005; 6: 312–324.

  53. 53.

    , , , , . Reelin secreted by GABAergic neurons regulates glutamate receptor homeostasis. PLoS One 2009; 4: e5505.

  54. 54.

    , . Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 2006; 7: 850–859.

  55. 55.

    , , , . Long-term depression in the CNS. Nat Rev Neurosci 2010; 11: 459–473.

  56. 56.

    , , , . Calcyon upregulation in adolescence impairs response inhibition and working memory in adulthood. Mol Psychiatry 2011; 16: 672–684.

  57. 57.

    , , , , , et al. Overexpression of αCaMKII impairs behavioral flexibility and NMDAR-dependent long-term depression in the medial prefrontal cortex. Neuroscience 2015; 310: 528–540.

  58. 58.

    , , , . Chronic high fat diet consumption impairs sensorimotor gating in mice. Psychoneuroendocrinology 2013; 38: 2562–2574.

  59. 59.

    , , . The contextual brain: implications for fear conditioning, extinction and psychopathology. Nat Rev Neurosci 2013; 14: 417–428.

  60. 60.

    , , , , , et al. Reelin supplementation enhances cognitive ability, synaptic plasticity, and dendritic spine density. Learn Mem 2011; 18: 558–564.

  61. 61.

    , , , , , . Experience and the developing prefrontal cortex. Proc Natl Acad Sci USA 2012; 109(Suppl): 17186–17193.

  62. 62.

    , , , . Developmental disruption of gamma-aminobutyric acid function in the medial prefrontal cortex by noncontingent cocaine exposure during early adolescence. Biol Psychiatry 2013; 74: 490–501.

  63. 63.

    , , , , . Impact of adolescent sucrose access on cognitive control, recognition memory, and parvalbumin immunoreactivity. Learn Mem 2015; 22: 215–224.

  64. 64.

    , , , , . Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine. Biol Psychiatry 2013; 73: 574–582.

  65. 65.

    , , , . The sugar-fat relationship revisited: differences in consumption between men and women of varying BMI. Int J Obes Relat Metab Disord 1998; 22: 1053–1061.

  66. 66.

    , , . Neuropsychiatric comorbidity in obesity: role of inflammatory processes. Front Endocrinol (Lausanne) 2014; 5: 74.

  67. 67.

    . Models and mechanisms for hippocampal dysfunction in obesity and diabetes. Neuroscience 2015; 309: 125–139.

  68. 68.

    , , , , , et al. Myeloid-cell-derived VEGF maintains brain glucose uptake and limits cognitive impairment in obesity. Cell 2016; 165: 882–895.

  69. 69.

    , , , , , et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 2014; 384: 766–781.

  70. 70.

    , , , , . Shifts in the recent distribution of energy intake among U.S. children aged 2–18 years reflect potential abatement of earlier declining trends. J Nutr 2014; 144: 1291–1297.

  71. 71.

    , , . Food intake and reward mechanisms in patients with schizophrenia: implications for metabolic disturbances and treatment with second-generation antipsychotic agents. Neuropsychopharmacology 2006; 31: 2091–2120.

  72. 72.

    , . The dynamics of DNA methylation in schizophrenia and related psychiatric disorders. Neuropsychopharmacology 2012; 38: 138–166.

  73. 73.

    , . Decreased dendritic spine density on prefrontal cortical pyramidal neurons in schizophrenia. Arch Gen Psychiatry 2000; 57: 65–73.

  74. 74.

    , , , , , et al. Association of metabolic syndrome and inflammation with neurocognition in patients with schizophrenia. Psychiatry Res 2013; 210: 381–386.

  75. 75.

    , , , . Decisive role of reelin signaling during early stages of Alzheimer’s disease. Neuroscience 2013; 246: 108–116.

Download references

Acknowledgements

This work was supported by the Swiss National Science Foundation (Grant No. 310030_146217) and the European Union Seventh Framework Program (FP7/2007–2011) (Grant No. 259679) (to UM), by INSERM (to PC), by ETH Zurich (to WL) and by MINECO (Spain, SAF2013-42445R) (to ES). ACR is the recipient of an Australian Research Council Discovery Early Career Research Award (DE140101071). We are grateful to F Mouttet, E Weber, F Müller, S Giovanoli and S Kaufman for assistance in experimentation or genotyping; M Riva and D Ramachandran for helpful discussions; N Jejelava and M Arnold for advice on surgery; and the animal technician team for contribution to animal husbandry. We thank the National Institute of Mental Health's Chemical Synthesis and Drug Supply Program for providing CNQX, NBQX and D-APV.

Author contributions

MAL designed the study, analyzed data, wrote the original manuscript and performed the behavioral, surgical, metabolic and imaging experiments. OL performed and analyzed the electrophysiology experiments. JR and MAL did the western blots. UW contributed to behavior and surgeries. JI developed the LTD protocol. TN, TG and MAL did the immunostainings. LP and ES generated the transgenic mice and contributed to writing. AR, CL and WL contributed to data interpretation and writing. PC and UM designed and supervised the entire study, analyzed data and wrote the manuscript.

Author information

Author notes

    • P Chavis
    •  & U Meyer

    Current address: New York State Psychiatric Institute, Kolb 3rd Floor, 1051 Riverside Drive, Columbia University, New York, NY 10032, USA.

    • M A Labouesse

    These authors share senior authorship.

Affiliations

  1. Physiology and Behavior Laboratory, ETH Zurich, Schwerzenbach, Switzerland

    • M A Labouesse
    • , U Weber-Stadlbauer
    • , W Langhans
    •  & U Meyer
  2. Institute of Pharmacology and Toxicology, University of Zurich–Vetsuisse, Zurich, Switzerland

    • M A Labouesse
    • , J Richetto
    • , U Weber-Stadlbauer
    • , T Notter
    •  & U Meyer
  3. INSERM, INMED UMR S 901, Aix-Marseille Université, Marseille, France

    • O Lassalle
    • , J Iafrati
    •  & P Chavis
  4. Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland

    • T Gschwind
  5. Department of Cell Biology, Physiology and Immunology, University of Barcelona, Barcelona, Spain

    • L Pujadas
    •  & E Soriano
  6. Centro de Investigación en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain

    • L Pujadas
    •  & E Soriano
  7. Vall D́Hebron Institut de Recerca (VHIR), Barcelona, Spain

    • L Pujadas
    •  & E Soriano
  8. Institució Catalana de Recerca i Estudis Avançats (ICREA Academia), Barcelona, Spain

    • E Soriano
  9. School of Health and Biomedical Sciences, RMIT, Melbourne, VIC, Australia

    • A C Reichelt
  10. Laboratory of Cell Biophysics, Ecole Polytechnique Federale de Lausanne, Lausanne, Switzerland

    • C Labouesse
  11. Wellcome Trust - Medical Research Council Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK

    • C Labouesse
  12. Neuroscience Center Zurich (ZNZ), University of Zurich, Zurich, Switzerland

    • U Meyer

Authors

  1. Search for M A Labouesse in:

  2. Search for O Lassalle in:

  3. Search for J Richetto in:

  4. Search for J Iafrati in:

  5. Search for U Weber-Stadlbauer in:

  6. Search for T Notter in:

  7. Search for T Gschwind in:

  8. Search for L Pujadas in:

  9. Search for E Soriano in:

  10. Search for A C Reichelt in:

  11. Search for C Labouesse in:

  12. Search for W Langhans in:

  13. Search for P Chavis in:

  14. Search for U Meyer in:

Competing interests

The authors declare no conflict of interest.

Corresponding authors

Correspondence to M A Labouesse or P Chavis or U Meyer.

Supplementary information

About this article

Publication history

Received

Revised

Accepted

Published

DOI

https://doi.org/10.1038/mp.2016.193

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

Further reading