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Nicotine reverses hypofrontality in animal models of addiction and schizophrenia

Nature Medicine volume 23, pages 347–354 (2017)Cite this article

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Abstract

The prefrontal cortex (PFC) underlies higher cognitive processes1 that are modulated by nicotinic acetylcholine receptor (nAChR) activation by cholinergic inputs2. PFC spontaneous default activity3 is altered in neuropsychiatric disorders4, including schizophrenia5—a disorder that can be accompanied by heavy smoking6. Recently, genome-wide association studies (GWAS) identified single-nucleotide polymorphisms (SNPs) in the human CHRNA5 gene, encoding the α5 nAChR subunit, that increase the risks for both smoking and schizophrenia7,8. Mice with altered nAChR gene function exhibit PFC-dependent behavioral deficits9,10,11, but it is unknown how the corresponding human polymorphisms alter the cellular and circuit mechanisms underlying behavior. Here we show that mice expressing a human α5 SNP exhibit neurocognitive behavioral deficits in social interaction and sensorimotor gating tasks. Two-photon calcium imaging in awake mouse models showed that nicotine can differentially influence PFC pyramidal cell activity by nAChR modulation of layer II/III hierarchical inhibitory circuits. In α5-SNP-expressing and α5-knockout mice, lower activity of vasoactive intestinal polypeptide (VIP) interneurons resulted in an increased somatostatin (SOM) interneuron inhibitory drive over layer II/III pyramidal neurons. The decreased activity observed in α5-SNP-expressing mice resembles the hypofrontality observed in patients with psychiatric disorders, including schizophrenia and addiction5,12. Chronic nicotine administration reversed this hypofrontality, suggesting that administration of nicotine may represent a therapeutic strategy for the treatment of schizophrenia, and a physiological basis for the tendency of patients with schizophrenia to self-medicate by smoking13.

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Figure 1: α5SNP mice exhibit reduced pyramidal cell activity, whereas α7KO and β2KO mice show increased activity, in layers II/III of the prelimbic cortex.
Figure 2: Targeted nicotinic acetylcholine receptor re-expression in layers II/III of the prelimbic cortex.
Figure 3: Nicotinic acetylcholine receptors modulate prefrontal cortex activity through inhibitory neurons.
Figure 4: Effect of chronic nicotine on the prelimbic cortex activity of WT and α5SNP mice and desensitization of β2 nicotinic acetylcholine receptor subunits.

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References

  1. Dehaene, S. & Changeux, J.-P. Experimental and theoretical approaches to conscious processing. Neuron 70, 200–227 (2011).

    Article  CAS  PubMed  Google Scholar 

  2. Bloem, B., Poorthuis, R.B. & Mansvelder, H.D. Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity. Front. Neural Circuits 8, 17 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Raichle, M.E. The brain's default mode network. Annu. Rev. Neurosci. 38, 433–447 (2015).

    Article  CAS  PubMed  Google Scholar 

  4. Buckner, R.L., Andrews-Hanna, J.R. & Schacter, D.L. The brain's default network: anatomy, function, and relevance to disease. Ann. NY Acad. Sci. 1124, 1–38 (2008).

    Article  PubMed  Google Scholar 

  5. Barch, D.M. et al. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch. Gen. Psychiatry 58, 280–288 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. de Leon, J. & Diaz, F.J. A meta-analysis of worldwide studies demonstrates an association between schizophrenia and tobacco smoking behaviors. Schizophr. Res. 76, 135–157 (2005).

    Article  PubMed  Google Scholar 

  7. Tobacco and Genetics Consortium. Genome-wide meta-analyses identify multiple loci associated with smoking behavior. Nat. Genet. 42, 441–447 (2010).

  8. Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  9. Young, J.W. et al. Impaired attention is central to the cognitive deficits observed in α7 deficient mice. Eur. Neuropsychopharmacol. 17, 145–155 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Guillem, K. et al. Nicotinic acetylcholine receptor β2 subunits in the medial prefrontal cortex control attention. Science 333, 888–891 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Bailey, C.D.C., De Biasi, M., Fletcher, P.J. & Lambe, E.K. The nicotinic acetylcholine receptor α5 subunit plays a key role in attention circuitry and accuracy. J. Neurosci. 30, 9241–9252 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Hong, L.E. et al. A genetically modulated, intrinsic cingulate circuit supports human nicotine addiction. Proc. Natl. Acad. Sci. USA 107, 13509–13514 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Adler, L.E. et al. Schizophrenia, sensory gating, and nicotinic receptors. Schizophr. Bull. 24, 189–202 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Robbins, T.W. & Roberts, A.C. Differential regulation of fronto-executive function by the monoamines and acetylcholine. Cereb. Cortex 17 (Suppl. 1), i151–i160 (2007).

    Article  PubMed  Google Scholar 

  15. Poorthuis, R.B. et al. Layer-specific modulation of the prefrontal cortex by nicotinic acetylcholine receptors. Cereb. Cortex 23, 148–161 (2013).

    Article  PubMed  Google Scholar 

  16. Sarter, M., Parikh, V. & Howe, W.M. Phasic acetylcholine release and the volume transmission hypothesis: time to move on. Nat. Rev. Neurosci. 10, 383–390 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sinkus, M.L. et al. The human CHRNA7 and CHRFAM7A genes: a review of the genetics, regulation, and function. Neuropharmacology 96 (Part B), 274–288 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Bierut, L.J. et al. Variants in nicotinic receptors and risk for nicotine dependence. Am. J. Psychiatry 165, 1163–1171 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Sciaccaluga, M. et al. Crucial role of nicotinic α5 subunit variants for Ca2+ fluxes in ventral midbrain neurons. FASEB J. 29, 3389–3398 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Proulx, E., Piva, M., Tian, M.K., Bailey, C.D.C. & Lambe, E.K. Nicotinic acetylcholine receptors in attention circuitry: the role of layer VI neurons of prefrontal cortex. Cell. Mol. Life Sci. 71, 1225–1244 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Derntl, B. & Habel, U. Deficits in social cognition: a marker for psychiatric disorders? Eur. Arch. Psychiatry Clin. Neurosci. 261 (Suppl. 2), S145–S149 (2011).

    Article  PubMed  Google Scholar 

  22. Nadler, J.J. et al. Automated apparatus for quantitation of social approach behaviors in mice. Genes Brain Behav. 3, 303–314 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Braff, D.L., Geyer, M.A. & Swerdlow, N.R. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.) 156, 234–258 (2001).

    Article  CAS  Google Scholar 

  24. Porter, J.T. et al. Selective excitation of subtypes of neocortical interneurons by nicotinic receptors. J. Neurosci. 19, 5228–5235 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Pi, H.-J. et al. Cortical interneurons that specialize in disinhibitory control. Nature 503, 521–524 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Poorthuis, R.B., Bloem, B., Verhoog, M.B. & Mansvelder, H.D. Layer-specific interference with cholinergic signaling in the prefrontal cortex by smoking concentrations of nicotine. J. Neurosci. 33, 4843–4853 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kawaguchi, Y. & Kubota, Y. GABAergic cell subtypes and their synaptic connections in rat frontal cortex. Cereb. Cortex 7, 476–486 (1997).

    Article  CAS  PubMed  Google Scholar 

  28. McGehee, D.S. & Role, L.W. Physiological diversity of nicotinic acetylcholine receptors expressed by vertebrate neurons. Annu. Rev. Physiol. 57, 521–546 (1995).

    Article  CAS  PubMed  Google Scholar 

  29. Sander, J.D. & Joung, J.K. CRISPR–Cas systems for editing, regulating and targeting genomes. Nat. Biotechnol. 32, 347–355 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Pfeffer, C.K., Xue, M., He, M., Huang, Z.J. & Scanziani, M. Inhibition of inhibition in visual cortex: the logic of connections between molecularly distinct interneurons. Nat. Neurosci. 16, 1068–1076 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Levin, E.D., McClernon, F.J. & Rezvani, A.H. Nicotinic effects on cognitive function: behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl.) 184, 523–539 (2006).

    Article  CAS  Google Scholar 

  32. Hambsch, B. et al. Chronic nicotine improves short-term memory selectively in a G72 mouse model of schizophrenia. Br. J. Pharmacol. 171, 1758–1771 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Matta, S.G. et al. Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl.) 190, 269–319 (2007).

    Article  CAS  Google Scholar 

  34. Morel, C. et al. Nicotine consumption is regulated by a human polymorphism in dopamine neurons. Mol. Psychiatry 19, 930–936 (2014).

    Article  CAS  PubMed  Google Scholar 

  35. Orr-Urtreger, A. et al. Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. J. Neurosci. 17, 9165–9171 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Picciotto, M.R. et al. Abnormal avoidance learning in mice lacking functional high-affinity nicotine receptor in the brain. Nature 374, 65–67 (1995).

    Article  CAS  PubMed  Google Scholar 

  37. Salas, R. et al. The nicotinic acetylcholine receptor subunit α5 mediates short-term effects of nicotine in vivo. Mol. Pharmacol. 63, 1059–1066 (2003).

    Article  CAS  PubMed  Google Scholar 

  38. Fuchs, E.C. et al. Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation. Proc. Natl. Acad. Sci. USA 98, 3571–3576 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tolu, S. et al. A versatile system for the neuronal subtype specific expression of lentiviral vectors. FASEB J. 24, 723–730 (2010).

    Article  CAS  PubMed  Google Scholar 

  40. Arroyo, S., Bennett, C., Aziz, D., Brown, S.P. & Hestrin, S. Prolonged disynaptic inhibition in the cortex mediated by slow, non-α7 nicotinic excitation of a specific subset of cortical interneurons. J. Neurosci. 32, 3859–3864 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Prönneke, A. et al. Characterizing VIP neurons in the barrel cortex of VIPcre/tdTomato mice reveals layer-specific differences. Cereb. Cortex 25, 4854–4868 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Choi, G.B. et al. The maternal interleukin-17a pathway in mice promotes autism-like phenotypes in offspring. Science 351, 933–939 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Holtmaat, A. et al. Long-term, high-resolution imaging in the mouse neocortex through a chronic cranial window. Nat. Protoc. 4, 1128–1144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Naldini, L. et al. In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272, 263–267 (1996).

    Article  CAS  PubMed  Google Scholar 

  45. Maskos, U. et al. Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors. Nature 436, 103–107 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Lepousez, G. & Lledo, P.-M. Odor discrimination requires proper olfactory fast oscillations in awake mice. Neuron 80, 1010–1024 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Guo, Z.V. et al. Procedures for behavioral experiments in head-fixed mice. PLoS One 9, e88678 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Besson, M. et al. Long-term effects of chronic nicotine exposure on brain nicotinic receptors. Proc. Natl. Acad. Sci. USA 104, 8155–8160 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank S. Pons for valuable support and discussions on lentiviral constructs, and M. Soudant for production of lentiviral vectors. We also acknowledge the Pasteur Institute Shared Neuroscience Department imaging facility funded by Ile-de-France Domaine d'Intérêt Majeur (DIM/NeRF). We acknowledge the GENIE Program and the Janelia Research Campus and specifically V. Jayaraman, D.S. Kim, L.L. Looger and K. Svoboda from the GENIE Project, Janelia Research Campus, Howard Hughes Medical Institute for making AAV.Syn.GCaMP6f and AAV.Syn.Flex.GCaMP6f available. Finally, we thank G. Fond and M. Groszer for comments on the manuscript. F.K. is a scholar of the Pasteur Paris University Doctoral Program (PPU) and received a stipend from the Stavros Niarchos Foundation. This work was supported by the CNRS UMR 3571, the Fondation de la Recherche Médicale (FRM grant DPA20140629803), the Agence Nationale de la Recherche (ANR), the Laboratoire d'Excellence BIO-PSY (including salary support to F.K., AAP Fin de Thèse 2015), the program PasteurInnov 2012, the FP7 ERANET program NICO-GENE, Grant Agreement n009 BLANC 20092009BLANC 20, the European Commission FP7 RTD Project HEALTH-2009-Neurocyp.08-202088 Grant 242167, French National Cancer Institute Grant CANCEROPOLE IDF 2016-1-TABAC-01-IP-1 MASKOS (all to U.M.), and NIH grants CA089392 and DA015663 (to J.S.). The laboratories of U.M., B.S.G. and D.A.D. are part of the École des Neurosciences de Paris Ile-de-France RTRA network. U.M. and D.A.D. are members of the Laboratory of Excellence, LabEx BIO-PSY. As such, this work was supported by French state funds managed by the ANR within the Investissements d'Avenir program under reference ANR-11-IDEX-0004-02. B.S.G. is a member of the Laboratory of Excellence, LabEx IEC. B.S.G. acknowledges support from the Russian Academic Excellence Project '5-100'.

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Authors and Affiliations

  1. Institut Pasteur, Neurobiologie Intégrative des Systèmes Cholinergiques, Paris, France

    Fani Koukouli & Uwe Maskos

  2. CNRS UMR 3571, Paris, France

    Fani Koukouli, Kurt A Sailor, Jean-Pierre Changeux, David A DiGregorio & Uwe Maskos

  3. Département d'Études Cognitive, Group for Neural Theory, Laboratoire de Neurosciences Cognitives, INSERM Unité 969, École Normale Supérieure, Paris, France

    Marie Rooy & Boris S Gutkin

  4. Institut Pasteur, Structural Bioinformatics Unit, CNRS UMR 3528, Paris, France

    Dimitrios Tziotis & Michael Nilges

  5. Institut Pasteur, Perception and Memory Unit, Paris, France

    Kurt A Sailor

  6. Institute for Behavioral Genetics, University of Colorado, Boulder, Colorado, USA

    Heidi C O'Neill, Josien Levenga, Charles A Hoeffer & Jerry A Stitzel

  7. Institute for Neuroanatomy, Universitätsmedizin Göttingen, Georg-August-Universität, Göttingen, Germany

    Mirko Witte

  8. Centre for Cognition and Decision Making, National Research University Higher School of Economics, Moscow, Russia

    Boris S Gutkin

  9. Institut Pasteur, Dynamic Neuronal Imaging Unit, Paris, France

    David A DiGregorio

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Contributions

F.K. and U.M. conceived and designed research. F.K. performed experiments. F.K., K.A.S. and D.A.D. established the imaging technique. F.K., M.R., D.T. and D.A.D. designed the analysis code. F.K. and M.R. analyzed data. H.C.O'N., J.L. and C.A.H. performed behavioral experiments. M.W. contributed the VIP-Cre/tdTomato mice. J.A.S. developed the α5SNP mouse line. M.N., J.-P.C. and B.S.G. provided advice. F.K. wrote the original manuscript, which was reviewed and edited by D.A.D. and U.M. and edited by all other authors. U.M. supervised the research.

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Correspondence to Uwe Maskos.

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Koukouli, F., Rooy, M., Tziotis, D. et al. Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nat Med 23, 347–354 (2017). https://doi.org/10.1038/nm.4274

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