Skip to main content
SpringerLink
Log in

Nicotinic Acetylcholine Receptor Density in the “Higher-Order” Thalamus Projecting to the Prefrontal Cortex in Humans: a PET Study

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

The parcellation of the thalamus into different nuclei involved in different corticothalamocortical loops reflects its functional diversity. The connections between the mediodorsal nucleus and the prefrontal cortex play a major role in cognition, particularly in the rapid processing of behaviorally relevant information. The thalamus is the brain region with the highest density in α4β2 nicotinic acetylcholine receptors, the main human nicotinic acetylcholine receptor subtype. The aim of this study was to investigate the possible role of the nicotinic cholinergic system in the thalamo-cortical loops measuring receptor density in different subregions of the thalamus, based on their cortical connectivity.

Procedures

We studied α4β2 nicotinic acetylcholine receptors using positron emission tomography and [18F]Fluoro-A-85380, a radiotracer specific for this receptor subtype, in 36 non-smoking male subjects, including 12 healthy controls and 24 patients with epilepsy. [18F]Fluoro-A-85380 ratio index of binding potential was compared by a repeated measures general linear model, including the thalamic subregions and the brain hemisphere as within-subject factor and clinical groups as between-subject factor.

Results

The “prefrontal” thalamus, the subregion including the mediodorsal nucleus, had a significantly higher nicotinic acetylcholine receptor density than all other thalamic subregions. These findings were confirmed when analyzing solely the 12 healthy controls.

Conclusions

This particular neurochemical organization of the thalamus supports a major role of the cholinergic system in the loops between the thalamus and the prefrontal cortex. The highest nicotinic acetylcholine receptor density in the « higher-order thalamus » could partly explain the beneficial effect of acute nicotine on attentional and executive functions and possibly the pathophysiology of some neuropsychiatric disorders.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1.
Fig. 2.

Similar content being viewed by others

References

  1. Klein JC, Rushworth MF, Behrens TE et al (2010) Topography of connections between human prefrontal cortex and mediodorsal thalamus studied with diffusion tractography. Neuroimage 51:555–564

    Article  PubMed  Google Scholar 

  2. Alcaraz F, Marchand AR, Courtand G, Coutureau E, Wolff M (2016) Parallel inputs from the mediodorsal thalamus to the prefrontal cortex in the rat. Eur J Neurosci 44:1972–1986

    PubMed  Google Scholar 

  3. Behrens TE, Johansen-Berg H, Woolrich MW et al (2003) Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging. Nat Neurosci 6:750–757

    Article  CAS  PubMed  Google Scholar 

  4. Giguere M, Goldman-Rakic PS (1988) Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys. J Comp Neurol 277:195–213

    Article  CAS  PubMed  Google Scholar 

  5. Mitchell AS (2015) The mediodorsal thalamus as a higher order thalamic relay nucleus important for learning and decision-making. Neurosci Biobehav Rev 54:76–88

    Article  PubMed  Google Scholar 

  6. Schmitt LI, Wimmer RD, Nakajima M, Happ M, Mofakham S, Halassa MM (2017) Thalamic amplification of cortical connectivity sustains attentional control. Nature 545:219–223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Changeux JP (2006) The Ferrier lecture 1998. The molecular biology of consciousness investigated with genetically modified mice. Philos Trans R Soc Lond Ser B Biol Sci 361:2239–2259

    Article  CAS  Google Scholar 

  8. Dineley KT, Pandya AA, Yakel JL (2015) Nicotinic ACh receptors as therapeutic targets in CNS disorders. Trends Pharmacol Sci 36:96–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Walsh RM Jr, Roh SH, Gharpure A et al (2018) Structural principles of distinct assemblies of the human alpha4beta2 nicotinic receptor. Nature 557:261–265

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sadaghiani S, Ng B, Altmann A, Poline JB, Banaschewski T, Bokde ALW, Bromberg U, Büchel C, Burke Quinlan E, Conrod P, Desrivières S, Flor H, Frouin V, Garavan H, Gowland P, Gallinat J, Heinz A, Ittermann B, Martinot JL, Paillère Martinot ML, Lemaitre H, Nees F, Papadopoulos Orfanos D, Paus T, Poustka L, Millenet S, Fröhner JH, Smolka MN, Walter H, Whelan R, Schumann G, Napolioni V, Greicius M (2017) Overdominant effect of a CHRNA4 polymorphism on cingulo-opercular network activity and cognitive control. J Neurosci 37:9657–9666

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Valentine G, Sofuoglu M (2018) Cognitive effects of nicotine: recent Progress. Curr Neuropharmacol 16:403–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wong DF, Kuwabara H, Horti AG, Roberts JM, Nandi A, Cascella N, Brasic J, Weerts EM, Kitzmiller K, Phan JA, Gapasin L, Sawa A, Valentine H, Wand G, Mishra C, George N, McDonald M, Lesniak W, Holt DP, Azad BB, Dannals RF, Kem W, Freedman R, Gjedde A (2018) Brain PET imaging of alpha7-nAChR with [18F]ASEM: reproducibility, occupancy, receptor density, and changes in schizophrenia. Int J Neuropsychopharmacol 21:656–667

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Spurden DP, Court JA, Lloyd S, Oakley A, Perry R, Pearson C, Pullen RGL, Perry EK (1997) Nicotinic receptor distribution in the human thalamus: autoradiographical localization of [3H]nicotine and [125I] alpha-bungarotoxin binding. J Chem Neuroanat 13:105–113

    Article  CAS  PubMed  Google Scholar 

  14. Adem A, Jossan SS, d'Argy R, Brandt I, Winblad B, Nordberg A (1988) Distribution of nicotinic receptors in human thalamus as visualized by 3H-nicotine and 3H-acetylcholine receptor autoradiography. J Neural Transm 73:77–83

    Article  CAS  PubMed  Google Scholar 

  15. Pimlott SL, Piggott M, Ballard C, McKeith I, Perry R, Kometa S, Owens J, Wyper D, Perry E (2006) Thalamic nicotinic receptors implicated in disturbed consciousness in dementia with Lewy bodies. Neurobiol Dis 21:50–56

    Article  CAS  PubMed  Google Scholar 

  16. Xuereb JH, Perry EK, Candy JM, Bonham JR, Perry RH, Marshall E (1990) Parameters of cholinergic neurotransmission in the thalamus in Parkinson's disease and Alzheimer's disease. J Neurol Sci 99:185–197

    Article  CAS  PubMed  Google Scholar 

  17. Zilles K, Palomero-Gallagher N, Schleicher A (2004) Transmitter receptors and functional anatomy of the cerebral cortex. J Anat 205:417–432

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Sullivan JP, Donnelly-Roberts D, Briggs CA, Anderson DJ, Gopalakrishnan M, Piattoni-Kaplan M, Campbell JE, McKenna DG, Molinari E, Hettinger AM, Garvey DS, Wasicak JT, Holladay MW, Williams M, Arneric SP (1996) A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand. Neuropharmacology 35:725–734

    Article  CAS  PubMed  Google Scholar 

  19. Gallezot JD, Bottlaender M, Gregoire MC et al (2005) In vivo imaging of human cerebral nicotinic acetylcholine receptors with 2-18F-fluoro-A-85380 and PET. J Nucl Med 46:240–247

    CAS  PubMed  Google Scholar 

  20. Picard F, Bruel D, Servent D, Saba W, Fruchart-Gaillard C, Schöllhorn-Peyronneau MA, Roumenov D, Brodtkorb E, Zuberi S, Gambardella A, Steinborn B, Hufnagel A, Valette H, Bottlaender M (2006) Alteration of the in vivo nicotinic receptor density in ADNFLE patients: a PET study. Brain 129:2047–2060

    Article  CAS  PubMed  Google Scholar 

  21. Garibotto V, Wissmeyer M, Giavri Z et al (2018) Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy. Eur J Nucl Med Mol Imaging 46:385–395

    Article  CAS  PubMed  Google Scholar 

  22. Okada H, Ouchi Y, Ogawa M et al (2013) Alterations in alpha4beta2 nicotinic receptors in cognitive decline in Alzheimer's aetiopathology. Brain 136:3004–3017

    Article  PubMed  Google Scholar 

  23. Schain M, Toth M, Cselenyi Z et al (2012) Quantification of serotonin transporter availability with [11C]MADAM--a comparison between the ECAT HRRT and HR systems. Neuroimage 60:800–807

    Article  CAS  PubMed  Google Scholar 

  24. Harri M, Mika T, Jussi H, Nevalainen Olli S, Jarmo H (2007) Evaluation of partial volume effect correction methods for brain positron emission tomography: quantification and reproducibility. J Med Phys 32:108–117

    Article  PubMed  PubMed Central  Google Scholar 

  25. Maldjian JA, Laurienti PJ, Kraft RA, Burdette JH (2003) An automated method for neuroanatomic and cytoarchitectonic atlas-based interrogation of fMRI data sets. Neuroimage 19:1233–1239

    Article  PubMed  Google Scholar 

  26. Sabri O, Kendziorra K, Wolf H et al (2008) Acetylcholine receptors in dementia and mild cognitive impairment. Eur J Nucl Med Mol Imaging 35(Suppl 1):S30–S45

    Article  CAS  PubMed  Google Scholar 

  27. Gutierrez D, Montandon ML, Assal F, Allaoua M, Ratib O, Lövblad KO, Zaidi H (2012) Anatomically guided voxel-based partial volume effect correction in brain PET: impact of MRI segmentation. Comput Med Imaging Graph 36:610–619

    Article  PubMed  Google Scholar 

  28. Kessler RM, Ellis JR, Eden M (1984) Analysis of emission tomographic scan data: limitations imposed by resolution and background. J Comput Assist Tomogr 8:514–522

    Article  CAS  PubMed  Google Scholar 

  29. Soret M, Riddel C, Hapdey S, Buvat I (2002) Biases affecting the measurements of tumor-to-background activity ratio in PET. IEEE Trans Nucl Sci 49:2112–2118

    Article  Google Scholar 

  30. Eickhoff SB, Stephan KE, Mohlberg H, Grefkes C, Fink GR, Amunts K, Zilles K (2005) A new SPM toolbox for combining probabilistic cytoarchitectonic maps and functional imaging data. Neuroimage 25:1325–1335

    Article  PubMed  Google Scholar 

  31. Van der Werf YD, Witter MP, Groenewegen HJ (2002) The intralaminar and midline nuclei of the thalamus. Anatomical and functional evidence for participation in processes of arousal and awareness. Brain Res Brain Res Rev 39:107–140

    Article  PubMed  Google Scholar 

  32. Eckert U, Metzger CD, Buchmann JE, Kaufmann J, Osoba A, Li M, Safron A, Liao W, Steiner J, Bogerts B, Walter M (2012) Preferential networks of the mediodorsal nucleus and centromedian-parafascicular complex of the thalamus--a DTI tractography study. Hum Brain Mapp 33:2627–2637

    Article  PubMed  Google Scholar 

  33. Johansen-Berg H, Behrens TE, Sillery E et al (2005) Functional-anatomical validation and individual variation of diffusion tractography-based segmentation of the human thalamus. Cereb Cortex 15:31–39

    Article  PubMed  Google Scholar 

  34. Le Reste PJ, Haegelen C, Gibaud B, Moreau T, Morandi X (2016) Connections of the dorsolateral prefrontal cortex with the thalamus: a probabilistic tractography study. Surg Radiol Anat 38:705–710

    Article  PubMed  Google Scholar 

  35. Golden EC, Graff-Radford J, Jones DT, Benarroch EE (2016) Mediodorsal nucleus and its multiple cognitive functions. Neurology 87:2161–2168

    Article  PubMed  Google Scholar 

  36. Bolkan SS, Stujenske JM, Parnaudeau S, Spellman TJ, Rauffenbart C, Abbas AI, Harris AZ, Gordon JA, Kellendonk C (2017) Thalamic projections sustain prefrontal activity during working memory maintenance. Nat Neurosci 20:987–996

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Seeley WW, Menon V, Schatzberg AF, Keller J, Glover GH, Kenna H, Reiss AL, Greicius MD (2007) Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 27:2349–2356

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chakraborty S, Kolling N, Walton ME, Mitchell AS (2016) Critical role for the mediodorsal thalamus in permitting rapid reward-guided updating in stochastic reward environments. Elife 5

  39. Metzger CD, Eckert U, Steiner J et al (2010) High field FMRI reveals thalamocortical integration of segregated cognitive and emotional processing in mediodorsal and intralaminar thalamic nuclei. Front Neuroanat 4:138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lioudyno MI, Birch AM, Tanaka BS, Sokolov Y, Goldin AL, Chandy KG, Hall JE, Alkire MT (2013) Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics. J Neurosci 33:16310–16322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Picard F, Sadaghiani S, Leroy C, Courvoisier DS, Maroy R, Bottlaender M (2013) High density of nicotinic receptors in the cingulo-insular network. Neuroimage 79:42–51

    Article  CAS  PubMed  Google Scholar 

  42. Yasuno F, Suhara T, Okubo Y, Sudo Y, Inoue M, Ichimiya T, Takano A, Nakayama K, Halldin C, Farde L (2004) Low dopamine D2 receptor binding in subregions of the thalamus in schizophrenia. Am J Psychiatry 161:1016–1022

    Article  PubMed  Google Scholar 

  43. Ferguson BR, Gao WJ (2014) Development of thalamocortical connections between the mediodorsal thalamus and the prefrontal cortex and its implication in cognition. Front Hum Neurosci 8:1027

    PubMed  Google Scholar 

  44. Buchmann A, Dentico D, Peterson MJ, Riedner BA, Sarasso S, Massimini M, Tononi G, Ferrarelli F (2014) Reduced mediodorsal thalamic volume and prefrontal cortical spindle activity in schizophrenia. Neuroimage 102(Pt 2):540–547

    Article  PubMed  Google Scholar 

  45. Anticevic A, Haut K, Murray JD, Repovs G, Yang GJ, Diehl C, McEwen SC, Bearden CE, Addington J, Goodyear B, Cadenhead KS, Mirzakhanian H, Cornblatt BA, Olvet D, Mathalon DH, McGlashan TH, Perkins DO, Belger A, Seidman LJ, Tsuang MT, van Erp TGM, Walker EF, Hamann S, Woods SW, Qiu M, Cannon TD (2015) Association of Thalamic Dysconnectivity and Conversion to psychosis in youth and young adults at elevated clinical risk. JAMA Psychiatry 72:882–891

    Article  PubMed  PubMed Central  Google Scholar 

  46. Majdi A, Kamari F, Vafaee MS, Sadigh-Eteghad S (2017) Revisiting nicotine's role in the ageing brain and cognitive impairment. Rev Neurosci 28:767–781

    Article  CAS  PubMed  Google Scholar 

  47. Vafaee MS, Gjedde A, Imamirad N, Vang K, Chakravarty MM, Lerch JP, Cumming P (2015) Smoking normalizes cerebral blood flow and oxygen consumption after 12-hour abstention. J Cereb Blood Flow Metab 35:699–705

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Koukouli F, Rooy M, Tziotis D, Sailor KA, O'Neill HC, Levenga J, Witte M, Nilges M, Changeux JP, Hoeffer CA, Stitzel JA, Gutkin BS, DiGregorio DA, Maskos U (2017) Nicotine reverses hypofrontality in animal models of addiction and schizophrenia. Nat Med 23:347–354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kumari V, Postma P (2005) Nicotine use in schizophrenia: the self medication hypotheses. Neurosci Biobehav Rev 29:1021–1034

    Article  CAS  PubMed  Google Scholar 

  50. Orekhova EV, Stroganova TA (2014) Arousal and attention re-orienting in autism spectrum disorders: evidence from auditory event-related potentials. Front Hum Neurosci 8:34

    Article  PubMed  PubMed Central  Google Scholar 

  51. Picard F, Megevand P, Minotti L et al (2007) Intracerebral recordings of nocturnal hyperkinetic seizures: demonstration of a longer duration of the pre-seizure sleep spindle. Clin Neurophysiol 118:928–939

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Statistical support was provided by the Clinical Research Center of the University Hospitals of Geneva (Prof. T. Perneger).

Funding

The work was funded by the Swiss National Science Foundation (no. 320030_127608).

Author information

Authors and Affiliations

  1. Nuclear Medicine and Molecular Imaging Division, Diagnostic Department, University Hospitals of Geneva, 4 rue Gabrielle-Perret-Gentil, 1211, 14, Genève, Switzerland

    Valentina Garibotto, Michael Wissmeyer & Osman Ratib

  2. Faculty of Medicine, Geneva University, 1211, Geneva, Switzerland

    Valentina Garibotto & Fabienne Picard

  3. Department of Electrical and Computer Engineering, National Technical University of Athens, Athens, Greece

    Zoi Giavri

  4. EEG and Epilepsy Unit, Department of Neurology, University Hospitals of Geneva and Medical School of Geneva, 4 rue Gabrielle-Perret-Gentil, 1211, 14, Genève, Switzerland

    Fabienne Picard

Authors
  1. Valentina Garibotto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael Wissmeyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Zoi Giavri
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Osman Ratib
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fabienne Picard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Valentina Garibotto or Fabienne Picard.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in this study were in accordance with the national ethical standards and with the 1964 Helsinki declaration and its later amendments; the study protocol was approved by the Ethics Committee of the Geneva University Hospitals (CER 10-041) and by the Swiss agency for medications (Swissmedic: study no 2011DR1031).

Informed Consent

Written informed consent was obtained from all participants.

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

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Garibotto, V., Wissmeyer, M., Giavri, Z. et al. Nicotinic Acetylcholine Receptor Density in the “Higher-Order” Thalamus Projecting to the Prefrontal Cortex in Humans: a PET Study. Mol Imaging Biol 22, 417–424 (2020). https://doi.org/10.1007/s11307-019-01377-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-019-01377-8

Key words

Search

Navigation