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CHRM2 Genotype Affects Inhibitory Control Mechanisms During Cognitive Flexibility

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Abstract

The cholinergic system is one of the most important neurotransmitter systems, but knowledge about the relevance of the cholinergic muscarinergic receptor system for cognitive functions is still scarce. Evidence suggests that the cholinergic muscarinic 2 receptor (CHRM2) plays an important role in the processing of cueing/prior information that help to increase the efficacy of lower-level attentional processes. In the current study, we investigated whether this is also the case for higher-level cognitive flexibility mechanisms. To this end, we tested N = 210 healthy adults with a backward inhibition task, in which prior information needs to be used to guide cognitive flexibility mechanisms. Testing different polymorphisms of the CHRM2 gene, we found that variation in this gene play a role in cognitive flexibility. It could be demonstrated that rs8191992 TT genotype carriers are better able to suppress no longer relevant information and to use prior information for cognitive flexibility, compared to A allele carriers. We further found that rs2350780 GG genotype carriers performed worse than A allele carriers. The results broaden the relevance of the CHRM2 system for cognitive functions beyond attentional selection processes. Corroborating recent theories on the relevance of the cholinergic system for cognitive processes, these results suggest that CHRM2 is important to process of “prior information” needed to inform subsequent cognitive operations. Considering the importance of prior information for adaptive behavioral control, it is possible that CHRM2 also modulates other instances of higher-level cognitive processes as long as these require the processing of “prior information.”

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References

  1. Mash D, Flynn D, Potter L (1985) Loss of M2 muscarine receptors in the cerebral cortex in Alzheimer’s disease and experimental cholinergic denervation. Science 228:1115–1117. https://doi.org/10.1126/science.3992249

    Article  CAS  PubMed  Google Scholar 

  2. Zhou C, Fryer AD, Jacoby DB (2001) Structure of the human M2 muscarinic acetylcholine receptor gene and its promoter. Gene 271:87–92. https://doi.org/10.1016/S0378-1119(01)00494-2

    Article  CAS  PubMed  Google Scholar 

  3. Cannon D, Klaver J, Gandhi S, Solorio G, Peck SA, Erickson K, Akula N, Savitz J et al (2011) Genetic variation in cholinergic-muscarinic-2 receptor gene modulates muscarinic2-receptor binding in vivo and accounts for reduced binding in bipolar disorder. Mol Psychiatry 16:407–418. https://doi.org/10.1038/mp.2010.24

    Article  CAS  PubMed  Google Scholar 

  4. Comings DE, Wu S, Rostamkhani M, McGue M, Iacono WG, MacMurray JP (2002) Association of the muscarinic cholinergic 2 receptor(CHRM2) gene with major depression in women. Am J Med Genet 114:527–529. https://doi.org/10.1002/ajmg.10406

    Article  PubMed  Google Scholar 

  5. Luo X, Kranzler HR, Zuo L, Wang S, Blumberg HP, Gelernter J (2005) CHRM2 gene predisposes to alcohol dependence, drug dependence and affective disorders: Results from an extended case–control structured association study. Hum Mol Genet 14:2421–2434. https://doi.org/10.1093/hmg/ddi244

    Article  CAS  PubMed  Google Scholar 

  6. Rajji TK, Chow TW, Voineskos AN, Links KA, Miranda D, Mamo DC, Ismail Z, Pollock BG et al (2012) Cholinergic pathways and cognition in patients with schizophrenia: a pilot study. Schizophr Res 139:46–52. https://doi.org/10.1016/j.schres.2012.06.006

    Article  PubMed  Google Scholar 

  7. Lai M-C, Lombardo MV, Chakrabarti B, Sadek SA, Pasco G, Wheelwright SJ, Bullmore ET, Baron-Cohen S et al (2010) A shift to randomness of brain oscillations in people with autism. Biol Psychiatry 68:1092–1099. https://doi.org/10.1016/j.biopsych.2010.06.027

    Article  PubMed  Google Scholar 

  8. Donaldson C, Lam D, Mathews A (2007) Rumination and attention in major depression. Behav Res Ther 45:2664–2678. https://doi.org/10.1016/j.brat.2007.07.002

    Article  PubMed  Google Scholar 

  9. Paradiso S, Lamberty GJ, Garvey MJ, Robinson RG (1997) Cognitive impairment in the euthymic phase of chronic unipolar depression. J Nerv Ment Dis 185:748–754

    Article  CAS  PubMed  Google Scholar 

  10. Tham A, Engelbrektson K, Mathé AA et al (1997) Impaired neuropsychological performance in euthymic patients with recurring mood disorders. J Clin Psychiatry 58:26–29. https://doi.org/10.4088/JCP.v58n0105

    Article  CAS  PubMed  Google Scholar 

  11. Trichard C, Martinot JL, Alagille M, Masure MC, Hardy P, Ginestet D, Féline A (1995) Time course of prefrontal lobe dysfunction in severely depressed in-patients: A longitudinal neuropsychological study. Psychol Med 25:79–85. https://doi.org/10.1017/S0033291700028105

    Article  CAS  PubMed  Google Scholar 

  12. Weiland-Fiedler P, Erickson K, Waldeck T, Luckenbaugh DA, Pike D, Bonne O, Charney DS, Neumeister A (2004) Evidence for continuing neuropsychological impairments in depression. J Affect Disord 82:253–258. https://doi.org/10.1016/j.jad.2003.10.009

    Article  PubMed  Google Scholar 

  13. Clark L, Iversen SD, Goodwin GM (2002) Sustained attention deficit in bipolar disorder. Br J Psychiatry 180:313–319. https://doi.org/10.1192/bjp.180.4.313

    Article  PubMed  Google Scholar 

  14. Braff DL (1993) Information processing and attention dysfunctions in schizophrenia. Schizophr Bull 19:233–259. https://doi.org/10.1093/schbul/19.2.233

    Article  CAS  PubMed  Google Scholar 

  15. Cornblatt BA, Kellp JG (1994) Genetics, and the pathophysiology of schizophrenia

  16. Gold JM, Thaker GK (2002) Current progress in schizophrenia research. 2

  17. Posner MI (1988) Asymmetries in hemispheric control of attention in schizophrenia. Arch Gen Psychiatry 45:814–821. https://doi.org/10.1001/archpsyc.1988.01800330038004

    Article  CAS  PubMed  Google Scholar 

  18. Lawrence AD, Sahakian BJ (1995) Alzheimer disease, attention, and the cholinergic system. [editorial]. Alzheimer Dis Assoc Disord 1995:37–49

  19. Perry RJ (1999) Attention and executive deficits in Alzheimer’s disease: a critical review. Brain 122:383–404. https://doi.org/10.1093/brain/122.3.383

    Article  Google Scholar 

  20. Perry RJ, Watson P, Hodges JR (2000) The nature and staging of attention dysfunction in early (minimal and mild) Alzheimer’s disease: relationship to episodic and semantic memory impairment. Neuropsychologia 38:252–271. https://doi.org/10.1016/S0028-3932(99)00079-2

    Article  CAS  PubMed  Google Scholar 

  21. Erskine FF, Ellis JR, Ellis KA, Stuber E, Hogan K, Miller V, Moore E, Bartholomeusz C et al (2004) Evidence for synergistic modulation of early information processing by nicotinic and muscarinic receptors in humans. Hum Psychopharmacol Clin Exp 19:503–509. https://doi.org/10.1002/hup.613

    Article  CAS  Google Scholar 

  22. Furey ML, Pietrini P, Haxby JV, Drevets WC (2008) Selective effects of cholinergic modulation on task performance during selective attention. Neuropsychopharmacology 33:913–923. https://doi.org/10.1038/sj.npp.1301461

    Article  CAS  PubMed  Google Scholar 

  23. Goldberg JA, Reynolds JNJ (2011) Spontaneous firing and evoked pauses in the tonically active cholinergic interneurons of the striatum. Neuroscience 198:27–43. https://doi.org/10.1016/j.neuroscience.2011.08.067

    Article  CAS  PubMed  Google Scholar 

  24. Mentis MJ, Sunderland T, Lai J, Connolly C, Krasuski J, Levine B, Friz J, Sobti S et al (2001) Muscarinic versus nicotinic modulation of a visual task: a PET study using drug probes. Neuropsychopharmacology 25:555–564. https://doi.org/10.1016/S0893-133X(01)00264-0

    Article  CAS  PubMed  Google Scholar 

  25. Morris G, Arkadir D, Nevet A, Vaadia E, Bergman H (2004) Coincident but distinct messages of midbrain dopamine and striatal Tonically active neurons. Neuron 43:133–143. https://doi.org/10.1016/j.neuron.2004.06.012

    Article  CAS  PubMed  Google Scholar 

  26. Greenwood PM, Lin M-K, Sundararajan R, Fryxell KJ, Parasuraman R (2009) Synergistic effects of genetic variation in nicotinic and muscarinic receptors on visual attention but not working memory. Proc Natl Acad Sci U S A 106:3633–3638. https://doi.org/10.1073/pnas.0807891106

    Article  PubMed  PubMed Central  Google Scholar 

  27. Stock A-K, Friedrich J, Beste C (2016) Subliminally and consciously induced cognitive conflicts interact at several processing levels. Cortex 85:75–89. https://doi.org/10.1016/j.cortex.2016.09.027

    Article  PubMed  Google Scholar 

  28. Yu AJ, Dayan P (2005) Uncertainty, neuromodulation, and attention. Neuron 46:681–692. https://doi.org/10.1016/j.neuron.2005.04.026

    Article  CAS  PubMed  Google Scholar 

  29. Friston K (2005) A theory of cortical responses. Philos Trans R Soc Lond Ser B Biol Sci 360:815–836. https://doi.org/10.1098/rstb.2005.1622

    Article  Google Scholar 

  30. Pezzulo G, Rigoli F, Friston K (2015) Active inference, homeostatic regulation and adaptive behavioural control. Prog Neurobiol 134:17–35. https://doi.org/10.1016/j.pneurobio.2015.09.001

    Article  PubMed  PubMed Central  Google Scholar 

  31. Diamond A (2013) Executive functions. Annu Rev Psychol 64:135–168. https://doi.org/10.1146/annurev-psych-113011-143750

    Article  PubMed  Google Scholar 

  32. Mayr U, Keele SW (2000) Changing internal constraints on action: the role of backward inhibition. J Exp Psychol Gen 129:4–26

    Article  CAS  PubMed  Google Scholar 

  33. Hendershot CS, Bryan AD, Feldstein Ewing SW, Claus ED, Hutchison KE (2011) Preliminary evidence for associations of CHRM2 with substance use and disinhibition in adolescence. J Abnorm Child Psychol 39:671–681. https://doi.org/10.1007/s10802-011-9511-9

    Article  PubMed  PubMed Central  Google Scholar 

  34. Hill SY, Jones BL, Holmes B, Steinhauer SR, Zezza N, Stiffler S (2013) Cholinergic receptor gene (CHRM2) variation and familial loading for alcohol dependence predict childhood developmental trajectories of P300. Psychiatry Res 209:504–511. https://doi.org/10.1016/j.psychres.2013.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Jung MH, Park BL, Lee B-C, Ro Y, Park R, Shin HD, Bae JS, Kang TC et al (2011) Association of CHRM2 polymorphisms with severity of alcohol dependence. Genes Brain Behav 10:253–256. https://doi.org/10.1111/j.1601-183X.2010.00663.x

    Article  CAS  PubMed  Google Scholar 

  36. Mobascher A, Rujescu D, Mittelstraß K, Giegling I, Lamina C, Nitz B, Brenner H, Fehr C et al (2010) Association of a variant in the muscarinic acetylcholine receptor 2 gene (CHRM2) with nicotine addiction. Am J Med Genet B Neuropsychiatr Genet 153B:684–690. https://doi.org/10.1002/ajmg.b.31011

    Article  CAS  PubMed  Google Scholar 

  37. Porjesz B, Rangaswamy M (2007) Neurophysiological endophenotypes, CNS disinhibition, and risk for alcohol dependence and related disorders. Sci World J 7:131–141. https://doi.org/10.1100/tsw.2007.203

    Article  Google Scholar 

  38. Wang JC (2004) Evidence of common and specific genetic effects: association of the muscarinic acetylcholine receptor M2 (CHRM2) gene with alcohol dependence and major depressive syndrome. Hum Mol Genet 13:1903–1911. https://doi.org/10.1093/hmg/ddh194

    Article  CAS  PubMed  Google Scholar 

  39. Beck AT, Ward CH, Mendelson M et al (1961) An inventory for measuring depression. Arch Gen Psychiatry 4:561–571

    Article  CAS  Google Scholar 

  40. Koch I, Gade M, Philipp AM (2004) Inhibition of response mode in task switching. Exp Psychol 51(7):52–58

    Article  PubMed  Google Scholar 

  41. Beste C, Steenbergen L, Sellaro R, Grigoriadou S, Zhang R, Chmielewski W, Stock AK, Colzato L (2016) Effects of concomitant stimulation of the GABAergic and norepinephrine system on inhibitory control—a study using transcutaneous Vagus nerve stimulation. Brain Stimul 9:811–818. https://doi.org/10.1016/j.brs.2016.07.004

    Article  PubMed  Google Scholar 

  42. Zhang R, Stock A-K, Beste C (2016) The neurophysiological basis of reward effects on backward inhibition processes. NeuroImage 142:163–171. https://doi.org/10.1016/j.neuroimage.2016.05.080

    Article  PubMed  Google Scholar 

  43. Zhang R, Stock A-K, Fischer R, Beste C (2016) The system neurophysiological basis of backward inhibition. Brain Struct Funct 221:4575–4587. https://doi.org/10.1007/s00429-016-1186-0

    Article  CAS  PubMed  Google Scholar 

  44. Zhang R, Stock A-K, Rzepus A, Beste C (2017) Self-regulatory capacities are depleted in a domain-specific manner. Front Syst Neurosci 11(70). https://doi.org/10.3389/fnsys.2017.00070

  45. Schuch S, Koch I (2003) The role of response selection for inhibition of task sets in task shifting. 15

  46. Ellis JR, Ellis KA, Bartholomeusz CF, Harrison BJ, Wesnes KA, Erskine FF, Vitetta L, Nathan PJ (2005) Muscarinic and nicotinic receptors synergistically modulate working memory and attention in humans. Int J Neuropsychopharmacol 9:175. https://doi.org/10.1017/S1461145705005407

    Article  CAS  PubMed  Google Scholar 

  47. Perry E, Walker M, Grace J, Perry R (1999) Acetylcholine in mind: a neurotransmitter correlate of consciousness? Trends Neurosci 22:273–280. https://doi.org/10.1016/S0166-2236(98)01361-7

    Article  CAS  PubMed  Google Scholar 

  48. Giller F, Zhang R, Roessner V, Beste C (2018) The neurophysiological basis of developmental changes during sequential cognitive flexibility between adolescents and adults. Hum Brain Mapp 40:552–565. https://doi.org/10.1002/hbm.24394

    Article  PubMed  Google Scholar 

  49. Wolff N, Giller F, Buse J, Roessner V, Beste C (2018) When repetitive mental sets increase cognitive flexibility in adolescent obsessive-compulsive disorder. J Child Psychol Psychiatry 59:1024–1032. https://doi.org/10.1111/jcpp.12901

    Article  PubMed  Google Scholar 

  50. Zink N, Zhang R, Chmielewski WX, Beste C, Stock AK (2018) Detrimental effects of a high-dose alcohol intoxication on sequential cognitive flexibility are attenuated by practice. Prog Neuro-Psychopharmacol Biol Psychiatry 89:97–108. https://doi.org/10.1016/j.pnpbp.2018.08.034

    Article  CAS  Google Scholar 

  51. Jones KA, Porjesz B, Almasy L, Bierut L, Dick D, Goate A, Hinrichs A, Rice JP et al (2006) A cholinergic receptor gene (CHRM2) affects event-related oscillations. Behav Genet 36:627–639. https://doi.org/10.1007/s10519-006-9075-6

    Article  PubMed  Google Scholar 

  52. Gibbons AS, Scarr E, McLean C, Sundram S, Dean B (2009) Decreased muscarinic receptor binding in the frontal cortex of bipolar disorder and major depressive disorder subjects. J Affect Disord 116:184–191. https://doi.org/10.1016/j.jad.2008.11.015

    Article  CAS  PubMed  Google Scholar 

  53. Gibbons AS, Jeon WJ, Scarr E, Dean B (2016) Changes in muscarinic M2 receptor levels in the cortex of subjects with bipolar disorder and major depressive disorder and in rats after treatment with mood stabilisers and antidepressants. Int J Neuropsychopharmacol 19:pyv118. https://doi.org/10.1093/ijnp/pyv118

    Article  CAS  PubMed  Google Scholar 

  54. Hu Z, Bruno AE (2011) The influence of 3′ UTRs on MicroRNA function inferred from human SNP data. Comp Funct Genomics 2011:1–9

    Article  CAS  Google Scholar 

  55. Dick DM, Aliev F, Kramer J, Wang JC, Hinrichs A, Bertelsen S, Kuperman S, Schuckit M et al (2007) Association of CHRM2 with IQ: converging evidence for a gene influencing intelligence. Behav Genet 37:265–272. https://doi.org/10.1007/s10519-006-9131-2

    Article  PubMed  Google Scholar 

  56. Stock A-K, Wolff N, Beste C (2017) Opposite effects of binge drinking on consciously vs. subliminally induced cognitive conflicts. NeuroImage 162:117–126. https://doi.org/10.1016/j.neuroimage.2017.08.066

    Article  PubMed  Google Scholar 

  57. Zink N, Bensmann W, Beste C, Stock A-K (2018) Alcohol hangover increases conflict load via faster processing of subliminal information. Front Hum Neurosci 12:316. https://doi.org/10.3389/fnhum.2018.00316

    Article  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by a Grant from the Deutsche Forschungsgemeinschaft (DFG) SFB 940 project B8.

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  1. Ann-Kathrin Stock and Christian Beste shared senior authorship

Authors and Affiliations

  1. Cognitive Neurophysiology, Department of Child and Adolescent Psychiatry, Faculty of Medicine of the TU Dresden, Schubertstraße 42, 01309, Dresden, Germany

    Nicolas Zink, Wiebke Bensmann, Ann-Kathrin Stock & Christian Beste

  2. Department of Human Genetics, Ruhr-University Bochum, Bochum, Germany

    Larissa Arning

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  1. Nicolas Zink
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  2. Wiebke Bensmann
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Correspondence to Christian Beste.

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The study was approved by the local ethics committee of the TU Dresden, Germany.

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Zink, N., Bensmann, W., Arning, L. et al. CHRM2 Genotype Affects Inhibitory Control Mechanisms During Cognitive Flexibility. Mol Neurobiol 56, 6134–6141 (2019). https://doi.org/10.1007/s12035-019-1521-6

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