Abstract
Traditional methods of drug discovery often rely on a unidirectional, “bottom-up” approach: A search for molecular compounds that target a particular neurobiological substrate (e.g., a receptor type), the refinement of those compounds, testing in animal models using high-throughput behavioral screening methods, and then human testing for safety and effectiveness. Many attempts have found the “effectiveness” criterion to be a major stumbling block, and we and others have suggested that success may be improved by an alternative approach that considers the neural circuits mediating the effects of genetic and molecular manipulations on behavior and cognition. We describe our efforts to understand the cholinergic system’s role in attention using parallel approaches to test main hypotheses in both rodents and humans as well as generating converging evidence using methods and levels of analysis tailored to each species. The close back-and-forth between these methods has enhanced our understanding of the cholinergic system’s role in attention both “bottom-up” and “top-down”—that is, the basic neuroscience identifies potential neuronal circuit-based mechanisms of clinical symptoms, and the patient and genetic populations serve as natural experiments to test and refine hypotheses about its contribution to specific processes. Together, these studies have identified (at least) two major and potentially independent contributions of the cholinergic system to attention: a neuromodulatory component that influences cognitive control in response to challenges from distractors that either make detection more difficult or draw attention away from the distractor, and a phasic or transient cholinergic signal that instigates a shift from ongoing behavior and the activation of cue-associated response. Right prefrontal cortex appears to play a particularly important role in the neuromodulatory component integrating motivational and cognitive influences for top-down control across populations, whereas the transient cholinergic signal involves orbitofrontal regions associated with shifts between internal and external attention. Understanding how these two modes of cholinergic function interact and are perturbed in schizophrenia will be an important prerequisite for developing effective treatments.
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References
Akitsuki Y, Sugiura M, Watanabe J, Yamashita K, Sassa Y, Awata S, Kawashima R (2003) Context-dependent cortical activation in response to financial reward and penalty: an event-related fMRI study. Neuroimage 19(4):1674–1685. doi:10.1016/s1053-8119(03)00250-7
Alexander MP, Stuss DT, Shallice T, Picton TW, Gillingham S (2005) Impaired concentration due to frontal lobe damage from two distinct lesion sites. Neurology 65(4):572–579. doi:10.1212/01.wnl.0000172912.07640.92
Apostol G, Abi-Saab W, Kratochvil CJ, Adler LA, Robieson WZ, Gault LM, Saltarelli MD (2012) Efficacy and safety of the novel alpha(4)beta(2) neuronal nicotinic receptor partial agonist ABT-089 in adults with attention-deficit/hyperactivity disorder: a randomized, double-blind, placebo-controlled crossover study. Psychopharmacology 219(3):715–725. doi:10.1007/s00213-011-2393-2
Apparsundaram S, Martinez V, Parikh V, Kozak R, Sarter M (2005) Increased capacity and density of choline transporters situated in synaptic membranes of the right medial prefrontal cortex of attentional task-performing rats. J Neurosci 25(15):3851–3856. doi:10.1523/jinneurosci.0505.-05.2005
Bain EE, Robieson W, Pritchett Y, Garimella T, Abi-Saab W, Apostol G, Saltarelli MD (2013) A randomized, double-blind, placebo-controlled phase 2 study of alpha 4 beta 2 agonist ABT-894 in adults with ADHD. Neuropsychopharmacology 38(3):405–413. doi:10.1038/npp.2012.194
Barch DM, Dowd EC (2010) Goal representations and motivational drive in schizophrenia: the role of prefrontal-striatal interactions. Schizophr Bull 36(5):919–934. doi:10.1093/schbul/sbq068
Bauer M, Kluge C, Bach D, Bradbury D, Heinze HJ, Dolan RJ, Driver J (2012) Cholinergic enhancement of visual attention and neural oscillations in the human brain. Curr Biol 22(5):397–402. doi:10.1016/j.cub.2012.01.022
Belujon P, Grace AA (2008) Critical role of the prefrontal cortex in the regulation of hippocampus-accumbens information flow. J Neurosci 28:9797–9805
Bentley P, Driver J, Dolan RJ (2011) Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging. Prog Neurobiol 94(4):360–388. doi:10.1016/j.pneurobio.2011.06.002
Berry AS, Demeter E, Sabhapathy S, English BA, Blakely RD, Sarter M, Lustig C (2014) Disposed to distraction: genetic variation in the cholinergic system influences distractibility but not time-on-task effects. J Cogn Neurosci 26(9):1981–1991. doi:10.1162/jocn_a_00607
Berry AS, Blakely RD, Sarter M, Lustig C (2015) Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics. Neuroimage 108:386–395. doi:10.1016/j.neuroimage.2014.12.036
Berry AS, Sarter M, Lustig C (in prep) Frontoparietal correlates of attentional effort during challenges to attention
Berry AS, Sarter M, Gehring WJ, Lustig C (in prep) Going in: frontoparietal responses associated with shifts from perceptual to reflective attention
Blatow M, Rozov A, Katona I, Hormuzdi SG, Meyer AH, Whittington MA, Monyer H (2003) A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex. Neuron 38(5):805–817. doi:10.1016/s0896-6273(03)00300-3
Bloem B, Poorthuis RB, Mansvelder HD (2014a) Cholinergic modulation of the medial prefrontal cortex: the role of nicotinic receptors in attention and regulation of neuronal activity. Frontiers Neural Circ 8. doi:10.3389/fncir.2014.00017
Bloem B, Schoppink L, Rotaru DC, Faiz A, Hendriks P, Mansvelder HD, van de Berg WD, Wouterlood FG (2014b) Topographic mapping between basal forebrain cholinergic neurons and the medial prefrontal cortex in mice. J Neurosci 34:16234–16246
Bowie CR, Leung WW, Reichenberg A, McClure MM, Patterson TL, Heaton RK, Harvey PD (2008) Predicting schizophrenia patients’ real-world behavior with specific neuropsychological and functional capacity measures. Biol Psychiatry 63(5):505–511. doi:10.1016/j.biopsych.2007.05.022
Brady AM, O’Donnell P (2004) Dopaminergic modulation of prefrontal cortical input to nucleus accumbens neurons in vivo. J Neurosci 24:1040–1049
Braver TS (2012) The variable nature of cognitive control: a dual mechanisms framework. Trends Cogn Sci 16(2):106–113. doi:10.1016/j.tics.2011.12.010
Briand LA, Gritton H, Howe WM, Young DA, Sarter M (2007) Modulators in concert for cognition: modulator interactions in the prefrontal cortex. Prog Neurobiol 83(2):69–91. doi:10.1016/j.pneurobio.2007.06.007
Burgess PW, Dumontheil I, Gilbert SJ (2007) The gateway hypothesis of rostral prefrontal cortex (area 10) function. Trends Cogn Sci 11(7):290–298. doi:10.1016/j.tics.2007.05.004
Cader S, Cifelli A, Abu-Omar Y, Palace J, Matthews PM (2006) Reduced brain functional reserve and altered functional connectivity in patients with multiple sclerosis. Brain 129:527–537. doi:10.1093/brain/awh670
Cairo TA, Woodward TS, Ngan ETC (2004) An event-related fMRI study of maintenance brain activity in schizophrenia during the performance of a variable load working memory task. Schizophr Res 67(1):262
Callaway E III, Jones RT, Donchin E (1970) Auditory evoked potential variability in schizophrenia. Electroencephalogr Clin Neurophysiol 29(5):421–428
Callicott JH, Mattay VS, Bertolino A, Finn K, Coppola R, Frank JA, Weinberger DR (1999) Physiological characteristics of capacity constraints in working memory as revealed by functional MRI. Cereb Cortex 9(1):20–26. doi:10.1093/cercor/9.1.20
Cappell KA, Gmeindl L, Reuter-Lorenz PA (2010) Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load. Cortex 46(4):462–473. doi:10.1016/j.cortex.2009.11.009
Carr DB, Sesack SR (2000) Projections from the rat prefrontal cortex to the ventral tegmental area: target specificity in the synaptic associations with mesoaccumbens and mesocortical neurons. J Neurosci 20:3864–3873
Castellanos FX, Sonuga-Barke EJS, Scheres A, Di Martino A, Hyde C, Walters JR (2005) Varieties of attention-deficit/hyperactivity disorder-related intra-individual variability. Biol Psychiatry 57(11):1416–1423. doi:10.1016/j.biopsych.2004.12.005
Castro-Alamancos MA, Gulati T (2014) Neuromodulators produce distinct activated states in neocortex. J Neurosci 34:12353–12367
Chun MM, Johnson MK (2011) Memory: enduring traces of perceptual and reflective attention. Neuron 72(4):520–535. doi:10.1016/j.neuron.2011.10.026
Cole VT, Weinberger DR, Dickinson D (2011) Intra-individual variability across neuropsychological tasks in schizophrenia: a comparison of patients, their siblings, and healthy controls. Schizophr Res 129(1):91–93. doi:10.1016/j.schres.2011.03.007
Cornblatt BA, Keilp JG (1994) Impaired attention, genetics, and the pathophysiology of schizophrenia. Schizophr Bull 20(1):31–46
Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699–729
Deco G, Thiele A (2011) Cholinergic control of cortical network interactions enables feedback-mediated attentional modulation. Eur J Neurosci 34(1):146–157. doi:10.1111/j.1460-9568.2011.07749.x
Demeter E, Sarter M, Lustig C (2008) Rats and humans paying attention: cross-species task development for translational research. Neuropsychology 22(6):787–799. doi:10.1037/a0013712
Demeter E, Hernandez-Garcia L, Sarter M, Lustig C (2011) Challenges to attention: a continuous arterial spin labeling (ASL) study of the effects of distraction on sustained attention. Neuroimage 54(2):1518–1529. doi:10.1016/j.neuroimage.2010.09.026
Demeter E, Guthrie SK, Taylor SF, Sarter M, Lustig C (2013) Increased distractor vulnerability but preserved vigilance in patients with schizophrenia: evidence from a translational sustained attention task. Schizophr Res 144(1–3):136–141. doi:10.1016/j.schres.2013.01.003
Demeter E, de Alburquerque D, Woldorff M (2015) The effects of distraction on the brain processes underlying signal detection. Poster presented at the Cognitive Neuroscience Society Meeting, New York
Deserno L, Boehme R, Heinz A, Schlagenhauf F (2013) Reinforcement learning and dopamine in schizophrenia: dimensions of symptoms or specific features of a disease group? Frontiers Psychiatry 4:172. doi:10.3389/fpsyt.2013.00172
Dima D, Dietrich DE, Dillo W, Emrich HM (2010) Impaired top-down processes in schizophrenia: a DCM study of ERPs. Neuroimage 52(3):824–832. doi:10.1016/j.neuroimage.2009.12.086
Disney AA, Aoki C (2008) Muscarinic acetylcholine receptors in macaque v1 are most frequently expressed by parvalbumin-immunoreactive neurons. J Comp Neurol 507(5):1748–1762. doi:10.1002/cne.21616
Donchin E, Callaway E, Jones RT (1970) Auditory evoked potential variability in schizophrenia.2. Application of discriminant analysis. Electroencephalogr Clin Neurophysiol 29(5):429. doi:10.1016/0013-4694(70)90060-x
Egeland J, Rund BR, Sundet K, Landro NI, Asbjornsen A, Lund A, Hugdahl K (2003) Attention profile in schizophrenia compared with depression: differential effects of processing speed, selective attention and vigilance. Acta Psychiatr Scand 108(4):276–284. doi:10.1034/j.1600-0447.2003.00146.x
Flagel SB, Akil H, Robinson TE (2009) Individual differences in the attribution of incentive salience to reward-related cues: implications for addiction. Neuropharmacology 56:139–148. doi:10.1016/j.neuropharm.2008.06.027
Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, Akil H (2011) A selective role for dopamine in stimulus-reward learning. Nature 469(7328):53–63. doi:10.1038/nature09588
Fletcher PC, McKenna PJ, Frith CD, Grasby PM, Friston KJ, Dolan RJ (1998) Brain activations in schizophrenia during a graded memory task studied with functional neuroimaging. Arch Gen Psychiatry 55:1001–1008. doi:10.1001/archpsyc.55.11.1001
Floresco SB (2015) The nucleus accumbens: an interface between cognition, emotion, and action. Annu Rev Psychol 66(66):25–52. doi:10.1146/annurev-psych-010213-115159
Ford JM, White P, Lim KO, Pfefferbaum A (1994) Schizophrenics have fewer and smaller p300s—a single-trial analysis. Biol Psychiatry 35(2):96–103. doi:10.1016/0006-3223(94)91198-3
Foster DJ, Choi DL, Conn PJ, Rook JM (2014) Activation of M-1 and M-4 muscarinic receptors as potential treatments for Alzheimer’s disease and schizophrenia. Neuropsychiatr Dis Treat 10:183–191. doi:10.2147/ndt.s55104
Fukushima J, Morita N, Fukushima K, Chiba T, Tanaka S, Yamashita I (1990) Voluntary control of saccadic eye-movements in patients with schizophrenic and affective-disorders. J Psychiatr Res 24(1):9. doi:10.1016/0022-3956(90)90021-h
Gagne A-M, Hebert M, Maziade M (2015) Revisiting visual dysfunctions in schizophrenia from the retina to the cortical cells: a manifestation of defective neurodevelopment. Prog Neuropsychopharmacol Biol Psychiatry 62:29–34. doi:10.1016/j.pnpbp.2015.04.007
Gaykema RP, van Weeghel R, Hersh LB, Luiten PG (1991) Prefrontal cortical projections to the cholinergic neurons in the basal forebrain. J Comp Neurol 303:563–583
Giesbrecht B, Woldorff MG, Song AW, Mangun GR (2003) Neural mechanisms of top-down control during spatial and feature attention. Neuroimage 19(3):496–512. doi:10.1016/s1053-8119(03)00162-9
Gilmour G, Gastambide F, Marston H, Walton ME (2015) Using intermediate cogntiive endpoints to facilitate translational research in schizophrenia. Curr Opin Behav Sci 4:128–135
Goghari VM (2011) Executive functioning-related brain abnormalities associated with the genetic liability for schizophrenia: an activation likelihood estimation meta-analysis. Psychol Med 41(6):1239–1252. doi:10.1017/s0033291710001972
Gold JM, Fuller RL, Robinson BM, Braun EL, Luck SJ (2007) Impaired top-down control of visual search in schizophrenia. Schizophr Res 94(1–3):148–155. doi:10.1016/j.schres.2007.04.023
Gorka AX, Hanson JL, Radtke SR, Hariri AR (2014) Reduced hippocampal and medial prefrontal gray matter mediate the association between reported childhood maltreatment and trait anxiety in adulthood and predict sensitivity to future life stress. Biol Mood Anxiety Disord 4:12. doi:10.1186/2045-5380-4-12
Gracitelli CPB, Abe RY, Diniz-Filho A, Vaz-de-Lima FB, Paranhos A Jr, Medeiros FA (2015) Ophthalmology issues in schizophrenia. Curr Psychiatr Rep 17(5). doi:10.1007/s11920-015-0569-x
Green MF (1996) What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153(3):321–330
Grillon C, Courchesne E, Ameli R, Geyer MA, Braff DL (1990) Increased distractibility in schizophrenic-patients—electrophysiologic and behavioral evidence. Arch Gen Psychiatry 47(2):171–179
Hahn B, Robinson BM, Kaiser ST, Matveeva TM, Harvey AN, Luck SJ, Gold JM (2012) Kraepelin and bleuler had it right: people with schizophrenia have deficits sustaining attention over time. J Abnorm Psychol 121(3):641–648. doi:10.1037/a0028492
Hangya B, Ranade SP, Lorenc M, Kepecs A (2015) Central cholinergic neurons are rapidly recruited by reinforcement feedback. Cell 162(5):1155–1168. doi:10.1016/j.cell.2015.07.057
Hasselmo ME, McGaughy J (2004) High acetylcholine levels set circuit dynamics for attention and encoding and low acetylcholine levels set dynamics for consolidation. In: Descarries L, Krnjevic K, Steriade M (eds) Acetylcholine in the cerebral cortex 145:207–231
Hasselmo ME, Sarter M (2011) Modes and models of forebrain cholinergic neuromodulation of cognition. Neuropsychopharmacology 36(1):52–73. doi:10.1038/npp.2010.104
Hasselmo ME, Anderson BP, Bower JM (1992) Cholinergic modulation of cortical associative memory function. J Neurophysiol 67(5):1230–1246
Higley MJ, Picciotto MR (2014) Neuromodulation by acetylcholine: examples from schizophrenia and depression. Curr Opin Neurobiol 29C:88–95
Himmelheber AM, Sarter M, Bruno JP (2000) Increases in cortical acetylcholine release during sustained attention performance in rats. Brain Res Cogn Brain Res 9(3):313–325
Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull 35:549–562
Howe WM, Ji J, Parikh V, Williams S, Mocaer E, Trocme-Thibierge C, Sarter M (2010) Enhancement of attentional performance by selective stimulation of alpha 4 beta 2*nAChRs: underlying cholinergic mechanisms. Neuropsychopharmacology 35(6):1391–1401. doi:10.1038/npp.2010.9
Howe WM, Berry AS, Francois J, Gilmour G, Carp JM, Tricklebank M, Sarter M (2013) Prefrontal cholinergic mechanisms instigating shifts from monitoring for cues to cue-guided performance: converging electrochemical and fMRI evidence from rats and humans. J Neurosci 33(20):8742–8752. doi:10.1523/jneurosci.5809-12.2013
Jablensky A (2015) Schizophrenia or schizophrenias? The challenge of genetic parsing of a complex disorder. Am J Psychiatr 172(2):105–107. doi:10.1176/appi.ajp.2014.14111452
Javitt DC, Spencer KM, Thaker GK, Winterer G, Hajos M (2008) Neurophysiological biomarkers for drug development in schizophrenia. Nat Rev Drug Discov 7(1):68–83. doi:10.1038/nrd2463
Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Kapur S (2008) The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 33(3):473–479. doi:10.1038/sj.npp.1301437
Ji W, Gămănuţ R, Bista P, D’Souza RD, Wang Q, Burkhalter A (2015) Modularity in the organization of mouse primary visual cortex. Neuron 87:632–643
Jimura K, Locke HS, Braver TS (2010) Prefrontal cortex mediation of cognitive enhancement in rewarding motivational contexts. Proc Nat Acad Sci USA 107(19):8871–8876. doi:10.1073/pnas.1002007107
Kaiser S, Roth A, Rentrop M, Friederich H-C, Bender S, Weisbrod M (2008) Intra-individual reaction time variability in schizophrenia, depression and borderline personality disorder. Brain Cogn 66(1):73–82. doi:10.1016/j.bandc.2007.05.007
Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 27:1081–1090
Keefe RSE, Vinogradov S, Medalia A, Silverstein SM, Bell MD, Dickinson D, Stroup TS (2011) Report from the working group conference on multisite trial design for cognitive remediation in schizophrenia. Schizophr Bull 37(5):1057–1065. doi:10.1093/schbul/sbq010
Koch K, Wagner G, Schultz C, Schachtzabel C, Nenadic I, Axer M, Schloesser RGM (2009) Altered error-related activity in patients with schizophrenia. Neuropsychologia 47(13):2843–2849. doi:10.1016/j.neuropsychologia.2009.06.010
Koch K, Schachtzabel C, Wagner G, Schikora J, Schultz C, Reichenbach JR, Sauer H, Schlosser RGM (2010) Altered activation in association with reward-related trial-and-error activity in patients with schizophrenia. NeuroImage 50:223–232
Kogoj A, Pirtosek Z, Tomori M, Vodusek DB (2005) Event-related potentials elicited by distractors in an auditory oddball paradigm in schizophrenia. Psychiatry Res 137(1–2):49–59. doi:10.1016/j.psychres.2005.07.017
Kozak R, Bruno JP, Sarter M (2006) Augmented prefrontal acetylcholine release during challenged attentional performance. Cereb Cortex 16(1):9–17. doi:10.1093/cercor/bhi079
Kozak R, Martinez V, Young D, Brown H, Bruno JP, Sarter M (2007) Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia: disruption of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing, rats. Neuropsychopharmacology 32(10):2074–2086. doi:10.1038/sj.npp.1301352
Krebs M, Boehler N, Roberts C, Song W, Woldorff G (2012) The involvement of the dopaminergic midbrain and cortico-striatal-thalamic circuits in the integration of reward prospect and attentional task demands. Cereb Cortex 22:607–615
Kruse AC, Weiss DR, Rossi M, Hu J, Hu K, Eitel K, Shoichet BK (2013) Muscarinic receptors as model targets and antitargets for structure-based ligand discovery. Mol Pharmacol 84(4):528–540. doi:10.1124/mol.113.087551
Kucinski A, Sarter M (2015) Modeling parkinson’s disease falls associated with brainstem cholinergic systems decline. Behav Neurosci 129(2):96–104. doi:10.1037/bne0000048
Kucinski A, Paolone G, Bradshaw M, Albin RL, Sarter M (2013) Modeling fall propensity in parkinson’s disease: deficits in the attentional control of complex movements in rats with cortical-cholinergic and striatal-dopaminergic deafferentation. J Neurosci 33(42):16522–16539. doi:10.1523/jneurosci.2545-13.2013
Kucinski AJ, Koshy Cherian A, Valuskova P, Yegla B, Parikh V, Robinson T, Sarter M (2015) Prone to addiction as well as to falls: poor attention in sign-tracking rats extends to complex movement control and is associated with regression of choline transporter capacity. Society for Neuroscience Annual Meeting, Chicago, IL
Lambe EK, Picciotto MR, Aghajanian GK (2003) Nicotine induces glutamate release from thalamocortical terminals in prefrontal cortex. Neuropsychopharmacology 28(2):216–225. doi:10.1038/sj.npp.1300032
Laycock R, Crewther SG, Crewther DP (2007) A role for the ‘magnocellular advantage’ in visual impairments in neuro developmental and psychiatric disorders. Neurosci Biobehav Rev 31(3):363–376. doi:10.1016/j.neubiorev.2006.10.003
Leonard CJ, Robinson BM, Hahn B, Gold JM, Luck SJ (2014) Enhanced distraction by magnocellular salience signals in schizophrenia. Neuropsychologia 56:359–366. doi:10.1016/j.neuropsychologia.2014.02.011
Lesh TA, Niendam TA, Minzenberg MJ, Carter CS (2011) Cognitive control deficits in schizophrenia: mechanisms and meaning. Neuropsychopharmacology 36(1):316–338. doi:10.1038/npp.2010.156
Luck SJ, Gold JM (2008) The construct of attention in schizophrenia. Biol Psychiatry 64(1):34–39. doi:10.1016/j.biopsych.2008.02.014
Luck SJ, Ford JM, Sarter M, Lustig C (2012) CNTRICS final biomarker selection: control of attention. Schizophr Bull 38(1):53–61. doi:10.1093/schbul/sbr065
Lukatch HS, MacIver MB (1997) Physiology, pharmacology, and topography of cholinergic neocortical oscillations in vitro. J Neurophysiol 77(5):2427–2445
Lustig C, Jantz T (2015) Questions of age differences in interference control: When and how, not if? Brain Res 1612:59–69
Lustig C, Kozak R, Sarter M, Young JW, Robbins TW (2013) CNTRICS final animal model task selection: control of attention. Neurosci Biobehav Rev 37(9):2099–2110. doi:10.1016/j.neubiorev.2012.05.009
MacDonald SWS, Nyberg L, Backman L (2006) Intra-individual variability in behavior: links to brain structure, neurotransmission and neuronal activity. Trends Neurosci 29(8):474–480. doi:10.1016/j.tins.2006.06.011
Manoach DS (2003) Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res 60(2–3):285–298. doi:10.1016/s0920-9964(02)00294-3
Manoach DS, Press DZ, Thangaraj V, Searl MM, Goff DC, Halpern E, Warach S (1999) Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 45(9):1128–1137. doi:10.1016/s0006-3223(98)00318-7
Manoach DS, Gollub RL, Benson ES, Searl MM, Goff DC, Halpern E, Rauch SL (2000) Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 48(2):99–109. doi:10.1016/s0006-3223(00)00227-4
Markou A, Chiamulera C, Geyer MA, Tricklebank M, Steckler T (2009) Removing obstacles in neuroscience drug discovery: the future path for animal models. Neuropsychopharmacology 34(1):74–89. doi:10.1038/npp.2008.173
Markou A, Salamone JD, Bussey TJ, Mar AC, Brunnerd D, Gilmour G, Balsam P (2013) Measuring reinforcement learning and motivation constructs in experimental animals: relevance to the negative symptoms of schizophrenia. Neurosci Biobehav Rev 37(9):2149–2165. doi:10.1016/j.neubiorev.2013.08.007
Martinez V, Sarter M (2004) Lateralized attentional functions of cortical cholinergic inputs. Behav Neurosci 118(5):984–991. doi:10.1037/0735-7044.118.5.984
Mattay VS, Fera F, Tessitore A, Hariri AR, Berman KF, Das S, Weinberger DR (2006) Neurophysiological correlates of age-related changes in working memory capacity. Neurosci Lett 392(1–2):32–37. doi:10.1016/j.neulet.2005.09.025
Matthysse S, Levy DL, Wu YN, Rubin DB, Holzman P (1999) Intermittent degradation in performance in schizophrenia. Schizophr Res 40(2):131–146. doi:10.1016/s0920-9964(99)00038-9
McGaughy J, Sarter M (1995) Behavioral vigilance in rats—task validation and effects of age, amphetamine, and benzodiazepine receptor ligands. Psychopharmacology 117(3):340–357. doi:10.1007/bf02246109
McGaughy J, Sarter M (1999) Effects of ovariectomy, 192 IgG-saporin-induced cortical cholinergic deafferentatino, and administration of estradiol on sustained attention performance in rats. Behav Neurosci 113:1216–1232
Mechawar N, Cozzari C, Descarries L (2000) Cholinergic innervation in adult rat cerebral cortex: a quantitative immunocytochemical description. J Comp Neurol 428:305–318
Meltzer HY (2015) Pharmacotherapy of cognition in schizophrenia. Curr Opin Behav Sci 4:115–121
Mendelsohn A, Pine A, Schiller D (2014) Between thoughts and actions: motivationally salient cues invigorate mental action in the human brain. Neuron 207–217. DOI: 10.1016/j.neuron.2013.10.019
Meyer PJ, Lovic V, Saunders BT, Yager LM, Flagel SB, Morrow JD, Robinson TE (2012) Quantifying individual variation in the propensity to attribute incentive salience to reward cues. Plos One 7(6). doi:10.1371/journal.pone.0038987
Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC (2009) Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Arch Gen Psychiatry 66(8):811–822
Money TT, Scarr E, Udawela M, Gibbons AS, Jeon WJ, Seo MS, Dean B (2010) Treating schizophrenia: novel targets for the cholinergic system. Cns Neurol Disord Drug Targets 9(2):241–256
Muñoz W, Rudy B (2014) Spatiotemporal specificity in cholinergic control of neocortical function. Curr Opin Neurobiol 26C:149–160
Neigh GN, Arnold HM, Rabenstein RL, Sarter M, Bruno JP (2004) Neuronal activity in the nucleus accumbens is necessary for performance-related increases in cortical acetylcholine release. Neuroscience 123:635–645
Nelson CL, Sarter M, Bruno JP (2005) Prefrontal cortical modulation of acetylcholine release in posterior parietal cortex. Neuroscience 132:347–359
Newman EL, Gupta K, Climer JR, Monaghan CK, Hasselmo ME (2012) Cholinergic modulation of cognitive processing: insights drawn from computational models. Frontiers Behav Neurosci 6. doi:10.3389/fnbeh.2012.00024
Nielsen MO, Rostrup E, W S, Bak N, Broberg BV, Lublin H, Glenthoj B (2012) Improvement of brain reward abnormalities by antipsychotic monotherapy in schizophrenia. Arch Gen Psychiatry 69(12):1195–1204. doi:10.1001/archgenpsychiatry.2012.847
Nikolaus S, Hautzel H, Mueller H-W (2014) Neurochemical dysfunction in treated and nontreated schizophrenia—a retrospective analysis of in vivo imaging studies. Rev Neurosci 25(1):25–96. doi:10.1515/revneuro-2013-0063
Nuechterlein KH, Dawson ME (1984) Information-processing and attentional functioning in the developmental course of schizophrenic disorders. Schizophr Bull 10(2):160–203
Nuechterlein KH, Luck SJ, Lustig C, Sarter M (2009) CNTRICS final task selection: control of attention. Schizophr Bull 35(1):182–196. doi:10.1093/schbul/sbn158
O’Connell RG, Dockree PM, Robertson IH, Bellgrove MA, Foxe JJ, Kelly SP (2009) Uncovering the neural signature of lapsing attention: electrophysiological signals predict errors up to 20s before they occur. J Neurosci 29(26):8604–8611. doi:10.1523/jneurosci.5967-08.2009
Paolone G, Angelakos CC, Meyer PJ, Robinson TE, Sarter M (2013a) Cholinergic control over attention in rats prone to attribute incentive salience to reward cues. J Neurosci 33:8321–8335
Paolone G, Mallory CS, Cherian AK, Miller TR, Blakely RD, Sarter M (2013b) Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: a model of cholinergic capacity limits. Neuropharmacology 75:274–285
Parikh V, Kozak R, Martinez V, Sarter M (2007) Prefrontal acetylcholine release controls cue detection on multiple timescales. Neuron 56(1):141–154. doi:10.1016/j.neuron.2007.08.025
Parikh V, Man K, Decker MW, Sarter M (2008) Glutamatergic contributions to nicotinic acetylcholine receptor agonist-evoked cholinergic transients in the prefrontal cortex. J Neurosci 28(14):3769–3780. doi:10.1523/jneurosci.5251-07.2008
Parikh V, Ji J, Decker MW, Sarter M (2010) Prefrontal beta 2 subunit-containing and alpha 7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling. J Neurosci 30(9):3518–3530. doi:10.1523/jneurosci.5712-09.2010
Parikh V, Peters MS, Blakely RD, Sarter M (2013) The presynaptic choline transporter imposes limits on sustained cortical acetylcholine release and attention. J Neurosci 33(6):2326–2337. doi:10.1523/jneurosci.4993-12.2013
Parry AMM, Scott RB, Palace J, Smith S, Matthews PM (2003) Potentially adaptive functional changes in cognitive processing for patients with multiple sclerosis and their acute modulation by rivastigmine. Brain 126:2750–2760. doi:10.1093/brain/awg284
Peters MS, Demeter E, Lustig C, Bruno JP, Sarter M (2011) Enhanced control of attention by stimulating mesolimbic-corticopetal cholinergic circuitry. J Neurosci 31(26):9760–9771. doi:10.1523/jneurosci.1902-11.2011
Picciotto MR, Higley MJ, Mineur YS (2012) Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron 76(1):116–129. doi:10.1016/j.neuron.2012.08.036
Raizada RDS, Poldrack RA (2007) Challenge-driven attention: interacting frontal and brainstem systems. Frontiers Hum Neurosci 1:3. doi:10.3389/neuro.09.003.2007
Reinhart RMG, Zhu J, Park S, Woodman GF (2015) Synchronizing theta oscillations with direct-current stimulation strengthens adaptive control in the human brain. Proc Nat Acad Sci USA 112(30):9448–9453. doi:10.1073/pnas.1504196112
Reuter-Lorenz PA, Lustig C (2005) Brain aging: reorganizing discoveries about the aging mind. Curr Opin Neurobiol 15(2):245–251. doi:10.1016/j.conb.2005.03.016
Reuter-Lorenz PA, Cappell KA (2008) Neurocognitive aging and the compensation hypothesis. Curr Dir Psychol Sci 17(3):177–182. doi:10.1111/j.1467-8721.2008.00570.x
Riedel G, Platt B, van der Zee E (eds) (2015) Special issue of brain research: the cholinergic system and brain function. Brain Res 221
Robbins TW (2002) The 5-choice serial reaction time task: behavioural pharmacology and functional neurochemistry. Psychopharmacology 163(3–4):362–380. doi:10.1107/s00213-002-1154-7
Robinson L, Platt B, Riedel G (2011) Involvement of the cholinergic system in conditioning and perceptual memory. Behav Brain Res 221(2):443–465. doi:10.1016/j.bbr.2011.01.055
Roche MW, Silverstein SW, Lenzenweger MF (2015) Intermittent degradation and schizotypy. Schizophr Res Cogn 2:100–104
Roschke J, Wagner P, Mann K, Fell J, Grozinger M, Frank C (1996) Single trial analysis of event related potentials: a comparison between schizophrenics and depressives. Biol Psychiatry 40(9):844–852. doi:10.1016/0006-3223(95)00652-4
Ross RG, Stevens KE, Proctor WR, Leonard S, Kisley MA, Hunter SK, Adams CE (2010) Research review: cholinergic mechanisms, early brain development, and risk for schizophrenia. J Child Psychol Psychiatry 51(5):535–549. doi:10.1111/j.1469-7610.2009.02187.x
Roth A, Roesch-Ely D, Bender S, Weisbrod M, Kaiser S (2007) Increased event-related potential latency and amplitude variability in schizophrenia detected through wavelet-based single trial analysis. Int J Psychophysiol 66(3):244–254. doi:10.1016/j.ijpsycho.2007.08.005
Rowe AR, Mercer L, Casetti V, Sendt K-V, Giaroli G, Shergill SS, Tracy DK (2015) Dementia praecox redux: a systematic review of the nicotinic receptor as a target for cognitive symptoms of schizophrenia. J Psychopharmacol 29(2):197–211. doi:10.1177/0269881114564096
Sahakian BJ, Jones G, Levy R, Gray J, Warburton D (1989) The effects of nicotine on attention, information processing, and short-term memory in patients with dementia of the Alzheimer type. Br J Psychiatr 154(6):797–800. doi:10.1192/bjp.154.6.797
Sahakian BJ, Owen AM, Morant NJ, Eagger SA, Boddington S, Crayton L, Levy R (1993) Further analysis of the cognitive effects of tetrahydroaminoacridine (tha) in alzheimers-disease—assessment of attentional and mnemonic function using cantab. Psychopharmacology 110(4):395–401. doi:10.1007/bf02244644
Sarter M (2015) Behavioral-cognitive targets for cholinergic enhancement. Curr Opin Behav Sci 4:22–26
Sarter M, Tricklebank M (2012) Revitalizing psychiatric drug discovery. Nat Rev Drug Discov 11(6):423–424. doi:10.1038/nrd3755
Sarter M, Nelson CL, Bruno JP (2005) Cortical cholinergic transmission and cortical information processing in schizophrenia. Schizophr Bull 31(1):117–138. doi:10.1093/schbul/sbi006
Sarter M, Gehring WJ, Kozak R (2006) More attention must be paid: the neurobiology of attentional effort. Brain Res Rev 51(2):145–160. doi:10.1016/j.brainresrev.2005.11.002
Sarter M, Martinez V, Kozak R (2009a) A neurocognitive animal model dissociating between acute illness and remission periods of schizophrenia. Psychopharmacology 202(1–3):237–258. doi:10.1007/s00213-008-1216-6
Sarter M, Parikh V, Howe WM (2009b) PERSPECTIVES phasic acetylcholine release and the volume transmission hypothesis: time to move on. Nat Rev Neurosci 10(5):383–386. doi:10.1038/nrn2635
Sarter M, Lustig C, Taylor SF (2012) Cholinergic contributions to the cognitive symptoms of schizophrenia and the viability of cholinergic treatments. Neuropharmacology 62(3):1544–1553. doi:10.1016/j.neuropharm.2010.12.001
Sarter M, Lustig C, Howe WM, Gritton H, Berry AS (2014) Deterministic functions of cortical acetylcholine. Eur J Neurosci 39(11):1912–1920. doi:10.1111/ejn.12515
Sarter M, Howe WM, Gritton H (2015) Cortical cholinergic transients for cue detection and attentional mode shifts. In: Wilson GS, Michael AC (eds) Compendium of in vivo monitoring in real-time molecular neuroscience. World Scientific, Singapore, pp 27–44
Saunders BT, Robinson TE (2012) The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses. Eur J Neurosci 36(4):2521–2532. doi:10.1111/j.1460-9568.2012.08217.x
Scarr E, Cowie TF, Kanellakis S, Sundram S, Pantelis C, Dean B (2009) Decreased cortical muscarinic receptors define a subgroup of subjects with schizophrenia. Mol Psychiatr 14(11):1017–1023. doi:10.1038/mp.2008.28
Schneider-Garces NJ, Gordon BA, Brumback-Peltz CR, Shin E, Lee Y, Sutton BP, Fabiani M (2010) Span, CRUNCH, and beyond: working memory capacity and the aging brain. J Cogn Neurosci 22(4):655–669. doi:10.1162/jocn.2009.21230
Scognamiglio C, Houenou J (2014) A meta-analysis of fMRI studies in healthy relatives of patients with schizophrenia. Aust N Z J Psychiatr 48(10):907–916. doi:10.1177/0004867414540753
Sebastian A, Baldermann C, Feige B, Katzev M, Scheller E, Hellwig B, Kloeppel S (2013) Differential effects of age on subcomponents of response inhibition. Neurobiol Aging 34(9):2183–2193. doi:10.1016/j.neurobiolaging.2013.03.013
Seo MS, Scarr E, Dean B (2014) An investigation of the factors that regulate muscarinic receptor expression in schizophrenia. Schizophr Res 158(1–3):247–254. doi:10.1016/j.schres.2014.06.039
Sesack SR, Grace AA (2010) Cortico-basal ganglia reward network: microcircuitry. Neuropsychopharmacology 35:27–47
Shoshina II, Shelepin YE, Semenova NB (2014) Frequency-contrast sensitivity of visual stimulus perception in patients with schizophrenia treated with atypical and typical antipsychotics. Hum Physiol 40(1):35–39. doi:10.1134/s0362119714010150
Silverstein SM, Matteson S, Knight RA (1996) Reduced top-down influence in auditory perceptual organization in schizophrenia. J Abnorm Psychol 105(4):663–667
Skottun BC, Skoyles JR (2007) Contrast sensitivity and magnocellular funciton in schizophrenia. Vision Res 47:2923–2933
Small DM, Gitelman D, Simmons K, Bloise SM, Parrish T, Mesulam MM (2005) Monetary incentives enhance processing in brain regions mediating top-down control of attention. Cereb Cortex 15:1855–1865
Smiley JF, Subramanian M, Mesulam MM (1999) Monoaminergic-cholinergic interactions in the primate basal forebrain. Neuroscience 93:817–829
Theeuwes J (1992) Perceptual selectivity for color and form. Percept Psychophys 51(6):599–606. doi:10.3758/bf03211656
Thiele A (2013) Muscarinic signaling in the brain. Annu Rev Neurosci 36(36):271–294. doi:10.1146/annurev-neuro-062012-170433
Torgalsboen A-K, Mohn C, Rund BR (2014) 2 Neurocognitive predictors of remission of symptoms and social and role functioning in the early course of first-episode schizophrenia. Psychiatr Res 216(1):1–5. doi:10.1016/j.psychres.2014.01.031
Torgalsboen A-K, Mohn C, Czajkowski N, Rund BR (2015) Relationship between neurocognition and functional recovery in first-episode schizophrenia: results from the second year of the Oslo multi-follow-up study. Psychiatr Res 227(2–3):185–191. doi:10.1016/j.psychres.2015.03.037
Umbriaco D, Watkins KC, Descarries L, Cozzari C, Hartman BK (1994) Ultrastructural and morphometric features of the acetylcholine innervation in adult rat parietal cortex: an electron microscopic study in serial sections. J Comp Neurol 348:351–373
Van Snellenberg JX, Torres IJ, Thornton AE (2006) Functional neuroimaging of working memory in schizophrenia: task performance as a moderating variable. Neuropsychology 20(5):497–510. doi:10.1037/0894-4105.20.5.497.supp
Van Snellenberg JX, Girgis RR, Read C, Thompson JL, Weber J, Wager TD, Slifstein M, Lieberman JA, Abi-Dargham A, Smith EE (2013) Individuals with schizophrenia fail to show normative inverted-U activation in response to fine-grained working memory load manipulation. Schizophr Bull 39:S251–S252 (Abstract)
Van Snellenberg JX, Slifstein M, Read C, Weber J, Thompson JL, Wager TD, Smith EE (2015) Dynamic shifts in brain network activation during supracapacity working memory task performance. Hum Brain Mapp 36(4):1245–1264. doi:10.1002/hbm.22699
Watanabe M, Sakagami M (2007) Integration of cognitive and motivational context information in the primate prefrontal cortex. Cereb Cortex 17:I101–I109. doi:10.1093/cercor/bhm067
Weinberger DR, Harrison P (2011) Schizophrenia, 3rd edn. Wiley, New York
Wohlberg GW, Kornetsk C (1973) Sustained attention in remitted schizophrenics. Arch Gen Psychiatr 28(4):533–537
Wolkin A, Sanfilipo M, Wolf AP, Angrist B, Brodie JD, Rotrosen J (1992) Negative symptoms and hypofrontality in chronic schizophrenia. Arch Gen Psychiatr 49(12):959–965
Wong EHF, Yocca F, Smith MA, Lee C-M (2010) Challenges and opportunities for drug discovery in psychiatric disorders: the drug hunters’ perspective. Int J Neuropsychopharmacol 13(9):1269–1284. doi:10.1017/s1461145710000866
Xiang Z, Huguenard JR, Prince DA (1998) Cholinergic switching within neocortical inhibitory networks. Science 281:985–988
Young JW, Markou A (2015) Translational rodent paradigms to investigate neuromechanisms underlying behaviors relevant to amotivation and altered reward processing in schizophrenia. Schizophr Bull 41(5):1024–1034. doi:10.1093/schbul/sbv093
Young JW, Light GA, Marston HM, Sharp R, Geyer MA (2009) The 5-choice continuous performance test: evidence for a translational test of vigilance for mice. Plos One 4(1). doi:10.1371/journal.pone.0004227
Young JW, Zhou X, Geyer MA (2010) Animal models of schizophrenia. In: Swerdlow NR (ed) Behavioral neurobiology of schizophrenia and its treatment, vol 4, pp 391–433
Zaborszky L, Cullinan WE (1992) Projections from the nucleus accumbens to cholinergic neurons of the ventral pallidum: a correlated light and electron microscopic double-immunolabeling study in rat. Brain Res 570:92–101
Zaborszky L, Cullinan WE (1996) Direct catecholaminergic-cholinergic interactions in the basal forebrain. I. Dopamine-β-hydroxylase-and tyrosine hydroxylase input to cholinergic neurons. J Comp Neurol 374:535–554
Zaborszky L, Gaykema RP, Swanson DJ, Cullinan WE (1997) Cortical input to the basal forebrain. Neuroscience 79:1051–1078
Zaborszky L, Buhl DL, Pobalashingham S, Bjaalie JG, Nadasdy Z (2005) Three-dimensional chemoarchitecture of the basal forebrain: spatially specific association of cholinergic and calcium binding protein-containing neurons. Neuroscience 136:697–713
Zaborszky L, Hoemke L, Mohlberg H, Schleicher A, Amunts K, Zilles K (2008) Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain. Neuroimage 42:1127–1141
Zaborszky L, van den Pol A, Gyengesi E (2012) The basal forebrain cholinergic projection system in mice. In: The mouse nervous system. Elsevier, Pennsylvania, pp 684–718
Zaborszky L, Csordas A, Mosca K, Kim J, Gielow MR, Vadasz C, Nadasdy Z (2015a) Neurons in the basal forebrain project to the cortex in a complex topographic organization that reflects corticocortical connectivity patterns: an experimental study based on retrograde tracing and 3D reconstruction. Cereb Cortex 25:118–137
Zaborszky L, Duque A, Gielow M, Gombkoto P, Nadasdy Z, Somogyi J (2015b) Organization of the basal forebrain cholinergic projection system: specific or diffuse? In: Paxinos G (ed) The Rat Nervous System. Academic Press, San Diego, pp 491–507
Acknowledgments
The authors’ research was supported by PHS grants MH086530, MH101697, MH093888, DA031656, DA032259, NS091856, and NS078435. We thank Jessica Nicosia and Rohith Pentaparthy for assistance in preparing Fig. 3. We also thank Barbara Sahakian and Trevor Robbins for their comments on an earlier manuscript draft.
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Lustig, C., Sarter, M. (2015). Attention and the Cholinergic System: Relevance to Schizophrenia. In: Robbins, T.W., Sahakian, B.J. (eds) Translational Neuropsychopharmacology. Current Topics in Behavioral Neurosciences, vol 28. Springer, Cham. https://doi.org/10.1007/7854_2015_5009
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