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      Two distinct profiles of fMRI and neurophysiological activity elicited by acetylcholine in visual cortex

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          fMRI changes are typically assumed to be due to changes in neural activity, although whether this remains valid under the influence of neuromodulators is relatively unknown. Here, we found evidence that intracortical acetylcholine elicits distinct profiles of fMRI and electrophysiological activity in visual cortex. Two patterns of cholinergic activity were observed, depending on the distance to the injection site, although neurovascular coupling was preserved. Our results illustrate the effects of neuromodulators on fMRI and electrophysiological responses and show that these depend on neuromodulator concentration and kinetics.

          Abstract

          Cholinergic neuromodulation is involved in all aspects of sensory processing and is crucial for processes such as attention, learning and memory, etc. However, despite the known roles of acetylcholine (ACh), we still do not how to disentangle ACh contributions from sensory or task-evoked changes in functional magnetic resonance imaging (fMRI). Here, we investigated the effects of local injection of ACh on fMRI and neural signals in the primary visual cortex (V1) of anesthetized macaques by combining pharmaco-based MRI (phMRI) with electrophysiological recordings, using single electrodes and electrode arrays. We found that local injection of ACh elicited two distinct profiles of fMRI and neurophysiological activity, depending on the distance from the injector. Near the injection site, we observed an increase in the baseline blood oxygen-level-dependent (BOLD) and cerebral blood flow (CBF) responses, while their visual modulation decreased. In contrast, further from the injection site, we observed an increase in the visually induced BOLD and CBF modulation without changes in baseline. Neurophysiological recordings suggest that the spatial correspondence between fMRI responses and neural activity does not change in the gamma, high-gamma, and multiunit activity (MUA) bands. The results near the injection site suggest increased inhibitory drive and decreased metabolism, contrasting to the far region. These changes are thought to reflect the kinetics of ACh and its metabolism to choline.

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          Most cited references81

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          Cholinergic innervation of cortex by the basal forebrain: cytochemistry and cortical connections of the septal area, diagonal band nuclei, nucleus basalis (substantia innominata), and hypothalamus in the rhesus monkey.

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            Basal Forebrain Activation Enhances Cortical Coding of Natural Scenes

            The nucleus basalis (NB) of the basal forebrain is an essential component of the neuromodulatory system controlling the behavioral state of an animal, and it is thought to play key roles in regulating arousal and attention. However, the effect of NB activation on sensory processing remains poorly understood. Using polytrode recording in rat visual cortex, we show that NB stimulation causes prominent decorrelation between neurons and marked improvement in the reliability of neuronal responses to natural scenes. The decorrelation depends on local activation of cortical muscarinic acetylcholine receptors, while the increased reliability involves distributed neural circuits, as evidenced by NB-induced changes in thalamic responses. Further analysis showed that the decorrelation and increased reliability improve cortical representation of natural stimuli in a complementary manner. Thus, the basal forebrain neuromodulatory circuit, which is known to be activated during aroused and attentive states, acts through both local and distributed mechanisms to improve sensory coding.
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              Fast Modulation of Visual Perception by Basal Forebrain Cholinergic Neurons

              The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. Optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhanced visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.
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                Author and article information

                Journal
                Proc Natl Acad Sci U S A
                Proc. Natl. Acad. Sci. U.S.A
                pnas
                pnas
                PNAS
                Proceedings of the National Academy of Sciences of the United States of America
                National Academy of Sciences
                0027-8424
                1091-6490
                18 December 2018
                3 December 2018
                3 December 2018
                : 115
                : 51
                : E12073-E12082
                Affiliations
                [1] aDepartment Physiology of Cognitive Processes, Max Planck Institute for Biological Cybernetics , D-72076 Tübingen, Germany;
                [2] bCentre for Imaging Sciences, University of Manchester , M13 9PT Manchester, United Kingdom;
                [3] cInstitute of Neuroscience and Psychology, School of Psychology, University of Glasgow , G12 8QB Glasgow, United Kingdom
                Author notes
                1To whom correspondence should be addressed. Email: Daniel.Zaldivar@ 123456tuebingen.mpg.de .

                Edited by Marcus E. Raichle, Washington University in St. Louis, St. Louis, MO, and approved November 6, 2018 (received for review May 18, 2018)

                Author contributions: D.Z., A.R., and N.K.L. designed research; D.Z., A.R., and J.G. performed research; D.Z., N.K.L., and J.G. contributed new reagents/analytic tools; D.Z. analyzed data; D.Z. and J.G. wrote the paper; and N.K.L. and J.G. supervised the research.

                2Present address: Section on Cognitive Neurophysiology and Imaging, National Institute of Mental Health, Bethesda, MD 20892.

                Author information
                http://orcid.org/0000-0002-6838-355X
                Article
                201808507
                10.1073/pnas.1808507115
                6304994
                30510000
                f03a9c64-b6e0-406f-b178-b1b73f257cc0
                Copyright © 2018 the Author(s). Published by PNAS.

                This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

                History
                Page count
                Pages: 10
                Funding
                Funded by: Max-Planck-Gesellschaft (MPG) 501100004189
                Award ID: Max-Planck-Institut für biologische Kybernetik
                Award Recipient : Daniel Zaldivar Award Recipient : Alexander Rauch Award Recipient : Nikos K. Logothetis Award Recipient : Jozien Goense
                Funded by: Deutsche Forschungsgemeinschaft (DFG) 501100001659
                Award ID: ZA991/1-1; 392021668
                Award Recipient : Daniel Zaldivar
                Categories
                PNAS Plus
                Biological Sciences
                Neuroscience
                PNAS Plus

                bold-fmri,cbf-fmri,nonhuman primate,electrophysiology,visual cortex

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