title: Global and local fMRI signals driven by neurons defined optogenetically by type and wiring.
abstract: Despite a rapidly-growing scientific and clinical brain imaging literature based on functional magnetic resonance imaging (fMRI) using blood oxygenation level-dependent (BOLD) signals, it remains controversial whether BOLD signals in a particular region can be caused by activation of local excitatory neurons. This difficult question is central to the interpretation and utility of BOLD, with major significance for fMRI studies in basic research and clinical applications. Using a novel integrated technology unifying optogenetic control of inputs with high-field fMRI signal readouts, we show here that specific stimulation of local CaMKIIalpha-expressing excitatory neurons, either in the neocortex or thalamus, elicits positive BOLD signals at the stimulus location with classical kinetics. We also show that optogenetic fMRI (of MRI) allows visualization of the causal effects of specific cell types defined not only by genetic identity and cell body location, but also by axonal projection target. Finally, we show that of MRI within the living and intact mammalian brain reveals BOLD signals in downstream targets distant from the stimulus, indicating that this approach can be used to map the global effects of controlling a local cell population. In this respect, unlike both conventional fMRI studies based on correlations and fMRI with electrical stimulation that will also directly drive afferent and nearby axons, this of MRI approach provides causal information about the global circuits recruited by defined local neuronal activity patterns. Together these findings provide an empirical foundation for the widely-used fMRI BOLD signal, and the features of of MRI define a potent tool that may be suitable for functional circuit analysis as well as global phenotyping of dysfunctional circuitry.
authors.affiliation: Department of Electrical Engineering, Psychiatry and Biobehavioral Sciences, Bioengineering, and Radiology, University of California, Los Angeles, California 90095, USA. ljinhy@gmail.com
authors.forename: Jin Hyung
authors.initials: JH
authors.lastname: Lee
authors.forename: Remy
authors.initials: R
authors.lastname: Durand
authors.forename: Viviana
authors.initials: V
authors.lastname: Gradinaru
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.forename: Inbal
authors.initials: I
authors.lastname: Goshen
authors.forename: Dae-Shik
authors.initials: DS
authors.lastname: Kim
authors.forename: Lief E
authors.initials: LE
authors.lastname: Fenno
authors.forename: Charu
authors.initials: C
authors.lastname: Ramakrishnan
authors.forename: Karl
authors.initials: K
authors.lastname: Deisseroth
mesh_terms: D000200:Action Potentials / Q000528:radiation effects; D000758:Anesthesia; D000818:Animals; D001921:Brain / Q000033:anatomy & histology / Q000098:blood supply / Q000166:cytology* / Q000528:radiation effects*; D002560:Cerebrovascular Circulation / Q000528:radiation effects; D000460:Chlorophyta; D008163:Luminescent Measurements; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D009044:Motor Cortex / Q000098:blood supply / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D009434:Neural Pathways / Q000528:radiation effects*; D009474:Neurons / Q000145:classification / Q000166:cytology / Q000378:metabolism* / Q000528:radiation effects*; D010100:Oxygen / Q000097:blood / Q000378:metabolism; D010775:Photic Stimulation; D051381:Rats; D012243:Rhodopsin / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects; D013788:Thalamus / Q000098:blood supply / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects
chemical_list: D008164:Luminescent Proteins; D012243:Rhodopsin; D010100:Oxygen
references.citation: J Neural Eng. 2007 Sep;4(3):S143-56
references.pmid: 17873414
references.citation: Nature. 2008 Jun 12;453(7197):869-78
references.pmid: 18548064
references.citation: Cereb Cortex. 2009 Sep;19(9):2065-77
references.pmid: 19174446
references.citation: Proc Natl Acad Sci U S A. 1992 Jul 1;89(13):5951-5
references.pmid: 1631079
references.citation: Nat Neurosci. 2005 Sep;8(9):1263-8
references.pmid: 16116447
references.citation: Nat Neurosci. 2008 May;11(5):523-4; author reply 524
references.pmid: 18437185
references.citation: Philos Trans R Soc Lond B Biol Sci. 1999 Jul 29;354(1387):1195-213
references.pmid: 10466146
references.citation: Nat Rev Neurosci. 2007 Aug;8(8):577-81
references.pmid: 17643087
references.citation: Magn Reson Med. 1995 May;33(5):624-35
references.pmid: 7596266
references.citation: Nature. 2001 Jul 12;412(6843):150-7
references.pmid: 11449264
references.citation: Neuron. 2002 Oct 10;36(2):193-8
references.pmid: 12383776
references.citation: Nature. 2007 Apr 5;446(7136):633-9
references.pmid: 17410168
references.citation: J Physiol. 1991;440:735-69
references.pmid: 1666655
references.citation: Magn Reson Med. 2008 May;59(5):1099-110
references.pmid: 18421687
references.citation: J Neurosci. 2006 Oct 11;26(41):10380-6
references.pmid: 17035522
references.citation: Nat Methods. 2006 Oct;3(10):785-92
references.pmid: 16990810
references.citation: Nat Protoc. 2010 Mar;5(3):439-56
references.pmid: 20203662
references.citation: J Neurosci. 2004 Oct 13;24(41):8940-9
references.pmid: 15483113
references.citation: Nature. 2009 Jan 22;457(7228):475-9
references.pmid: 19158795
references.citation: Magn Reson Med. 1998 Jun;39(6):855-64
references.pmid: 9621908
references.citation: Cell. 2010 Apr 2;141(1):154-165
references.pmid: 20303157
references.citation: J Comp Neurol. 2008 Sep 1;510(1):100-16
references.pmid: 18615539
references.citation: Magn Reson Med. 2006 Dec;56(6):1261-73
references.pmid: 17075857
references.citation: J Neurosci. 1996 Jul 1;16(13):4207-21
references.pmid: 8753882
references.citation: Science. 2009 Apr 17;324(5925):354-9
references.pmid: 19299587
references.citation: Cereb Cortex. 2007 Apr;17(4):942-50
references.pmid: 16731882
references.citation: Nat Rev Neurosci. 2005 Jan;6(1):77-85
references.pmid: 15611729
references.citation: Magn Reson Med. 2003 Dec;50(6):1276-85
references.pmid: 14648576
references.citation: Nature. 2009 Jun 4;459(7247):698-702
references.pmid: 19396159