Global and local fMRI signals driven by neurons defined optogenetically by type and wiring - PubMed (original) (raw)

Global and local fMRI signals driven by neurons defined optogenetically by type and wiring

Jin Hyung Lee et al. Nature. 2010.

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.

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Conflict of interest statement

COMPETING FINANCIAL INTERESTS

The authors declare that they have no competing financial interests.

Figures

Figure 1

Figure 1. ofMRI: optogenetic excitation of CaMKIIα neocortical cells drives local positive BOLD

a, Transduced cells (triangles), light, and locations (1..9) of coronal slices. b, Confocal images of ChR2-EYFP expression in M1 (left); higher magnification (right). c, Optrode recordings during 473nm optical stimulation (20 Hz/15 ms pulsewidth; blue); spiking is significantly elevated (two-sample t-test; p<0.001; n=3). d, BOLD activation observed with AAV5-CaMKIIα::ChR2-EYFP but not with saline injection (p<0.001; asterisk: optical stimulation). e, Left, ofMRI hemodynamic response (averaged across activated voxels in motor cortex) during 20s (n=3) and 30s (n=8) optical stimuli. Right, Mean over stimulus repetitions; baseline: mean pre-stimulation signal.

Figure 2

Figure 2. Nonlocal mapping of causal role of cells defined by location and genetic identity

a, AAV5-CaMKIIα::ChR2-EYFP injection and optical stimulation in M1. Slices in (c): “1” and “2”. b, Fluorescence/bright-field: ChR2-EYFP in thalamus (left); confocal image reveals expression limited to axons. c, Thalamic ofMRI during M1 optical stimulation (top); superimposed on Paxinos atlas (bottom). d, ofMRI-HRF summary. e, M1 optrode and thalamic electrode. f, Thalamic spiking follows M1 optical stimulation; delay consistent with BOLD. g, Typical M1 and thalamus spikes with M1 optical excitation. h, M1 and thalamus spiking summary (two-sample t-test; p<0.001; n=5). i, Spike-frequency time histograms.

Figure 3

Figure 3. Control of cells defined by location, genetic identity, and wiring during ofMRI

a, M1 injection of AAV5-CaMKIIα::ChR2-EYFP and optical stimulation of thalamus. Coronal slices shown in (c) marked as “1..6” and “7..12”. b, ChR2 expression pattern confirming expression in cortical neurons (left) and cortico-thalamic projections (right; see also Supplementary Fig. 5). c, BOLD ofMRI data obtained in thalamus (above) and cortex (below). d, ofMRI-HRF for cortical (gray) and thalamic (black) BOLD signals elicited by optical stimulation of cortico-thalamic fibers in thalamus. Both ofMRI-HRFs ramp slowly by comparison with intracortical results in Figure 1.

Figure 4

Figure 4. Recruitment of bilateral cortices by anterior thalamus

a, Thalamic injection of AAV5-CaMKIIα::ChR2-EYFP and posterior/anterior optical stimulation. Coronal slices marked “A1...A12” and “B1...B12”. b, Fluorescence overlaid onto bright-field (left) and confocal image (right) illustrating transduction in thalamus (left) and cortical projections in internal and external capsule (right). c, Posterior thalamus stimulation-evoked ofMRI signal in ipsilateral thalamus and somatosensory cortex. d, ofMRI-HRFs. Excited volumes: 5.5±1.3mm3 (thalamus); 8.6±2.5mm3 (somatosensory cortex) (n=3). e, Anterior thalamus stimulation-evoked ofMRI signal in ipsilateral thalamus and bilateral motor cortex. f, ofMRI-HRFs. Excited volumes: 1.5mm3 (thalamus); 10.1mm3 (ipsilateral cortex); 3.7mm3 (contralateral cortex).

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