Arousal responses linked to locus coeruleus noradrenergic (LC-NA) activity affect cognition. However, the mechanisms that control modes of LC-NA activity remain unknown. Here, we reveal a local population of GABAergic neurons (LC-GABA) capable of modulating LC-NA activity and arousal. Retrograde tracing shows that inputs to LC-GABA and LC-NA neurons arise from similar regions, though a few regions provide differential inputs to one subtype over the other. Recordings in the locus coeruleus demonstrate two modes of LC-GABA responses whereby spiking is either correlated or broadly anticorrelated with LC-NA responses, reflecting anatomically similar and functionally coincident inputs, or differential and non-coincident inputs, to LC-NA and LC-GABA neurons. Coincident inputs control the gain of LC-NA-mediated arousal responses, whereas non-coincident inputs, such as from the prefrontal cortex to the locus coeruleus, alter global arousal levels. These findings demonstrate distinct modes by which an inhibitory locus coeruleus circuit regulates arousal in the brain.
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We thank I. Wickersham (Massachusetts Institute of Technology) for his gift of the AAV helpers and dG-Rabies virus used for monosynaptic tracing. We thank V. Pham and L. Gunter for technical assistance on histology experiments. We thank S. Flavell, A. Bari, R. Huda, G. Sipe, and other members of the Sur laboratory for helpful comments. This work was supported by NIH grants EY007023 (M.S.), EY028219 (M.S.), and NS090473 (M.S.), and postdoctoral fellowships from FRQS (31677) and NSERC (PDF-48724-2016) (V.B.-P.).
The authors declare no competing interests.
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Integrated supplementary information
Supplementary Figure 1 Injection of Cre-dependent virus in the LC of Gad2-IRES-Cre mice targets inhibitory neurons that contact LC-NA neurons.
a–d, Confocal images of fixed coronal sections of the LC of Cre-dependent Flox-mCherry-injected Gad2-Cre mice. Gad2-mCherry-positive neurons were colabeled for GABA (a), GAD67 (b), TH (c), and neuropeptide S (NPS) (d) as revealed by immunohistochemistry techniques. e, Distribution of the proportion of Gad-mCherry-expressing neurons colocalizing with different neuronal markers of the LC. Experiments in a–e were repeated in n = 17, 13, 18, and 5 fields of view from N = 5, 2, 5, and 2 mice for GABA, GAD67, TH, and NPS conditions, respectively. Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+). f, Gad2-Cre mice were injected with AAV-Flex-tdTomato virus to infect LC-GABA neurons. Coronal slices were stained for TH to reveal the location of LC-NA somas. g, Example from the boxed area in f of an axon from a tdTomato-expressing LC-GABA neuron apposed to a TH-expressing soma in the LC (arrow). Staining against VGAT reveals the presence of presynaptic GABAergic terminals. Similar results were found in ten fields of view from slices from two mice. Scale bars, 50 μm (a–d), 100 μm (f), and 5 μm (g).
a, (Top) AAV-Flex-GCaMP6s virus was injected in TH-Cre mice and a cranial window was implanted over either visual cortex or PFC. (Bottom) Four weeks after injection, we imaged the calcium activity of NA+ axons in the cortex using two-photon microscopy. b, Example traces of simultaneous recording of pupil size and NA axon GCaMP6s activity in the visual cortex (axon 1) or PFC (axon 2). c, Cumulative probability distribution of all of the Pearson correlation coefficients of NA axon responses with pupil size. Pearson correlation coefficients less in the gray area are non-significant (P <0.05). n = 31 axons in 5 mice in c–f. d, Raster plot of NA axon responses aligned to pupil dilation onset. Note the increase in activity during pupil dilation. e, Population average of the NA activity during pupil dilation for all recorded axons. f, Normalized cross-correlation values for different lag times between axon activity and pupil dilation. The dashed line indicates mean delay between axon and pupil. g, Raster plot of the activity of a LC-NA photo-tagged unit aligned to pupil dilation. The bottom trace displays the session average for spike rate and pupil size. h, Average increase in activity for 19 LC-NA photo-tagged units. The average firing activity of LC-NA neurons before pupil dilation is 6.5 ± 0.8 Hz. Data displayed as mean ± s.e.m.
a, Simultaneous recordings of pupil size and movement of ears, paws, neck, and nose for an example mouse. The average of all four movement traces is shown in the average movement trace. Quiet (red) and active (white) periods of movement were isolated using a threshold of the average movement trace. b, Methods to evaluate mouse movements. Regions of interest were drawn around each body part and the movement was extracted by pixel analysis. We calculated the average difference in pixel value for each frame, normalized by the reference region of interest. c, Example cumulative histogram comparing pupil size distribution of active and quiet epochs of movement. d,e, Average and standard deviation of pupil size are larger during active epochs (***P = 0.00099 and **P = 0.0085 using a two-tailed paired t-test with t4 = −9.89 and t4 = −4.83 values, respectively). f, Normalized cross-correlation of pupil versus movement. We observed an increase in movement preceding pupil dilation. N = 5 mice for d–f.
Supplementary Figure 4 Pupil dilation following LC-NA neuron activation depends on the baseline level of arousal and optogenetic activation frequency and duration.
a, Scatter plot showing the influence of baseline pupil size on pupil dilation associated with LC-NA-ChR2 neuron activation for one mouse. Light activation was on for 2 s at a frequency of 10 Hz. Trials with no laser stimulation are shown as control. b, Influence of baseline pupil size on pupil dilation following LC-NA-ChR2 activation. Data displayed as mean ± s.e.m (***P <0.001 and *P <0.05 using unpaired two-tailed t-test: t8 = 6.42, t10 = 8.86, t10 = 7.14, t10 = 2.43; N = 6 mice) c, Average pupil trace following LC-NA-ChR2 optical activation at different durations. d, Influence of the frequency or duration of LC-NA-ChR2 laser activation on pupil dilation. Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+). *P <0.05, **P <0.01, and ***P <0.001 using two-tailed paired t-test comparing the mean with zero; P = 0.291 (t5 = 1.18), P = 0.011 (t5 = 3.93), P = 0.00003 (t5 = 14.55), and P = 0.00052 (t5 = 7.91) for 3, 5, 10, and 30-Hz pulse frequencies; P = 0.0342 (t5 = 2.89), P = 0.0105 (t5 = 3.98), P = 0.00004 (t5 = 13.24), and P = 0.000004 (t5 = 21.81) for 0.1, 0.5, 1, and 2-s pulse durations. N = 6 mice.
a, Classification of FS and regular-spiking units using peak duration and valley FWHM values (see inset for definition). The two clusters were extracted by fitting a Gaussian mixture model to the data (n = 433 units from 13 mice). Photo-tagged Dbh and Gad2 units were overlaid on the graph for reference. b,c, Comparison of spontaneous spike rate (b) and spike duration (c) for FS and regular-spiking units (***P = 0.00049, two-tailed unpaired t-test, t315 = −3.523; and ***P = 3 × 10−125, two-tailed unpaired t-test, t315 = 39.925). d, Cumulative probability distribution of the Pearson correlation coefficient of LC unit spike rate with pupil size for all units. The gray area marks the region where Pearson correlation coefficients are non-significant (P <0.05 using Student’s t-distribution). e, Percentage of regular-spiking and FS units that are positively or negatively correlated with pupil size. Proportions were significantly different for the two groups (107 of 124 versus 109 of 182 in the regular-spiking and FS groups; χ2: 24.76; P = 6 × 10−7). The gray portion indicates units not significantly correlated with pupil size (P <0.05 using Student’s t-distribution). FS− and FS+ denote units with negative and positive pupil correlation, respectively. f,g, Normalized cross-correlation and delay of pupil size to LC firing activity for the classes of units sorted in d and e (one-way ANOVA, F2,298 = 21.48, ***P = 1.9 × 10−9 using Tukey post-hoc test). Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+). Error bars in f indicate s.e.m. In b–e, n = 124 and 182 FS and regular-spiking units. In f and g, n = 107, 109, and 68 regular-spiking, FS+ and FS− units.
a, Pupil size traces were band-pass filtered at 0.1–2 Hz and the time points of minimas and maximas were located. b, Activity of the three different types of units was aligned to all pupil dilation events. n = 3,213 dilation events from 13 mice. Horizontal lines indicate a pupil z-score value of zero. Data displayed as mean ± s.e.m. c, Average spike rate values calculated over a 0.5-s window following the onset of dilation. Box plots indicate the median (center line), first quartiles (box edges), and minimum/maximum values (whiskers). n = 19, 11, and 6 Dbh, Gad2+, and Gad2− units taken from 13 mice. **P = 0.0017 using one-way ANOVA with Tukey post-hoc test; F2,28 = 8.08.
a,b, Average of spike delays and jitters following light activation for Gad2-ChR2 neurons classified as Gad2+ or Gad2− defined by their correlation with pupil size. c,d, Comparison of spontaneous spike rate and waveform parameters. No difference is observed between the two types of responses. Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+). n = 8 and 13 for Gad2+ and Gad2−, respectively; P = 0.763, t15 = −0.304 for a; P = 0.379, t15 = −0.891 for b; P = 0.565, t15 = −0.588 for c; P = 0.457, t15 = 0.763 for d; using two-tailed unpaired t-test.
a, Simultaneous recordings of pupil size and NA axon calcium signals in the cortex. NA axons of Dbh-Cre mice injected with GCaMP6s are imaged through a cranial window using two-photon imaging. During these recordings, tone pips were played at different intervals. b, Average response of pupil and NA axon calcium signal to tone pips; n = 23 axons from 5 mice. c, Silencing NA activity using Dbh-Cre mice expressing ArchT prevents pupil size increase observed after presentation of tone pips. Traces are normalized to a 1-s window preceding tone onset. Inset shows the same trace but normalized to a 1-s window preceding laser onset. Average of 38 trials from 1 mouse. d, Average change in pupil size when silencing LC-NA neurons during tone pip presentation. N = 4 mice. *P = 0.0184 using two-tailed paired t-test; t3 = 4.6819. Data are displayed as mean ± s.e.m in b and c.
Supplementary Figure 9 Gain control effect of LC-GABA neurons on pupil response to tone pips is independent of tone frequency.
a, Example of pupil size raster for trials with and without LC-GABA activation in a Gad2-Cre ChR2-injected mouse. Left to right columns are for different tone intensities. The bottom traces show the session average for no laser (black) and laser (green) conditions. The vertical red line indicates the tone onset. In each condition, 71–128 trials were used from 1 mouse. Data are displayed as mean ± s.e.m. b, Pupil dilation increase with tone intensity for all three frequencies tested. Gray lines show the average response per mouse; the bold color lines show a linear fit and the P value is for significance of the correlation using one-way ANOVA (F4,35 = 4.08, 3.32, and 7.19 for 8, 9, and 10-kHz frequencies). N = 8 mice. c, Average pupil response at maximum tone intensity compared for all frequencies tested. No significant difference was reported using one-way ANOVA (P = 0.1854, F2,21 = 1.83). N = 8 mice. Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+). d, Average normalized suppression of pupil dilation to tone pips produced by activation of LC-GABA in Gad2-Cre ChR2-injected mice for each frequency tested. N = 4 mice. The P value is for significance of the correlation using one-way ANOVA (F4,15 = 4.80, 2.52, and 5.79 for 8, 9, and 10-kHz frequencies). Data are displayed as mean ± s.e.m.
Supplementary Figure 10 VGAT-ChR2 mouse experiments also demonstrate that LC-GABA neurons control the gain of LC-NA-mediated pupil responses.
a, Average traces of 50 trials where 72-dB tones were presented (red arrow) with and without laser activation of LC-GABA neurons for 1 mouse. The dashed box delineates the averaging window for calculating the tonic effect of VGAT-ChR2 activation (panels b–d). b, Pupil size at different tone intensities, with and without laser activation, for the example mouse in a using a 7-s averaging window after tone onset. c, Normalized suppression of tonic pupil response due to activation of LC-GABA neurons. Suppression was calculated by subtracting the response of laser-on from the laser-off trials and normalizing to maximum value (P = 0.0284 using one-way ANOVA, F4,20 = 3.39; Tukey post-hoc test reveals that only the 66 and 71-dB conditions were significantly different). d, Comparison of laser to no laser trials for all trials regardless of tone intensity or frequency (***P = 2 × 10−149 using two-tailed unpaired t-test: t1673 = 28.91). e, Average traces of 50 trials for the same mouse and condition as in a, showing the phasic post-tone-onset response. To compare response amplitudes, the traces were normalized to a baseline of 0.5 s preceding the tone onset. The dashed box delineates the averaging window for calculating the phasic effect of VGAT-ChR2 activation (panels f–h). f, Pupil size at different tone intensities, with and without laser activation, for the same example mouse using a 1.5-s averaging window after tone onset. g. Normalized suppression of phasic pupil response to tone intensity due to activation of LC-GABA neurons (P = 0.00023 using one-way ANOVA, F4,20 = 9.13). h, Comparison of laser to no laser trials for all trials regardless of tone intensity or frequency (***P = 4 × 10−34 using two-tailed unpaired t-test: t1673 = 12.46). i, Average normalized suppression of pupil dilation to tone pips produced by activation of LC-GABA in VGAT-YFP-ChR2 mice for each frequency tested. The P value is for significance of the correlation using one-way ANOVA.
a, Fraction of the total LC inputs contributed by different frontal cortices as determined with tracing experiments using targeted modified rabies virus to LC-NA and LC-GABA populations. n = 8 and 4 mice for LC-NA and GABA, respectively. *P = 0.0294 and **P = 0.0057 using two-tailed unpaired t-test with t10 = −3.50 and −2.54 for orbitofrontal cortex and all PFC conditions. Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+). b, Coronal section at the level of the orbitofrontal cortex showing an example of the injection site of CaMKII-ChR2-tdTomato virus in the orbitofrontal cortex of mice that were implanted with an optic fiber in the LC. Slice was counterstained with DAPI (blue). A corresponding section of the mouse brain (from ref. 41) is shown on the left for reference. M1/M2, motor cortices; AI, anterior insular cortex; LO, VO, and MO, lateral, ventral, and medial orbitofrontal cortices.
a, Traces with and without laser activation of PFC axons in LC normalized on a baseline period of 1 s before the onset of laser. All trials for all tone intensities are averaged together. The dashed box delineates the average window used to calculate the effect of PFC axons in LC activation pupil size in panel f. N = 3 mice. Data are displayed as mean ± s.e.m. b, Average pupil size response to laser activation of PFC axons in LC. N = 3 mice. *P = 0.00037 using two-tailed unpaired t-test; t544 = −3.58. Box plots indicate the median (center line), first quartiles (box edges), minimum/maximum values (whiskers), and outliers (+).
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Breton-Provencher, V., Sur, M. Active control of arousal by a locus coeruleus GABAergic circuit. Nat Neurosci 22, 218–228 (2019). https://doi.org/10.1038/s41593-018-0305-z
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