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Locus coeruleus activation enhances thalamic feature selectivity via norepinephrine regulation of intrathalamic circuit dynamics

Abstract

We investigated locus coeruleus (LC) modulation of thalamic feature selectivity through reverse correlation analysis of single-unit recordings from different stages of the rat vibrissa pathway. LC activation increased feature selectivity, drastically improving thalamic information transmission. We found that this improvement was dependent on both local activation of α-adrenergic receptors and modulation of T-type calcium channels in the thalamus and was not due to LC modulation of trigeminothalamic feedforward or corticothalamic feedback inputs. Tonic spikes with LC stimulation carried three times the information as did tonic spikes without LC stimulation. Modeling confirmed norepinephrine regulation of intrathalamic circuit dynamics led to the improved information transmission. Behavioral data demonstrated that LC activation increased the perceptual performance of animals performing tactile discrimination tasks through LC–norepinephrine optimization of thalamic sensory processing. These results suggest a new subdimension within the tonic mode in which brain state can optimize thalamic sensory processing through modulation of intrathalamic circuit dynamics.

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Fig. 1: White noise reverse-correlation analysis for estimation of thalamic feature selectivity during different LC activation conditions.
Fig. 2: LC activation increased VPm feature selectivity and improved information transmission while decreasing firing rate.
Fig. 3: LC-activation-induced increase in thalamic information transmission was not due to modulation of the trigeminothalamic feedforward or corticothalamic feedback inputs.
Fig. 4: LC-activation-induced increase in thalamic information transmission was dependent on the action of alpha-adrenergic receptors in the thalamus.
Fig. 5: LC-activation modulated intrathalamic circuit dynamics.
Fig. 6: LC activation improved thalamic information transmission through modulation of T-type calcium channel activity.
Fig. 7: Modeling results indicated that NE action in both the VPm and TRN is optimal for enhancing thalamic information transmission.
Fig. 8: Photostimulation of LC improved behavioral performance in tactile discrimination tasks through LC–NE optimization of thalamic sensory processing.

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank J. M. Alonso for comments at various points of this work and R. L. Stornetta for sharing lentiviral vectors with us. This work was supported by the National Institutes of Health (NIH R01MH112267 to Q.W.).

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Contributions

Q.W. and C.R. designed the project. C.R, Y.L., and Q.W. performed in vivo experiments. C.R. analyzed the data and performed modeling with Q.W.’s guidance. B.J.S. performed and analyzed behavioral experiments. Q.W. supervised the entire project. Q.W. and C.R. wrote the manuscript with input from Y.L and B.J.S.

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Correspondence to Qi Wang.

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Integrated supplementary information

Supplementary Figure 1 Experimental setup and electrophysiology of VPm neurons.

(a) Example voltage traces of evoked single-unit VPm activity from the beginning (top), ~2 hours (middle) and ~3.5 hours (bottom) of a recording. Inset: corresponding VPm spike waveforms; shaded area represents ±s.d. (n=300 spikes). (b) Measured spectrum of the WGN deflection provided by the custom modified galvomotor.

Supplementary Figure 2 LC activation increased thalamic feature selectivity and improved information transmission.

(a) Population average of peak-to-peak amplitude of significant features for VPm neurons under varying LC stimulation conditions (1.49±0.22 without LC stimulation vs 1.85±0.28 during 2 Hz LC stimulation and 2.38±0.36 during 5 Hz LC stimulation, n=41 features across 22 neurons across 15 animals, Bonferroni corrected α=0.025, p=1.3x10-6 and =2.5x10-8 respectively, Wilcoxon signed-rank test). Each circle represents a significant feature. (b) Population average of information transmission efficiency (bits/spike) for VPm neurons under varying LC stimulation conditions (0.15±0.03 bits/spike without LC stimulation vs 0.32±0.12 bits/spike during 2 Hz LC stimulation and 0.60±0.16 bits/spike during 5 Hz LC stimulation, n=41 features across 22 neurons across 15 animals, Bonferroni corrected α = 0.025, p=6.7x10-6 and =2.5x10-8 respectively, Wilcoxon signed-rank test). Each circle represents a significant feature. (c) Population average of information transmission rate (bits/second) for VPm neurons under varying LC stimulation conditions (0.97±0.17 bits/sec without LC stimulation vs 1.43±0.37 bits/sec during 2 Hz LC stimulation and 2.0±0.40 bits/sec during 5 Hz LC stimulation, n=41 features across 22 neurons across 15 animals, Bonferroni corrected α = 0.025, p=3.0x10-3 and =2.5x10-6 respectively, Wilcoxon signed-rank test). Each circle represents a significant feature. Error bars indicate ±s.e.m.

Supplementary Figure 3 Optogenetic LC stimulation improved thalamocortical information transmission.

(a) Example of recovered features for a VPm neuron under varying LC photostimulation conditions. Inset: the nonlinear tuning functions of the same neuron. (b) Population average of information transmission efficiency (bits/spike) for VPm neurons under varying LC photostimulation conditions (0.12±0.03 bits/spike without LC stimulation vs 0.26±0.06 bits/spike during 2 Hz LC stimulation and 0.50±0.12 bits/spike during 5 Hz LC stimulation, n=18 features across 10 neurons across 4 animals, Bonferroni corrected α=0.025, p=0.012 and =3.7x10-3 respectively, paired t-test). Each circle represents a significant feature. (c) Population average of information transmission rate (bits/second) for VPm neurons under varying LC photostimulation conditions (1.47±0.59 bits/sec without LC stimulation vs 2.40±0.64 bits/sec during 2 Hz LC stimulation and 3.34±0.88 bits/sec during 5 Hz LC stimulation, n=18 features across 10 neurons across 4 animals, Bonferroni corrected α=0.025, p=0.033 and =0.013 respectively, paired t-test). Each circle represents a significant feature. Error bars indicate ±s.e.m.

Supplementary Figure 4 LC activation improved feature selectivity and information transmission in the awake VPm.

(a) Example single-unit activity in awake VPm. Shaded area represents ±s.d. (n=500 spikes) (b) Example of recovered features for a VPm neuron with and without LC stimulation. Inset: corresponding nonlinear tuning functions. (c) Population average of feature modulation factor for VPm neurons with and without LC stimulation in awake rats (1 without LC stimulation vs 1.11±0.04 during 5 Hz LC stimulation, n=19 features across 13 neurons across 4 animals, α=0.05, p=0.013, paired t-test). Each circle represents a significant feature. (d) Normalized changes in information transmission efficiency (bits/spike) for VPm neurons with and without LC stimulation in awake rats (194±36% of the control during 5 Hz LC stimulation, n=19 features across 13 neurons across 4 animals, α=0.05, p=0.018, paired t-test). Each circle represents a significant feature. Error bars indicate ±s.e.m.

Supplementary Figure 5 The LC-activation-induced improvement in thalamic information transmission was not inherited from the PrV.

(a) Example single-unit PrV response to a punctate stimulation of its principal whisker, with arrow marking stimulation onset. Inset: example PrV waveform; shaded area represents ±s.d. (n=56 spikes) (b) PrV firing rate in response to WGN whisker stimulation under varying LC stimulation conditions (40±5 Hz without LC stimulation vs 39±5 Hz during 2 Hz LC stimulation and 40±5 Hz during 5 Hz LC stimulation, n=13 neurons across 8 animals, Bonferroni corrected α=0.025, p=0.28 and =0.72 respectively, paired t-test). Each circle represents a PrV neuron. (c) Population average of information transmission efficiency (bits/spike) for PrV neurons under varying LC stimulation conditions (2.06±0.65 bits/spike without LC stimulation vs 2.09±0.64 bits/spike during 2 Hz LC stimulation and 2.08±0.63 bits/spike during 5 Hz LC stimulation, n=24 features across 13 neurons across 8 animals, Bonferroni corrected α=0.025, p=0.19 and =0.89 respectively, Wilcoxon signed-rank test). Each circle represents a significant feature. Error bars indicate ±s.e.m.

Supplementary Figure 6 Inactivation of the barrel cortex by muscimol injection did not alter LC-activation-induced improvements in thalamic information transmission.

(a) Example single-unit barrel cortex response to a punctate stimulation of its principal whisker, with arrow marking stimulation onset. Inset: example barrel cortex waveform; shaded area represents ±s.d. (n=1398 spikes) (b) Example average LFP response in barrel cortex to a punctate stimulation of the cortical barrel column’s principal whisker before and after muscimol injection. Shaded area represents ±s.e.m (n=313 and =308 trials respectively). Similar results were observed in another animal. (c) Population average of information transmission efficiency (bits/spike) for VPm neurons, post cortical inactivation, under varying LC stimulation conditions (0.33±0.13 bits/spike without LC stimulation vs 0.54±0.18 bits/spike during 2 Hz LC stimulation and 0.90±0.31 bits/spike during 5 Hz LC stimulation, n=8 features across 7 neurons across 4 animals, Bonferroni corrected α=0.025, p=0.017 and =0.028 respectively, paired t-test). Each circle represents a significant feature. Error bars indicate ±s.e.m.

Supplementary Figure 7 The LC-activation-induced increase in thalamic information transmission was due to the action of NE in the thalamus.

(a) Population average of information transmission efficiency (bits/spike) for VPm neurons, prior to phentolamine injection, under varying LC stimulation conditions (0.21±0.09 bits/spike without LC stimulation vs 0.75±0.49 bits/spike during 2 Hz LC stimulation and 1.23±0.60 bits/spike during 5 Hz LC stimulation, n=10 features across 6 neurons across 4 animals, Bonferroni corrected α=0.025, p=0.002 and =0.078, respectively, paired t-test). Each circle represents a significant feature. (b) Population average of information transmission efficiency (bits/spike) for VPm neurons, post phentolamine injection, under varying LC stimulation conditions (0.33±0.12 bits/spike without LC stimulation vs 0.32±0.12 bits/spike during 2 Hz LC stimulation and 0.32±0.11 bits/spike during 5 Hz LC stimulation, n=10 features across 5 neurons across 4 animals, Bonferroni corrected α=0.025, p=0.64 and =0.76 respectively, paired t-test). Each circle represents a significant feature. (c) Population average of information transmission efficiency (bits/spike) for VPm neurons, post saline injection, under varying LC stimulation conditions (0.05±0.01 bits/spike without LC stimulation vs 0.10±0.02 bits/spike during 2 Hz LC stimulation and 0.13±0.02 bits/spike during 5 Hz LC stimulation, n=7 features across 4 neurons across 4 animals, Bonferroni corrected α=0.025, p=0.037 and =1.7x10-4 respectively, paired t-test). Each circle represents a significant feature. Error bars indicate ±s.e.m.

Supplementary Figure 8 LC activation did not significantly alter the precision of spike timing within events for VPm neurons.

VPm precision in response to WGN whisker stimulation under varying LC stimulation conditions (2.3±0.1 ms without LC stimulation vs 2.5±0.2 ms during 2 Hz LC stimulation and 2.8±0.4 ms during 5 Hz LC stimulation, n=22 neurons across 15 animals, Bonferroni corrected α=0.025, p=0.16 and =0.14, respectively, paired t-test). Each circle represents a VPm neuron.

Supplementary Figure 9 LC activation modulated intrathalamic circuit dynamics by reducing burst firing in both the TRN and VPm.

(a) Population average of percent of spikes in bursts for VPm and TRN neurons under varying LC stimulation conditions (VPm: 26±2% without LC stimulation vs 21±2% during 2 Hz LC stimulation and 14±2% during 5 Hz LC stimulation, n=22 neurons across 15 animals, Bonferroni corrected α=0.025, p=3.8x10-4 and =1.1x10-7, respectively, paired t-test; TRN: 17±3% without LC stimulation vs 10±3% during 2 Hz LC stimulation and 8±3% during 5 Hz LC stimulation, n=21 neurons across 10 animals, Bonferroni corrected α=0.025, p=0.031 and =0.007, respectively, paired t-test). (b) Example plots from the same VPm neuron showing inter-spike-intervals (ISIs) before vs after each spike in response to WGN whisker stimulation. Left: without LC stimulation. Right: with 5 Hz LC stimulation. (c) Example single-unit TRN response to a punctate stimulation of its principal whisker, with arrow marking whisker stimulation onset. Inset: example TRN waveform; shaded area represents ±s.d. (n=220 spikes) (d) Example plots from the same TRN neuron showing ISIs before and after each spike in response to WGN whisker stimulation. Left: without LC stimulation. Right: with 5 Hz LC stimulation. Error bars indicate ±s.e.m.

Supplementary Figure 10 LC-activation-induced increases in thalamic information transmission were inversely correlated with changes in bursting rate in awake rats.

A similar trend of suppression of thalamic bursts correlating with an increase in information transmission efficiency during LC activation was observed in both anesthetized and awake animals (r=-0.31, Pearson’s coefficient).

Supplementary Figure 11 NE effects on the variance of membrane potential and coefficient of variation of interspike intervals for VPm neurons.

(a) NE activation in the modelled intrathalamic circuit decreased the variance of membrane potential of VPm neurons (74±4% of the control for NE in both VPm and TRN, n=13 modelled VPm neurons, α=0.05, p=3.9x10-5, paired t-test). (b) Coefficient of variation of VPm inter-spike-intervals under varying LC stimulation conditions (1.56±0.04 without LC stimulation vs 1.57±0.10 during 2 Hz LC stimulation and 1.36±0.05 during 5 Hz LC stimulation, n=22 neurons across 15 animals, Bonferroni corrected α=0.025, p=0.90 and =4.0 x10-4 respectively, Wilcoxon signed-rank test). Each dot represents a VPm neuron. Error bars indicate ±s.e.m.

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Rodenkirch, C., Liu, Y., Schriver, B.J. et al. Locus coeruleus activation enhances thalamic feature selectivity via norepinephrine regulation of intrathalamic circuit dynamics. Nat Neurosci 22, 120–133 (2019). https://doi.org/10.1038/s41593-018-0283-1

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