Arousal dependent modulation of thalamo-cortical functional interaction

Iain Stitt, Zhe Charles Zhou, Susanne Radtke-Schuller, Flavio Fröhlich, Iain Stitt, Zhe Charles Zhou, Susanne Radtke-Schuller, Flavio Fröhlich

Abstract

Ongoing changes in arousal influence sensory processing and behavioral performance. Yet the circuit-level correlates for this influence remain poorly understood. Here, we investigate how functional interaction between posterior parietal cortex (PPC) and lateral posterior (LP)/Pulvinar is influenced by ongoing fluctuations in pupil-linked arousal, which is a non-invasive measure of neuromodulatory tone in the brain. We find that fluctuations in pupil-linked arousal correlate with changes to PPC to LP/Pulvinar oscillatory interaction, with cortical alpha oscillations driving activity during low arousal states, and LP/Pulvinar driving PPC in the theta frequency band during higher arousal states. Active visual exploration by saccadic eye movements elicits similar transitions in thalamo-cortical interaction. Furthermore, the presentation of naturalistic video stimuli induces thalamo-cortical network states closely resembling epochs of high arousal in the absence of visual input. Thus, neuromodulators may play a role in dynamically sculpting the patterns of thalamo-cortical functional interaction that underlie visual processing.

Conflict of interest statement

The UNC has filed provisional patents on brain stimulation technology with F.F. as the lead inventor. No licensing has occurred. F.F. is the founder and majority shareholder of Pulvinar Neuro LLC. The work presented here has no relationship except the company is named after the senior author’s favorite brain structure. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Experimental setup and anatomical connectivity between LP/Pulvinar and PPC. a Diagram illustrating how neural signals from PPC and LP/Pulvinar were simultaneously recorded with pupil diameter. Inset image shows a typical view of the ferret infrared eye tracking, with the pupil outlined in white. Below are raw traces of ongoing fluctuations pupil diameter and co-recorded spiking and LFP activity in PPC and LP/Pulvinar. Note that pupil diameter spontaneously fluctuates on both short and long timescales. b Anterograde (rAAV5-CaMKII-mCherry) and retrograde (CTB-488) tracers were injected into PPC in the left and right hemispheres, respectively. c Brightfield image of a brain section containing the PPC injection sites overlaid with green and red fluorescence channels. Fluorescent blobs show the location of anterograde and retrograde tracer in PPC. d Brightfield image of thalamus overlaid with fluorescence from red and green channels. Retrograde labeling of cell bodies (green) and anterograde labeling of axonal projections (red) in corresponding locations of LP/Pulvinar illustrate reciprocal connectivity between PPC and LP/Pulvinar in the ferret. LG lateral gyrus, PPC posterior parietal cortex
Fig. 2
Fig. 2
Neuronal spiking rate and LFP spectral power in PPC and LP/Pulvinar are modulated with pupil diameter. a A representative example of how pupil diameter time series were divided up into bins (each bin represents 12.5% of all samples). Neurophysiological data were then analyzed according to pupil diameter bin. b The normalized spiking rate in both PPC and LP/Pulvinar increases with pupil dilation. Color denotes pupil diameter, as indicated in a. c The mean (±SEM) z-scored LFP power in PPC as a function of carrier frequency across pupil diameter bins. Low (<30 Hz) and high (>30 Hz) frequency LFP power displayed opposing relationships to pupil diameter. d the same as c but for LP/Pulvinar LFP power. Note the antagonism between low- and high-frequency LFP oscillatory power is similar to PPC, with the exception of the theta band (∼4 Hz), which displays increased power during large pupil diameter states
Fig. 3
Fig. 3
Thalamo-cortical synchronization varies with ongoing fluctuations in pupil-linked arousal. a PLV measured between LP/Pulvinar and PPC as a function of LFP frequency and pupil diameter. Pupil diameter is denoted by color (see legend). Note the prominent thalamo-cortical phase synchronization in the theta (∼4 Hz) and alpha (12–17 Hz) carrier frequency bands. Significant modulation across pupil diameter bins is indicated by bars plotted below PLV traces (one-way ANOVA, FDR-corrected P-values). PLV in the theta band significantly increased with pupil dilation, while alpha PLV significantly decreased with pupil dilation. b The phase synchronization (PLV) of spiking activity to LFP rhythms recorded within the same brain structure (top row), as well as between regions (bottom row). Spike PLV both locally within PPC and LP/Pulvinar, as well as between PPC and LP/Pulvinar revealed phase locking of spiking activity to alpha oscillations. Significant modulation of spike PLV across pupil diameter bins is indicated by color bars plotted below PLV traces (one-way ANOVA, FDR-corrected P-values). Note that the strongest alpha band spike PLV was observed between LP/pulvinar spikes and PPC LFP phase
Fig. 4
Fig. 4
Arousal level determines the direction and carrier frequency of thalamo-cortical causal interaction. a Spectrally resolved Granger causality shows the carrier frequencies of directed interaction from LP/Pulvinar to PPC (magenta), and PPC to LP/Pulvinar (green, ±SEM). LP/Pulvinar has a causal influence on PPC in the theta and alpha frequency bands. In the opposing direction, PPC has a causal influence on LP/Pulvinar in the alpha band. b Granger causality was measured for time periods where the pupil diameter was small (<25%, dark blue) and large (>25%, light blue), respectively. Data were subsampled to match power distributions between conditions. The causal influence of PPC alpha oscillations on LP/Pulvinar was significantly stronger during small pupil diameter epochs (left plot, P = 0.018, t-test). In contrast, the causal influence of LP/Pulvinar theta oscillations on PPC was significantly greater during large pupil diameter epochs (right plot, P = 0.0015, t-test)
Fig. 5
Fig. 5
Visual processing induced changes in thalamo-cortical network dynamics. a Animals passively viewed a collection of naturalistic images or videos. During the interstimulus interval a gray screen was presented. The image “Running Cheetah” by Freder is licensed under the Standard iStock Photo License (Getty Images). b Population mean spike rate in PPC and LP/Pulvinar during presentation of video stimuli. The gray bar at the top of the plot indicates the duration of stimulation. c Population LFP spectrograms from PPC (left) and LP/Pulvinar (right) during presentation of naturalistic videos. LFP power was normalized to the period −5 to −1 s before stimulus onset. Note the decrease in alpha oscillatory power in PPC during stimulus presentation. d Across-session average thalamo-cortical phase synchronization in response to naturalistic video stimuli. PLV in the theta band is elevated during stimulus presentation, while alpha PLV is weaker. e Time and frequency resolved Granger causality analysis computed between PPC and LP/Pulvinar LFP signals for naturalistic video stimuli. The onset of video stimuli leads to a breakdown of PPC causal influence on LP/Pulvinar in the alpha band (left plot), and an increase of LP/Pulvinar causal influence on PPC in the theta frequency band (right plot)
Fig. 6
Fig. 6
Saccades link visual sensory processing and pupil-linked arousal-related changes in thalamo-cortical dynamics. a Distribution of inter saccade interval (top, ±SEM) shows that ferrets actively sample the visual environment rhythmically. The relationship between saccade magnitude and peak velocity (bottom) reflects the ballistic nature of saccades in ferrets. b Saccade rate during naturalistic video presentation illustrates that animals actively sample visual stimuli by showing an elevated rate of saccades (n = 26 sessions). c Saccade rate as a function of pupil diameter in the dark. The rate of saccades during large pupil diameter states is comparable to the rate of saccades when animals are actively sampling naturalistic videos. d Mean (±SEM) fluctuations in pupil diameter time locked to saccadic eye movements in the dark. Transient increases in pupil diameter precede saccades (P = 0.004, t-test). e Population average LFP power spectrograms in PPC (left) and LP/Pulvinar (right) time locked to saccades in the dark. LFP power was z-score normalized across the entire recording session. f Population average PPC to LP/Pulvinar PLV time locked to saccades in the dark. Dotted line indicates a break in the color scale, as shown to the right of the figure. g Across-session average time and frequency resolved Granger causality between PPC and LP/Pulvinar around the occurrence of saccades in the dark. Active sampling by saccades was associated with a decrease in PPC causal influence on LP/Pulvinar in the alpha band and an increase in LP/Pulvinar on PPC in the theta band
Fig. 7
Fig. 7
Thalamo-cortical synchronization and pupil-linked arousal correlate with saccade behavior. a Correlation of thalamo-cortical phase synchronization in the theta (left) and alpha (right) carrier frequency bands and the number of saccades performed during presentation of naturalistic video stimuli. Theta PLV displays a significant positive correlation with saccadic sampling of stimuli, whereas alpha PLV displays a significant negative correlation. b Correlation of prestimulus pupil diameter to the latency of the first saccade for subsequent naturalistic video stimulus presentation. Significant negative correlation illustrates that animals sample visual stimuli more rapidly when they are in a more aroused state
Fig. 8
Fig. 8
Rapid fluctuations in pupil diameter correlate with the reorganization of thalamo-cortical functional connectivity. a Raw pupil diameter (top) and pupil diameter derivative (middle) traces for one example recording (blinks have been removed from trace), and a histogram of pupil derivative time series broken into eight bins of equal size (bottom). Dark colors correspond to rapid pupil constriction, light colors correspond to rapid pupil dilation, and intermediate colors correspond to epochs of little change in pupil diameter. b The mean (±SEM) z-scored LFP power in PPC (left) and LP/Pulvinar (right) as a function of carrier frequency across pupil derivative bins. The insets in each figure illustrate how LFP power in theta, alpha, and gamma frequency bands changes across pupil derivative bins (frequency band indicated by asterisk). c PLV measured between LP/Pulvinar and PPC as a function of LFP frequency and the derivative of pupil diameter. d The phase synchronization (PLV) of spiking activity to LFP rhythms recorded within the same brain structure (top row), as well as between regions (bottom row) as a function of pupil derivative. Significant modulation of PLV and spike PLV across pupil derivative bins is indicated by color bars plotted below traces (one-way ANOVA, FDR-corrected P-values). Note the distinctive ‘U’ and inverted ‘U’ shape of many inset figures, indicating alpha synchronization/power is maximized during epochs of constant pupil diameter, and theta synchronization/power is maximized during epochs of rapid change in pupil diameter

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