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Sensory and behavioral modulation of thalamic head-direction cells

Nature Neuroscience volume 27, pages 28–33 (2024)Cite this article

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Abstract

Head-direction (HD) neurons are thought to exclusively encode directional heading. In awake mice, we found that sensory stimuli evoked robust short-latency responses in thalamic HD cells, but not in non-HD neurons. The activity of HD cells, but not that of non-HD neurons, was tightly correlated to brain-state fluctuations and dynamically modulated during social interactions. These data point to a new role for the thalamic compass in relaying sensory and behavioral-state information.

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Fig. 1: Sensory-evoked activity in HD neurons.
Fig. 2: HD activity correlates to spontaneous behavioral-state fluctuations during quiet wakefulness.
Fig. 3: Social interactions dynamically modulated the gain of the HD representation.

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Data availability

Preprocessed raw data are available at: https://github.com/BurgalossiPublic/HDcells-brain-state-modulation. Source data are provided with this paper.

Code availability

Custom code associated with this study is available at: https://github.com/BurgalossiPublic/HDcells-brain-state-modulation.

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Acknowledgements

We thank M. Brecht for comments on previous versions of the manuscript, C. Schwarz for discussions, H. Chen and P. Goyal for contributing to analysis routines, A. Levina for advice on the linear mixed-model analysis, F. Monteiro for excellent technical assistance, S. Ishiyama for illustrations, and M. Li Silva Prieto and R. Roy Chowdhury for technical advice on whisker stimulation. This work was supported by the Eberhard Karls University of Tübingen, the German Research Foundation, DFG grants BU 3126/2-1 (A.B.), BU 3126/3-1 (A.B.), PR 2204/1-1 (P.P.-F.), and the Athene Grant (P.P.-F.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

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Author notes

  1. These authors contributed equally: Eduardo Blanco-Hernández, Giuseppe Balsamo.

Authors and Affiliations

  1. Institute of Neurobiology, University of Tübingen, Tübingen, Germany

    Eduardo Blanco-Hernández, Giuseppe Balsamo, Patricia Preston-Ferrer & Andrea Burgalossi

  2. Werner-Reichardt Centre for Integrative Neuroscience, Tübingen, Germany

    Eduardo Blanco-Hernández, Giuseppe Balsamo, Patricia Preston-Ferrer & Andrea Burgalossi

  3. Graduate Training Centre of Neuroscience, IMPRS, Tübingen, Germany

    Giuseppe Balsamo

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  1. Eduardo Blanco-Hernández
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  3. Patricia Preston-Ferrer
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Contributions

E.B.-H., A.B. and P.P.-F. conceived and designed the experiments, E.B.-H. and G.B. performed experiments and analyzed the data, G.B. and E.B.-H. drafted the paper and A.B. wrote the manuscript. All authors revised and edited the manuscript.

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Correspondence to Patricia Preston-Ferrer or Andrea Burgalossi.

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Nature Neuroscience thanks Kate Jeffery and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Juxtacellularly recorded and identified HD and non-HD neurons in the mouse anterior thalamus.

(a) Schematic showing juxtacellular recordings in the anterior thalamic nuclei (ATN) of a head-fixed mouse during passive rotations. (b) Polar plots (left) and spike-trajectory plots (right) for a representative HD (blue) and non-HD neuron (black) recorded as in (a). Peak firing rates are indicated. Blue and black dots indicate spikes. (c) Bimodal distribution of HD indices in the ATN, and separation between HD cells (blue, n = 386) and non-HD cells (black; n = 166). Nmice = 37 (Methods). (d) Superimposed average tuning curves of HD (blue) and non-HD neurons (black). Dashed lines indicate ± SD. (e) Spike half-widths (top) and superimposed average spike waveforms (bottom) for HD and non-HD neurons (as in (c)). p = 8.24e-37, two-sided Wilcoxon rank sum test. Scalebar = 0.5 ms. (f) Schematic outline of the mouse thalamus from parasagittal sections at three mediolateral levels: lateral (left), intermediate (middle), and medial (right). The lateral distance from the midline is indicated. Anterior thalamic nuclei are indicated in red. Blue dots represent the somatic location of all juxtacellularly-labelled and identified HD cells (n = 25); black dots represent non-HD cells (n = 17). (g) Fluorescence image of a parasagittal section, showing two identified HD neurons in the anterodorsal nucleus (AD, green). LD, laterodorsal; AV, anteroventral. Scale bar = 400 µm. (h) Morphological reconstructions (left) and HD polar plots (right) for the two representative HD cells showed in (g). Scale bar = 200 µm. (i) Color-coded distribution of preferred direction for all HD neurons. Each row represents the firing rate of a single neuron (normalized relative to its peak firing rate; yellow). color range, 0-1. (j) Image of a DAB-stained sagittal section, showing three identified non-HD cells in the anteroventral nucleus (AV, orange). LD, laterodorsal. Scale bar = 400 µm. (k) High-magnification image from (j) (left) and HD polar plots (right) for the three identified neurons in the AV. Scale bar = 100 µm. (l) Same as in (i), but for non-HD neurons.

Source data

Extended Data Fig. 2 Electrophysiological properties of HD cells in the anterior thalamus and in the dorsal presubiculum.

(a-d) Boxplots showing electrophysiological properties of anterior thalamic HD cells (blue, n = 386; see Extended Data Fig. 1c) and presubicular HD cells (green, n = 125; from ref. 9), juxtacellularly recorded during passive rotation (recording configuration as in Extended Data Fig. 1a). (a) Average firing rates (b) peak firing rates (c) burst index (defined as the proportion of spikes fired at interspike intervals < 6 ms) and (d) HD Index. p values are indicated (two-sided Wilcoxon rank sum test). These differences recapitulate previous observations in freely-moving animals12. (e) Left, superimposed average spike waveforms of anterior thalamic HD cells (blue, n = 386) (blue) and PreS HD cells (green, n = 125). Right, box plot showing the distribution of spike half-width for thalamic and PreS HD cells. p value is indicated (two-sided Wilcoxon rank sum test).

Source data

Extended Data Fig. 3 Sound-evoked responses in HD cells during freely-moving behaviour and passive rotation.

(a) Schematic of the recording configuration: juxtacellular recordings and sound stimulation in freely-moving mice. (b) Spike-trajectory plot (top), juxtacellular spike trace and polar plot (bottom) for a representative HD cell recorded as in (a). Red dots indicate spikes. Scalebar = 0.2 s (horizontal), 0.5 mV (vertical). (c) Raster plots (top) and peristimulus time histograms (bottom, 1 ms bins) from the HD cell in (b) aligned to the auditory stimulus onset (red line). (d) Mean z-scored activity for all HD neurons recorded as in (a) (n = 6, N mice = 1), aligned to the onset of the auditory stimulus. Dashed lines indicate ± SD. Mean response latency (time-to-peak) = 11.2 ± 2.6 ms (n = 4, see Methods for inclusion criteria). (e) Schematic of the recording configuration for closed-loop sound stimulation during passive rotation. (f) Representative HD cell recording (top) and summary histogram (bottom) showing auditory stimulus locations within (green, n = 47) and outside (orange, n = 23) the HD receptive field. The dashed line indicates the population median tuning curve (n = 47, N mice = 3). (g) Representative juxtacellular spike trace (top), raster plots (middle) and peristimulus time histogram (bottom) from a representative HD cell showing sound-evoked responses both inside (left, green) and outside (right, orange) its HD receptive field (HD polar plot shown in (f)). Scalebar = 1 mV. (h) Cell-by-cell peristimulus time histograms (top) and mean z-scored activity (bottom, 2.5 ms bins) for all HD neurons aligned to the auditory stimulus onset inside (left, green; n = 47, N mice = 3) and outside (right, orange; n = 23) their HD receptive field. Dashed lines indicate ± SD. Left, color range: -2 to 10 z-score; right, color range: -2 to 60 z-score. Mean response latencies (time-to-peak): in PD, 9.3 ± 1.7 ms, n = 20; out of PD, 9.7 ± 1.9 ms, n = 12 (see Methods for inclusion criteria). (i) Scatter-plot showing average firing rates before and after stimulus onset for HD neurons stimulated inside or outside their HD receptive field (same n and conventions as in (h)). (j) Firing rate modulation indices for stimulations delivered inside (green) and outside (orange) the HD receptive fields (same data as in (i)). p value is indicated (LMM).

Source data

Extended Data Fig. 4 Sensory stimulation in HD neurons evokes a long-latency response, which is associated with changes in brain state.

(a) Mean z-scored activity for all HD cells (blue, n = 110, N mice = 6) aligned to the auditory stimulus onset (arrowhead). Close-up magnification from (c) below. Dashed lines indicate ± SD. Note the clear separation between the fast (short-latency) and the slow (long-latency) components (see also13,14). (b) Same as (a) but for all non-HD cells (black, n = 75, N mice = 5). (c) Top, same as in (a) but on a larger time window. Bottom, normalized mean whisker-pad motion (cyan) and pupil area (magenta) aligned to the auditory stimulus onset (red line). (d) Same as (c) but for non-HD cells. In both HD and non-HD recordings, auditory stimuli evoked a detectable change in pupil area (and whisker-pad motion), with similar kinetics as shown in previous work13,55,56; however, an evoked response was observed only in HD neurons, and not in non-HD cells.

Source data

Extended Data Fig. 5 Sound-evoked activity in anterodorsal thalamic neurons of anesthetized mice.

(a) Left, low magnification fluorescence image of a parasagittal section showing one identified neuron in the anterodorsal nucleus (AD, green) recorded during isoflurane anesthesia (Methods). Scale bar = 400 µm. Right, high-magnification inset showing the labelled neurons (arrowhead). Scale bar = 100 µm. (b) Juxtacellular spike trace (top) and normalized pupil area (bottom; see Methods) from the neuron shown in (a). Arrowheads and dashed line indicate the onset of sound stimuli. Top inset, high-magnification view on a single trial. (c) Raster plot from the cell in (a), aligned to stimulus onset (red line). (d) Mean normalized pupil area (left, magenta) and whisker pad motion (right, cyan) aligned to the auditory stimulus onset. For direct comparability with data in Extended Data Fig. 4c,d, pupil area and whisker pad motion energy are normalized to the awake data (Methods); Dashed lines indicate ± SD. (e) Cell-by-cell peristimulus time histogram (top, 2.5 ms bins, color range: 0 to 30 z-score) and mean z-score activity (bottom) from all responsive anterodorsal neurons (peak z-score >5; n = 45, N mice = 6) recorded during anesthesia. Dashed lines indicate ± SD. Note the absence of the ‘late’ sensory evoked component (see comparison with awake data in Extended Data Fig. 4a). Note the longer (and more variable) latency of the fast sensory-evoked component (mean latency, 16.2 ± 3.5 ms; range, 6.0-29.0 ms; n = 45) compared to the awake data (for example Figure 1d) - possibly accounted for by anesthesia effects and/or variability in the depth of anesthesia, as shown by previous work in sensory systems57,58,59.

Source data

Extended Data Fig. 6 Stability of HD and non-HD cell firing over time.

Left, peak-normalized average firing rates for all HD neurons recorded for ≥ 150 s while the animal’s head was maintained at the preferred direction (n = 81, N mice = 4). Right, same as left, but for non-HD neurons (n = 49, N mice = 4) while the animal’s head was maintained at a random direction. Bin size, 3 s; Dashed lines indicate ± SEM.

Source data

Extended Data Fig. 7 Event-triggered averages and EEG power analysis during the pupil microdilation/constriction cycle.

(a) Average traces showing pupil area (left, magenta) and whisker-pad motion (right, cyan) aligned at the onset of long-lasting pupil dilation (left) and whisker-pad motion events (right). These panels relate to Fig. 2c for the HD cell dataset. Scale bars: vertical, pupil, 10% of max; whisker pad motion, 10% of max. n,N and conventions as in Fig. 2c. (b) Same as (a), but for non-HD neurons. n,N and conventions as in Fig. 2d. (c) Representative recording showing HD cell activity during rapid brain state fluctuations (same conventions as in Fig. 2b). (d) Average z-scored EEG power (1-10 Hz) for HD cell (blue) and non-HD cell recordings (black) aligned to the pupil microdilation cycle derived from the Hilbert transform (red dotted line; see Methods). N recordings = 22; N mice = 2. Dashed lines indicate ± SD. (e) Quantifications from the data in (d), showing z-scored EEG power for HD (blue) and non-HD (black) recordings during period of pupil dilations (left) and constrictions (right). p = 1.73e-10, Kruskal-Wallis test, Tukey post-hoc test. P values (from left to right): Dilation HD vs Dilation non-HD, p = 0.70; Dilation HD vs Constriction HD, p = 2.26e-07; Dilation non-HD vs Constriction non-HD, p = 2.82e-04; Constriction HD vs Constriction non-HD, p = 0.89. *** p < 0.001. Note that unlike firing activities (Fig. 2g,h) EEG power did not significantly differ between the two cell populations.

Source data

Extended Data Fig. 8 Time-lag analysis between pass-by-pass firing rates and pupil area.

(a) From top to bottom, polar plot for a HD cell recorded during passive rotation; spike trajectory plot showing 4 representative passes through the preferred direction; pass-by-pass activity at the preferred direction (juxtacellular spike trace, blue; firing rate histogram, black) and simultaneous tracking of the pupil area (magenta, bottom). (b) Firing rate of individual passes at the preferred direction window (time 0) were correlated with pupil average collected at each time points (−2.5 to 2.5 s, Methods). Log 10 p-values (black) and R2 (orange) from a linear mixed-model with fixed effect for pupil area and random effects for subjects are shown for each correlation. Dashed line indicates the p-value threshold of 0.05. Note that p-value is minimum at 1.25 s, where R2 is maximal (n,N and conventions as in Fig. 2i). (c) Same as (b), but for non-HD cells. Note the non-significant correlation, and the difference in R2 magnitude (y axis, right) compared to (b) (n,N and conventions as in Fig. 2i).

Source data

Supplementary information

Supplementary Information

Supplementary Table 1.

Reporting Summary

Supplementary Video 1

The video shows 15 representative whisker stimulation trials, performed while juxtacellularly recording from a thalamic HD neuron (recording configuration as in Fig. 1g). Video speed, ×5. Voltage transients at stimulus onsets were blanked from the juxtacellular spike trace for display purposes. HD polar plot, raster plot and peristimulus time histogram with all trials (n = 52) are shown at the end of the video.

Source data

Source Data Fig. 1

Statistical Source Data for Fig. 1.

Source Data Fig. 2

Statistical Source Data for Fig. 2.

Source Data Fig. 3

Statistical Source Data for Fig. 3.

Source Data Extended Data Fig. 1

Statistical Source Data for Extended Fig. 1.

Source Data Extended Data Fig. 2

Statistical Source Data for Extended Fig. 2.

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Blanco-Hernández, E., Balsamo, G., Preston-Ferrer, P. et al. Sensory and behavioral modulation of thalamic head-direction cells. Nat Neurosci 27, 28–33 (2024). https://doi.org/10.1038/s41593-023-01506-1

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