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The cholinergic basal forebrain provides a parallel channel for state-dependent sensory signaling to auditory cortex

Nature Neuroscience volume 26, pages 810–819 (2023)Cite this article

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Abstract

Cholinergic basal forebrain (CBF) signaling exhibits multiple timescales of activity with classic slow signals related to brain and behavioral states and fast, phasic signals reflecting behavioral events, including movement, reinforcement and sensory-evoked responses. However, it remains unknown whether sensory cholinergic signals target the sensory cortex and how they relate to local functional topography. Here we used simultaneous two-channel, two-photon imaging of CBF axons and auditory cortical neurons to reveal that CBF axons send a robust, nonhabituating and stimulus-specific sensory signal to the auditory cortex. Individual axon segments exhibited heterogeneous but stable tuning to auditory stimuli allowing stimulus identity to be decoded from population activity. However, CBF axons displayed no tonotopy and their frequency tuning was uncoupled from that of nearby cortical neurons. Chemogenetic suppression revealed the auditory thalamus as a major source of auditory information to the CBF. Finally, slow fluctuations in cholinergic activity modulated the fast, sensory-evoked signals in the same axons, suggesting that a multiplexed combination of fast and slow signals is projected from the CBF to the auditory cortex. Taken together, our work demonstrates a noncanonical function of the CBF as a parallel channel for state-dependent sensory signaling to the sensory cortex that provides repeated representations of a broad range of sound stimuli at all points on the tonotopic map.

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Fig. 1: Robust, nonhabituating and stimulus-specific auditory responses of cholinergic axons.
Fig. 2: Frequency-specific tuning of cholinergic axons.
Fig. 3: Frequency tuning of cholinergic axons is uncoupled from tuning of cortical neurons.
Fig. 4: Suppression of auditory thalamus but not auditory cortex attenuates sound-evoked cholinergic responses.
Fig. 5: State-dependent tonic cholinergic activity modulates sound-evoked cholinergic responses.

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Acknowledgements

We thank C. Connor., R. C. Froemke., C. Honey., D. Lee. and S. P. Mysore for helpful comments on the manuscript and C. Drieu. and Z. Zhu for the assistance with cortical tonotopic measurements. This work was supported by grants from the NIH (grant nos. R01 DC018650, R00DC015014, NSF CAREER 2145247 and BBRF NARSAD to K.V.K.), a JHU Science of Learning Institute Fellowship to F.Z., and by fellowships from the Fondation Fyssen and Kavli Institute to J.L.

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Authors and Affiliations

  1. Department of Psychological and Brain Sciences, Johns Hopkins University, Baltimore, MD, USA

    Fangchen Zhu, Sarah Elnozahy, Jennifer Lawlor & Kishore V. Kuchibhotla

  2. Department of Neuroscience, Johns Hopkins Medical Institute, Baltimore, MD, USA

    Kishore V. Kuchibhotla

  3. Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA

    Kishore V. Kuchibhotla

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  1. Fangchen Zhu
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Contributions

K.V.K. and F.Z. designed the study. F.Z. and S.E. performed experiments. F.Z. analyzed the data with input from all authors. J.L. provided analytical support. K.V.K. and F.Z. wrote the manuscript.

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Correspondence to Kishore V. Kuchibhotla.

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Extended data

Extended Data Fig. 1 Immunohistochemistry for cre-dependent cholinergic neurons targeting.

a, Schematic of imaging site for basal forebrain (cyan box) adapted from Allen Mouse Brain Coronal Atlas. AC, auditory cortex; BLA, basolateral amygdala; CP, caudate putamen; GP, globus pallidus; SI, substantia innominate; TH, thalamus. b, Basal forebrain stained for inhibitory ChAT (red), axon-GCaMP6s (green), and DAPI (blue). Scale bar, 50 μm. c, Percentage of basal forebrain neurons that express both axon-GCaMP6s and ChAT (black), ChAT-only (red), or axon-GCaMP6s-only (green) (n = 6 animals, 126 cells). Error bars indicate s.e.m.

Extended Data Fig. 2 Robust and non-habituating response to multiple complex sounds.

a, Heatmap of average evoked response to up-sweeps for all identified axon segments (n = 15,777). b, Spatial distribution of axon segments responsive to up-sweeps (blue) in one example animal, ‘mse012’. Shaded boxes indicate recording sites. Scale bar, 100 μm. c, Heatmap of average evoked response to down-sweeps for all identified axon segments (n = 15,777). d, Spatial distribution of axon segments responsive to down-sweeps (orange) in one example animal, ‘mse012’. Shaded boxes indicate recording sites. Scale bar, 100 μm. e, Percentage of identified axon segments that are responsive to white noise (black), up-sweeps (blue), and down-sweeps (orange) in eight animals. Error bars indicate s.e.m. f, Amplitude of evoked response for up-sweeps across 20 presentations for all animals. Faded lines indicate individual animals (n = 8 animals) and shaded region indicates s.e.m. g, Amplitude of evoked response for down-sweeps across 20 presentations for all animals. Faded lines indicate individual animals (n = 8 animals) and shaded region indicates s.e.m. h, Axon segments respond to multiple stimuli in all animals (n = 8). Percentage of pure-tone-responsive axons that response to other stimuli (green). Percentage of white-noise-responsive axons that response to other stimuli (gray). Percentage of up-sweep-responsive axons that response to other stimuli (blue). Percentage of down-sweep-responsive axons that response to other stimuli (orange). All data are presented as mean ± s.e.m.

Extended Data Fig. 3 Cholinergic axons respond to auditory stimuli at low intensity and after repeated presentation.

a, Mean fluorescence trace of all responsive axon segments for white noise presented at 70 dB SPL (blue), 60 dB SPL (red), and 50 dB SPL (green) (n = 653 axon segments; F(2,156) = 1.51, P = 0.224, one-way ANOVA). Vertical gray line indicates presentation of white noise and shaded region indicates s.e.m. b, Normalized evoked response to white noise, up-sweeps, and down-sweeps at 50–70 dB SPL. (*P < 0.05, **P < 0.01, one-way ANOVA). c, Proportion of axon segments that responded to white noise, up-sweeps, and down-sweeps at 50–70 dB SPL all animals (n = 3). Error bars indicate s.e.m. d, Normalized evoked response to pure tones at 50–70 dB SPL for 3 animals. e, Amplitude of evoked response for white noise across 110 presentations for all animals (n = 3). Faded lines indicate individual animals and shaded region indicates s.e.m. f, Mean evoked response of all responsive axon segments for 1–55 (blue) and 56–110 (red) presentations of white noise (t(54) = 1.00, P = 0.321, two-tailed paired t-test). Vertical gray line indicates presentation of white noise and shaded region indicates s.e.m.

Extended Data Fig. 4 Movements are associated with some but not all phasic cholinergic transients.

a, Movement signal validation with videography. Example traces of Suite2p-identified x–y offset and videography pose estimation with DeepLabCut. b, Pearson’s correlation between Suite2p-identified x–y offset and videography pose estimation with DeepLabCut in 5 mice. Error bar indicates s.e.m. c, Example stimulus-synchronous phasic cholinergic transients from one example axon segments that are associated with movement (left) and not associated with movement (right). Vertical gray line indicates presentation of the auditory stimulus. d, Percentage of stimulus-synchronous phasic transients that are associated with movements. e, Movement during sound onset does not significantly modulate amplitude of sound-evoked transients. Box plots show median (center line), upper and lower quartiles (boxes), non-outlier maxima and minima (whiskers), and outliers greater than 1.5x interquartile range (points) (n = 179 movement-associated trials, and n = 792 stationary trials; Z = 1.664, P = 0.096, Wilcoxon signed-rank test).

Extended Data Fig. 5 Robust stimulus-specific decoding of complex sounds and pure tones.

a, Average pairwise decoding accuracy for each complex sound removing nth percentile of most influential ROIs. b, Pairwise decoder accuracy for complex sounds on population activity of responsive axon segments in animals with more than 100 responsive axon segments. All sound-pairs are significantly above chance. c, Average pairwise decoding accuracy for each pure tone removing nth percentile of most influential ROIs. d, Pairwise decoder accuracy for pure tones on population activity of responsive axon segments in animals with more than 100 responsive axon segments. 97.6 ± 0.1% of sound-pairs are significantly above chance.

Extended Data Fig. 6 Similarity in tuning between axon segments is not predicted by inter-axon distance.

a, Tuning curves of an example axon segment (black) and nearby axon segments (green). b, Pearson’s correlation between inter-axon distance and mean axon tuning correlation at each distance bin (r(59) = −0.004, P = 0.976).

Extended Data Fig. 7 Tonotopic gradient of excitatory neurons in primary auditory cortex.

a, Example field-of-view of cortical neurons in primary auditory cortex (left, CaMKII-GCaMP6f) and identified neurons colored by best frequency of cortical neurons (right) in an example animal, ‘mse236’. Analysis was performed on primary auditory cortex in four animals. Scale bar, 50 μm. b, Progression of best frequency of neurons in a along the rostro-caudal axis. Each gray dot indicates the best frequency of a neuron in frequency space (y axis) projected onto the rostro-caudal axis (x axis). Slope of line of best fit (red line) reflects progression of best frequency.

Extended Data Fig. 8 Cortical neurons are co-tuned to nearby cortical neurons but un-coupled from nearby cholinergic axons.

a, Schematic of example neuron (red) and nearby neurons (pink) and responsive axon segments (green). Scale bar, 10 μm. b, Frequency tuning curve of example neuron (black) and nearby neurons (red) and axon segments (green) in a. Shaded region indicates s.e.m. c, Histogram of Pearson’s correlation coefficient between tuning of auditory cortical neurons with nearby cortical neurons (red) and nearby axon segments (green), (D = 0.600, P < 0.001, two-sample Kolmogorov–Smirnov test).

Extended Data Fig. 9 Chemogenetic suppression of auditory thalamus and auditory cortex attenuate sound-evoked cortical responses only in animals expressing DREADDs.

a, Validation of suppression of thalamic activity using chemogenetics. Schematic of injection strategy for suppression of the MGB using hM4Di DREADDs (n = 2 animals). Inset: auditory cortical neurons expressing GCaMP6f (green). b, Evoked cortical response to pure tones after intraperitoneal saline and CNO injection (n = 95 cells for saline condition, n = 55 cells for CNO condition; F(1,1184) = 3.57, P = 0.0589, two-way ANOVA with Tukey’s HSD). Shaded region significantly responsive tones identified post saline injection (9.5–18 kHz). Error bars indicate s.e.m. c, Mean evoked response after intraperitoneal saline and CNO injection for each significantly responsive tone (n = 3 tones; t(2) = 6.12, P < 0.05, two-tailed paired t-test). d, Validation of suppression of cortical activity using chemogenetics. Schematic of injection strategy for suppression of the auditory cortex using hM4Di DREADDs (n = 2 animals). Inset: cortical neurons expressing GCaMP6f (green), inhibitory DREADDs hM4Di (red) and overlaid image. e, Evoked cortical response to pure tones after intraperitoneal saline and CNO injection (n = 232 cells for saline condition, n = 113 cells for CNO condition; F(1,2744) = 13.34, P < 0.001, two-way ANOVA with Tukey’s HSD). Shaded region represents significantly responsive tones identified post saline injection (4.8–19 kHz). Error bars indicate s.e.m. f, Mean evoked response after intraperitoneal saline and CNO injection for each significantly responsive tone (n = 5 tones; t(4) = 6.95, P < 0.01, two-tailed paired t-test). g, Schematic of injection strategy in animals without hM4Di designer receptors (n = 3 animals) h, Evoked cortical response to pure tones after intraperitoneal saline and CNO injection (n = 743 cells for saline condition, n = 664 cells for CNO condition, F(1,11240) = 0.45, P = 0.505, two-way ANOVA with Tukey’s HSD). Shaded region significantly responsive tones identified post saline injection (4.8–27 kHz and 54 kHz). Error bars indicate s.e.m. i, Mean evoked response after intraperitoneal saline and CNO injection for each significantly responsive tone (n = 7 tones; t(6) = 0.219, P = 0.834, two-tailed paired t-test).

Extended Data Fig. 10 State-dependent tonic cholinergic activity is coupled with tonic cortical activity and modulates cholinergic response to pure tones and up- and down-sweeps.

a, Fluorescence activity of neurons in one example recording site (top) and the nearby axons of the respective neurons (middle) and movement of the animal during the recording session (bottom). b, Histogram of Pearson’s correlation coefficient of cell tonic activity and tonic activity of nearby axons (red) compared to shuffled data (gray) (D = 0.718, P < 0.001, two-sample Kolmogorov–Smirnov test). c, Scatterplot of mean evoked response to 9.5–19 kHz at different tonic cholinergic baseline. Histogram for normalized tonic activity (top) and evoked response (right). d, Median evoked response to 9.5–19 kHz across range of tonic activity. Red line indicates best polynomial fit. e, Scatterplot of mean evoked response to up- and down-sweeps at different tonic cholinergic baseline. Histogram for normalized tonic activity (top) and evoked response (right). f, Median evoked response to up- and down-sweeps across range of tonic activity. Red line indicates best polynomial fit.

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Zhu, F., Elnozahy, S., Lawlor, J. et al. The cholinergic basal forebrain provides a parallel channel for state-dependent sensory signaling to auditory cortex. Nat Neurosci 26, 810–819 (2023). https://doi.org/10.1038/s41593-023-01289-5

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