Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types

Abstract

Basal forebrain cholinergic neurons (BFCNs) modulate synaptic plasticity, cortical processing, brain states and oscillations. However, whether distinct types of BFCNs support different functions remains unclear. Therefore, we recorded BFCNs in vivo, to examine their behavioral functions, and in vitro, to study their intrinsic properties. We identified two distinct types of BFCNs that differ in their firing modes, synchronization properties and behavioral correlates. Bursting cholinergic neurons (Burst-BFCNs) fired synchronously, phase-locked to cortical theta activity and fired precisely timed bursts after reward and punishment. Regular-firing cholinergic neurons (Reg-BFCNs) were found predominantly in the posterior basal forebrain, displayed strong theta rhythmicity and responded with precise single spikes after behavioral outcomes. In an auditory detection task, synchronization of Burst-BFCNs to the auditory cortex predicted the timing of behavioral responses, whereas tone-evoked cortical coupling of Reg-BFCNs predicted correct detections. We propose that differential recruitment of two basal forebrain cholinergic neuron types generates behavior-specific cortical activation.

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Fig. 1: In vivo recordings revealed two types of central cholinergic neurons, Burst-BFCNs and Reg-BFCNs.
Fig. 2: In vitro recordings confirmed two types of central cholinergic neurons.
Fig. 3: Cholinergic bursts transmit phasic information about reinforcers.
Fig. 4: Bursting cholinergic neurons show synchronous activity.
Fig. 5: Cholinergic bursts are coupled to cortical activity.
Fig. 6: Cortex–BFCN synchrony predicts behavior in an auditory detection task.
Fig. 7: The horizontal diagonal band contains few regular firing cholinergic neurons.
Fig. 8: Tonic and phasic cholinergic effects.

Data availability

Statistics source data underlying the figures are provided in Excel format. The datasets analyzed during the current study are available from the corresponding author on reasonable request.

Code availability

Data analysis was performed by built-in and custom written Matlab code (Mathworks) available at: https://github.com/hangyabalazs/nb_sync_subimtted.

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Acknowledgements

We thank J. Szabadics, V. Varga, L. Acsády, N. Hádinger and G. Buzsáki for insightful discussions and comments on the manuscript and K. Sviatkó for help with graphics in Fig. 8. This work was supported by the ‘Lendület’ Program of the Hungarian Academy of Sciences (LP2015-2/2015), NKFIH KH125294 and the European Research Council Starting (grant no. 715043) to B.H., NKFIH K115441 and KH124345 to A.G., NINDS R01NS088661, R01NS075531 and McKnight Cognitive Disorders Award to A.K., ÚNKP-19-3 New National Excellence Program of the Ministry for Innovation and Technology to P.H., and EFOP-3.6.3-VEKOP-16-2017-00009 to D.S. and T.L. B.H. is a member of the FENS-Kavli Network of Excellence.

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Authors

Contributions

B.H. conceived the project, B.H. recorded in vivo data under the supervision of A.K. P.H. recorded in vivo data under the supervision of B.H. D.S. recorded and analyzed in vitro data under the supervision of A.G. and T.F.F. T.L., P.H. and B.H. analyzed in vivo data. B.H., T.L. and D.S. wrote the manuscript, with comments from all authors.

Corresponding author

Correspondence to Balázs Hangya.

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The authors declare no competing interests.

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Peer review information Nature Neuroscience thanks Anita Disney, Shih-Chieh Lin 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 Optogenetically identified and putative cholinergic neurons behave similarly.

a, Average auto-correlogram of Burst-BFCN-SBs (red), Burst-BFCN-PLs (orange) and Reg-BFCNs (green). Left, optogenetically identified; right, putative. While nominal normalized magnitudes may differ due to varying noise levels and moderate sample sizes, the auto-correlation curves are qualitatively similar. Solid lines, mean; shading, s.e.m. b, Response to punishment of identified cholinergic neurons (left, identified NB; right, identified HDB). Solid lines, mean; shading, s.e.m. c, Response to punishment of putative cholinergic neurons. HDB neurons showed somewhat slower and more variable responses. Note also the longer response latencies of two regular pChAT neurons. Solid lines, mean; shading, s.e.m. d, Burst index vs. relative refractory period for identified (circle; red, n = 26 Burst-BFCN-SBs; orange, n = 17 Burst-BFCN-PLs; green, n = 13 Reg-BFCNs) and putative (triangle; red, n = 12 Burst-BFCN-SBs; orange, n = 8 Burst-BFCN-PLs; green, n = 2 Reg-BFCNs) cholinergic neurons. e, Pearson’s correlation between theta index and relative refractory period. No systematic difference between identified (circle; red, n = 26 Burst-BFCN-SBs; orange, n = 17 Burst-BFCN-PLs; green, n = 13 Reg-BFCNs) and putative (triangle; red, n = 12 Burst-BFCN-SBs; orange, n = 8 Burst-BFCN-PLs; green, n = 2 Reg- BFCNs) cholinergic neurons were detected (p = 0.0007 for n = 15 Reg-BFCNs, one-sided F-test, F(1,13) = 19.67). f, Baseline firing rate did not show systematic differences between identified (circle; red, n = 26 Burst-BFCN-SBs; orange, n = 17 Burst-BFCN-PLs; green, n = 13 Reg-BFCNs) and putative (triangle; red, n = 12 Burst-BFCN-SBs; orange, n = 8 Burst-BFCN-PLs; green, n = 2 Reg-BFCNs) cholinergic neurons. Source data

Extended Data Fig. 2 Burst selectivity and model fitting.

a, Identified (left, p = 0.00021, two-sided Wilcoxon signed rank test) and putative (right, p = 0.0005, two-sided Wilcoxon signed rank test) Burst-BFCN-SBs exhibited similar burst selectivity. Solid lines, mean; shading, s.e.m.; bars, median. b, The same for Burst-BFCN-PLs (left, identified, p = 0.0084, two-sided Wilcoxon signed rank test; right, putative, p = 0.0078, two-sided Wilcoxon signed rank test). Solid lines, mean; shading, s.e.m.; bars, median. c, A mixture of Gaussian distributions from 1 to 5 modes were fitted on the logarithm of refractory period distribution. Refractory period of BFCNs (n = 78) showed bimodal distribution, confirmed by AIC (red) and BIC (blue) model selection measures (lowest value corresponds to best fit model). Source data

Extended Data Fig. 3 Many regular rhythmic basal forebrain neurons are cholinergic.

a-c, Auto-correlations of untagged bursting (a), Poisson-like (b), and regular rhythmic (c) NB neurons. d, Average auto-correlations (red, n = 559 untagged strongly bursting; orange, n = 692 Poisson-like; green, n = 17 regular rhythmic basal forebrain neurons). Solid lines, mean; shading, s.e.m. e, Scatter plot showing burst index and refractory period of the same neurons. f, Pearson’s correlation between refractory period and theta index (p = 6.36 × 10-6 for n = 17 regular rhythmic basal forebrain neurons (green), one-sided F-test, F(1,15) = 45.77; red, n = 559 untagged strongly bursting; orange, n = 692 Poisson-like basal forebrain neurons). g, Median theta index (red, n = 559 untagged strongly bursting; orange, n = 692 Poisson-like; green, n = 17 regular rhythmic basal forebrain neurons; ***, p < 0.001; strongly bursting vs. Poisson-like, p = 1.99 × 10-24; strongly bursting vs. regular rhythmic, p = 4.41 × 10-8; Poisson-like vs. regular rhythmic, 6.04 × 10-11; two-sided Mann-Whitney U-test). Bars, median. h, Predictive value of regular rhythmic firing pattern for cholinergic identity as a function of relative refractory period. Black line and right y-axis correspond to the ratio of (identified or putative) cholinergic neurons to all neurons in the bin. Source data

Extended Data Fig. 4 Similar testing conditions resulted in robust spike delay difference between Burst-BFCNs and Reg-BFCNs, while spike delays were comparable at depolarized membrane potentials.

a, Statistical comparison of spike delay as function of pre-polarization membrane potential. To confirm that late spiking property of Reg-BFCNs was not due to different testing conditions, we compared pre-polarization membrane potentials between groups (n = 31 late-firing and n = 29 early firing cholinergic cells, two-sample, two-sided Kolmogorov-Smirnov test). Bars show median. b, Example traces of a Reg-BFCN (left) and Burst-BFCN (right) spike response at hyperpolarized and depolarized membrane potentials. Note that the late-firing property of Reg-BFCNs is characteristic to hyperpolarized membrane potentials. c, Minimum spike delay of each recorded cell vs. burst index (green, Reg-BFCNs; red, Burst-BFCNs). d, Minimum spike delay group statistics (n = 31 late-firing and n = 29 early firing cholinergic cells). Box-whisker plots show median, interquartile range, non-outlier range and outliers. Source data

Extended Data Fig. 5 Cholinergic bursts transmit phasic information about reinforcers.

a, Raster plots (left) and corresponding peri-event time histograms (PETH, right) aligned to reward (blue) and punishment (brown) of a Reg-BFCN. After the precise phasic response, the intrinsic theta oscillation resumes. b, Raster plots (left) and corresponding PETHs (right) aligned to reward (blue) and punishment (brown) of an optogenetically identified tonically active cholinergic interneuron (TAN) recorded from the nucleus accumbens. Note the lack of precisely timed action potentials after reinforcement. Instead, TANs show well-characterized so-called ‘pause-burst’ responses after reward. c, Average PETH aligned to reward (blue) and punishment (brown) at two different time scales of n = 5 optogenetically identified TANs from caudate putamen (n = 3) and nucleus accumbens (n = 2) Solid lines, mean; shading, s.e.m. d, PETHs aligned to punishment (left) and reward (right) for all recorder TANs. e, Burst-BFCN-PLs showed similar burst selectivity after punishment as Burst-BFCN-SBs (p = 0.0004, two-sided Wilcoxon signed rank test). Solid lines, mean; shading, s.e.m.; bars, median. f, BFCNs responded phasically to reward (red, n = 38 Burst-BFCN-SBs; orange, n = 25 Burst-BFCN-PLs; green, n = 15 Reg-BFCNs). Solid lines, mean; shading, s.e.m. g, Bursts of Burst-BFCN-SBs (n = 33) appeared selectively after reward (p = 0.0093, two-sided Wilcoxon signed rank test). Solid lines, mean; shading, s.e.m.; bars, median. Source data

Extended Data Fig. 6 Individual cross-correlations for all BFCN pairs.

a, Pairs of Burst-BFCN-SBs. b, Pairs containing Burst-BFCN-PLs and Burst-BFCN-SBs. c, Pairs containing Reg-BFCNs. Grey lines indicate 95% bootstrap confidence intervals calculated with the shift predictor method.

Extended Data Fig. 7 Bursting and regular rhythmic cholinergic neurons respond differently to hyperpolarization in vitro.

a, Peak latency statistics of auditory LFP average triggered on BF spikes in vivo (see Fig. 5b-c; red, n = 16 Burst-BFCN-SBs; orange, n = 12 Burst-BFCN-PLs; green, n = 9 Reg-BFCNs; *, p < 0.05; Burst-BFCN-SBs vs. Burst- BFCN-PLs, p = 0.546; Burst-BFCN-SBs vs. Reg-BFCNs, p = 0.014; Burst-BFCN-PLs vs. Reg-BFCNs, p = 0.017; two-sided Mann-Whitney U-test). Bars, median. b, Representative responses of a Burst-BFCN (top, red) and Reg-BFCN (bottom, green) upon short (20 ms) hyperpolarizing somatic current injection in vitro. Spike rasters of 30 consecutive current injection sessions are displayed below. c, Distribution of the first spike latencies following hyperpolarization. Individual cells (horizontal bar plots) are shown above summary histogram (red, n = 4 Burst-BFCNs, green, n = 6 Reg-BFCNs, p = 6.47 × 10-44, two-sided Mann-Whitney U-test; box plots show median, interquartile range and non-outlier range). Source data

Extended Data Fig. 8 Some auditory cortical neurons are synchronous with local LFP.

a-d, Example cortical neurons that show synchrony with local LFP. Left, STA; middle, STS power; right, STS phase (a, n = 50000 spikes; b, n = 21765 spikes; c, n = 4083 spikes; d, n = 7834 spikes). Solid line, mean; shading, s.e.m.

Extended Data Fig. 9 HDB contains few regular rhythmic neurons.

Auto-correlograms of all unidentified HDB neurons (left, bursting, n = 274; middle, Poisson-like, n = 274; right, regular rhythmic, n = 12). HDB had only 12/560 regular rhythmic neurons.

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Laszlovszky, T., Schlingloff, D., Hegedüs, P. et al. Distinct synchronization, cortical coupling and behavioral function of two basal forebrain cholinergic neuron types. Nat Neurosci (2020). https://doi.org/10.1038/s41593-020-0648-0

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