Anatomically segregated basal ganglia pathways allow parallel behavioral modulation

Abstract

In the basal ganglia (BG), anatomically segregated and topographically organized feedforward circuits are thought to modulate multiple behaviors in parallel. Although topographically arranged BG circuits have been described, the extent to which these relationships are maintained across the BG output nuclei and in downstream targets is unclear. Here, using focal trans-synaptic anterograde tracing, we show that the motor-action-related topographical organization of the striatum is preserved in all BG output nuclei. The topography is also maintained downstream of the BG and in multiple parallel closed loops that provide striatal input. Furthermore, focal activation of two distinct striatal regions induces either licking or turning, consistent with their respective anatomical targets of projection outside of the BG. Our results confirm the parallel model of BG function and suggest that the integration and competition of information relating to different behavior occur largely outside of the BG.

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Fig. 1: Topographically organized projection from BG input to output nuclei.
Fig. 2: Projections of BG output nuclei to downstream targets maintain segregated topography.
Fig. 3: The BG output via Pf forms segregated and closed loops.
Fig. 4: BG output via VM forms segregated closed loops via cortical layer 1.
Fig. 5: Focal optogenetic stimulation of neurons in striatum using TF optics.
Fig. 6: Stimulation of direct pathway projection neurons in VLS induces contralateral licking.
Fig. 7: dSPN stimulation outside of VLS does not interfere with cue-evoked licking.
Fig. 8: DMS and VMS direct pathway stimulation induce contralateral turning.

Data availability

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

Code availability

The code used for analysis (MATLAB) is also available from the corresponding author upon reasonable request. Detailed information about software and methods used is available online in the Nature Research Reporting Summary.

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Acknowledgements

We thank members of the Sabatini laboratory, W. Regehr, M. Andermann and N. Uchida for discussions. We thank J. Levasseur for mouse husbandry and genotyping, and J. Saulnier and L. Worth for laboratory administration. We thank W. Kuwamoto, J. Grande, M. Ambrosino, B. Pryor and E. Lubbers for assistance with behavioral experiments and histology. This work was supported by the NIH (grant no. NINDS R01NS103226), a P30 Core Center Grant (grant no. NINDS NS072030), an Iljou Foundation scholarship and a grant from the Simons Collaborative on the Global Brain.

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Contributions

J.L. and B.L.S. conceptualized the study, wrote the original draft, and reviewed and edited the manuscript. J.L. performed and participated in all experiments and W.W. performed the slice electrophysiology experiments. B.L.S. supervised the study and was responsible for acquisition of funding.

Corresponding author

Correspondence to Bernardo L. Sabatini.

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Competing interests

B.L.S. is a founder of and holds private equity in Optogenix. Tapered fibers commercially available from Optogenix were used as tools in the research.

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Peer review information Nature Neuroscience thanks Marc Fuccillo and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Extended Data Fig. 1 Topography is maintained across the AP axis of SNr.

a, Example histology section in anterior SNr and posterior SNr (see main text and methods for injection protocol). Row represent AP coordinates and each column indicates the location of the AAV1.cre for anterograde tracing (see main text). Scale bar, 500um. Topographical labelling was also observed in anterior part of SNr. Similar results were obtained in n = 9 mice (n = 3 for each site).

Extended Data Fig. 2 EP to LHb projection is topographic.

a, Experiment protocol. AAV1-cre and AAV1-Flpo in medial and lateral striatum respectively, followed by a cocktail of viruses encoding either DIO-Tdtom or fDIO-EYFP in EP. b, left, histological sections showing the anterogradely labelled cells from medial (red) and lateral (green) striatum. right, Axonal fibers innervating LHb in a non-overlapping fashion. Similar results were obtained in n = 2 mice. Scale bar, 1mm, 1mm, 0.1mm from left to right panel.

Extended Data Fig. 3 Topography of SNr output is consistent across mice.

a, Histology sections for all injected mice for experiment in Fig. 2c. First row represents column the injection site, and second to fourth column represent axonal fibers in Pf, VM and SC. Each row represents individual mouse. Scale bar, 250um.

Extended Data Fig. 4 SNr output to SC segregated both across medial-lateral axis and across layers.

a, left, Example histology section with mSNr axons (red) and lSNr axons (green) from experiment described in Fig. 2c. right, Cartoon diagram summarizing the region and layer specificity of lSNr and mSNr observed. lSNr innervated the lateral SC (abbreviations: Zo: Zona layer of the superior colliculus, Op: optic nerve layer of the superior colliculus, InG: Intermediate gray layer of the superior colliculus, InWh: Intermediate white layer of the superior colliculus, DpG: Deep gray layer of the superior colliculus). lSNr innervated the lSC in InWh, and extending to upper layer of InWh in mSC. mSNr innervated the superfifical part of InG and deeper part of InWh in mSC. Similar results were obtained in n = 4 mice. Scale bar, 500um. b, left, Example histological section with VLSSNr (yellow), DLSSNr (cyan), and DMSSNr (magenta) axons in SC (images reproduced from Fig. 2f). right, Carton diagram summarizing the region and layer specificity of VLSSNr, DLSSNr, and DMSSNr observed. VLSSNr targeted the InWh part of lSC, DLSSNr targeted the central part of SC, extending to the upper layer of InWh in mSC, and DMSSNr targeted the upper InG and the lower InWh. Thus, lSNr axons seem to be a combination of VLSSNr and DLSSNr. Scale bar, 500um. Similar results were obtained in n = 9 mice, 3 for each site.

Extended Data Fig. 5 SNr output to Zona Incerta is topographically organized.

a, Example coronal section showing mSNr (red:TdTom)and lSNr (green:EYFP) axon fibers in zona incerta, from experiment described in Fig. 2a. Similar results were obtained in n = 4 mice. b, Example coronal sections showing DMSSNr (magenta:TdTom), DLSSNr (cyan:TdTom) and VLSSNr (yellow:TdTom), axon fibers in zona incerta, from experiment described in Fig. 2e. Similar results were obtained in n = 9 mice, n = 3 for each site.

Extended Data Fig. 6 Brain regions targeted by SNr.

a, Example histology section of brain regions targeted by DMSSNr, DLSSNr, and VLSSNr. Each row represent a brain region, and each column is a different SNr subpopulation labelled from distinct striatal regions (see experiment described in Fig. 2e). b, top left, Quantification of normalized fluorescence intensity across brain regions for DMSSNr, DLSSNr, and VLSSNr (see Methods). bottom right, Similar quantification of brain stem regions, IRt and PCRt, but normalized only to total fluorescence in brain stem. Abbreviations. VM/VA: ventromedial/ventral anterior thalamus, PC/CL/CM: paracentral/centrolateral/central medial thalamus, Pf: parafascicular nucleus, LH: lateral hypothalamus, IC: inferior colliculus, SC: superior colliculus, ZI: zona incerta, PAG: paracqeuductal gray, MA3: medial accessory oculomotor nucleus, MLR: mesencephalic locomotor region, PnO: pontine reticular nucleus, oral part, LDTg: laterodorsal tegmental nucleus, PB: parabrachical nuecleus, IRt: intermediate reticular nucleus, PCRt: parvicellular reticular nucelus, Gi: gigantocellular reticular nucleus (DMSSNr: n=2 mice; DLSSNr: n=3 mice; VLSSNr: n=3 mice).

Extended Data Fig. 7 Anterogradely labelled putative dopamine axons in striatum.

a, Example coronal sections showing putative dopamine axons in striatum (from experiment described in Fig. 2e). Each row represent a distinct striatal injection of AAV1.cre from DMS, DLS and VLS. Injection site is shown in green (H2b-EGFP), dopamine axons in red (TdTom). For all three striatal injections, dopamine axons tend to co-localize with the injection site. Similar results were obtained in n = 9 mice, 3 for each site. b, Schematic showing experiment for validating that the axons observed in striatum are dopamine axons. AAV1-Flpo was injected striatum, followed by a mixture of AAV-DIO-TdTom and AAV-Coff/Fon-EYFP in SNr/SNc, in a Slc6a3-IRES-Cre mouse, where Cre is expressed in dopamine neurons. This allowed us to anterogradely label SNr neurons, similar to experiment in Fig. 2e, but excluding the dopamine neurons (DA-/STR recipient), while also labelling dopamine neurons as a control. c, Example sagittal section showing the injection site. Dopamine neurons are expressing TdTom (red) whereas non-dopaminergic/anterogradely labelled cells are expressing EYFP (green). Similar results were obtained in n = 2 mice. d, Sagittal sections showing axons in striatum (left), thalamus (middle) and SC (right). Dopaminergic axons (red:TdTom) were only seen in striatum, whereas non-dopaminergic/striatal recipient axon (green:EYFP) were only seen in thalamus and SC. Given the lack of EYFP fibers in striatum, axons seen in striatum from anterograde tracing at striatum (experiment in Fig. 2e) likely are dopamine axons. Similar results were obtained in n = 2 mice.

Extended Data Fig. 8 SC projects back to Pf and VM in a topographical fashion.

a, Overlap of SNr axons labelled via anterograde tracing in striatum (AAV1.Cre, see Fig. 2e) and cortical axons. Scale bar, 500um. bottom, from Allen Institute for Brain Science. Allen Mouse Brain Connectivity Atlas (2011). Available from https://connectivity.brain-map.org/. b, Experimental protocol for labelling medial and lateral SC. Two anterograde tracers (AAV1.Cre and AAV1.Flpo) were injected in ACA/tjM1 respectively, followed by AAV.DIO.TdTom or AAV.fDIO.EYFP in medial or lateral SC. This allowed labelling of mSC and lSC without leaking into other regions outside SC. c, Example coronal section showing the injection site in SC (mSC in red, lSC in green). Similar results were obtained in n = 3 mice. Scale bar, 1mm. d, Example coronal sections showing the axonal targets of mSC and lSC. We observed topography in both Pf and VM, similar to SNr topography (see main Text). Similar results were obtained in n = 3 mice. Scale bar, 1mm.

Extended Data Fig. 9 Detailed optical setup for TF stimulation.

The optical setup allows depth dependent optical illumination combined with TF. The main components are: P1: pockel cell (or any power modulator), S1: shutter, M1: piezo mirror, M3: small mirror (0.5” diameter), M2: galvo mirror, L1: Achromatic doublet (AC508-200-A-ML, f=200mm, diameter 2”, Thorlabs), L2: Aspheric condenser (ACL5040-A, f=40mm, diameter 50mm, Thorlabs), X1: XY translation cage mount + Z-axis translation mount (Thorlabs). M2 galvo mirror was used to change the incident angle onto the patchcord attached at the end of X1. M1 was used to correct for any misalignment for each angle.

Extended Data Fig. 10 dSPNs VLS stimulation engage cortical and collicular BG loops.

a, Schematic showing protocol for recording activity in tjM1 and lSC while stimulating VLS dSPNs. Mice were implanted with a single tapered fiber targeting VLS, and injected with AAV-DIO-CoChR in VLS, similar to experiment described in Fig. 6a (see methods). Extracellular recording with a silicon probe was done in tjM1 and lSC, on the same side (right hemisphere) as the stimulation side in striatum (n = 2 mice). b, Mean firing rate during the inter-trial-interval where mice were required to withhold licking, and during which VLS dSPNs stimulation caused contralateral licking (Fig. 6). Mean firing rate of both tjM1 (left) and lSC (right) increased during stimulation (blue, 100 ms stim) relative to no stimulation trial (grey). Shaded light blue represents laser on period (100ms) (n = 102 units in tjM1, n = 65 units in lSC) (mean ± s.e.m across neurons). c, Fraction of cells that were significantly modulated by dSPNs stimulation in VLS in tjM1 (top) and SC (bottom). Cells are categorized into either excited (blue), inhibited (red) or no sigficant change (grey). The majority of cells recorded (53% in tjM1, 68% in lSC) were excited by the stimulation (0-500 ms window relative to laser onset, p<0.05, Mann–Whitney U test, see Methods). d, Mean firing rate, during tone presentation, of cells that were significantly modulated during ITI stimulation. Firing rate for tjM1 (left) and lSC (right) in left trials and right trials. Firing rate during no stim (grey) and during stim trials (blue). Shaded light blue represents laser on period (100ms) (n=102 units in tjM1, n=65 units in lSC) (mean ± s.e.m across neurons).

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Lee, J., Wang, W. & Sabatini, B.L. Anatomically segregated basal ganglia pathways allow parallel behavioral modulation. Nat Neurosci 23, 1388–1398 (2020). https://doi.org/10.1038/s41593-020-00712-5

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