Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum
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Evaluation Summary:
The paper is of broad interest to neuroscientists studying Parkinson's disease, dopamine (DA) modulation and striatum. The authors use a layered in vivo calcium imaging approach with cell-type reporters and universal GCaMP expression to simultaneously evaluate striatal projection neurons in the direct and indirect pathways (dSPNs, iSPNs) during basic locomotion. The authors report relationships between dSPN and iSPN ensemble sizes and DA pharmacology and dopamine depletion states. These results advance understanding of DA modulation and Parkinson's disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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Abstract
Dopamine (DA) is a critical modulator of brain circuits that control voluntary movements, but our understanding of its influence on the activity of target neurons in vivo remains limited. Here, we use two-photon Ca 2+ imaging to monitor the activity of direct and indirect-pathway spiny projection neurons (SPNs) simultaneously in the striatum of behaving mice during acute and prolonged manipulations of DA signaling. We find that increasing and decreasing DA biases striatal activity towards the direct and indirect pathways, respectively, by changing the overall number of SPNs recruited during behavior in a manner not predicted by existing models of DA function. This modulation is drastically altered in a model of Parkinson’s disease. Our results reveal a previously unappreciated population-level influence of DA on striatal output and provide novel insights into the pathophysiology of Parkinson’s disease.
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Reviewer #3 (Public Review):
Maltese et al performed 2p imaging of both dSPNs and iSPNs at the same time, while focusing on correlates of forward locomotion. The modulation of dSPN ensembles in response to DA agonism or antagonism was mostly consistent with classic models, although they also observed an 'inverted U-shape' response to D1R agonsists. In addition, they found distinct modulation of dSPN and iSPN ensembles in DA-intact and Parkinsonian mice.
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Reviewer #2 (Public Review):
In this manuscript, the authors use in vivo calcium imaging of many individual neurons to investigate how dopamine regulates striatal dynamics. They aim to determine whether manipulations of dopamine signaling, on acute and chronic timescales, change the rate of activity in individual neurons, but also how the number of neurons activated (the size of the ensemble) may also change. This is a very important question, which is challenging to address with traditional methods in mouse models. Single-unit electrophysiology, especially in mice, yields modest numbers of neurons (typically <<50) during any one recording. In addition, acute electrophysiology tends to be biased: higher firing rates make it much easier to detect single units. In relatively quiet brain regions, including the striatum, these factors make …
Reviewer #2 (Public Review):
In this manuscript, the authors use in vivo calcium imaging of many individual neurons to investigate how dopamine regulates striatal dynamics. They aim to determine whether manipulations of dopamine signaling, on acute and chronic timescales, change the rate of activity in individual neurons, but also how the number of neurons activated (the size of the ensemble) may also change. This is a very important question, which is challenging to address with traditional methods in mouse models. Single-unit electrophysiology, especially in mice, yields modest numbers of neurons (typically <<50) during any one recording. In addition, acute electrophysiology tends to be biased: higher firing rates make it much easier to detect single units. In relatively quiet brain regions, including the striatum, these factors make it very hard to compare the total number of neurons recruited during a specific behavior across conditions.
One of the major strengths of this manuscript is that the authors make use of a strength of their method (the ability to capture activity across hundreds of neurons), rather than trying to use it merely as a surrogate for a traditional method (by measuring the rate of activity). Another strength is the alignment of neural activity to specific behavior (locomotion), and attempts to control for changes in overall behavior with each of their dopamine signaling manipulations.
Weaknesses, which the authors to some degree acknowledge, include the fact that calcium imaging is not equivalent to action potential firing; changes in the activation across a population may represent a change in the firing rate or pattern. For example, a doubling of the number of neurons that are "active" during a behavior may represent a shift of completely silent neurons to firing above a certain threshold rate, and/or a shift to burst firing mode, without a change in overall rate. Another weakness, partly driven by the head-fixed/treadmill configuration, is the laser focus on locomotion (starts, stops, velocity), though the dorsolateral striatum is likely to regulate other behaviors (grooming, licking, rearing, etc). Finally, again related to their methods, the findings are observational, shedding minimal light on the mechanisms (direct effects on SPN cell bodies? Indirect effects via local GABAergic signaling, dopamine terminals, or glutamatergic inputs?) by which dopamine signaling manipulations lead to changes in SPN ensemble activity.
Despite these weaknesses, I suspect this manuscript, together with other recent studies, will change how other basal ganglia physiologists think about neural activity. Much as the field has emphasized dynamics and synchrony as potential ways neural activity regulates behavior, hard data regarding the spatiotemporal activation of neurons is relatively new. It is also likely to be thought-provoking for investigators working on Parkinson's Disease, as it suggests more cellular/mechanistic lines of research are needed to explain the massive changes in dSPN ensemble size seen in healthy vs 6-OHDA-treated and L-DOPA treated mice.
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Reviewer #1 (Public Review):
This study investigates roles of DA modulation in projection neuron ensembles in DA-intact mice and Parkinson's disease mouse model using two-photon calcium imaging of direct and indirect SPNs (dSPNs and iSPNs) simultaneously in head-fixed mice locomoting on a freely rotating or motorized circular treadmill. The study begins with careful validation efforts related to their particular imaging conditions and reporter usage. Major findings are: 1) In DA-intact mice, they found that reducing DA receptor signaling by administration of D1/2R antagonists increased iSPN ensemble size (fraction of imaged iSPN active during locomotion) and decreased dSPNs ensemble size, resulting in an imbalance of striatal outputs in favor of indirect pathway. Consistently, elevating DA receptor signaling by D1/2R agonists yielded a …
Reviewer #1 (Public Review):
This study investigates roles of DA modulation in projection neuron ensembles in DA-intact mice and Parkinson's disease mouse model using two-photon calcium imaging of direct and indirect SPNs (dSPNs and iSPNs) simultaneously in head-fixed mice locomoting on a freely rotating or motorized circular treadmill. The study begins with careful validation efforts related to their particular imaging conditions and reporter usage. Major findings are: 1) In DA-intact mice, they found that reducing DA receptor signaling by administration of D1/2R antagonists increased iSPN ensemble size (fraction of imaged iSPN active during locomotion) and decreased dSPNs ensemble size, resulting in an imbalance of striatal outputs in favor of indirect pathway. Consistently, elevating DA receptor signaling by D1/2R agonists yielded a dose-dependent imbalance in favor of direct pathway. Interestingly, at one intermediate dose of D1/2R gonists, iSPN ensemble size remained unchanged while dSPN ensemble size increased, whereas at higher doses, both iSPN and dSPN ensemble sizes shrunk. They also showed that reward-induced and nomifensine-induced DA increase recapitulated the low and high dose effects of DA on SPNs, respectively. 2) In dopamine-depleted Parkinson's disease mouse model, the authors found that 6-hydroxydopamine (6-OHDA) treatment reduced dSPNs ensemble size acutely (within 24h) and chronically (after 30 days) and increased iSPNs ensemble size acutely. However, the active iSPN ensembles returned to pre-lesion levels within one week. Overall, ablation of SNc DA neurons biased the striatum output toward indirect pathway. Lastly, they evaluated the influence of L-DOPA on SPN ensembles in DA-depleted mice and found that l-DOPA increased the dSPNs ensembles by 10 fold and reduced the iSPN ensembles to below pre-ablation levels, resulting in strong bias toward direct pathway, a finding they suggest may relate to levodopa-induced dyskinesias. Together, this study introduces data to support the concept that SPN "ensemble size" may be relevant for long-standing pathway balance ideas concerning striatal circuitry in the control of normal movement and its demise in PD.
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Evaluation Summary:
The paper is of broad interest to neuroscientists studying Parkinson's disease, dopamine (DA) modulation and striatum. The authors use a layered in vivo calcium imaging approach with cell-type reporters and universal GCaMP expression to simultaneously evaluate striatal projection neurons in the direct and indirect pathways (dSPNs, iSPNs) during basic locomotion. The authors report relationships between dSPN and iSPN ensemble sizes and DA pharmacology and dopamine depletion states. These results advance understanding of DA modulation and Parkinson's disease.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)
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