Parvalbumin<sup>+</sup>and Npas1<sup>+</sup>Pallidal Neurons Have Distinct Circuit Topology and Function

Pamukcu, Arin; Cui, Qiaoling; Xenias, Harry S.; Berceau, Brianna L.; Augustine, Elizabeth C.; Fan, Isabel; Chalasani, Saivasudha; Hantman, Adam W.; Lerner, Talia N.; Boca, Simina M.; Chan, C. Savio

doi:10.1523/jneurosci.0361-20.2020

Cited by 59 publications

(73 citation statements)

References 183 publications

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“…At a circuit level, stimulation of iSPNs strongly suppresses firing of PV + neurons, thus disinhibiting the targets of PV + neurons, i.e., the STN and substantia nigra (Mastro et al, 2014; Hernandez et al, 2015; Saunders et al, 2016; Oh et al, 2017; Abecassis et al, 2020). As activity of PV + neurons promotes movement (Cherian et al, 2020; Pamukcu et al, 2020), the selective targeting of PV + neurons by iSPNs is in agreement with the movement suppressing role of DMS iSPNs (Kravitz et al, 2010; Durieux et al, 2012). Conversely, we found stimulation of DLS iSPNs promoted movement; this cannot be explained simply by the targeting properties of DLS iSPNs.…”

Section: Discussionsupporting

confidence: 59%

“…The distinct behavioral patterns resulting from stimulation of the same SPN types from different spatial subdomains were surprising as it is commonly assumed that the role of the dStr in the regulation of locomotor activity is generalizable across DMS and DLS. To ensure that the inference made from our observations was not simply an artifact of gain-of-function experiments with ChR2, we performed additional optogenetic interrogation with an inhibitory opsin (i.e., GtACR2) (Mahn et al, 2018; Pamukcu et al, 2020). As expected from the diametric responses induced with optogenetic stimulation of DMS dSPNs and DLS dSPNs, GtACR2 activation in DMS dSPNs and DLS dSPNs induced suppression and promotion of speed, respectively ( DMS dSPNs = –0.36 ± 0.13 fold, n = 8 mice, P = 0.016; DLS dSPNs = 0.27 ± 0.16 fold, n = 11 mice, P = 0.0020) ( Figure 3b ).…”

Section: Resultsmentioning

confidence: 99%

“…Segregation of neurotransmitter release has also been found in other systems (Zhang et al, 2015; Lee et al, 2016; Granger et al, 2020). Given that Npas1 + neurons and PV + neurons have opposite effects on motor control (Cherian et al, 2020; Pamukcu et al, 2020), the inhibition of Npas1 + neurons by GABA and excitation of PV + neurons by substance P should work in concert to reinforce the same behavioral outcomes.…”

Section: Discussionmentioning

confidence: 99%

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Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Cui¹,

Chang³

et al. 2020

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The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

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Section: Discussionsupporting

confidence: 59%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Cui¹,

Chang³

et al. 2020

Preprint

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“…Dysfunction within this circuit can be devastating, as seen in patients afflicted with Parkinson’s disease (PD) (Albin et al, 1989; DeLong, 1990; Graybiel et al, 1994; Mink, 1996; DeLong and Wichmann, 2007; Redgrave et al, 2010; Nelson and Kreitzer, 2014; Jahanshahi et al, 2015; Dudman and Krakauer, 2016; Grillner and Robertson, 2016; Klaus et al, 2019; Park et al, 2020). The external globus pallidus (GPe) is reciprocally connected with the dorsal striatum and subthalamic nucleus (STN) and is known to regulate motor output (Smith et al, 1998; Kita, 2007; Hernandez et al, 2015; Glajch et al, 2016; Hegeman et al, 2016; Pamukcu et al, 2020). Consistent with this idea, decorrelated, phasic changes in GPe neuron activity are observed with normal movements (Anderson and Horak, 1985; Shi et al, 2004; Turner and Anderson, 2005; Jin et al, 2014; Dodson et al, 2015; Mallet et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

Cherian

Cui

Pamukcu

et al. 2020

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We have previously established that PV+ neurons and Npas1+ neurons are distinct neuron classes in the GPe: they have different topographical, electrophysiological, circuit, and functional properties. Aside from Foxp2+ neurons, which are a unique subclass within the Npas1+ class, we lack driver lines that effectively capture other GPe neuron subclasses. In this study, we examined the utility of Kcng4-Cre, Npr3-Cre, and Npy2r-Cre mouse lines (both males and females) for the delineation of GPe neuron subtypes. By using these novel driver lines, we have provided the most exhaustive investigation of electrophysiological studies of GPe neuron subtypes to date. Corroborating our prior studies, GPe neurons can be divided into two statistically distinct clusters that map onto PV+ and Npas1+ classes. By combining optogenetics,, and machine learning-based tracking, we showed that optogenetic perturbation of GPe neuron subtypes generated unique behavioral structures. Our findings further highlighted the dissociable roles of GPe neurons in regulating movement and anxiety. We concluded that Npr3+ neurons and Kcng4+ neurons are distinct subclasses of Npas1+ neurons and PV+ neurons, respectively. Finally, by examining local collateral connectivity, we inferred the circuit mechanisms involved in the motor patterns observed with optogenetic perturbations. In summary, by identifying mouse lines that allow for manipulations of GPe neuron subtypes, we created new opportunities for interrogations of cellular and circuit substrates that can be important for motor function and dysfunction.

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“…The regulation of "arkypallidal" neuron activity by PV+ GPe neurons in vivo is consistent with powerful GABAergic inhibition of arkypallidal neurons by prototypic GPe neurons (Mallet et al, 2012;Aristieta et al, 2020;Ketzef and Silberberg, 2020). However, optogenetic silencing of prototypic PV+ GPe neurons also disinhibited hypoactive STN neurons, and given that STN neurons innervate arkypallidal neurons (Aristieta et al, 2020;Pamukcu et al, 2020), it is also possible that STN disinhibition contributed to the rescue of arkypallidal neuron firing in Q175 mice. The finding that the autonomous firing of putative arkypallidal neurons was unaffected in brain slices from Q175 mice further suggests that synaptic mechanisms are responsible for the hypoactivity of arkypallidal neurons in Q175 mice.…”

Section: Prototypic Pv+ Gpe and Arkypallidal Neuron Activitymentioning

confidence: 66%

Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington’s disease

Callahan

Wokosin

Bevan

2021

Preprint

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The psychomotor symptoms of Huntington’s disease (HD) are linked to degeneration of the basal ganglia indirect pathway. To determine how this pathway is perturbed prior to cell loss, optogenetic- and reporter-guided electrophysiological interrogation approaches were applied to early symptomatic 6-month-old Q175 HD mice. Although cortical activity was unaffected, indirect pathway striatal projection neurons were hypoactive in vivo, consistent with reduced cortical input strength and dendritic excitability. Downstream parvalbumin-expressing prototypic external globus pallidus (GPe) neurons were hyperactive in vivo and exhibited elevated autonomous firing ex vivo. Optogenetic inhibition of prototypic GPe neurons ameliorated the abnormal hypoactivity of postsynaptic subthalamic nucleus (STN) and putative arkypallidal neurons in vivo. In contrast to STN neurons, autonomous arkypallidal activity was unimpaired ex vivo. Together with previous studies, these findings demonstrate that basal ganglia indirect pathway neurons are highly dysregulated in Q175 mice through changes in presynaptic activity and/or intrinsic properties 6-12 months before cell loss.

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Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Cited by 59 publications

References 183 publications

Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington’s disease

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Parvalbumin+and Npas1+Pallidal Neurons Have Distinct Circuit Topology and Function

Cited by 59 publications

References 183 publications

Striatal Direct Pathway Targets Npas1+Pallidal Neurons

Striatal Direct Pathway Targets Npas1+Pallidal Neurons

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

Dysregulation of the basal ganglia indirect pathway prior to cell loss in the Q175 mouse model of Huntington’s disease

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Parvalbumin⁺and Npas1⁺Pallidal Neurons Have Distinct Circuit Topology and Function

Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons

Striatal Direct Pathway Targets Npas1⁺Pallidal Neurons