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

Abstract

The external globus pallidus (GPe) is a critical node within the basal ganglia circuit. Phasic changes in the activity of GPe neurons during movement and their alterations in Parkinson’s disease (PD) argue that the GPe is important in motor control. PV+ neurons and Npas1+ neurons are the two principal neuron classes in the GPe. The distinct electrophysiological properties and axonal projection patterns argue that these two neuron classes serve different roles in regulating motor output. However, the causal relationship between GPe neuron classes and movement remains to be established. Here, by using optogenetic approaches in mice (both males and females), we showed that PV+ neurons and Npas1+ neurons promoted and suppressed locomotion, respectively. Moreover, PV+ neurons and Npas1+ neurons are under different synaptic influences from the subthalamic nucleus (STN). Additionally, we found a selective weakening of STN inputs to PV+ neurons in the chronic 6-hydroxydopamine lesion model of PD. This finding reinforces the idea that the reciprocally connected GPe-STN network plays a key role in disease symptomatology and thus provides the basis for future circuit-based therapies.Significance StatementThe external pallidum is a key, yet an understudied component of the basal ganglia. Neural activity in the pallidum goes awry in neurological diseases, such as Parkinson’s disease. While this strongly argues that the pallidum plays a critical role in motor control, it has been difficult to establish the causal relationship between pallidal activity and motor (dys)function. This was in part due to the cellular complexity of the pallidum. Here, we showed that the two principal neuron types in the pallidum have opposing roles in motor control. In addition, we described the differences in their synaptic influence. Importantly, our research provides new insights into the cellular and circuit mechanisms that explain the hypokinetic features of Parkinson’s disease.

Differential Synaptic Input to External Globus Pallidus Neuronal SubpopulationsIn Vivo

“…The STN is reciprocally connected to the GPe and has been considered to be the main source of excitatory input to the GPe (Kita et al, 1983; Kita and Kitai, 1991; Pamukcu et al, 2020). To study the STN inputs to GPe, we expressed ChR2 in STN neurons using retrograde viral transduction in vglut2-Cre mice (Figure 5 A, see methods).…”

Dissociable Roles of Pallidal Neuron Subtypes in Regulating Motor Patterns

“…To allow for optogenetic manipulations, fiber optic cannulae were implanted bilaterally at the region of interest (Pamukcu et al, 2020) three weeks after stereotaxic injections. Each fiber cannula was assembled with an optical fiber (0.66 NA, 250 µm core) (Prizmatix) secured into a zirconia ferrule (1.25 mm O.D.)…”

“…Our previous studies established that PV + neurons and Npas1 + neurons play causal, but opposite roles in regulating locomotion-PV + neurons are movement-promoting and Npas1 + neurons are movement-suppressing (Glajch et al, 2016;Pamukcu et al, 2020). Consistent with our earlier observations, our analysis here showed that mice exhibited more mobile behavior (i.e., locomotion) when PV + neurons were optogenetically stimulated and more immobile behavior (i.e., fine movement and motionless) when Npas1 + neurons were optogenetically stimulated.…”

“…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 (dStr) and subthalamic nucleus (STN) and is expected 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).…”

Striatal Direct Pathway Targets Npas1+Pallidal Neurons

“…As the GPe contains a heterogenous population of neurons (Hernandez et al, 2015;Hegeman et al, 2016;Saunders et al, 2018;Abecassis et al, 2020;Cherian et al, 2020), the identity of neurons that receive dSPN input remains elusive. As we have established PV + neurons and Npas1 + neurons in the GPe have distinct circuit and functional roles (Cherian et al, 2020;Pamukcu et al, 2020), we hypothesized that dSPNs regulate motor output by targeting a select subset of these neurons. Here, using transgenic and molecular tools, we dissected the cellular and spatial organization of the striatopallidal system; using in vivo optogenetics and machine-learning approaches, we studied the behavioral relevance of the striatopallidal subcircuits.…”