Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits

Abstract

Cortico-basal ganglia-thalamic (CBT) neural circuits are critical modulators of cognitive and motor function. When compromised, these circuits contribute to neurological and psychiatric disorders, such as Parkinson's disease (PD). In PD, motor deficits correlate with the emergence of exaggerated beta frequency (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30) oscillations throughout the CBT network. However, little is known about how specific cell types within individual CBT brain regions support the generation, propagation, and interaction of oscillatory dynamics throughout the CBT circuit or how specific oscillatory dynamics are related to motor function. Here, we investigated the role of striatal cholinergic interneurons (SChIs) in generating beta and gamma oscillations in cortical-striatal circuits and in influencing movement behavior. We found that selective stimulation of SChIs via optogenetics in normal mice robustly and reversibly amplified beta and gamma oscillations that are supported by distinct mechanisms within striatal-cortical circuits. Whereas beta oscillations are supported robustly in the striatum and all layers of primary motor cortex (M1) through a muscarinic-receptor mediated mechanism, gamma oscillations are largely restricted to the striatum and the deeper layers of M1. Finally, SChI activation led to parkinsonianlike motor deficits in otherwise normal mice. These results highlight the important role of striatal cholinergic interneurons in supporting oscillations in the CBT network that are closely related to movement and parkinsonian motor symptoms.E xaggerated beta oscillations (15-30 Hz) within the cortico-basal ganglia-thalamic (CBT) neural network are putative electrophysiological correlates of bradykinesia and rigidity in Parkinson's disease (PD) (1-4). Therapies that effectively manage PD motor symptoms, such as dopamine replacement therapy and deep brain stimulation, are associated with a suppression of the exaggerated beta oscillations (4, 5). Beta oscillations are also found in the CBT circuits of patients with other movement-related disorders, such as epilepsy and dystonia (6, 7), and in normal, nonhuman primates (8, 9) and normal rodents (10, 11). Moreover, brief elevations (≤200 ms) of beta oscillations are observed in the basal ganglia of task-performing nonhuman primates and rodents during specific phases of behavioral tasks (10, 12, 13), indicating that beta oscillations may be important for motor and nonmotor functions. In contrast to the regulated temporal variability of beta oscillations in normal motor functions, temporal stability is correlated with the parkinsonian motor symptoms of bradykinesia and rigidity (2). Together, these findings suggest that brief epochs of beta oscillations are a normal aspect of basal ganglia dynamics, their temporal modulation is important for movement regulation, and loss of regulation or uncontrolled expression of beta oscillations may contribute to movement deficits, such as those observed in PD.Despite the clear link bet...

Striatal cholinergic receptor activation causes a rapid, selective and state‐dependent rise in cortico‐striatal β activity

“…In contrast to recent experimental work showing that optogenetic stimulation of striatal cholinergic interneurons (sChIs) induces broadband increases in oscillatory power in striatum and M1 (Kondabolu et al ., ), the current study shows a selective elevation of power in the β frequency range within cortico‐striatal circuits. These increases can be attributed to the stimulation of striatal cholinergic receptors.…”

“…While there is some suggestion that the striatal cholinergic system can modulate β oscillations in CBT circuits, evidence is lacking for specificity of modulation to the β frequency range. Previous studies optogenetically stimulating striatal cholinergic interneurons in normal mice elevated oscillatory power at all frequencies greater than approximately 10 Hz, including both β and broadband γ oscillations (Kondabolu et al ., ). Prior studies with carbachol‐induced β oscillations in striatum did not address specificity of elevation to the β frequency range (McCarthy et al ., ).…”

Intrastriatal administration of botulinum neurotoxin A normalizes striatal D2R binding and reduces striatal D1R binding in male hemiparkinsonian rats

“…Blockade of M 4 mAChR, located on D 1 MSNs (Lim et al, ), alleviates the akinetic dysfunction in a 6‐OHDA lesion model (Ztaou et al, ). ACh‐induced changes in electrophysiology of D 2 MSNs (Day, Wokosin, Plotkin, Tian, & Surmeier, ) provoke PD‐like akinesia in mice (Kondabolu et al, ; Maurice et al, ). In the present study, we detected dopamine receptor changes after BoNT‐A treatment, along with alleviated turning asymmetry described in the literature (Antipova et al, ; Wree et al, ).…”

Axial levodopa-induced dyskinesias and neuronal activity in the dorsal striatum

“…We do not observe consistent changes in FSI activity with dopamine depletion or repeated application of dopamine precursors. Dopamine depletion leads to complex changes in the circuitry of the striatum (Nisenbaum et al, 1986; Pang et al, 2001; Fino et al, 2007; Prosperetti et al, 2013; Corbit et al, 2016; Kondabolu et al, 2016). There have been few prior reports studying the activity of these striatal populations as LIDs develop (Picconi et al, 2003; Meissner et al, 2006; Liang et al, 2008; Belic et al, 2015).…”

“…FSIs also have dopamine receptors and provide strong feedforward inhibition of MSN activity, and thus may play a role in dyskinesias (Bracci et al, 2002; Centonze et al, 2003; Koos et al, 2004; Gittis et al, 2011b). Dopamine depletion can have complex effects on MSNs and FSIs as a result of altered input to striatum and/or remodeling of intrastriatal networks (Prosperetti et al, 2013; Corbit et al, 2016; Kondabolu et al, 2016). These may contribute to dysfunctional striatal networks and the emergence of synchrony at beta frequencies (Mallet et al, 2006; Jenkinson and Brown, 2011).…”