A Population of Indirect Pathway Striatal Projection Neurons Is Selectively Entrained to Parkinsonian Beta Oscillations

Abstract

Classical schemes of basal ganglia organization posit that parkinsonian movement difficulties presenting after striatal dopamine depletion stem from the disproportionate firing rates of spiny projection neurons (SPNs) therein. There remains, however, a pressing need to elucidate striatal SPN firing in the context of the synchronized network oscillations that are abnormally exaggerated in cortical–basal ganglia circuits in parkinsonism. To address this, we recorded unit activities in the dorsal striatum of dopamine-intact and dopamine-depleted rats during two brain states, respectively defined by cortical slow-wave activity (SWA) and activation. Dopamine depletion escalated striatal net output but had contrasting effects on “direct pathway” SPNs (dSPNs) and “indirect pathway” SPNs (iSPNs); their firing rates became imbalanced, and they disparately engaged in network oscillations. Disturbed striatal activity dynamics relating to the slow (∼1 Hz) oscillations prevalent during SWA partly generalized to the exaggerated beta-frequency (15–30 Hz) oscillations arising during cortical activation. In both cases, SPNs exhibited higher incidences of phase-locked firing to ongoing cortical oscillations, and SPN ensembles showed higher levels of rhythmic correlated firing, after dopamine depletion. Importantly, in dopamine-depleted striatum, a widespread population of iSPNs, which often displayed excessive firing rates and aberrant phase-locked firing to cortical beta oscillations, preferentially and excessively synchronized their firing at beta frequencies. Conversely, dSPNs were neither hyperactive nor synchronized to a large extent during cortical activation. These data collectively demonstrate a cell type-selective entrainment of SPN firing to parkinsonian beta oscillations. We conclude that a population of overactive, excessively synchronized iSPNs could orchestrate these pathological rhythms in basal ganglia circuits.SIGNIFICANCE STATEMENT Chronic depletion of dopamine from the striatum, a part of the basal ganglia, causes some symptoms of Parkinson's disease. Here, we elucidate how dopamine depletion alters striatal neuron firing in vivo, with an emphasis on defining whether and how spiny projection neurons (SPNs) engage in the synchronized beta-frequency (15–30 Hz) oscillations that become pathologically exaggerated throughout basal ganglia circuits in parkinsonism. We discovered that a select population of so-called “indirect pathway” SPNs not only fire at abnormally high rates, but are also particularly prone to being recruited to exaggerated beta oscillations. Our results provide an important link between two complementary theories that explain the presentation of disease symptoms on the basis of changes in firing rate or firing synchronization/rhythmicity.

Synchronized activation of striatal direct and indirect pathways underlies the behavior in unilateral dopamine‐depleted mice

“…The synchronization of striatal cells is common to both studies, with the Sharott et al. () having correlated the synchronous discharges of D2 cells with beta frequencies in the EEG in their anaesthetized animals; an effect we could not test in vitro. Parker et al.…”

Focused ultrasound in Parkinson's disease: A twofold path toward disease modification

“…An additional complementary possibility to explain glutamate‐dependent neuroprotection comes from our cortical pathogenic theory of PD, which directs attention to corticostriatal and more generally corticofugal, glutamatergic projections . In animal models of dopamine depletion and indirectly in PD patients, exaggerated corticostriatal activity is well documented in terms of excessive beta oscillations during wakefulness and abnormal slow‐wave activity during sleep . Subthalamotomy, but also STN‐DBS, drug treatment, and any intervention that tends to normalize the parkinsonian motor circuitopathy, may decrease corticostriatal drive .…”

Beta Oscillations and Indirect Pathway Spiny Projecting Neurons: A Selective Neuronal Mechanism Linked to Parkinsonian Pathophysiology?

“…Although this held true for both iSPN and dSPN during SWA in 6‐OHDA lesioned rats, increased firing rates in iSPNs, but not dSPNs, during the activation state recordings was identified. Furthermore, half of the identified iSPNs demonstrated this irregular firing was phase locked to the troughs of beta oscillations . It is well known that the 6‐OHDA lesioned rat models cause DA depletion in the striatum resulting from cell death of the SNpc neurons, which mirrors the dopamine‐related pathophysiology of human idiopathic PD.…”

“…Recently, Sharott and colleagues explored the potential link between dSPN/iSPN spike‐timing imbalances and exaggerated beta oscillations by examining in vivo single‐unit and electrocorticogram SPNs activity in the dorsal striatum in male rats with or without unilateral 6‐hydroxydopamine (6‐OHDA) lesions. Increased mean firing rates in STNs were found in lesioned rats during recordings in both slow‐wave activity (SWA) and activation states.…”

“…The iSPN neurons are characterized by anomalous fire around the peaks of cortical beta oscillations . In light of the results of the study by Sharott and colleagues, the gamma‐Aminobutyric acid (GABA)ergic iSPNs appear to be the principle generator of exaggerated beta oscillations in basal ganglia (BG) circuits in the dopamine‐depleted state. Indeed, these groups of neurons have the tendency to discharge around the frequency of beta oscillations in the condition of the dopamine‐depleted striatum.…”