Pallidostriatal Projections Promote β Oscillations in a Dopamine-Depleted Biophysical Network Model

Abstract

In the basal ganglia, focused rhythmicity is an important feature of network activity at certain stages of motor processing. In disease, however, the basal ganglia develop amplified rhythmicity. Here, we demonstrate how the cellular architecture and network dynamics of an inhibitory loop in the basal ganglia yield exaggerated synchrony and locking to ␤ oscillations, specifically in the dopamine-depleted state. A key component of this loop is the pallidostriatal pathway, a well-characterized anatomical projection whose function has long remained obscure. We present a synaptic characterization of this pathway in mice and incorporate these data into a computational model that we use to investigate its influence over striatal activity under simulated healthy and dopamine-depleted conditions. Our model predicts that the pallidostriatal pathway influences striatal output preferentially during periods of synchronized activity within GPe. We show that, under dopamine-depleted conditions, this effect becomes a key component of a positive feedback loop between the GPe and striatum that promotes synchronization and rhythmicity. Our results generate novel predictions about the role of the pallidostriatal pathway in shaping basal ganglia activity in health and disease.

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).…”

Untangling Basal Ganglia Network Dynamics and Function: Role of Dopamine Depletion and Inhibition Investigated in a Spiking Network Model

“…Here we assume that TA neurons connect twice as strongly to MSN D2 than to MSN D1 and that TA and TI neurons connect strongly to FSNs (Table 7) in accordance with Glajch et al (2016) and Saunders et al (2016). Additionally, we assume that the TA and TI synapses onto FSN are depressing (Corbit et al, 2016; Glajch et al, 2016). Because we did not have an estimate of the parameters for the depression, we used the same parameters as for FSN to MSN (Table 8).…”

“…Dopamine loss underlying PD (Hornykiewicz, 1966) causes alteration in many places in BG (Cepeda et al, 1993; Shen and Johnson, 2000; Bracci et al, 2002; Hernández-Echeagaray et al, 2004; Hernández et al, 2006; Baufreton and Bevan, 2008; Taverna et al, 2008; Zhou et al, 2009; Humphries et al, 2009a; Chan et al, 2011; Chuhma et al, 2011; Gittis et al, 2011; Miguelez et al, 2012). Computational modeling studies have given us valuable insights into the neural mechanisms behind PD (Terman et al, 2002; Humphries et al, 2006; Kumar et al, 2011; Damodaran et al, 2014, 2015; Corbit et al, 2016), but typically incorporated a subset of the alterations that dopamine depletion causes and investigated the effects in a subset of BG network components. Thus, to get a further understanding of the neural mechanisms in PD, we aimed to study them in a larger network context and try to relate function and dynamic features seen in experiments.…”

Changing views of the pathophysiology of Parkinsonism

“…Global activation of GPe activity in parkinsonian monkeys induces pathological STN neuron activity and can ameliorate parkinsonian motor signs, but may produce dyskinetic movements . Arkypallidal neurons, on the other hand, make abundant connections and strongly inhibit direct and indirect pathway striatal projection neurons and interneurons . Although this may play a role in normal basal ganglia function(s), the role of these cells in parkinsonism is not known .…”