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

Abstract

The basal ganglia are a crucial brain system for behavioral selection, and their function is disturbed in Parkinson’s disease (PD), where neurons exhibit inappropriate synchronization and oscillations. We present a spiking neural model of basal ganglia including plausible details on synaptic dynamics, connectivity patterns, neuron behavior, and dopamine effects. Recordings of neuronal activity in the subthalamic nucleus and Type A (TA; arkypallidal) and Type I (TI; prototypical) neurons in globus pallidus externa were used to validate the model. Simulation experiments predict that both local inhibition in striatum and the existence of an indirect pathway are important for basal ganglia to function properly over a large range of cortical drives. The dopamine depletion–induced increase of AMPA efficacy in corticostriatal synapses to medium spiny neurons (MSNs) with dopamine receptor D2 synapses (CTX-MSN D2) and the reduction of MSN lateral connectivity (MSN–MSN) were found to contribute significantly to the enhanced synchrony and oscillations seen in PD. Additionally, reversing the dopamine depletion–induced changes to CTX–MSN D1, CTX–MSN D2, TA–MSN, and MSN–MSN couplings could improve or restore basal ganglia action selection ability. In summary, we found multiple changes of parameters for synaptic efficacy and neural excitability that could improve action selection ability and at the same time reduce oscillations. Identification of such targets could potentially generate ideas for treatments of PD and increase our understanding of the relation between network dynamics and network function.

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

“…However, there were difficulties in relating this success to the electrophysiology of individual cells of the two types once they became identifiable by transgenesis. Some laboratories did find differences in the expected direction (Flores‐Barrera, Vizcarra‐Chacon, Bargas, Tapia, & Galarraga, ; Shen et al., ; Warre et al., ) but as the methodology became more sophisticated, the obvious interactions of both cell types with cortical activity and the beta power increase in the electrocorticogram, common in PD, has changed the emphasis from “faster or slower firing” to changes in the intrastriatal dynamics which result from the interactions of the many effects of DA removal on functional relationships within the striatal network (Cui et al., ; Klaus et al., ; Lindahl & Hellgren Kotaleski, ; Parker, Kim, Alberico, Emmons, & Narayanan, ; Parker et al., ; Perez‐Ortega et al., ; da Silva, Tecuapetla, Paixao, & Costa, ).…”

“…A contour detection snapshot of a recorded mouse illustrates the deviated posture typical of an ipsilateral DA depletion, but in this case in an intact mouse during optogenetic stimulation | 1521 JÁIDAR et Al. Shen et al, 2008;Warre et al, 2011) but as the methodology became more sophisticated, the obvious interactions of both cell types with cortical activity and the beta power increase in the electrocorticogram, common in PD, has changed the emphasis from "faster or slower firing" to changes in the intrastriatal dynamics which result from the interactions of the many effects of DA removal on functional relationships within the striatal network (Cui et al, 2013;Klaus et al, 2017;Lindahl & Hellgren Kotaleski, 2016;Parker, Kim, Alberico, Emmons, & Narayanan, 2016;Parker et al, 2018;Perez-Ortega et al, 2016; da Silva, Tecuapetla, Paixao, & Costa, 2018).…”

Cognitive Control and Brain Network Dynamics during Word Generation Tasks Predicted Using a Novel Event-Related Deep Brain Activity Method

“…This neural system is not only essential for reward [73], but also improves connectivity of large-scale networks of the human brain [74] [75] [76]. By contrast, according to small-scale network architectures [77] [78], network connectivity is dependent on the modularity of neural systems.…”

Insights into Parkinson’s disease from computational models of the basal ganglia

“…Many such models test the theory that the basal ganglia's normal function is to perform action selection through the interaction of the direct and indirect pathways [18,19]. Dopamine depletion in these models disrupts the balance of the two striatal output pathways, leading to action selection deficits [20][21][22]. The imbalance could arise either through direct effects on neural excitability, as reviewed above, or through aberrant cortico-striatal plasticity that follows dopamine depletion [21].…”

“…By what mechanisms does this loop produce oscillations under parkinsonian conditions of dopamine depletion? Models have uncovered multiple mechanisms that can cause this loop to shift from stable to oscillatory activity [22], but two have been prominently explored because they could plausibly follow from the loss of dopamine. One mechanism is the strengthening of the effect of input from D2-receptor striatal projection neurons to the pallidum [S50], possibly due to the increased excitability of D2 projection neurons (which is a predicted consequence of dopamine loss, as noted above).…”