(658g) Understanding the Basal Ganglia Dynamic Transition from the Healthy to the Parkinsonian State

Most of the existing basal ganglia (BG) computational models have focused on providing an understanding of the network pathology associated with the Parkinson’s Disease (PD) by analyzing the healthy and PD discrete states. However, these models do not describe the dynamic transition between the two states as a function of the loss of dopamine neurons [1] [2]. An understanding of the BG dynamic transition between these two states is important for the design of future experiments and development of novel therapeutically effective treatments of PD. To better understand this dynamic transition, we developed a computational model of the basal ganglia that describes the transition from the healthy state to PD state as a function of the depletion of dopamine neurons.

A marker of the PD state is the emergence of beta-oscillation in subthalamic nucleus (STN) of the BG and is believed to be the cause of motor dysfunctions associated with PD [3]. One hypothesis is that the oscillations arise from an imbalance in the direct and indirect pathways that originate in the striatum of the BG [1]. Due to the high density of dopaminergic projection to the striatum, the loss of dopamine neuron reduces the dopamine concentration to pathological levels. The disruption of the striatum homeostasis creates an imbalance in the activity of neurons in the direct and indirect pathway, which are the D1 and D2 medium spiny neurons (MSNs), respectively [1]. Recent experimental data suggests that the asymmetric activity of the D1 and D2 medium spiny neurons (MSNs) may be due to a combination of factors, such as, a difference in the dopamine binding concentration of D1 and D2 receptors [4], the excess release of acetyl choline [3], and the different muscarinic (acetyl choline) receptors on the MSNs [5]. Based on these experimental results, we expanded the existing BG multi-compartment model developed by Kumaravelu et al. by including detailed chemical-level description of dopamine and acetyl choline dynamics in the striatum [2] as well as the dopamine neurons of the substantia nigra (SN) and their projections to the striatum [6]. To simulate the progression of PD, neurons in the SN were sequentially removed from the BG network.

A core result of this presentation is the emergence of beta-oscillation from the neurochemical imbalance in the striatum as the dopamine neurons die. Our computational model of BG shows the removal of dopamine neurons produce a neurochemical imbalance in the striatum that disrupts the overall homeostasis of the BG. The neurochemical imbalance leads to an asymmetric activation of the direct and indirect pathways and drives the BG network from the healthy state to the PD state.

References

[1] Humphries, M., Obeso, J. and Dreyer, J.K., 2018. Insights into Parkinson's disease from computational models of the basal ganglia. bioRxiv, p.260992.

[2] Kumaravelu, K., Brocker, D.T. and Grill, W.M., 2016. A biophysical model of the cortex-basal ganglia-thalamus network in the 6-OHDA lesioned rat model of Parkinson’s disease. Journal of computational neuroscience, 40(2), pp.207-229.

[3] Kondabolu, K., Roberts, E.A., Bucklin, M., McCarthy, M.M., Kopell, N. and Han, X., 2016. Striatal cholinergic interneurons generate beta and gamma oscillations in the corticostriatal circuit and produce motor deficits. Proceedings of the National Academy of Sciences, 113(22), pp.E3159-E3168.

[4] Shen, W., Flajolet, M., Greengard, P. and Surmeier, D.J., 2008. Dichotomous dopaminergic control of striatal synaptic plasticity. Science, 321(5890), pp.848-851.

[5] Ztaou, S., Maurice, N., Camon, J., Guiraudie-Capraz, G., Kerkerian-Le Goff, L., Beurrier, C., Liberge, M. and Amalric, M., 2016. Involvement of striatal cholinergic interneurons and M1 and M4 muscarinic receptors in motor symptoms of Parkinson's disease. Journal of Neuroscience, 36(35), pp.9161-9172.

[6] Yu, N. and Canavier, C.C., 2015. A mathematical model of a midbrain dopamine neuron identifies two slow variables likely responsible for bursts evoked by SK channel antagonists and terminated by depolarization block. The Journal of Mathematical Neuroscience (JMN), 5(1), p.5.