Abstract
The basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g., in Parkinson’s disease; PD) result in aberrant changes in steady-state population activity (β band oscillations) and the transient response of the BG. Typically, a brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr; an output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While mechanisms underlying aberrant steady state activity are well studied, it is still unclear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also unclear whether mechanisms underlying the aberrant changes in steady-state activity and transient response are the same. Here, we used numerical simulations of a network model of BG to identify the key factors that determine the shape of the transient responses. We show that an aberrant transient response of the SNr in the low-dopamine state involves changes in the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and subthalamic nucleus (STN). However, the connections from D2-type spiny projection neurons (D2-SPN) to GPe are most crucial in shaping the transient response and by restoring them to their healthy level, we could restore the shape of transient response even in low-dopamine state. Finally, we show that the changes in BG that result in aberrant transient response are also sufficient to generate pathologic oscillatory activity in the steady state.
Highlights
Parkinson’s disease (PD) is a debilitating neurodegenerative brain disease with multiple cognitive and motor symptoms
We show that an aberrant transient response of the substantia nigra pars reticulata (SNr) in the low-dopamine state involves changes in the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and subthalamic nucleus
We found that input and local connectivity within the globus pallidus externa are crucial for shaping the transient response
Summary
Parkinson’s disease (PD) is a debilitating neurodegenerative brain disease with multiple cognitive and motor symptoms. Transient cortical stimulation elicits predominantly a triphasic response (composed of early excitation, inhibition, and late excitation) in most neurons of the BG output nuclei i.e. globus pallidus interna (GPi) or substantia nigra pars reticulata (SNr) (Sano et al, 2013; Chiken and Nambu, 2013; Ozaki et al, 2017). Consistent with experimental data (Sano and Nambu, 2019) and the feedforward model of the BG (Albin et al, 1989), in healthy state, the SNr showed triphasic responses for brief cortical inputs at the population level. By changing the strength of synapses along the direct (D1-SPN→SNr) and indirect pathways (D2-SPN→GPe-TI, and GPe-TI→STN) it was possible to observe the triphasic responses even in low-dopamine state. The same changes underlie both the emergence of pathological β-band oscillations, and pathological transient response
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