2021-01-13 at 12:43 #1046WebmasterKeymaster
Preprint available at: https://www.biorxiv.org/content/10.1101/2021.01.05.425413v1
Kingshuk Chakravarty, Sangheeta Roy, Aniruddha Sinha, View ORCID ProfileAtsushi Nambu, View ORCID ProfileSatomi Chiken, Jeanette Hellgren Kotaleski, View ORCID ProfileArvind Kumar
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), result in aberrant changes in steady-state population activity (β-band oscillations) and transient response of the BG. Typically, brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr, output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While it is relatively well understood how changes in BG result in aberrant steady state activity, it is not clear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also not clear whether the same or different mechanisms underlie the aberrant changes in steady-state activity and aberrant transient response. 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 low-dopamine state, involves changes in both, the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and sub-thalamic nucleus. We found that the connections from D2-type spiny projection neurons 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 pathological oscillatory activity.
Significance statement To understand how changes induced by low-dopamine (e.g. in Parkinson’s disease, PD) affect basal ganglia (BG) function, we need to identify the factors that determine the shape of BG responses to brief cortical stimuli. We show that transient response of the BG is also affected by recurrent interactions within the subnuclei of the BG, and not just feedforward pathways. We found that input and local connectivity within the globus pallidus externa are crucial for shaping the transient response. We also show that the same network changes may underlie both, pathological β-band oscillations and aberrant transient responses. Our results highlight the importance of the recurrent connectivity within the BG and provide a coherent view of emergence of pathological activity in PD.
Competing Interest Statement
The authors have declared no competing interest.
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