Chemogenetic restoration of autonomous subthalamic nucleus activity ameliorates Parkinsonian motor dysfunction

El, McIver; H, Chu; Jf, Atherton; Chen, Ke; Kondapalli, Jyothisri; Wokosin, David L.; Surmeíer, D. James; Mark, D. Humphries

doi:10.1101/385443

Cited by 3 publications

(3 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overall, our findings are in line with recent work by Bevan and colleagues, demonstrating that the key pathological feature of the STN in PD could be the change in the ratio of intrinsically driven to input driven spiking (McIver EL et al 2018). Beta-frequency synchronisation between cortex and STN could be the most common manifestation of the disruption of this ratio due to an underlying selectivity for these frequencies in the surrounding microcircuit.…”

Section: Beta Frequency Cortical Input Selectively Reduces Spike-timesupporting

confidence: 92%

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Baaske

Kormann

Holt

et al. 2019

Preprint

View full text Add to dashboard Cite

Abnormally sustained beta-frequency synchronisation between the motor cortex and subthalamic nucleus (STN) is associated with motor symptoms in Parkinson's disease (PD).It is currently unclear whether STN neurons have a preference for beta-frequency input (12-35Hz), rather than cortical input at other frequencies, and how such a preference would arise following dopamine depletion. To address this question, we combined analysis of cortical and STN recordings from awake PD patients undergoing deep brain stimulation surgery with recordings of identified STN neurons in anaesthetised rats. In PD patients, we demonstrate that a subset of STN neurons are strongly and selectively sensitive to fluctuations of cortical beta oscillations over time, linearly increasing their phase-locking strength with respect to full range of instantaneous amplitude. In rats, we probed the frequency response of STN neurons more precisely, by recording spikes evoked by short bursts of cortical stimulation with variable frequency (4-40Hz) and constant amplitude. In both healthy and dopaminedepleted animals, only beta-frequency stimulation selectively led to a progressive reduction in the variability of spike timing through the stimulation train. We hypothesize, that abnormal activation of the indirect pathway, via dopamine depletion and/or cortical stimulation, could trigger an underlying sensitivity of the STN microcircuit to beta-frequency input. Brown P. 2008. Highfrequency stimulation of the subthalamic nucleus suppresses oscillatory beta activity in patients with Parkinson's disease in parallel with improvement in motor performance. The Journal of neuroscience : the official journal of the Society for Neuroscience. 28:6165-6173. Kuhn AA, Trottenberg T, Kivi A, Kupsch A, Schneider GH, Brown P. 2005. The relationship between local field potential and neuronal discharge in the subthalamic nucleus of patients with Parkinson's disease. Experimental neurology. 194:212-220. Kühn AA, Tsui A, Aziz T, Ray N, Brucke C, Kupsch A, Schneider GH, Brown P. 2009. Pathological synchronisation in the subthalamic nucleus of patients with Parkinson's disease relates to both bradykinesia and rigidity. Exp Neurol. 215:380-387. Lachaux JP, Rodriguez E, Martinerie J, Varela FJ. 1999. Measuring phase synchrony in brain signals. Human brain mapping. 8:194-208. Lalo E, Thobois S, Sharott A, Polo G, Mertens P, Pogosyan A, Brown P. 2008. Patterns of bidirectional communication between cortex and basal ganglia during movement in patients with Parkinson disease. J Neurosci. 28:3008-3016. Levy R, Ashby P, Hutchison WD, Lang AE, Lozano AM, Dostrovsky JO. 2002. Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease. Brain : a journal of neurology. 125:1196-1209. Little S, Pogosyan A, Kuhn AA, Brown P. 2012. Beta band stability over time correlates with Parkinsonian rigidity and bradykinesia. Exp Neurol. 236:383-388.

show abstract

Section: Beta Frequency Cortical Input Selectively Reduces Spike-timesupporting

confidence: 92%

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Baaske

Kormann

Holt

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…However, dopamine is known to interact with several more ion channels that are involved in linearizing the current-firing rate curve and regularizing autonomous pacemaking of STN neurons (Loucif et al, 2008; Ramanathan et al, 2008; Yang et al, 2016) which are not included in the STN cell model used here (Gillies and Willshaw, 2005). Recent evidence suggests that the loss of autonomous spiking is a necessary condition for the exaggerated cortical patterning of STN related to motor dysfunction (McIver et al, 2018). Better characterization of the ion channels involved in pacemaking and their response to dopamine depletion will enable the systematic exploration of their contribution to STN response properties and pathological firing patterns.…”

Section: Discussionmentioning

confidence: 99%

Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Koelman

Lowery

2019

Front. Comput. Neurosci.

View full text Add to dashboard Cite

Increased beta-band oscillatory activity in the basal ganglia network is associated with Parkinsonian motor symptoms and is suppressed with medication and deep brain stimulation (DBS). The origins of the beta-band oscillations, however, remains unclear with both intrinsic oscillations arising within the subthalamic nucleus (STN)—external globus pallidus (GPe) network and exogenous beta-activity, originating outside the network, proposed as potential sources of the pathological activity. The aim of this study was to explore the relative contribution of autonomous oscillations and exogenous oscillatory inputs in the generation of pathological oscillatory activity in a biophysically detailed model of the parkinsonian STN-GPe network. The network model accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network's endogenous oscillation frequency. The frequency at which this resonance peak occurred was determined by the net level of excitatory drive to the network. Intrinsic or endogenously generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations.

show abstract

“…429 However, dopamine is known to interact with several ion channels that are involved in 430 linearizing the current-firing rate curve and regularizing autonomous pacemaking of 431 April 11, 2019 13/33 STN neurons [64][65][66] which are not all included in the STN cell model used here [43]. 432 Recent evidence suggests that this loss of autonomous spiking is a necessary condition 433 for the exaggerated cortical patterning of STN that is related to motor dysfunction [67]. 434 Better characterization of the ion channels involved in pacemaking and their response to 435 dopamine depletion will enable the systematic exploration of their contribution to STN 436 response properties and pathological firing patterns.…”

mentioning

confidence: 99%

Autonomous oscillations and phase-locking in a biophysically detailed model of the STN-GPe network

Koelman

Lowery

2019

Preprint

View full text Add to dashboard Cite

The aim of this study was to understand the relative role of autonomous oscillations and patterning by exogenous oscillatory inputs in the generation of pathological oscillatory activity within the subthalamic nucleus (STN) -external globus pallidus (GPe) network in Parkinson's disease. A biophysically detailed model that accounts for the integration of synaptic currents and their interaction with intrinsic membrane currents in dendritic structures within the STN and GPe was developed. The model was used to investigate the development of beta-band synchrony and bursting within the STN-GPe network by changing the balance of excitation and inhibition in both nuclei, and by adding exogenous oscillatory inputs with varying phase relationships through the hyperdirect cortico-subthalamic and indirect striato-pallidal pathways. The model showed an intrinsic susceptibility to beta-band oscillations that was manifest in weak autonomously generated oscillations within the STN-GPe network and in selective amplification of exogenous beta-band synaptic inputs near the network's endogenous oscillation frequency. The resonant oscillation frequency was determined by the net level of excitatory drive in the loop. Intrinsically generated oscillations were too weak to support a pacemaker role for the STN-GPe network, however, they were considerably amplified by sparse cortical beta inputs when their frequency range overlapped and were further amplified by striatal beta inputs that promoted anti-phase firing of the cortex and GPe, resulting in maximum transient inhibition of STN neurons. The model elucidates a mechanism of cortical patterning of the STN-GPe network through feedback inhibition whereby intrinsic susceptibility to beta-band oscillations can lead to phase locked spiking under parkinsonian conditions. These results point to resonance of endogenous oscillations with exogenous patterning of the STN-GPe network as a mechanism of pathological synchronization, and a role for the pallido-striatal feedback loop in amplifying beta oscillations. Author summaryExaggerated beta-frequency neuronal synchrony is observed throughout the basal ganglia in Parkinson's disease and is reduced with medication and during deep brain stimulation. The power of beta-band oscillations is increasingly used as a biomarker to guide antiparkinsonian therapies. Despite their importance as a clinical target, the mechanisms by which pathological beta-band oscillations are generated are not yet clearly understood. In vitro electrophysiological recordings support a theory of enhanced phase locking of the reciprocally connected subthalamo-pallidal network to beta-band April 11, 2019 1/33 cortical inputs but this has not yet been clearly demonstrated in a model. We present a new model of the subthalamo-pallidal network consisting of biophysically detailed cell models that captures the interaction between synaptic and intrinsic currents in dendritic structures. The model shows how phase locking of subthalamic and pallidal neurons and exaggerated bursting in s...

show abstract

Chemogenetic restoration of autonomous subthalamic nucleus activity ameliorates Parkinsonian motor dysfunction

Cited by 3 publications

References 81 publications

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Parkinson’s disease uncovers an underlying sensitivity of subthalamic nucleus neurons to beta-frequency cortical input

Beta-Band Resonance and Intrinsic Oscillations in a Biophysically Detailed Model of the Subthalamic Nucleus-Globus Pallidus Network

Autonomous oscillations and phase-locking in a biophysically detailed model of the STN-GPe network

Contact Info

Product

Resources

About