Preserved dichotomy but highly irregular and burst discharge in the basal ganglia in alert dystonic rats at rest

Kumbhare, Dinesh; Chaniary, Kunal D.; Baron, Mark S.

doi:10.1016/j.brainres.2015.07.018

Cited by 9 publications

(12 citation statements)

References 57 publications

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“…Supplemental digital content 1, http://links.lww.com/WNR/A714 for plots of EP overall discharge rates and burstiness). Burstiness is a novel metric to estimate tendency of bursting in a neuron, based on burst parameters, including burst percentage, burst tendency, and burst entropy [8,19]. Its values range from 0 (no unit) to 1 representing neuronal firing in a pure burst mode.…”

Section: Resultsmentioning

confidence: 99%

“…In this study, computational modeling was used to investigate the influence of GPi signaling on the thalamic discharge activity in the healthy state and in dystonia, as a representative pathological movement condition. The neuronal simulations were derived and modeled from extracellular neuronal recordings in EP and VA-VL thalamus performed in alert healthy and dystonic rats [7,8,15],. The results of the present computational modeling support an essential role for GPi/EP as a firing mode controller of thalamic burst versus tonic discharge.…”

Section: Discussionmentioning

confidence: 99%

“…In the GP lesion model, the extremity involvement is confined to the side contralateral to the GP lesion. Refer to [8,14,15], for additional details.…”

Section: Methodsmentioning

confidence: 99%

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Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation

Kumbhare,

Azam,

Hadimani

et al. 2023

NeuroReport

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The mechanisms by which the basal ganglia influence the pallidal-receiving thalamus remain to be adequately defined. Our prior in vivo recordings in fully alert normal and dystonic rats revealed that normally fast tonic discharging entopeduncular [EP, rodent equivalent of the globus pallidus internus (GPi)] neurons are pathologically slow, highly irregular, and bursty under dystonic conditions. This, in turn, induces pallidal-receiving thalamic movement-related neurons to change from a healthy burst predominant to a pathological tonic-predominant resting firing mode. This study aims to understand the pallidal influence on thalamic firing modes using computational simulations. We inputted various combinations of healthy and pathological (dystonic) in vivo neuronal recordings to the Rubin and Terman’s computational model of low threshold spiking pallidothalamic neurons. The input sets consist of representative tonic, burst, irregular tonic and irregular burst inputs collected from EP/GPi in our animal lab. Initial test combinations of EP/ GPi input to the model were identical to the neuronal population distributions observed in vivo. The thalamic neuron model outputted similar firing rate and mode as observed in corresponding in-vivo thalamus. Further influence of each individual patterns was also delineated. By simulating the firing properties of encountered neurons, the basal ganglia output is suggested to critically act as firing mode selector for thalamic motor relay neurons. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, GPi neurons are in position to precisely orchestrate thalamocortical burst motor signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation

Kumbhare,

Azam,

Hadimani

et al. 2023

NeuroReport

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“…Irrespective, the combination of fast and irregular GPi discharge activity in primates would be expected to have similar combined effects on Vop neurons as observed for VL in rats. Further, under movement disorder conditions, both rodents Kumbhare and Chaniary 2015) and primates (Starr et al 2005;McClelland et al 2016;Xiao et al 2010) similarly show prominent reductions in pallidal firing rates. Per our modeling, this pathological reduction in the pallidal firing rate is the principal cause for our experimentally observed alteration in VL from a predominant burst to the tonic firing mode.…”

Section: Discussionmentioning

confidence: 96%

A Computational Model of Thalamic Tonic-burst Motor Projection Neurons and Their Regulation by Pallidal GABAergic Neurons

Azam

Kumbhare

Hadimani

et al. 2019

Preprint

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A modified computational model of pallidal receiving ventral oral posterior (Vop) thalamocortical motor relay neurons was adapted based on in vivo observations in our rodent model. The model accounts for different input neuronal firing patterns in the primary motor output nucleus of basal ganglia, the globus pallidus interna (GPi) and subsequently generate Vop outputs as observed in vivo under different conditions. Hyperpolarizing input de-inactivates its T-type calcium channel and sets the thalamic neurons in the preferable burst firing mode over a tonic mode and induces low threshold spikes (LTS). In the hyperpolarized state, both spontaneously and in response to excitatory (e.g. corticothalamic) inputs, burst spiking occurs on the crest of the LTS. By selecting and determining the timing and extent of opening of thalamic T-type calcium channels via GABAergic hyperpolarizing input, the GPi precisely regulates Vopcortical burst motor signaling. Different combinations of tonic, burst, irregular tonic and irregular burst inputs from GPi were used to verify our model. In vivo data obtained from recordings in the entopedunucular nucleus (EP; rodent equivalent of GPi) from resting head restrained healthy and dystonic rats were used to simulate the influences of different inputs from GPi. In all cases, GPi neuronal firing patterns are demonstrated to act as a firing mode selector for thalamic Vop neurons.

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“…Prior to viral tracer injection, the location of the GP dystonia or parkinsonian hotspot target was con rmed via stereotaxic microelectrode recording (MER), typically over 2-3 penetrations, utilizing ultra ne 100µm heptodes (Thomas Recording, GmbH) mounted in a 7-heptode capacity Eckhorn manipulator (Thomas Recording) attached to the KOPF stereotaxic system. Refer to our prior publication 57 for additional details of the mapping procedures.…”

Section: Surgery and Target Localizationmentioning

confidence: 99%

Parkinsonism originates in a discrete secondary and dystonia in a primary motor cortical-basal ganglia subcircuit

Baron

Kumbhare

Weistroffer

et al. 2022

Preprint

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Although manifesting contrasting phenotypes, Parkinson’s disease and dystonia originate from similar pathophysiology. Previously, we lesioned a discrete dorsal region in the globus pallidus (rodent equivalent to globus pallidus externa) in rats and produced parkinsonism, while lesioning a nearby ventral hotspot induced dystonia. Presently, we injected anterograde fluorescent-tagged anterograde multi-synaptic tracers into these pallidal hotspots. Viral injections in the Parkinson’s hotspot fluorescent labeled a circumscribed region in the secondary motor cortex, while injections in the dystonia hotspot labeled within the primary motor cortex. Custom probability mapping and N200 staining affirmed the segregation of the cortical territories for Parkinsonism and dystonia to the secondary and primary motor cortices. Intracortical microstimulation localized territories specifically to their respective rostral and caudal microexcitable zones. Parkinsonian features are thus explained by pathological signaling within a secondary motor subcircuit normally responsible for initiation and scaling of movement, while dystonia is explained by abnormal (and excessive) basal ganglia signaling directed at primary motor corticospinal transmission.

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Preserved dichotomy but highly irregular and burst discharge in the basal ganglia in alert dystonic rats at rest

Cited by 9 publications

References 57 publications

Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation

Healthy and pathological pallidal regulation of thalamic burst versus tonic mode firing: a computational simulation

A Computational Model of Thalamic Tonic-burst Motor Projection Neurons and Their Regulation by Pallidal GABAergic Neurons

Parkinsonism originates in a discrete secondary and dystonia in a primary motor cortical-basal ganglia subcircuit

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