Dataset Information

Intraoperative Microelectrode Recordings in Substantia Nigra Pars Reticulata in Anesthetized Rats.

ABSTRACT: The Substantia Nigra pars reticulata (SNr) is a promising target for deep brain stimulation (DBS) to treat the gait and postural disturbances in Parkinson's disease (PD). Positioning the DBS electrode within the SNr is critical for the development of preclinical models of SNr DBS to investigate underlying mechanisms. However, a complete characterization of intraoperative microelectrode recordings in the SNr to guide DBS electrode placement is lacking. In this study, we recorded extracellular single-unit activity in anesthetized rats at multiple locations in the medial SNr (mSNr), lateral SNr (lSNr), and the Ventral Tegmental Area (VTA). Immunohistochemistry and fluorescently dyed electrodes were used to map neural recordings to neuroanatomy. Neural recordings were analyzed in the time domain (i.e., firing rate, interspike interval (ISI) correlation, ISI variance, regularity, spike amplitude, signal-to-noise ratio, half-width, asymmetry, and latency) and the frequency domain (i.e., spectral power in frequency bands of interest). Spike amplitude decreased and ISI correlation increased in the mSNr versus the lSNr. Spike amplitude, signal-to-noise ratio, and ISI correlation increased in the VTA versus the mSNr. ISI correlation increased in the VTA versus the lSNr. Spectral power in the VTA increased versus: (1) the mSNr in the 20-30 Hz band and (2) the lSNr in the 20-40 Hz band. No significant differences were observed between structures for any other feature analyzed. Our results shed light on the heterogeneity of the SNr and suggest electrophysiological features to promote precise targeting of SNr subregions during stereotaxic surgery.

SUBMITTER: Li H

PROVIDER: S-EPMC7201294 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Intraoperative Microelectrode Recordings in Substantia Nigra Pars Reticulata in Anesthetized Rats.

Li Hanyan H McConnell George C GC

Frontiers in neuroscience 20200429

The Substantia Nigra pars reticulata (SNr) is a promising target for deep brain stimulation (DBS) to treat the gait and postural disturbances in Parkinson's disease (PD). Positioning the DBS electrode within the SNr is critical for the development of preclinical models of SNr DBS to investigate underlying mechanisms. However, a complete characterization of intraoperative microelectrode recordings in the SNr to guide DBS electrode placement is lacking. In this study, we recorded extracellular sin ...[more]

PMID: 32410946

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Project description:ObjectiveGenetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNRanterior and SNRposterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance.MethodsAdult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNRanterior or SNRposterior . In another experiment, PRV-ir in SNRanterior and SNRposterior and TH-ir in SNRposterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations).ResultsBilateral SNRposterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNRanterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNRposterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNRposterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups.SignificanceThe kindling resistance in GAERS is mediated by the SNRposterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNRposterior of GAERS but not NEC rats, implicate GABAergic SNRposterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNRposterior is unrelated to kindling resistance.

Project description:The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis, we implemented an ad hoc behavioral protocol for rats in which systemic administration of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.SIGNIFICANCE STATEMENT The cannabinergic system has been the target of multiple studies to master its potential use as a therapeutic agent. However, significant advances have been precluded by the lack of mechanistic explanations for the variety of its desirable/undesirable effects. Here, we have combined electrophysiological recordings, pharmacological and optogenetic manipulations, and an ad hoc behavioral protocol to understand how basal ganglia (BG) is affected by cannabinoids. We found that cannabinoids principally affect inhibitory inputs, potentially from the direct pathway, resulting in unbalanced responses in the substantia nigra pars reticulata (SNr) and suggesting a mechanism for the cannabinoid-related slowness of movements. This possibility was confirmed by behavioral experiments in which cannabinoid-related slowness of purposeful movements was reverted by cannabinoid receptor type 1 (CB1r) manipulations directly into the SNr.

Project description:The electrophysiological correlates of parkinsonism in the basal ganglia have been well studied in patients with Parkinson's disease and animal models. Separately, striatal dopaminergic cell transplantation has shown promise in ameliorating parkinsonian motor symptoms. However, the effect of dopaminergic grafts on basal ganglia electrophysiology has not thoroughly been investigated. In this study, we transplanted murine foetal ventral mesencephalic cells into rats rendered hemiparkinsonian by 6-hydroxydopamine injection. Three months after transplantation, extracellular and local field potential recordings were taken under urethane anaesthesia from the substantia nigra pars reticulata and subthalamic nucleus along with cortical electroencephalograms and were compared to recordings from normal and hemiparkinsonian controls. Recordings from cortical slow-wave activity and global activation states were analysed separately. Rats with histologically confirmed xenografts showed behavioural improvement measured by counting apomorphine-induced rotations and with the extended body axis test. Firing rates in both nuclei were not significantly different between control and grafted groups. However, burst firing patterns in both nuclei in the slow-wave activity state were significantly reduced (P < 0.05) in rats with large surviving grafts, compared to hemiparkinsonian controls. The neuronal firing entropies and oscillations in both nuclei were restored to normal levels in the large-graft group. Electroencephalogram spike-triggered averages also showed normalization in the slow-wave activity state (P < 0.05). These results suggest that local continuous dopaminergic stimulation exerts a normalizing effect on the downstream parkinsonian basal ganglia firing patterns. This novel finding is relevant to future preclinical and clinical investigations of cell transplantation and the development of next-generation therapies for Parkinson's disease that ameliorate pathophysiological neural activity and provide optimal recovery of function.

Dataset Information

Intraoperative Microelectrode Recordings in Substantia Nigra Pars Reticulata in Anesthetized Rats.

Publications

Intraoperative Microelectrode Recordings in Substantia Nigra Pars Reticulata in Anesthetized Rats.

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