J Korean Neurosurg Soc.  2023 Mar;66(2):121-132. 10.3340/jkns.2022.0106.

Hyperkinetic Rat Model Induced by Optogenetic Parafascicular Nucleus Stimulation

• Chung M
• Park YS

• KMID: 2539873
• DOI: http://doi.org/10.3340/jkns.2022.0106

Abstract

Objective
: The parafascicular nucleus (PF) plays important roles in controlling the basal ganglia. It is not well known whether the PF affects the development of abnormal involuntary movements (AIMs). This study was aimed to find a role of the PF in development of AIMs using optogenetic methods in an animal model.
Methods
: Fourteen rats were underwent stereotactic operation, in which they were injected with an adeno-associated virus with channelrhodopsin (AAV2-hSyn-ChR2-mCherry) to the lateral one third of the PF. Behavior test was performed with and without optical stimulation 14 days after the injection of the virus. AIM of rat was examined using AIM score. After the behavior test, rat’s brain was carefully extracted and the section was examined using a fluorescence microscope to confirm transfection of the PF.
Results
: Of the 14 rats, seven rats displayed evident involuntary abnormal movements. AIM scores were increased significantly after the stimulation compared to those at baseline. In rats with AIMs, mCherry expression was prominent in the PF, while the rats without AIM lacked with the mCherry expression.
Conclusion
: AIMs could be reversibly induced by stimulating the PF through an optogenetic method.

Keyword

Dystonia; Dystkinesias; Parafascicular nucleus; Optogenetic technique

Figure

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  Fig. 1. Summary of the present experiment. The present experiment was planned for a 4-week schedule (A). After injection of virus, an optic cannula was fixed on the skull (B). The scalp was closed leaving a small skin opening for light stimulation through the cannula.

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  Fig. 2. Abnormal involuntary movements resembling dyskinesia or dystonia. This figure shows representative abnormal involuntary movements (AIMs) observed in the open-field test. Rat numbers are shown in the left column. Before stimulation (baseline, second column images), every rat did not show any abnormal involuntary movement. With blue light optical stimulation (with stimulation, third column images), each rat showed specific AIMs, and schematic illustration of these movements are shown in the right column. Rats 1, 9, 12, and 13 showed AIMs, with the whole body being rotated counter-clockwise (long arrows). Rotation movements were accompanied by abnormal limb motions (short arrows). Rats 4, 8, and 14 showed AIMs restricted to upper body or neck motions (long arrows), which were resembling laterocollis, torticollis, and anterocollis, respectively.

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  Fig. 3. Statistical analyses of behavior tests. After blue light stimulation, the average abnormal involuntary movement (AIM) score was significantly increased compared to the baseline (A). The AIM scores rated by the two individual observers (observers 1 and 2) showed a significant correlation (B). Spontaneous alternating behavior and lateralization score were not significantly changed after the light stimulation (C and d). CI : confidence interval.

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  Fig. 4. Histological findings of the rats. Rats with abnormal involuntary movements (AIMs) (the left column, rats 1, 4, 8, 9, and 12−14) exhibited prominent expression of the mCherry encompassing the parafascicular (PF) nucleus. In contrast, rats without abnormal involuntary movement (the right column; rats 2, 3, 5−7, 10, and 11) rarely presented the mCherry expressions.

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  Fig. 5. Location of tip of the optic cannula. The averaged location of the tips was illustrated with reference with the Paxinos and Watson atlas (A). The tip was found to be located at the lateral one third of the PF. Optic cannula tip locations of each rat were plotted on the lateral distance (mm) and depth (mm) plane (B). fr : fasciculus retroflexus, PF : parafascicular nucleus, AIM : abnormal involuntary movement.

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  Fig. 6. Schematic illustration of relevant brain networks. The striatal medium spiny neuron (MSN) receives two major inputs from the pyramidal cell (Py) of the cerebral cortex and the parafascicular nucleus (PF). A driver neuron (A) of the PF sends glutamatergic efferent to the MSN, called thalamostriatal circuit that provides a potent stimulatory signal to the MSN. The MSN relays γ-aminobutyric acid (GABA) signal to entopeduncular nucleus (EP), the homologous structure of globus pallidus internus in the human. A projector neuron (B) of the EP releases GABAergic efferent to the PF and the ventral lateral/ventral anterior (VA/VL). A driver neuron (C) of the VA/VL relays glutamatergic signal to the motor cortex, activating the basal ganglia−thalamocortical loop. Optogenetic stimulation of the PF (blue box) may increase glutamatergic signal to the MSN (blue arrow). It activates the MSN followed by facilitation of the basal ganglia-thalamocortical loop, which will induce abnormal involuntary movements.

Reference

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