Summary: KAIST researchers have identified a new mechanism that causes tremors associated with Parkinson’s disease. The findings, researchers say, overturn long standing assumptions about how tremors occur in Parkinson’s disease.
Source: KAIST.
A KAIST research team has identified a new mechanism that causes the hallmark symptoms of Parkinson’s disease, namely tremors, rigidity, and loss of voluntary movement.
The discovery, made in collaboration with Nanyang Technological University in Singapore, presents a new perspective to three decades of conventional wisdom in Parkinson’s disease research. It also opens up new avenues that can help alleviate the motor problems suffered by patients of the disease, which reportedly number more than 10 million worldwide. The research was published in Neuron on August 30.
The research team was led by Professor Daesoo Kim from the Department of Biological Sciences at KAIST and Professor George Augustine from the Lee Kong Chian School of Medicine at NTU. Dr. Jeongjin Kim, a former postdoctoral fellow at KAIST who now works at the Korea Institute of Science and Technology (KIST), is the lead author.
It is known that Parkinson’s disease is caused by a lack of dopamine, a chemical in the brain that transmits neural signals. However, it remains unknown how the disease causes the motor problems that plague Parkinson’s disease patients.
Smooth, voluntary movements, such as reaching for a cup of coffee, are controlled by the basal ganglia, which issue instructions via neurons (nerve cells that process and transmit information in the brain) in the thalamus to the cortex. These instructions come in two types: one that triggers a response (excitatory signals) and the other that suppresses a response (inhibitory signals). Proper balance between the two controls movement.
A low level of dopamine causes the basal ganglia to severely inhibit target neurons in the thalamus, called an inhibition. Scientists have long assumed that this stronger inhibition causes the motor problems of Parkinson’s disease patients.
To test this assumption, the research team used optogenetic technology in an animal model to study the effects of this increased inhibition of the thalamus and ultimately movement. Optogenetics is the use of light to control the activity of specific types of neurons within the brain.
They found that when signals from the basal ganglia are more strongly activated by light, the target neurons in the thalamus paradoxically became hyperactive. Called rebound excitation, this hyperactivity produced abnormal muscular stiffness and tremor. Such motor problems are very similar to the symptoms of Parkinson’s disease patients. When this hyperactivity of thalamic neurons is suppressed by light, mice show normal movments without Parkinson’s disease symptoms. Reducing the levels of activity back to normal caused the motor symptoms to stop, proving that the hyperactivity caused the motor problems experienced by Parkinson’s disease patients.
Professor Kim at KAIST said, “This study overturns three decades of consensus on the provenance of Parkinsonian symptoms.” The lead author, Dr Jeongjin Kim said, “The therapeutic implications of this study for the treatment of Parkinsonian symptoms are profound. It may soon become possible to remedy movement disorders without using L-DOPA, a pre-cursor to dopamine.”
Professor Augustine at NTU added, “Our findings are a breakthrough, both for understanding how the brain normally controls the movement of our body and how this control goes awry during Parkinson’s disease and related dopamine-deficiency disorders.”
The study took five years to complete, and includes researchers from the Department of Bio & Brain Engineering at KAIST.
The research team will move forward by investigating how hyperactivity in neurons in the thalamus leads to abnormal movement, as well as developing therapeutic strategies for the disease by targeting this neural mechanism.
Funding: The work was supported by National Leading Research Laboratory Program (2016-015167 to D.K.)-World Class Institute (WCI) program of the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (WCI 2009-003).
Source: Younghye Cho – KAIST
Image Source: NeuroscienceNews.com image is credited to KAIST.
Video Source: Video credited to KAIST.
Original Research: Abstract for “Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus” by Jeongjin Kim, Youngsoo Kim, Ryuichi Nakajima, Anna Shin, Minju Jeong, Ah Hyung Park, Yongcheol Jeong, Seonmi Jo, Seungkyoung Yang, Hosung Park, Sung-Hwan Cho, Kwang-Hyun Cho, Insop Shim, Jae Hoon Chung, Se-Bum Paik, George J. Augustine, and Daesoo Kim in Neuron. Published online August 30 2017 doi:10.1016/j.neuron.2017.08.028
[cbtabs][cbtab title=”MLA”]KAIST “Overturning the Theory of Tremors in Parkinson’s.” NeuroscienceNews. NeuroscienceNews, 26 September 2017.
<https://neurosciencenews.com/parkinsons-tremor-theory-7584/>.[/cbtab][cbtab title=”APA”]KAIST (2017, September 26). Overturning the Theory of Tremors in Parkinson’s. NeuroscienceNews. Retrieved September 26, 2017 from https://neurosciencenews.com/parkinsons-tremor-theory-7584/[/cbtab][cbtab title=”Chicago”]KAIST “Overturning the Theory of Tremors in Parkinson’s.” https://neurosciencenews.com/parkinsons-tremor-theory-7584/ (accessed September 26, 2017).[/cbtab][/cbtabs]
Abstract
Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus
Highlights
•Inhibitory basal ganglia inputs induce excitatory motor signal in the thalamus
•The motor signal depends on the number of thalamic neurons with rebound firing
•In a low dopamine state, thalamic neurons with rebound firing are abnormally increased
•Inhibition of rebound firing prevents Parkinson disease-like motor abnormalities
Summary
Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities.
“Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus” by Jeongjin Kim, Youngsoo Kim, Ryuichi Nakajima, Anna Shin, Minju Jeong, Ah Hyung Park, Yongcheol Jeong, Seonmi Jo, Seungkyoung Yang, Hosung Park, Sung-Hwan Cho, Kwang-Hyun Cho, Insop Shim, Jae Hoon Chung, Se-Bum Paik, George J. Augustine, and Daesoo Kim in Neuron. Published online August 30 2017 doi:10.1016/j.neuron.2017.08.028
