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Stimulation of specialized ganglion restores full motor function in mice with Parkinson’s Disease

A research group from the University of Copenhagen have identified a specific area of neurons that when stimulated, restores full movement function in mice presenting Parkinson’s Disease. (Credit: A mouse undergoing deep brain stimulation therapy. Sarah-Anna Hescham/Maastricht University)

Parkinson’s disease is a neurological illness in which dopaminergic neurons in the brainstem slowly die. Many individuals with Parkinson’s disease have tremor and walking problems as movement symptoms. Nearly a quarter of Parkinson’s patients will eventually manifest these symptoms, freezing on the spot and collapsing, resulting in many becoming housebound.

Deep brain stimulation (DBS) therapy for walking difficulties in Parkinson’s disease might be improved by targeting certain neurons in the brainstem, according to a study done in mice by the University of Copenhagen. This could help more than 7 to 10 million individuals worldwide who suffer from the condition.

Scientists believed that walking difficulties in Parkinson’s disease may be relieved based on earlier animal studies of motor circuits, which are responsible for the planning, control, and execution of voluntary movements. They thought this would necessitate using DBS to activate neurons in the brainstem’s pedunculopontine nucleus (PPN). The PPN was believed to transmit impulses from the brain to the spinal cord, causing movement.

“However, initial results from clinical trials with DBS of the PPN had very variable effect on movement recovery, particularly in patients who experience freezing of walking,” said co-author Ole Kiehn. “It has therefore been debated where within the brainstem an optimal stimulation should be. Our study brings new knowledge to the table regarding the best area for DBS in order to alleviate this particular symptom.”

Doctors have used medicine to replace the lost dopamine resulting from the death dopaminergic neurons since the 1960s, but it’s notoriously difficult to keep symptoms under control as the condition develops.

Debora Masini, postdoc and first author of the study explained the study’s results, saying, “When we stimulated these specific neurons in the caudal area of the PPN, the animals were able to walk normally, across longer distances and with normal walking speed, as opposed to before the stimulation, where they would display symptoms of Parkinson’s Disease.”

“We systematically compared stimulation of different locations and cell types in a series of complementary experiments. And they all pointed towards the same conclusion. It strongly indicates these excitatory neurons in the caudal PPN are an ideal target for recovery of movement loss,” she stated.

The researchers anticipate that the new study could help physicians decide where to place DBS in the brainstem.

The study was published in Nature Communications on January 26th, 2022.

Abstract. The pedunculopontine nucleus (PPN) is a locomotor command area containing glutamatergic neurons that control locomotor initiation and maintenance. These motor actions are deficient in Parkinson’s disease (PD), where dopaminergic neurodegeneration alters basal ganglia activity. Being downstream of the basal ganglia, the PPN may be a suitable target for ameliorating parkinsonian motor symptoms. Here, we use in vivo cell-type specific PPN activation to restore motor function in two mouse models of parkinsonism made by acute pharmacological blockage of dopamine transmission. With a combination of chemo- and opto-genetics, we show that excitation of caudal glutamatergic PPN neurons can normalize the otherwise severe locomotor deficit in PD, whereas targeting the local GABAergic population only leads to recovery of slow locomotion. The motor rescue driven by glutamatergic PPN activation is independent of activity in nearby locomotor promoting glutamatergic Cuneiform neurons. Our observations point to caudal glutamatergic PPN neurons as a potential target for neuromodulatory restoration of locomotor function in PD.

Masini, D., Kiehn, O. Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism. Nat Commun 13, 504 (2022).

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