Billions of neurons are found in the brain, leading to neuronal circuits responsible for behavior control to be packed tightly together. As they are in a tangled web, neurons make it difficult for scientists to see which circuits do what. Researchers from Caltech are hoping to address this concern by mapping out neuron pathways, particularly those linked to motor impairments common in people diagnosed with Parkinson's disease.

In a study published in the journal Neuron, the researchers noted that balancing trouble and gait disorders are commonly caused by deterioration in cholinergic neurons in a part of the brainstem called the pedunculopontine nucleus (PPN). Additionally, damage to neurons in the PPN is associated with behaviors and disorders based on rewards like addiction.

Earlier, researchers have not been able to map out neural circuits originating from the PPN, making it difficult to understand how motor impairments and addiction come about from the same set of cells. Consequently, this led to difficulty in treating motor symptoms. Deep brain stimulation can be used to administer electrical pulses but it is ineffective, given a target area cannot be identified exactly.

According to Viviana Gradinaru, one of the authors for the study, neuronal circuits responsible for behavior control are not lined up nicely, with sides for reward and locomotion neatly delineated, and this disorderly arrangement stems from how neurons are structured.

Think of neurons as trees, with cell bodies and long string-like axons that can project into a different part of the brain. By taking into consideration a neuron's shape, researchers figured out they could follow its roots to a part in the brain roomier than the PPN where it would be easier to observe where the motor and reward behaviors are being implemented.

To facilitate neuronal observation, the researchers used the Passive CLARITY Technique (PACT), where a chemical solution renders a part of the brain transparent, allowing fluorescent markers to be more easily seen and followed. Different markers are assigned to different neurons in the brain.

Thanks to PACT, the researchers traced PPN neuron axons extending into two midbrain regions: the ventral substantia nigra, the region associated with motor impairments connected to Parkinson's disease, and the ventral tegmental area, the region associated with reward behavior.

They then turned to optogenetics, a method to manipulate activity in the neurons by using different light colors, to confirm that the neurons they were observing communicate downstream and were responsible for motor impairments and reward-based behavior.

"Our results show that the cholinergic neurons from the PPN indeed have a role in controlling both behaviors," said Gradinaru.

While these results can already aid in developing new treatments for Parkinson's disease, the researchers are pushing for brain-wide anatomical and functional maps to better observe long-range projections from neurons.

Other authors for the study include: Cheng Xiao, Bin Yang, Sheri McKinney, Ken Chan, Jennifer Treweek, Chunyi Zhou and Jounhong Ryan Cho.

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