Parkinson's disease is a progressive neurodegenerative disorder that manifests
itself through a diverse range of motor and non-motor symptoms, including
shaking and stiffness of the limbs, as well as difficulties in maintaining
balance and coordination, walking and talking. As the disease progresses,
these symptoms typically evolve and become increasingly severe.
Diagnosing Parkinson's disease in its early stages can be highly
challenging, as the most evident symptoms, those affecting a patient's
movements, generally start manifesting at a later stage of the disease. To
devise new diagnostic tools and more effective treatment strategies,
neuroscientists have been trying to gain more insight about the neural
underpinnings of the disease's individual symptoms.
Past studies suggest that the impairments associated with Parkinson's
disease could be linked to progressive changes in the basal ganglia, an area
of the brain that regulates a number of motor and cognitive functions.
However, the organization and functions of different basal ganglia circuits
are still poorly understood.
Researchers at University of California in San Diego recently set out to
investigate the functional roles of different parvalbumin-expressing
neuronal populations in the external globus pallidus (GPe-PV), a small brain
area that is part of the basal ganglia. Their paper, published in Nature
Neuroscience, sheds light on the contributions of these neuronal populations
to different behaviors associated with Parkinson's disease.
"Diagnosing Parkinson's disease early can be very difficult," Byung Kook
Lim, one of the researchers who carried out the study, told Medical Xpress.
"This is mainly because of the strong focus on the disease's motor symptoms,
rather than on its non-motor symptoms, which usually occur at the earlier
stage of Parkinson's disease. Our work identifies differential changes in
different brain areas that are involved in motor and non-motor symptoms of
Parkinson's disease exhibited throughout its progression."
To examine the neural basis of non-motor behaviors that resemble those
observed in patients with Parkinson's disease, the researchers examined mice
that were completing a reversal learning task. This type of task is designed
specifically to assess and measure cognitive flexibility (i.e., the ability
to switch between thinking about different things or to think about several
concepts simultaneously).
"Poor cognitive flexibility is one of the major non-motor symptoms of
Parkinson's disease," Lim explained. "Using cutting-edge fiber photometric
measurement of the activity of specific projections and
optogenetic/chemogenetic manipulation of this circuitry, we anatomically and
functionally identified distinct parvalbumin-expressing neuronal populations
in the external globus pallidus and observed their contributions to
different behaviors associated with Parkison's disease."
Lim and his colleagues found that manipulating substantia nigra pars
reticulata (SNr)-projecting neurons in the external globus pallidus
alleviated the mice's locomotor deficits, while manipulating parafascicular
thamalus (PF)-projecting neurons improved their performance on the reversal
learning task. These findings highlight the crucial role that these two
GPe-PV neuronal populations could play in the progressive development of
motor and non-motor symptoms of Parkison's disease.
"Parkinson's disease is a progressive neurodegenerative disorder," Lim said.
"However, how different brain areas are involved in the different symptoms
exhibited at different stages of the disorder's development has not been
fully elucidated yet. Our findings highlight a need to study
circuit-specific adaptations at different stages of Parkinson's disease to
unveil stage-specific and symptom-specific treatments that could delay its
progression."
In the future, the results of this recent study could inform the development
of more effective strategies to diagnose or treat different symptoms of
Parkinson's disease at different stages of its progression. In their next
studies, Lim and his colleagues plan to examine the role that other brain
circuits play in the disorder's development over time, to gain a better
understanding of its underlying neural mechanisms.
Reference:
Divergent pallidal pathways underlying distinct Parkinsonian behavioral
deficits. Nature Neuroscience(2021). DOI:
10.1038/s41593-021-00810-y