Unraveling a Potential Source of Dopamine-resistant Parkinson's Symptoms
For both healthy relationships and brains, communication is key. In the brain, this communication is done by neurons relaying messages from region to region using neurotransmitters such as dopamine. Parkinson’s disease (PD) disrupts these lines of communication, breaking down important messaging neurons and preventing neurotransmitter release.
Levodopa, widely considered the first-line drug for the management of PD symptoms, works by restoring dopamine levels in the brain to keep neuronal communication going. However, this dopamine restoration does not alleviate all symptoms of PD, raising the question of what other neurons and neurotransmitters are involved. Rebekah Evans, PhD, recipient of a Parkinson’s Foundation Stanley Fahn Junior Faculty Award, has devoted her research to answering this question.
Dr. Evans suspects that cholinergic neurons, which communicate using the neurotransmitter acetylcholine as opposed to dopamine, might be linked to balance and gait symptoms of PD that are not relieved by levodopa or other dopamine-based treatments. Specifically, she believes that in PD, cholinergic neurons in the pedunculopontine nucleus (PPN) region of the might break down. This, in turn, forces other PPN neurons to inefficiently pick up the slack, leading to the balance and gait symptoms.
To investigate this hypothesis, Dr. Evans and her team at Georgetown University in Washington, DC will be damaging PPN cholinergic neurons in the brains of mice and seeing how other PPN neurons functionally adapt and change in response. Next, she will measure how these adapted PPN neurons activate during different mouse behaviors such as exploring, running and grooming, comparing their activity to those of control mice without cholinergic neuron damage.
Finally, Dr. Evans will look into whether the adapted PPN neurons change their communication patterns with neighboring brain regions. She expects that these neurons become “overly-talkative” with other cholinergic neurons outside of the PPN but maintain normal communication with PD-associated dopamine neurons, contributing to the dopamine-resistant symptoms observed.
With the support of this award, Dr. Evans is excited to start uncovering the mysteries and impacts of cholinergic neuron loss in PD: “Understanding these downstream effects will lay a foundation for developing focused treatments and interventions to prevent pathological circuit alterations in the early, pre-dopaminergic-degeneration stages of Parkinson’s disease… I am so excited to be able to continue this line of research and to fully invest in it to push it forward quickly and rigorously.”
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