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Impacts of Parkinsonian Neuro-degeneration on Dopamine Circuit Structure and Function
Parkinson’s disease is a neurodegenerative disorder that primarily affects dopamine neurons. It causes problems with movement, balance, and coordination. It is also linked to depression, cognitive impairment, fatigue, pain, and sleep disruptions. In the Lerner Lab, we apply our expertise in dissecting the functions of heterogeneous dopamine subcircuits to understand how the slow death of dopamine neurons during Parkinson’s disease progression alters the operation of specific functional, interacting subcircuits as part of a complex cascade of damage and compensation. We are particularly interested in understanding the changes in function occurring in the earliest stages of Parkinson’s disease, which will help us to identify patients early and design interventions to halt the neurodegenerative process. We also aim to design better therapies to treat symptoms like cognitive function and depression, which are not well addressed by currently available medications.
Dopamine across timescales and cell types: Relevance for phenotypes in Parkinson’s disease progression (Seiler et al., Experimental Neurology, 2024).
Here, review recent conceptual advances in our basic understanding of the dopamine system – including our rapidly advancing knowledge of dopamine neuron heterogeneity – with special attention to their importance for understanding PD. In PD patients, dopamine neuron degeneration progresses from lateral SNc to medial SNc, suggesting clinically relevant heterogeneity in dopamine neurons. This figure summarizes potential adaptions of heterogeneous dopamine neuron subpopulations during Parkinson’s Disease progression based on current knowledge. Adaptions occurring in PD at multiple levels of dopamine neuron identity will continue to evolve as the disease progresses. Understanding how complex interactions of identities influence circuit function across PD progression will advance the field and provide inspiration for new interventions to alter the disease course.
An image of the midbrain showing dopamine neurons labeled via immunostaining for tyrosine hydroxylase (cyan).
In red are dopamine neurons that have been virally induced to overexpress human alpha-synuclein, the protein that aggregates into Lewy bodies in Parkinson’s disease (PD). Mice that overexpress alpha-synuclein in dopamine neurons can be used as a model to understand the impacts that this PD-relevant manipulation has on dopamine neuron function and degeneration in a cell type- and circuit-specific manner.
