Chronic Imaging of Striatal Subcircuits During the Progression of Parkinsonism

Lay Summary

Cellular imaging may determine which of two dueling Parkinson’s disease theories is correct

This cellular imaging study in the Parkinson’s disease animal model will explore which of two hypothesized neural signaling problems is responsible for loss of voluntary motor control.

People with Parkinson’s disease (PD) develop a characteristic gait. They walk slowly and shuffle and their arms stay at their sides rather than swinging astride. Patients’ muscles become rigid and slow moving, and patients have fine tremors when they are not moving. These characteristic problems evolve with the increased death of brain cells that are located deep in the middle of the brain (in the “substantia nigra”).

Cells in the substantia nigra ordinarily produce the neurotransmitter dopamine and use it to send signals to a structure in the front part of the brain (called the “striatum”) to produce smooth, purposeful muscle activity. There is no cure for PD. Patients are treated symptomatically with L-DOPA, which is converted into dopamine in the brain. Over time, though, L-DOPA can produce debilitating side effects like slurred speech, involuntary movements, cognitive decline and hallucinations. Some severely affected PD patients who cannot tolerate L-DOPA have responded to deep brain stimulation (DBS). Improved therapies await a better understanding of how the dopamine signaling network goes awry over the course of PD.

This network has two signaling pathways—“direct” and “indirect”—and the question is: what goes wrong in the signaling process within and between the two pathways? Two competing theories have not been fully explored because current structural and physiological imaging techniques cannot reach the network, which is located deep within the brain. Advances in cellular imaging that can only be used in the PD mouse model, however, may reveal which theory is correct and lead to more targeted therapies.

The two pathways are thought to work antagonistically to control voluntary movements. One pathway facilitates movement while the other inhibits it. How does PD affect these functions? One theory holds that PD alters the firing rate of the dopamine cells. This alateration produces an imbalance between the two pathways. The imbalance suppresses the motor cortex and produces a loss of voluntary movement. The other theory holds that neural signaling in both pathways oscillates in the same rhythm, becomes synchronized, cancels out one another’s signals and thereby prevents motor action. The study will explore which situation occurs in the animal model.

Investigators will combine deep brain fiber optical cellular imaging and “optogenetic” methods (which selectively “tag” each type of cell in both pathways) with electrophysiological techniques. Then they will monitor each cell type in each pathway before the disease process begins and during disease progression. Next, they will assess the effects of dopamine treatment on the PD-damaged network by comparing cellular and signaling changes in treated versus untreated mice. The results are anticipated to reveal dopamine’s role in the network, how this role is compromised when dopamine is depleted in PD and produces loss of motor control, and how L-DOPA affects the damaged network’s further functioning.

Significance: If this research reveals which theory of loss of motor control in PD is correct, researchers could test therapies that act precisely on the cellular and pathway targets involved.

Abstract

Chronic Imaging of Striatal Subcircuits During the Progression of Parkinsonism

Parkinson’s disease (PD) is a neurodegenerative disease affecting a large segment of the population. The disease is initiated by selective degeneration of dopaminergic neurons in the substantia nigra, followed by a series of changes in neural plasticity occurring in downstream circuits particularly in striatum and associated basal ganglia nuclei. There are two major hypotheses in the field about the network pathology of PD. One suggested that the firing rate gone awry causes imbalance in the direct vs. indirect pathway and leads to great suppression of motor cortex and results in akinesia, and another hypothesis proposed that the pathological oscillatory and synchronization of neural activity prevents action selection and causes PD symptoms. However, neither hypothesis has been precisely tested in the striatum at the cell-type and pathway-specific level, largely due to the lack of appropriate technique to separate and monitor the neuronal activity of direct vs. indirect pathway in vivo. In the present project, by combining a deep-brain fiber optic imaging technique with a genetically-encoded calcium indicator, the population striatal neuronal activity of direct vs. indirect pathway will be chronically monitored during the disease progression in a mouse model of PD. Single neuron electrophysiology with optogenetics-aided cell tagging will be employed complementarily to record and identify individual striatal neuron in direct vs. indirect pathway. The overall goal is to provide a mechanistic understanding of the physiology and plasticity in striatal direct vs. indirect pathway during PD, and to directly test the different PD hypotheses in vivo. The results will significantly advance our understanding of PD network physiopathology and facilitate the development of more effective therapeutic interventions for PD patients.