Cellular imaging may reframe current concepts about Parkinson’s disease processes

Nicolas Tritsch, Ph.D.

New York University

Funded in September, 2017: $200000 for 3 years
LAY SUMMARY . ABSTRACT .

LAY SUMMARY

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Cellular imaging may reframe current concepts about Parkinson’s disease processes

Parkinson’s disease (PD) is characterized by movement impairments and has long been known to arise following the death of a critical threshold of brain cells that use the neurotransmitter dopamine to communicate with one another. While the cells’ progressive death in the brain’s substantia nigra is clearly a defining feature of PD, several lines of evidence now suggest that the disease may not result from cell death alone. Rather, a contributing factor may be a dysfunction in the release of dopamine from axons. Ordinarily, movement is facilitated when axons release dopamine at “synapses” (the physical junction between two cells where communication takes place). The investigators hypothesize that dopamine release is controlled by nearby cells that release a chemical called acetylcholine. When these nearby cells malfunction, the ability of dopaminergic synapses to release dopamine from synapses at the appropriate time, location and quantity may be impaired, leading to movement impairments in the PD disease process.       

            If PD arises at least in part from these neural circuit communication problems, rather than solely from degenerative processes that kill dopamine-producing brain cells, it would explain several vexing questions about this complex and remarkably heterogeneous nature of PD. For instance, how does degeneration of non-dopamine neurons contribute to motor symptoms? Why is disease progression so variable among PD patients? And why are patients’ responses to dopamine replacement therapies so inconsistent? Could dysregulation of dopamine signaling prior to cell loss contribute to motor deficits and to the variable effectiveness of L-DOPA therapy, and could non-dopaminergic cells also contribute to the progression of the disease?

The investigators will work to test hypotheses designed to answer these questions using two-photon calcium imaging in animal models of PD. They will: 1) monitor the neural activity and interaction of dopamine cells’ axons with the acetylcholine-releasing cells located in the brain’s striatum; 2) examine the molecular and cellular factors that control dopamine release in mice with and without dopamine replacement therapies, using imaging along with molecular, genetic, and pharmacological approaches; and 3) determine whether changes in dopamine release by axons underlie motor impairments in the animal model.  Their work is expected to reveal that this small population of acetylcholine-releasing neurons in the striatum plays a key role in controlling when, where and how much dopamine is released from nerve fibers in the nearby substantia nigra.

Significance :  The findings could lead to development of new experimental treatment approaches to test in patients with PD.

ABSTRACT

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Functional imaging of dopaminergic axons in parkinsonism

Parkinson’s disease (PD) is a common neurodegenerative disorder defined clinically by motor impairments known as parkinsonism (tremor, rigidity, slowness of movement and postural imbalance), and pathologically by the progressive loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNc). Our current understanding of the pathophysiology of PD espouses a relatively static view of the nervous system, centered on the notion that parkinsonism arises when degeneration of SNc neurons exceeds a critical threshold. However, DA signaling is, like any other neurotransmitter system in the brain highly dynamic: DA neuron discharge is rapidly modulated during behavior, and DA release from axons is tightly regulated by local neuromodulators. Thus, an important unresolved question is the extent to which DA neuron dysfunction (whether cell-autonomous or not) contributes to the pathophysiology of Parkinson’s disease and to the heterogeneity in disease presentation, progression and response to DA replacement therapy. This proposal aims to uncover the cells and molecules that modulate DA release from nerve terminals in vivo under physiological and pathological conditions. Using a novel chronic, high-resolution two-photon Ca2+ imaging approach in awake behaving mice in combination with genetic, molecular, pharmacological and optogenetic manipulations, we will investigate the hypothesis that acetylcholine (ACh)-producing neurons in striatum – the main recipient nucleus of dopaminergic innervation – locally control the timing, location and magnitude of DA release from nigrostriatal synapses to enable movement. In addition, we postulate that motor impairments in mouse models of PD arise from dysregulation of DA release from nerve terminals in striatum, rather than from degeneration alone. This mechanistic distinction is of great importance clinically, as it may explain why atypical forms of PD are unresponsive to DA replacement therapy (if DA neurons are inactive, for instance, or unable to synaptically release DA), or why patients with classical presentations of the disease experience motor fluctuations (if DA neurons suddenly stop liberating DA) and dyskinesia (if prolonged levodopa treatment causes aberrant DA neuron activity) while on such treatment. The proposed work, while not directly translatable to humans at present, will force a reconsideration of the etiology of parkinsonism – favoring a more dynamic and circuit-level view of dopaminergic signaling as opposed to focusing exclusively on DA neuron number – and will point to novel therapeutic targets to alleviate parkinsonism in classical as well as atypical PD.

INVESTIGATOR BIOGRAPHIES

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Nicolas Tritsch, Ph.D.

Nicolas Tritsch is an Assistant Professor in the Department of Neuroscience and Physiology and a member of the Neuroscience Institute and Fresco Institute for Parkinson’s and Movement Disorders at NYU Langone Health. He obtained a Ph.D. in neuroscience from Johns Hopkins University under the mentorship of Dr. Dwight Bergles before completing postdoctoral training with Dr. Bernardo Sabatini at Harvard Medical School. Dr. Tritsch’s research uses a variety of optical, genetic and physiological approaches to reveal how brain circuits that control voluntary movements orchestrate the initiation, execution and learning of motor actions, and how motor disorders like Parkinson’s disease corrupt these processes.

KEYWORDS


Anatomy: Axons
Basal ganglia
Central nervous system
Dopamine
Synapses
Conditions: Neurodegenerative disease
Parkinson's disease
Function: Brain and behavior
Learning
Technology: