Honoring World Parkinson’s Day: Driving neural circuit advances in Parkinson’s therapeutics with Inscopix miniscopes

Parkinson’s disease (PD) is a neurological disorder that affects 6 hundred thousand to more than 1 million people in the United States, or over 6 million worldwide, making it the second most prevalent brain disease behind Alzheimer’s. This disease presents differently in every individual but is typically marked by motor symptoms such as resting tremors, difficulty with balance, and stiffness or slowness of movement. Some individuals may also experience other symptoms such as trouble sleeping, cognitive changes, and depression (source; The Michael J. Fox Foundation).

PD is caused when nerve cells in the basal ganglia become impaired or die. When this happens, neurons produce less dopamine, causing the motor symptoms associated with the disease. Individuals with PD also lose the nerve endings that produce norepinephrine which is a neurotransmitter that helps maintain blood pressure and heart rate (source; National Institute of Aging). In addition to these changes in the brain, Alpha-synuclein may accumulate to form Lewy bodies in neurons, which eventually causes their death (source; American Parkinson Disease Association). Unfortunately, there is no cure, and scientists do not know what causes these neurons to die. Therefore, there is an ongoing need for innovative new approaches to better understand the cells at play when this disease presents itself, and scientists all over the world are actively working in the lab or clinic to take on this challenge.

Despite not yet having a cure, PD patients have several treatments available to lessen symptoms. Medications exist for both motor and non-motor symptoms including dopamine replacement therapy using levodopa/carbidopa, adenosine receptor antagonists, and more. There are also surgical interventions, such as deep brain stimulation (DBS) and focused ultrasound (FUS), for certain symptoms (source; The Michael J. Fox Foundation). Despite best efforts, medications and surgical interventions don’t always work for every individual, and this has caused researchers to take creative new approaches to improve the lives of PD patients.

Here at Inscopix, our mission is to empower researchers with cutting-edge tools that aid in the understanding of brain function and accelerate therapeutic development for neurological and psychiatric disorders. The following four publications are great examples of pioneer researchers who used several experimental approaches including calcium imaging using Inscopix miniscopes, optogenetics and behavioral experiments to investigate the neurons, circuits, and pathways responsible for Parkinson’s disease—we hope you find them insightful and inspiring for your own work.

Identification of sclareol as a natural neuroprotective Cav1.3-antagonist using synthetic Parkinson-mimetic gene circuits and computer-aided drug discovery

Neuronal degeneration is a symptom of Parkinson’s disease caused by defective dopaminergic neurons (DANs). These neurons are typically characterized by the formation of Lewy bodies made up of ubiquitin and 𝛼-synuclein aggregates and poor calcium homeostasis. In this study by Wang, et al. from ETH Zurich, published in Advanced Science, these researchers wanted to take on the challenge of drug discovery by using nVoke for high-throughput screening of PD-relevant drug candidates. It is known that CaV 1.3-selective blockers without CaV 1.2-mediated cardiovascular side effects are currently considered elusive candidates for PD drug discovery. Therefore, they custom-designed a mammalian cell-based drug discovery platform for screening isoform-specific calcium channel blockers (CCBs).

The group found five plant-derived essential oils that could effectively block CaV 1.2 and CaV 1.3, with the Mediterranean medicinal herb Salvia sclarea standing out as a relevant bioactive compound for treating PD symptoms. The effectiveness of this compound was confirmed by one-photon, live calcium imaging.  This group is the first to tailor a multiplexed drug screening system for ion channel-related diseases and this study is a promising example of what researchers can accomplish with the combination of molecular medicine, high-throughput technologies, and artificial intelligence.

Dopamine neuron activity encodes the length of upcoming contralateral movement sequences

It is critical to perform the right actions at the appropriate time and vigor for survival. However, in Parkinson’s disease, the loss of DANs in the substantia nigra pars compacta (SNc) leads to changes in movement vigor like bradykinesia or slowed movement. In this study, published in Current Biology, Mendonça, et al. from the Champalimaud Foundation investigated the hypothesis that movement modulated DANs signal not only a general motivation to move but also invigorate aspects of contralateral movements. They developed a behavioral paradigm to investigate movement before using nVista for one-photon imaging of the activity of genetically identified SNc DANs during lever-press tasks.

Their results suggest that SNc dopaminergic activity comes before the execution of movement when invigorating the length of contralateral movements. This uncovers a previously unknown relationship between DANs before movement and the length of movements. Their study can also serve as a valuable resource for researchers trying to better understand the different clinical manifestations of PD.

Targeted activation of midbrain neurons restores locomotor function in mouse models of parkinsonism

Motion impairments including freezing of gait and akinesia are very prevalent in PD, but new research is investigating areas to target in the brain to restore function. In this study, Masini, et al. from the Kiehn research team at the University of Copenhagen, published in Nature Communications, investigated whether electrical stimulation of diverse pedunculopontine nucleus (PPN) neurons could revert a parkinsonian motor phenotype to normal. By employing nVoke to monitor cellular activity, researchers were able to assess the extent to which the Parkinsonian state is mirrored in basal ganglia and PPN neuronal populations. They studied the activity of medium spiny neurons from the basal ganglia direct pathway and glutamatergic PPN neurons in freely behaving mice before and after inducing dopamine signaling deficiency with drugs.

Ultimately, this group found that caudal glutamatergic PPN neurons are a promising target for neuromodulatory restoration of locomotion and function in PD patients as target activation of these neurons counteracted drug-induced akinesia and bradykinesia. This study is another strong example of how researchers are finding new approaches to help combat symptoms of PD using novel neurotechnology and experimental approaches.

Basal ganglia–spinal cord pathway that commands locomotor gait asymmetries in mice

Most recently, Cregg, et al., also members of Kiehn’s group from Copenhagen, published in Nature Neuroscience (2024), explored the neural pathways responsible for locomotor asymmetries in mice. They used intersectional viral tracing, cell-type-specific modulation, and calcium imaging with nVoke to uncover how basal ganglia interface with specific brainstem motor pathways. They also wanted to identify the distinct circuit motifs that facilitate the execution of motor actions at the spinal level.

At the conclusion of their study, researchers uncovered the functional organization of circuits that control left-right turning gait asymmetries in mice: basal ganglia → pontine reticular nucleus, oral part (PnO) → Chx10 Gi → spinal cord. Their results provide a better understanding of the pathways at play in PD and how modulation of these pathways is a promising target for DBS and alleviating turning disabilities in PD patients.

Parkinson’s disease is a neurological condition affecting millions of people around the world, and researchers are working hard to find the cure and treatments for symptoms in the lab, clinic, and at home. The publications in this blog include several examples of labs developing methods to overcome the challenges of unraveling this disease, and we are grateful that our Inscopix miniscope technology was an invaluable contributor to their work.

Keywords: striatum, locomotor activity, deep brain stimulation

Melissa Martin

Melissa Martin is the Life Science Writer for Bruker Fluorescence Microscopy with a B.S. in Zoology and Life Sciences Communication from the University of Wisconsin-Madison. She is passionate about a wide variety of scientific topics, including brain-neuron behavior and wildlife ecosystem adaptations during climate change. She enjoys conducting interviews and reading about researchers’ work in cell biology, neuroscience, and genomics and hopes to continue to share what she learns with others in an exciting and positive way.

Leave a Reply

Scroll to Top