Dopamine (DA) is well known to enable nerve cells to communicate with each other in the brain. In an effort to go deeper into understanding this process, the research team led by Dr. Marta Maltese, used two-photon calcium imaging to monitor activity in the brains of mice. As the mice ran on a treadmill, the scientists observed activity among the two types of neurons — the ones that incited movement, and the ones that directed a muscle to be still.

“This research is amazing because the activity of the neurons that create a balance between moving a muscle and not moving a muscle can be seen through the microscope while the mouse is moving on the treadmill,” says MBF Bioscience Research Liaison Dr. Dan Peruzzi. “Not only could they see the activity of the neurons, they could also differentiate which neurons activate the ‘do not move the muscle’ instructions and which neurons send signals to ‘move the muscle’.

Imaging striatal activity using two-photon microscopy or photometry.

The researchers found that when the mouse was on the treadmill, an equal number of both types of neurons were activated. But when they introduced drugs that reduced dopamine levels, mimicking what happens in Parkinson’s disease, the balance was upset — more of the neurons that tell a muscle not to move were activated.

“Our imaging approach therefore offers the ability to simultaneously monitor and compare the activity of hundreds of striatal neurons (mean ± SEM: 327 ± 13 per field of view, range: 131–442) belonging to both direct and indirect pathways with high spatial resolution during a simple behavior… Our results reveal that, in addition to its effects on firing rates, DA regulates striatal output by reconfiguring its movement-related ensemble code.” (Maltese et.al., 2021)

Maltese, M., March, J. R., Bashaw, A. G., & Tritsch, N. X. (2021). Dopamine differentially modulates the size of projection neuron ensembles in the intact and dopamine-depleted striatum. eLife, 10, e68041. https://doi.org/10.7554/eLife.68041

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Journeying along axons, microscopic powerhouses known as mitochondria provide cells with the energy they need to function. When something goes wrong with the axonal transport and mitochondria isn’t delivered, the system fails, and the cell body dies.

Scientists in the Department of Anatomy and Neurobiology at the Washington University School of Medicine in St. Louis study the cellular bases of neurological disorders. Their recent research focuses on Parkinson’s disease and identifies impaired axonal transport as a possible key player in this neurological disorder.

The research group, of Dr. Karen L. O’Malley, Dr. Jeong Sook Kim-Han, and Dr. Jo Ann Antenor-Dorsey studied axonal transport in dopamine (DA) neurons in the mouse brain—the cells most affiliated with Parkinson’s disease. They localized cell axons by using a microchamber system that separated axons from cell bodies and dendrites. They also introduced 1-methyl-4-phenylpyridinium ion (MPP+), a toxin known to disrupt axonal function and mimic Parkinson’s disease.

Stereo Investigator helped them quantify TH-positive cell bodies and neurites. As early as 12 hours after MPP+ treatment, they saw breaks in axons. After 24 hours, they began to see a significant reduction in cell bodies. “This study underscores the necessity of developing therapeutics aimed at axons as well as cell bodies so as to preserve circuitry and function,” they say in their paper “The Parkinsonian Mimetic, MPP+, Specifically Impairs Mitochondrial Transport in Dopamine Axons, published in the Journal of Neuroscience.

The use of Stereo Investigator saved the researchers time and hard drive space, according to Dr. Kim-Han. “We used to count cells after acquiring images from a fluorescent microscope and saving it to a computer, which took long time and a lot of space on the computer,” she said. “Also, the data was more convincing since the area for counting was selected automatically with the number of fields assigned.”

Read the full paper “The Parkinsonian Mimetic, MPP+, Specifically Impairs Mitochondrial Transport in Dopamine Axons“, in the Journal of Neuroscience.

[The Journal of Neuroscience, 11 May 2011, 31(19): 7212-7221; doi: 10.1523/ JNEUROSCI.0711-11.2011]

{IMG: Synapse Diagram – This file is licensed under the Creative Commons Attribution-Share Alike 1.0 Generic license}

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Patients suffering from Parkinson’s disease may have a new way to manage their illness: gene therapy. Scientists at seven leading gene therapy centers across the US saw improvements in patients when a gene that helps produce the inhibitory transmitter GABA was introduced to quiet the subthalamic nucleus, an overactive region of the brain in Parkinson’s patients.

Twenty-two subjects from a group of 45 patients aged 30-75 received AAV2-GAD infusions, while the rest underwent sham surgery. Over the course of six-months, the group that received gene therapy showed significant improvement in Parkinson’s symptoms, according to a study published this month in The Lancet Neurology.

Encouraged by the success of the trial and safety of the method, the investigators, including MBF Bioscience customer Dr. Michael G Kaplitt of Weill Cornell Medical College, plan to further their research with a larger clinical trial.

Read more about the study at nature.com and access the abstract and full article text at thelancet.com.

LeWitt, P. A. et al. Lancet Neurol. doi:10.1016/S1474-4422(11)70039-4 (2011).

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Optogenetics is a fairly new scientific field that combines optical stimulation with genetic engineering. According to a recent article in Wired magazine, neuroscientist, psychologist, and MBF Bioscience customer Dr. Karl Deisseroth and his team of researchers at Stanford University are making major optogenetic advancements – the kind that might lead to a cure for Parkinson’s Disease.

It all began in 1979, when one of the discoverers of DNA’s double helix, Francis Crick, acknowledged the need to “control neurons of only one cell type in one specific location.” The solution?  Light. The only genes known to respond to light were the ones found in plants. In the 1990s, German biologist Peter Hegemann was researching the affect of light on algae. When exposed to light, the algae cells moved.

Ten years ago, UC San Diego biologist Roger Tsien acquired some of Hegemann’s light-sensitive genes, and inserted them into a frog egg. Stimulated by a beam of light, the egg responded.

Enter Dr. Deisseroth. Aided by a team of graduate students, Dr. Deisseroth set out to discover whether or not “misbehaving cells” in the brains of patients suffering from depression or Parkinson’s could be “tagged genetically and controlled with light.” They were able to successfully control the movements of worms, make a mouse run in circles, and are currently carrying out research on primates.

Read the full article at wired.com to find out more about the history of optogenetics and its relevance to the treatment of Parkinson’s.

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