{"id":22506,"date":"2022-06-09T11:56:56","date_gmt":"2022-06-09T06:11:56","guid":{"rendered":"https:\/\/www.revoscience.com\/en\/?p=22506"},"modified":"2022-06-09T11:57:03","modified_gmt":"2022-06-09T06:12:03","slug":"three-distinct-brain-circuits-in-the-thalamus-contribute-to-parkinsons-symptoms","status":"publish","type":"post","link":"https:\/\/www.revoscience.com\/en\/three-distinct-brain-circuits-in-the-thalamus-contribute-to-parkinsons-symptoms\/","title":{"rendered":"Three distinct brain circuits in the thalamus contribute to Parkinson\u2019s symptoms"},"content":{"rendered":"\n

CAMBRIDGE, MA — Parkinson\u2019s disease is best-known as a disorder of movement. Patients often experience tremors, loss of balance, and difficulty initiating movement. The disease also has lesser-known symptoms that are nonmotor, including depression.<\/p>\n\n\n\n

In a study of a small region of the thalamus, MIT neuroscientists have now identified three distinct circuits that influence the development of both motor and nonmotor symptoms of Parkinson\u2019s. Furthermore, they found that by manipulating these circuits, they could reverse Parkinson\u2019s symptoms in mice.<\/p>\n\n\n\n

The findings suggest that those circuits could be good targets for new drugs that could help combat many of the symptoms of Parkinson\u2019s disease, the researchers say.<\/p>\n\n\n\n

\u201cWe know that the thalamus is important in Parkinson\u2019s disease, but a key question is how can you put together a circuit that that can explain many different things happening in Parkinson’s disease. Understanding different symptoms at a circuit level can help guide us in the development of better therapeutics,\u201d says Guoping Feng, the James W. and Patricia T. Poitras Professor in Brain and Cognitive Sciences at MIT, a member of the Broad Institute of Harvard and MIT, and the associate director of the McGovern Institute for Brain Research at MIT.<\/p>\n\n\n\n

\"\"<\/figure>\n\n\n\n

Feng is the senior author of the study, which appears today in Nature<\/em><\/a>. Ying Zhang, a J. Douglas Tan Postdoctoral Fellow at the McGovern Institute, and Dheeraj Roy, a NIH K99 Awardee and a McGovern Fellow at the Broad Institute, are the lead authors of the paper.<\/p>\n\n\n\n

Tracing circuits<\/strong><\/p>\n\n\n\n

The thalamus consists of several different regions that perform a variety of functions. Many of these, including the parafascicular (PF) thalamus, help to control movement. Degeneration of these structures is often seen in patients with Parkinson\u2019s disease, which is thought to contribute to their motor symptoms.<\/p>\n\n\n\n

In this study, the MIT team set out to try to trace how the PF thalamus is connected to other brain regions, in hopes of learning more about its functions. They found that neurons of the PF thalamus project to three different parts of the basal ganglia, a cluster of structures involved in motor control and other functions: the caudate putamen (CPu), the subthalamic nucleus (STN), and the nucleus accumbens (NAc).<\/p>\n\n\n\n

\u201cWe started with showing these different circuits, and we demonstrated that they\u2019re mostly nonoverlapping, which strongly suggests that they have distinct functions,\u201d Roy says.<\/p>\n\n\n\n

Further studies revealed those functions. The circuit that projects to the CPu appears to be involved in general locomotion, and functions to dampen movement. When the researchers inhibited this circuit, mice spent more time moving around the cage they were in.<\/p>\n\n\n\n

The circuit that extends into the STN, on the other hand, is important for motor learning \u2014 the ability to learn a new motor skill through practice. The researchers found that this circuit is necessary for a task in which the mice learn to balance on a rod that spins with increasing speed.<\/p>\n\n\n\n

Lastly, the researchers found that, unlike the others, the circuit that connects the PF thalamus to the NAc is not involved in motor activity. Instead, it appears to be linked to motivation. Inhibiting this circuit generates depression-like behaviors in healthy mice, and they will no longer seek a reward such as sugar water.<\/p>\n\n\n\n

Druggable targets<\/strong><\/p>\n\n\n\n

Once the researchers established the functions of these three circuits, they decided to explore how they might be affected in Parkinson\u2019s disease. To do that, they used a mouse model of Parkinson\u2019s, in which dopamine-producing neurons in the midbrain are lost.<\/p>\n\n\n\n

They found that in this Parkinson\u2019s model, the connection between the PF thalamus and the CPu was enhanced, and that this led to a decrease in overall movement. Additionally, the connections from the PF thalamus to the STN were weakened, which made it more difficult for the mice to learn the accelerating rod task.<\/p>\n\n\n\n

Lastly, the researchers showed that in the Parkinson\u2019s model, connections from the PF thalamus to the NAc were also interrupted, and that this led to depression-like symptoms in the mice, including loss of motivation.<\/p>\n\n\n\n

Using chemogenetics or optogenetics, which allows them to control neuronal activity with a drug or light, the researchers found that they could manipulate each of these three circuits and in doing so, reverse each set of Parkinson\u2019s symptoms. Then, they decided to look for molecular targets that might be \u201cdruggable,\u201d and found that each of the three PF thalamus regions have cells that express different types of cholinergic receptors, which are activated by the neurotransmitter acetylcholine. By blocking or activating those receptors, depending on the circuit, they were also able to reverse the Parkinson\u2019s symptoms.<\/p>\n\n\n\n

\u201cWe found three distinct cholinergic receptors that can be expressed in these three different PF circuits, and if we use antagonists or agonists to modulate these three different PF populations, we can rescue movement, motor learning, and also depression-like behavior in PD mice,\u201d Zhang says.<\/p>\n\n\n\n

Parkinson\u2019s patients are usually treated with L-dopa, a precursor of dopamine. While this drug helps patients regain motor control, it doesn\u2019t help with motor learning or any nonmotor symptoms, and over time, patients become resistant to it.<\/p>\n\n\n\n

The researchers hope that the circuits they characterized in this study could be targets for new Parkinson\u2019s therapies. The types of neurons that they identified in the circuits of the mouse brain are also found in the nonhuman primate brain, and the researchers are now using RNA sequencing to find genes that are expressed specifically in those cells.<\/p>\n\n\n\n

\u201cRNA-sequencing technology will allow us to do a much more detailed molecular analysis in a cell-type specific way,\u201d Feng says. \u201cThere may be better druggable targets in these cells, and once you know the specific cell types you want to modulate, you can identify all kinds of potential targets in them.\u201d<\/p>\n\n\n\n

The research was funded, in part, by the K. Lisa Yang and Hock E. Tan Center for Molecular Therapeutics in Neuroscience at MIT, the Stanley Center for Psychiatric Research at the Broad Institute, the James and Patricia Poitras Center for Psychiatric Disorders Research at MIT, the National Institutes of Health BRAIN Initiative, and the National Institute of Mental Health.<\/p>\n","protected":false},"excerpt":{"rendered":"

Parkinson\u2019s disease is best-known as a disorder of movement. Patients often experience tremors, loss of balance, and difficulty initiating movement.<\/p>\n","protected":false},"author":2,"featured_media":22507,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[6,17],"tags":[],"class_list":["post-22506","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-health","category-research"],"featured_image_urls":{"full":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",900,600,false],"thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-200x200.jpg",200,200,true],"medium":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-600x400.jpg",600,400,true],"medium_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-768x512.jpg",750,500,true],"large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-675x450.jpg",675,450,true],"1536x1536":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",900,600,false],"2048x2048":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",900,600,false],"ultp_layout_landscape_large":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",900,600,false],"ultp_layout_landscape":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",855,570,false],"ultp_layout_portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",600,400,false],"ultp_layout_square":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",600,400,false],"newspaper-x-single-post":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-760x490.jpg",760,490,true],"newspaper-x-recent-post-big":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-550x360.jpg",550,360,true],"newspaper-x-recent-post-list-image":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press-95x65.jpg",95,65,true],"web-stories-poster-portrait":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",640,427,false],"web-stories-publisher-logo":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",96,64,false],"web-stories-thumbnail":["https:\/\/www.revoscience.com\/en\/wp-content\/uploads\/2022\/06\/MIT-Park-Circuits-01-press.jpg",150,100,false]},"author_info":{"info":["RevoScience"]},"category_info":"Health<\/a> Research<\/a>","tag_info":"Research","comment_count":"0","_links":{"self":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/22506","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/comments?post=22506"}],"version-history":[{"count":0,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/posts\/22506\/revisions"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media\/22507"}],"wp:attachment":[{"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/media?parent=22506"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/categories?post=22506"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.revoscience.com\/en\/wp-json\/wp\/v2\/tags?post=22506"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}