Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Role of the basal ganglia

Larry H Bernstein, MD, FCAP, Curator

Leaders in Pharmaceutical Intelligence

 

Series E. 2; 5.8

 

Ann Graybiel
Investigator, McGovern Institute
Professor, Department of Brain and Cognitive Science

Ann Martin Graybiel (born 1942) is an Institute Professor and a faculty member in the Department of Brain and Cognitive Sciences at the Massachusetts Institute of Technology. She is also an investigator at the McGovern Institute for Brain Research. She is an expert on the basal ganglia and the neurophysiology of habit formation, and her work is relevant to Parkinson’s disease, Huntington’s disease, obsessive–compulsive disorder, substance abuse and other disorders that affect the basal ganglia.

Graybiel’s work is uncovering neural deficits related to these disorders, as well as the role the basal ganglia play in guiding normal behavior.

Graybiel receives the Medal of Science

For much of her career, Graybiel has focused on the physiology of the striatum, a basal ganglia structure implicated in the control of movement, cognition, habit formation, and decision-making. In the late 1970s, Graybiel discovered that while striatal neurons appeared to be an amorphous mass, they were in fact organized into chemical compartments, which she termed striosomes.^[1] Later research revealed links between striosomal abnormalities and neurological disorders, such as mood dysfunction in Huntingdon’s disease^[2] and depletion of dopamine in Parkinson’s disease.^[3]

Graybiel’s subsequent research demonstrated how modular organization of the striatum relates to cognition, learning, and habit formation. She found that neurons project from areas in the sensory and motor cortices governing the same body part and cluster together in the striatum, forming matrisomes.^[4] Graybiel went on to show that matrisomes exist for each body part and were organized into loops connecting the neocortex, a region responsible for cognition, perception and motor control, to the brain stem, a region coordinating movement.^[5]Studies of rodents and primates revealed that matrisomes were crucial to habit formation.^[6][7]

In later work, Graybiel demonstrated, first in the striatum and later in the infralimbic cortex, that a task-bracket or “chunking” pattern of neuronal activity emerges when a habit is formed, wherein neurons activate when a habitual task is initiated, show little activity during the task, and reactivate when the task is completed.^[7][8]

In more recent work, Graybiel has focused on identifying specific pathways underlying aspects of behavior such as habit formation, learning and cognition, and decision-making, including being the first to analyze the effect of dopamine depletion on the activity of neurons affected by Parkinson’s disease during behavioral tasks.^[9][10]

Beyond movement

The basal ganglia are best known for their control of movement. Parkinson’s disease, for example, results from the degeneration of neurons that release the neurotransmitter dopamine within the striatum, the largest part of the basal ganglia. It is becoming clear, however, that the basal ganglia do more than just control movement. These structures have been implicated in psychiatric diseases and addiction, and damage to the basal ganglia can affect not only movement but also mood and cognition. Graybiel believes that this broad range of functions reflects the capacity of the basal ganglia to influence how we select actions–motor actions as well as actions of thought.

Career

Graybiel majored in biology and chemistry at Harvard University, receiving her bachelor’s degree in 1964.^[11] After receiving an MA in biology from Tufts University in 1966, she began doctoral study in psychology and brain science at MIT under the direction of Hans-Lukas Teuber and Walle Nauta.^[11] She received her PhD in 1971 and joined the MIT faculty in 1973.^[12]

In 1994, she was named the Walter A. Rosenblith Professor Neuroscience in the Department of Brain and Cognitive Science and was named an Investigator at the MIT McGovern Institute for Brain research in 2001.^[12] She was named Institute Professor in 2008.^[13]

In 2001, Graybiel was awarded the President’s National Medal of Science for “her pioneering contributions to the understanding of the anatomy and physiology of the brain, including the structure, chemistry, and function of the pathways subserving thought and movement.”[14] In 2012, she was awarded the Kavli Prize in Neuroscience, along with Cornelia Bargmann and Winfried Denk, “for elucidating basic neuronal mechanisms underlying perception and decision.” [15]

She is a member of the US National Academy of Sciences, the American Academy of Arts and Sciences, and the Institute of Medicine.^[12]

References[edit]

Wikimedia Commons has media related to Ann Graybiel.

1. Jump up^ Graybiel, AM; Ragsdale, Jr., CW (November 1978). “Histochemically distinct compartments in the striatum of human, monkey, and cat demonstrated by acetylthiocholinesterase staining”. Proc Natl Acad Sci U S A (1978) 75 (11): 5723–26. doi:10.1073/pnas.75.11.5723. PMID 103101. Retrieved 23 October 2014.
2. Jump up^ Tippet, LJ; Waldvogel, HJ; Thomas, SJ; Hogg, VM; van Roon-Mom, W; Synek, BJ; Graybiel, AM; Faull, RL (Jan 2007). “Striosomes and mood dysfunction in Huntington’s disease”.Brain 130 (1): 206–21. doi:10.1093/brain/awl243. PMID 17040921. Retrieved 23 October 2014.
3. Jump up^ Roffler-Tarlov, S; Graybiel, AM (5 Jan 1984). “Weaver mutation has differential effects on the dopamine-containing innervation of the limbic and nonlimbic striatum”. Nature 307: 62–66. doi:10.1038/307062a0. Retrieved23 October 2014.
4. Jump up^ Flaherty, AW; Graybiel, AM (1991). “Corticostriatal transformations in the primate somatosensory system. Projections from physiologically mapped body-part representations.”. J Neurophysiol 66: 1249–63. Retrieved 23 October2014.
5. Jump up^ Graybiel, AM; Toshihiko, A; Flaherty, AW; Kimura, M (1994). “The basal ganglia and adaptive motor control”. Science 265 (5180): 1826–31. doi:10.1126/science.8091209. JSTOR 2884650.
6. Jump up^ Illing, R.-B.; Graybiel, AM (1994). “Pattern formation in the developing superior colliculus: Ontogeny of the periodic architecture in the intermediate layers”. Journal of Comparative Neurology 340 (3): 311–27.doi:10.1002/cne.903400303. Retrieved 23 October 2014.
7. ^ Jump up to:^{a b} Graybiel, AM (1998). “The Basal Gangila and Chunking of Action Repertoires”. Neurobiology of Learning and Memory 340 (3): 119–36. doi:10.1006/nlme.1998.3843. PMID 9753592. Retrieved 23 October 2014.
8. Jump up^ Smith, KS; Graybiel, AM (July 2013). “A dual operator view of habitual behavior reflecting cortical and striatal dynamics”. Neuron 79 (2): 361–74. doi:10.1016/j.neuron.2013.05.038. Retrieved 23 October 2014.
9. Jump up^ Hernandez, LF; Kubota, Y; Hu, D; Howe, MW; Lemaire, N; Graybiel, AM (2013). “Selective effects of dopamine depletion and L-DOPA therapy on learning-related firing dynamics of striatal neurons”. Journal of Neuroscience 33(11): 4782–95. doi:10.1523/JNEUROSCI.3746-12.2013. Retrieved 23 October 2014.
10. Jump up^ Trafton, Anne (12 March 2013). “MIT News”. Breaking down the Parkinson’s pathway. Retrieved 23 October 2014.
11. ^ Jump up to:^{a b} “Neuroscience Laureate Biographies”. The Kavli Foundation. Retrieved 23 October 2014.
12. ^ Jump up to:^{a b c} “Ann Graybiel”. McGovern Institute for Brain Research at MIT. Retrieved 23 October 2014.
13. Jump up^ Ann Graybiel named Institute Professor – MIT News Office. Web.mit.edu (2008-11-03). Retrieved on 2012-06-25.
14. Jump up^ US NSF – The President’s National Medal of Science: Recipient Details. Nsf.gov. Retrieved on 2012-06-25.
15. Jump up^ The Kavli Prize. Kavliprize.no. Retrieved on 2012-06-25.

Ann Graybiel: McGovern Institute Investigator

https://www.youtube.com/user/mittechtv

http://www.youtube.com/watch%3Fv%3D0Qi0B_jAMmw

 

https://www.youtube.com/playlist%3Flist%3DPL6D9E1BD5963BBF0C

 

Why We Do What We Do

http://www.technologyreview.com/article/522521/why-we-do-what-we-do/

Institute Professor Ann Graybiel, PhD ’71, has transformed our understanding of a “primitive” area of the brain.

• By Courtney Humphries SM ’04 on December 17, 2013

Institute Professor Ann Graybiel, PhD ’71, is at the forefront of this research, having devoted much of a career now in its fifth decade to understanding a seemingly humble set of brain structures called the basal ganglia. Once known only for helping to control movement, this region deep within the brain is now believed to play fundamental roles in how we learn, process emotions, make decisions, and adopt habits. And that shift in thinking is due in no small part to the research done in Graybiel’s lab.

Her work has already yielded insights into patterns of brain activity associated with movement disorders and psychiatric diseases. Recent studies using light to control individual brain cells, for instance, show how shutting off some of this activity can control habit formation or pessimistic decision-­making. Although this technique, known as optogenetics, is still just a research tool, she is convinced that such technological advances hold therapeutic promise—and that learning about these deep patterns in the brain will also be important for everyone who wonders: What makes me do what I do?

http://www.scientificamerican.com/author/ann-m-graybiel/

 

QnAs with Ann M. Graybiel

Nicholette Zeliadt, Science Writer

PNAS Oct 2013; 110(43).17166, http://dx.doi.org:/10.1073/pnas.1315012110

Ann M. Graybiel, a neuroscientist at the Massachusetts Institute of Technology and a National Academy of Sciences member, uncovers the neurobiological basis of how habits form and provides clues as to how habits can be changed.

PNAS: What is a habit?

Graybiel: A habit is something that we do routinely, that seems almost automatic, and that is fairly repetitive under certain circumstances. There are also extreme habits—such as addictions—and it’s an unresolved issue in the field whether the mechanisms underlying these are similar to those of our normal habits. Psychologists define habits as the kinds of behavior that a person does when acting as though no longer mindful of the outcome of the behavior. If we get to the point in a behavior at which it doesn’t matter whether the outcome is good or bad, then the behavior is almost automatic, not outcome-determined. We are using this outcome-sensitivity index to try to help us “define” a habit in our experiments.

 

PNAS: Many of your studies have involved recording the electrical activity in the striatum (a region of the basal ganglia) in rodents as they learn to navigate a maze to reach a reward and eventually develop a habit. What have you learned from these experiments?

Graybiel: We recorded in the part of the striatum that is active during motor behaviors and found that as animals learn to run mazes habitually, the neurons in this part of the striatum at first are active pretty much all during the runs; but then, as the animals become more automatic, the striatal neurons are mainly active at the beginning and end of the maze runs. It’s as though that entire habitual behavior becomes packaged in the neural representation, as though these beginning and end signals form a bracketing code for the learned behavior. And that reminded me of a very famous analogy that the psychologist George Miller made years ago. He said that it’s hard for us to remember long sequences of letters or numbers—for example, a really long phone number—and so what we do is “chunk” all those numbers together, and then all we have to do is remember the package. We think that the task-bracketing pattern we see might be a sign that once the behavior becomes habitual, it becomes chunked by the sensorimotor part of the striatum.

When we then recorded neural activity in the part of the striatum that former researchers had found to function in relation to being mindful of outcome, we didn’t find that bracketing pattern. Instead, what Katy Thorn in the laboratory found was that the strongest activity occurred when the animals had to make a decision about which way to turn in the maze. So we gradually built up the idea that there are different striatum-based neural circuits; some of them take care of one control feature, like forming the chunking pattern, at the same time that another circuit is encoding the deliberative part. Most interesting, these functional assignments actually have signatures in the spike patterns of the neurons. We hope that we are beginning to be able to link global population activation patterns to behaviors, and that this could turn out to be quite important when we face the issue of how to modify habits.

PNAS :In a 2012 PNAS paper, you disrupted the activity in one of these circuits. What did you find?

Graybiel: Kyle Smith and I recorded in two regions of the brain that are known to be habit-related: one was in the striatum, in its sensorimotor part where we had found that task-bracketing pattern, and the other one was in the prefrontal cortex. We found the same task-bracketing pattern in the sensorimotor striatum that we’ve now found over and over. However, in the prefrontal cortex we found that a bracketing pattern only formed very late in the learning process, when the behavioral habit became engrained. This made us think that the final settling of the bracketing pattern in the cortex might be necessary for the behavior to get set as a habit. So we tried to inhibit that small cortical zone to see whether the animals still would have a habit. We found they didn’t. Then, when we allowed the animal to develop a new habit, and we again inhibited that piece of cortex, the animal reverted to the original habit—it wasn’t gone after all! What the paper shows is that even though a behavior seems to be automatic, there is a bit of brain—in the case of our paper, it’s in the medial prefrontal cortex—that is monitoring things online. So, in fact, a behavior that seems automatic isn’t really automatic, because there’s a piece of brain that cannot only monitor the habit but also can veto the performance of the habit.

PNAS: How does understanding the neurobiology of the habit system advance our understanding of neurologic and psychiatric disorders?

Graybiel: In a number of neuropsychiatric conditions—for example, obsessive-compulsive disorder, Tourette syndrome, many forms of autism, schizophrenia—patients can develop repetitive behaviors, and these stereotyped behaviors are classic features of these disorders. These are behaviors that are repeated, semiautomatically, and they are under very poor volitional, deliberative, attentional control. These repetitive, overly focused behaviors may not rely on exactly the same circuits as “normal” habits, but the fundamental operation of the involved circuits may be similar. This is something we are intensely interested in.

 

2012 Neuroscience Laureate Biographies – CI Bargmann

Cornelia Isabella Bargmann was born in 1961 in Virginia and raised in Athens, Georgia, where she attended the University of Georgia. She then went north to study cancer-signalling genes and cloned the oncogene HER2, a key factor in breast cancer, in the laboratory of Robert Weinberg at the Whitehead Institute, Massachusetts Institute of Technology.

After receiving her Ph.D. in 1987, Professor Bargmann transferred to the laboratory of H. Robert Horvitz, at MIT, where she became acquainted with the tiny worm C. elegans. Professor Horvitz had already made major contributions to understanding neural development using C. elegans as a simple model organism. For this he shared the 2002 Nobel Prize in Physiology or Medicine with Sydney Brenner and John Sulston “for their discoveries concerning genetic regulation of organ development and programmed cell death”. Professor Bargmann then embarked upon what was to become a lifetime mission to define how genes and the environment influence behavior by dissecting the neural circuitry of C. elegans and the genes, receptors and signaling molecules involved in such behaviour as feeding and responses to odours.

In 1995 California beckoned, and Cornelia Bargmann took up an appointment as assistant professor at the University of California, San Francisco. In 1998, she was promoted to Professor, and in 1999 was named vice chair of the Department of Anatomy. In 2004 she returned to the east coast to take up the position of head of the Lulu and Anthony Wang Laboratory of Neural Circuits and Behaviour at Rockefeller University, New York, where she is now Torsten N. Weasel Professor and a Howard Hughes Medical Investigator. Rockefeller University president Paul Nurse welcomed her arrival saying, “Cori Bargmann typifies the Rockefeller scientist: she is bold and highly original in her thinking and her approach to studying the brain and other components of the nervous system”.

Professor Bargmann has received numerous awards, including the Charles Judson Herrick Award for comparative neurology in 2000, the Dargut and Milena Kemali International Prize for Research in the Field of Basic and Clinical Neurosciences in 2004, and the Richard Lounsbery Award from the US and French National Academies of Sciences in 2009. She is a member of the National Academy of Sciences and the American Academy of Arts and Sciences, and the European Molecular Biology Organisation.

Professor Bargmann has trained many students and postdocs in cutting-edge techniques and encouraged them to share her enthusiasm for research. She is as renowned for the quality of her presentations and breadth of knowledge as for her research.