Ledia F. Hernandez
Ken finds that one of the most interesting and least understood functions of the brain is its ability to organize purposeful behaviors to react to the environment, using an enormous amount of information ranging from perception to emotion. To study how the brain accomplishes this, Ken switched to neuroscience after receiving his BS in Physics from the Faculty of Integrated Human Studies, Kyoto University in 1997. Using mathematical techniques, Ken built a theoretical framework for stochastically spiking neurons, which can represent the population dynamics of biological neuronal models, under the supervision of Prof. Shin Ishii at the Theoretical Life Sciences Lab, Nara Institute of Science and Technology.
Many new theoretical approaches emerging in neuroscience today are contributing greatly to our understanding of brain function. To realize the full potential of the theoretical work, close cooperation of theory and experiment is needed. Ken was fortunate to have the opportunity to work directly with experimental researchers in the Lab of Cognitive Neurobiology, Hokkaido University Graduate School of Medicine, where he worked as an instructor after receiving his PhD from NAIST in 2001. In the lab he began to perform his own experiments in physiology under the supervision of Prof. Toshiyuki Sawaguchi. The main theme of his research was the integration of motivation and cognition in the prefrontal cortex. Based on extracellular recordings, the lab found that the reward expectation in the prefrontal cortex selectively enhanced the working memory used for decision of a motor command, suggesting that the prefrontal cortex is mainly involved in guiding a goal-directed behavior.
Following his training and research in neurophysiology, Ken joined the Graybiel Lab in 2005. Ken's present interests include, experimentally, the cooperative functions of the basal-ganglia and prefrontal cortex, and theoretically, statistical inference and neurodynamics. The long-term purpose of his research is to use a combined approach of theory and experiment to determine how the brain links emotion with behavior. An important step toward this goal would be to find out a causal link between neural activity and emotional decision. For this purpose, he is interested in combining multiple techniques to control the brain circuitry that governs decision-making behaviors. Using a variety of recording and manipulation techniques, he seeks to figure out the underlying mechanism of emotion and decision in primate brain.
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Satoko joins the Graybiel lab with a PhD in Medicine from Hokkaido University, Japan, where she studied the neuronal mechanism of set-shifting in the dorsolateral prefrontal cortex of macaque monkeys. Here at the Graybiel lab, in collaboration with Ken Amemori, she is studying cortico-basal ganglia circuits of non-human primates underlying conflict decision-making using neurophysiological, anatomical, and virus-based manipulation techniques.
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Working in the laboratories of Profs. Ann Graybiel and David Housman, I use genetic engineering in mice to study the molecular mechanisms that bias the selection of motor behaviors. We are particularly focused on neural microcircuits in the basal ganglia that are relevant to Huntington’s and Parkinson’s diseases, dystonia, drug addiction, and repetitive movement disorders such as autism and obsessive-compulsive disorder.
The motivation to perform one behavior and simultaneously inhibit inappropriate ones is dependent on striatal integration of incoming information about an animal’s physiological state, the environment, and past experience. The striatum is enriched in receptors for dopamine, acetylcholine, opioids, and endocannabinoids that modulate excitatory inputs and presumably bias our actions to maximize reward. Diseases and drugs that impact striatal signaling have both motoric and psychological consequences. For example, in Huntington’s disease, the death of striatal output neurons is correlated with uncontrollable movements, compulsive behaviors, and mood disturbances. In Parkinson’s disease, degeneration of dopaminergic inputs to the striatum results in the loss of voluntary movement and an increased risk of depression. By contrast, drugs of abuse over-stimulate the dopaminergic system, thereby elevating mood, hyperactivity, and compulsive behaviors including habitual drug use.
By generating mice with deletions in the gene encoding CalDAG-GEFI (a guanine nucleotide exchange factor for Rap GTPases), we discovered that this molecule is key for the seemingly distinct functions of blood clotting (more accurately, platelet adhesion) and the prevention of severe repetitive behaviors. Our publication of the CalDAG-GEFI signaling cascade in platelets led to the identification of CalDAG-GEFI mutations in dogs, cows and humans with similarly reduced platelet activation, thus defining a new type of RASopathy. Our studies of CalDAG-GEFI in the brain have also shown that CalDAG-GEFI levels are abnormally low in individuals with Huntington’s disease. However, reducing CalDAG-GEFI in vitro is neuroprotective. Thus, down-regulation of CalDAG-GEFI might be a compensatory mechanism for neuroprotection, but might also contribute to the repetitive/compulsive behaviors in Huntington’s disease.
Aberrant striatal signaling contributes to another serious movement disorder termed L-DOPA-induced dyskinesia, a complication of Parkinson’s disease therapy. We discovered that expression of both CalDAG-GEFI and its paralog, CalDAG-GEFII, is abnormal in a rat model of dyskinesia: CalDAG-GEFI is down-regulated whereas CalDAG-GEFII is up-regulated. This represents yet another motor disorder (in addition to Huntington’s disease and drug addiction), in which there is a correlation between excessive movement and low CalDAG-GEFI. The finding that CalDAG-GEFI and CalDAG-GEFII are oppositely changed in dyskinesia is intriguing for its potential effects on the balance of signaling from two major striatal compartments, the matrix (CalDAG-GEFI-enriched) and the striosomes (CalDAG-GEFII-enriched). With CalDAG-GEFI- and CalDAG-GEFII-EGFP BAC transgenic mice, we were able to see that projections from the striosome compartment target bundles of ventrally-extending dopamine dendrites (‘dendrons’) whereas projections from the matrix preferentially target the surrounding substantia nigra pars reticulata. We found that the subgroups of striosome-targeted dopamine cells project back to the entire dorsal striatum, with some preference for striosomes. Thus, striosome and and matrix projections are well-placed to synergistically control both local dopamine release within the midbrain, as well as the activity of the dopamine cells of the substantia nigra that project back to the striatum. These findings may help us to understand the imbalance in striosome versus matrix pathology that occurs in numerous brain disorders. For example, the increased striosome to matrix activity ratio observed in drug addiction models might be compensatory, serving to synergistically inhibit dopamine release. We are working to identify striosome-enriched genes and microcircuits with the ultimate goal of ameliorating symptoms related to basal ganglia dysfunction.
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After receiving B.S. and M.S. in Psychology from Peking University in China, Hu Dan came to the U.S. to experience the “front line” research of brain function. Years of work at the University of Illinois at Champaign-Urbana and the University of Texas at Austin not only gave her a PhD degree, but also left her with a big decision of staying in research (of brain function) camp. It was the postdoc experience from Dr. Ann Graybiel lab in MIT and from Dr. Judith Walters lab in NINDS settled her interests in studying the basal ganglia, a big subcortical brain structure related to cognitive motor function, procedure learning, several neurological diseases and more.
Since re-joining the Graybiel lab in 2004 as a research scientist, she has been involved in many research projects attempting to understand striatal neural activity pattern and the role of dopamine, accomplished while rats and mice acquired different learning tasks. Besides research life, she enjoys interacting with research fellows of the lab from all over the world and learning the culture of their home countries, and hopes that one day she will visit each of the countries her colleagues came from.
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Alexander joins the Graybiel lab with a PhD in Neuroscience from the Bar Ilan University, where he studied representations of depression and addiction in the brain. Now at the Graybiel lab, he pursues the neuronal decoding of decision making. Currently, he employs multi-electrode recordings, voltametry, optogenetics and brain imaging to explore relations between decision making and stress, as well as their representation in the striatum and its related circuits. The analysis of the simultaneous neuronal recording requires the development of innovative mathematical tools. In Graybiel lab Alexander develop novel approaches for data analysis and modeling.
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My day job is as a neuroscientist working on the circuit of motivation and mood; and the night job, a robot builder. I used to dream about building more ambitious ones like the fusion reactor and flying Santa’s sleigh, which could light up the face of children! But… I grew up; working on something more realistic: cure depression and make people live happier.
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Min Jung Kim has been studying, and will continue to study, the functional roles of dopamine in relation to the striatum that governs behavioral adaptations, such as learning, motivated actions and habit formation. There are ample evidences that dopamine in the striatum is a key neuromodulator enabling actions properly adapted according to what is needed, but the essential principles governing the functions are poorly understood. This requires multifaceted and the state of the art approach on behaving animals. To achieve this, she has utilized and will employ various in vivo methods, such as electrophysiological, electrochemical, optogenetic/pharmacological, and imaging techniques while animals perform various tasks. The results of her work will advance basic scientific knowledge about how the motivated behaviors are governed and how the striatal circuits interact with the dopamine system. Her research may also identify possible clinical targets for the treatment and/or prevention of Parkinson’s disease, mood disorders and other mental illnesses caused by abnormal regulation or loss of dopamine.
Outside of research, she spends most of her time with traveling, social activities with friends or meditating at a park. She loves walking on trails of Mt. Auburn cemetery or Fresh pond in the early mornings, watching night scenery of Charles river, and attending summer programs at Tanglewood. She easily discovers her delight with coffee, dark beer, pinot noir, dark chocolate, blue sky, and various sound of wind. During commute, she is dedicated to read mangas (Japanese comic books). She loves hiking a mountain but her sport-induced asthma prevents her doing it significantly (but she still challenges herself from time to time).
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Yasuo's interest is in the neural basis of learning and memory. He would like to answer such questions as which brain area is involved in acquiring new information, and how the newly learned information is stored by neurons. Humans often perform the same motor action and behavioral procedure repeatedly, and these acts become so routine that we carry them out almost without conscious effort. Much evidence suggests that the striatum and its related neural circuitry are preferentially involved in this habit learning, but little was known about the forms of neural representation underlying such learning.
In Yasuo's recent study, the team chose chronic ensemble recording with multiple tetrodes (electrodes with four recording channels) to monitor simultaneously the activity of 30-50 striatal neurons in the freely moving subject during acquisition and performance of a procedural learning task in a T-maze. In this task, subjects are trained to move forward when the start gate opens and to turn right or left, as instructed by two auditory cues, in order to obtain a food reward at the goal of the maze.
The research team has found striking changes in the task-related responses of neurons in the sensorimotor region of the striatum. At the beginning of training, many neurons in this area increased their firing frequencies during turning at the choice point of the maze. However, with training, units showing the turn-related response decreased significantly. Instead, there were significant increases in units that increased or decreased discharges in relation to the opening of the start-gate or initiation of locomotion (start-related response) and to reaching the goal area (goal-related response).
These results suggest that the neural representation of behaviors necessary to perform this learning task undergoes transformation during acquisition, and that the new pattern of representation that develops as a result of learning emphasizes the beginning and the end of the automatized behavioral procedure.
In future studies, Yasuo plans to examine what these acquired patterns of neuronal responses represent, how the neuronal network processes and stores task-related information, and how the striatum interacts with other connected brain structures in developing and maintaining such patterns.
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Hideki received an MD from Shimane University, Japan in 1992 and a PhD in Neurology/Medical Science from Kyoto University in 2000. Most recently Hideki served as the Director of Clinical Neurology at the Itsuki Hospital in Tokushima, Japan, a lecturer for Tokushima University's Department of Neurology, and a Research Fellow for the National Institute for Physiological Sciences in Okazaki.
He has studied the physiological interaction between the premotor cortex (area F5) and the primary motor cortex (M1); the treatment, physiological mechanisms and histological changes in various types of dystonia; as well as a physiological study of the changes in somatosensory evoked potentials (SEP) that occur in the thalamus.
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Bernard's main interest is in trying to understand the role of frontostriatal circuits in cognition and behavior. For this, he first studied the way acetylcholine modulates prefrontal circuits during his graduate work in Amsterdam. In 2014 he joined the Graybiel lab to investigate how striatal circuits subserve behavioral learning and decision making. Using optogenetics, electrophysiology and calcium imaging he is testing the functional involvement of different neuronal populations in learning.
When he is not working in the lab, Bernard likes to get out to travel, do sports, and explore new places and cultures.
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Leif Gibb (Research Scientist, Ph.D., University of California, San Diego) completed doctoral research in biologically realistic computational modeling of neural dynamics underlying complex behavioral sequences. He joined the Graybiel Lab in 2009 with the goal of combining experimental research and computational modeling. He was co-first author of a computational modeling paper proposing a function for the striosome compartment of the striatum, published in Frontiers in Human Neuroscience (2011), and he contributed to an experimental study, published in Cell (2015), which used optogenetics and electrophysiology to suggest different functions for the striosome and matrix compartments and their cortical inputs. He contributed to the development of an automated clustering algorithm for spike-sorting, published in PNAS (2015). He has also contributed to our lab’s effort to label striatal neuronal subtypes using viral methods and is using optogenetics, chemogenetics, calcium imaging, fast-scan cyclic voltammetry, and behavioral testing in awake, behaving mice to investigate the dynamics of striatal neurons and dopamine control.
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Daigo is interested the role of the mesostriatal dopaminergic system in animal behavior and neuronal plasticity. Because the dopaminergic dysfunction is widely implicated in many different neurological disorders, he thinks that it is important to know how the dopaminergic activity modulates the neuronal networks in different time scales and its impact on animal behavior.
As the predoctoral training, he investigated how the loss of dopamine affects the development and the aging of dopaminergic system in Dr. Ichinose lab at Tokyo Institute of Technology. He characterized the rodent models for dopa-responsive dystonia and Parkinson’s disease by neurobiological methods and electromyographic analyses.
He joined to Graybiel lab as a postdoc in 2013, and he has been studying the dopaminergic control of striatal neuronal activity and plasticity. He employs multiple different approaches, including electrochemical, electrophysiological and optogenetic methods, to examine how the dopaminergic activities correlate with striatal activities during the cognitive behaviors.
He is also interested in developing the new experimental and analytical methods for the measurement of extracellular dopamine concentration. There are growing evidences for multiple mechanisms for striatal dopamine release, which has been increasing a demand for local measurement of dopamine release. He is going to refine the methods for voltammetric measurement of dopamine to improve its sensitivity and kinetics.
He has been also studying the role of prefronto-striatal network on the value-based decision making as a collaboration with Alexander Freidman.
Through these experiences, he hopes to understand the function of the dopaminergic system at the different levels: molecular to network, and acute to chronic.
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Helen is working in the labs of Dr. Michael Cima and Dr. Ann Graybiel to develop better ways to treat and understand the brain and its disorders. Previously, she worked on wireless microsystems for passive (battery-less) recording and stimulation of neural activity.
B.S., Biomedical Engineering, Johns Hopkins University, 2008
M.S.E., Electrical and Computer Engineering, Johns Hopkins University, 2009
Ph.D., Electrical Engineering, Arizona State University, 2014
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Cody started working in the Graybiel lab in May, 2015. His goal is to learn and master many neuroscience techniques but his primary focus is to perfect fast scan cyclic voltammetry (FSCV) in both rats and mice. Cody graduated from the University of Michigan in 2015 with a B.S. in Neuroscience and a B.S. in Biomolecular Science. There, he worked in the Aragona and Robinson laboratories using FSCV to study the role of dopamine in addictive behaviors. In his free time, Cody enjoys reading, rowing and video games.
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Dan was born and raised in the Berkshire Hills of Massachusetts, a few miles from Tanglewood. According to legend, his first contact with MIT was at the age of 6 when he declared that MIT was the college of his choice. Dan later obtained a Bachelor's degree at MIT in Course 7 (Life Sciences).
While pursuing his doctorate at Johns Hopkins, he cultivated his loves for engineering, theory and music. After graduation, Dan pursued a path involving multiple forays into various types of music composition and performance, modern and Afro-ethnic dance, and software engineering in New York City.
A period of introspection and retrospection in the early aughts led Dan back to the MIT campus, where he was surprised to find a job listing in the campus newspaper that appeared to be written specifically to his resume. It turned out to be from the Graybiel Lab, which Dan joined in 2003.
A "mid-life" period of introspection and retrospection led Dan back to the MIT campus, to the Graybiel Lab. When not programming or analyzing electrophysiology data, Dan's interests include dance, playing the djimbe (an African drum), good food, and such theoretical areas as information and thermodynamic entropy and Maxwell's Demon, complexity science (Santa Fe Institute), and brain architecture. He badly misses playing with his Rush Tribute band from the NYC days, Power Windows.
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Henry Hall, a native of small desert town in Southern California, transplanted to New England in 1966. He attended MIT graduating in 1971 with a Bachelor's of Science.
Henry joined the Graybiel Lab technical staff in 1974.His personal interests include sailing (with strong ties to MIT's small boat sailing program), hiking & mountaineering, canines, and silver-grain photography.
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Samitha comes from a small town in India. She has medical degree from Stanley Medical College, joined Graybiel lab as a Technical assistant in April 2015. Before joining the Graybiel lab, she worked at Umass Boston as a research assistant.
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After receiving MD from Nagoya City University, Japan in 2008, Tomoko worked as a physician and got interested in movement disorders. To study cortico-basal ganglia network, she joined Graybiel Lab in 2013.
Her personal interests are socializing with friends and family, traveling and reading.
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