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Dr. Okihide Hikosaka: 2012 Sharp Lecture in Neural Circuits
The inaugural Sharp Lecture was given on March 1, 2012 by Okihide Hikosaka of the NIH, a leading expert on brain mechanisms of motivation and learning.
Many objects around us have values which have been acquired through our life-long history. This suggests that the values of individual objects are stored in the brain as long-term memories. Our recent experiments suggest that such object-value memories are represented in part of the basal ganglia including the tail of the caudate nucleus (CDt) and the substantia nigra pars reticulata (SNr). We had monkeys look at many visual objects repeatedly in association with different but consistent reward values: half of the objects associated with a large reward (good objects) and the other half associated with a small reward (bad objects). Initially there was little effect of the object-reward association learning. However, after learning sessions across several days, CDt and SNr neurons started showing differential responses to the good and bad objects. In the end, SNr neurons reliably classified surprisingly many visual objects (nearly 300 in each monkey, so far tested) into good and bad objects. This neuronal bias remained intact even after >100 days of no training, even though the monkey continued to learn many other objects. The object value signals in the CDt and SNr are likely used for controlling saccadic eye movements, because many of the SNr neurons projected to the superior colliculus and electrical stimulation in the CDt induced saccades. Our results suggest that choosing good objects among many depends on the basal ganglia-mediated long-term memories. This basal ganglia mechanism may play an underlying role in visuomotor and cognitive skills.
Video Profile: Michale Fee
Michale Fee, an investigator at the McGovern Institute for Brain Research, studies birdsong in order to understand how the brain learns and generates complex sequences of behavior.
Detecting the brain’s magnetic signals with MEG
Magnetoencephalography (MEG) is a noninvasive technique for measuring neuronal activity in the human brain. Electrical currents flowing through neurons generate weak magnetic fields that can be recorded at the surface of the head using very sensitive magnetic detectors known as superconducting quantum interference devices (SQUIDs).
MEG is a purely passive method that relies on detection of signals that are produced naturally by the brain. It does not involve exposure to radiation or strong magnetic fields, and there are no known hazards associated with MEG.
Magnetic signals from the brain are very small compared to the magnetic fluctuations that are produced by interfering sources such as nearby electrical equipment or moving metal objects. Therefore MEG scans are typically performed within a special magnetically shielded room that blocks this external interference.
It is fitting that MIT should have a state-of-the-art MEG scanner, since the MEG technology was pioneered by David Cohen in the early 1970s while he was a member of MIT’s Francis Bitter Magnet Laboratory.
MEG can detect the timing of magnetic signals with millisecond precision. This is the timescale on which neurons communicate, and MEG is thus well suited to measuring the rapid signals that reflect communication between different parts of the human brain.
MEG is complementary to other brain imaging modalities such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), which depend on changes in blood flow, and which have higher spatial resolution but much lower temporal resolution than MEG.
Our MEG scanner, an Elekta Neuromag Triux with 306 channels plus 128 channels for EEG, was installed in 2011 and is the first of its kind in North America. It is housed within a magnetically shielded room to reduce background noise.
The MEG lab is part of the Martinos Imaging Center at MIT, operating as a core facility, and accessible to all members of the local research community. Potential users should contact Dimitrios Pantazis for more information.
The MEG Lab was made possible through a grant from the National Science Foundation and through the generous support of the following donors: Thomas F. Peterson, Jr. ’57; Edward and Kay Poitras; The Simons Foundation; and an anonymous donor.
Video Profile: Yingxi Lin
Yingxi Lin, a member of the McGovern Institute for Brain Research, uses molecular, genetic, and electrophysiological methods to understand how inhibitory circuits form within the brain, and how they are shaped by activity and experience.
Understanding Parkinson’s Disease
Understanding Alzheimer’s Disease
2011 Scolnick Prize Lecture: Bruce S. McEwen
The 2011 Scolnick Prize in Neurosciece was awarded to Dr. Bruce McEwen for his contributions to understanding how hormones affect the brain. Dr. McEwen gave his prize lecture, entitled, “Sex, Stress, and the Brain: Hormone actions above the hypothalamus via novel mechanisms” at the McGovern Institute on September 26, 2011.
Video Profile: Nancy Kanwisher
Nancy Kanwisher, a founding member of the McGovern Institute for Brain Research, uses brain imaging to learn about the organization of the mind.
Re-creating autism, in mice
By mutating a single gene, researchers at MIT and Duke have produced mice with two of the most common traits of autism — compulsive, repetitive behavior and avoidance of social interaction.
They further showed that this gene, which is also implicated in many cases of human autism, appears to produce autistic behavior by interfering with communication between brain cells. The finding, reported in the March 20 online edition of Nature, could help researchers find new pathways for developing drugs to treat autism, says senior author Guoping Feng, professor of brain and cognitive sciences and member of the McGovern Institute for Brain Research at MIT.
About one in 110 children in the United States has an autism spectrum disorder, which can range in severity and symptoms but usually includes difficulties with language in addition to social avoidance and repetitive behavior. There are currently no effective drugs to treat autism, but the new finding could help uncover new drug targets, Feng says.
“We now have a very robust model with a known cause for autistic-like behaviors. We can figure out the neural circuits responsible for these behaviors, which could lead to novel targets for treatment,” he says.
The new mouse model also gives researchers a new way to test potential autism drugs before trying them in human patients.
A genetic disorder
In the past 10 years, large-scale genetic studies have identified hundreds of gene mutations that occur more frequently in autistic patients than in the general population. However, each patient has only one or a handful of those mutations, making it difficult to develop drugs against the disease.
In this study, the researchers focused on one of the most common of those genes, known as Shank3. The protein encoded by Shank3 is found in synapses — the junctions between brain cells that allow them to communicate with each other. Feng, who joined MIT and the McGovern Institute last year, began studying Shank3 a few years ago because he thought that synaptic proteins might contribute to autism and similar brain disorders, such as obsessive compulsive disorder.
At a synapse, one cell sends messages by releasing chemicals called neurotransmitters, which interact with the cell receiving the signal (known as the postsynaptic cell). This signal provokes the postsynaptic cell to alter its activity in some way — for example, turning a gene on or off. Shank3 is a “scaffold” protein, meaning that it helps to organize the hundreds of other proteins clustered on the postsynaptic cell membrane, which are necessary to coordinate the cell’s response to synaptic signals.
Feng targeted Shank3 because it is found primarily in a part of the brain called the striatum, which is involved in motor activity, decision-making and the emotional aspects of behavior. Malfunctions in the striatum are associated with several brain disorders, including autism and OCD. Feng theorized that those disorders might be caused by faulty synapses.
In a 2007 study, Feng showed that another postsynaptic protein found in the striatum, Sapap3, can cause OCD-like behavior in mice when mutated.
Communication problems
In the new Nature study, Feng and his colleagues found that Shank3 mutant mice showed compulsive behavior (specifically, excessive grooming) and avoidance of social interaction. “They’re just not interested in interacting with other mice,” he says.
The study, funded in part by the Simons Foundation Autism Research Initiative, offers the first direct evidence that mutations in Shank3 produce autistic-like behavior.
Guy Rouleau, professor of medicine at the University of Montreal, says the mouse model should give autism researchers a chance to understand the disease better and potentially develop new treatments. “It looks like this is going to be a good model that will be used to explore, more deeply, the physiology of the disorder,” says Rouleau, who was not involved in this research.
Even though only a small percentage of autistic patients have mutations in Shank3, Feng believes that many other cases may be caused by disruptions of other synaptic proteins. He is now doing a study, with researchers from the Broad Institute, to determine whether mutations in a group of other synaptic genes are associated with autism in human patients.
If that turns out to be the case, it should be possible to develop treatments that restore synaptic function, regardless of which particular synaptic protein is defective in the individual patient, Feng says.
Feng performed some of the research while at Duke, and several of his former Duke colleagues are authors on the Nature paper, including lead author Joao Peca and Professor Christopher Lascola.