Kay Tye Looks for Addiction’s Link to Anxiety and Depression
It seems like a dream come true to Kay Tye. Back in 2003 she felt lucky to graduate from MIT’s department of Brain and Cognitive... more
Neuroscience News
From the Director Li-Huei Tsai
I am pleased to announce two new programs that will bring together Picower Institute researchers and clinicians at top teaching hospitals and boost the institute’s initiatives targeting neurological disorders, particularly neurodegenerative disease. I would also like to welcome Kay Tye, a 2003 MIT graduate who will join the Picower Institute and the Department of Brain and Cognitive Sciences in January.
The Picower Clinical Fellowships in Neuroscience Program was designed to enable clinical researchers and/or physician scientists to conduct research at the Picower Institute. The program will draw clinicians from top teaching hospitals who seek to learn techniques of basic and applied scientific research in Picower Institute laboratories and form close collaborations with Picower scientists. After completing a one- to two-year fellowship, these clinicians will continue their medical careers with the added benefit of a close and collaborative relationship with the Institute, helping Picower scientists translate their scientific findings into medical treatments and therapies for neurological disease.
The Picower Neurological Disorder Research Fund (PNDRF) will allow Picower researchers to explore new fields of applied neuroscience and expand current work on Alzheimer's and Parkinson’s disease. The fund will aid our researchers in initiating projects into neurodegenerative conditions such as frontal temporal dementia, Huntington’s disease and traumatic brain injuries that pre-dispose individuals to Parkinson’s, amyotrophic lateral sclerosis- and multiple sclerosis-like neurodegenerative diseases.
The two new programs join the Picower Institute Innovation Fund (PIIF), which was created to provide financial support for Picower Institute faculty members for innovative neuroscience research activities and foundational laboratory support. The fund allows each of the eleven research labs to receive one year of support for research projects that offer potentially high risks and high rewards.
The Tye lab employs an interdisciplinary approach to elucidating a mechanistic explanation for how emotional and motivational states can influence learning and behavior. See the related story on Tye in this issue.
Kay Tye Looks for Addiction’s Link to Anxiety and Depression
It seems like a dream come true to Kay Tye. Back in 2003 she felt lucky to graduate from MIT’s department of Brain and Cognitive Sciences (BCS), and in January 2012 she will join the Picower Institute as an assistant professor. She will be using optogenetics and other techniques to dissect the neural circuitry underlying the positive and negative emotional valence of experiences to understand how addiction is linked to anxiety and depression. “It’s such an honor,” she says. “I love how people approach neuroscience here and the interdisciplinary nature of the Picower Institute.”
Tye’s emotional connection to MIT starts before she was born. Her parents first met on a boat on route from their native Hong Kong to their separate colleges in the US. They met again as MIT graduate students and married in the MIT chapel, which Tye could see from her college dorm. She had grown up in Ithaca, New York, where both parents were professors at Cornell University. She entered MIT eager to study theoretical questions like why we experience the world differently from one another. But while working in the lab of BCS professor Sue Corkin, she encountered HM, a famous patient who could not form new memories after a brain region called the hippocampus was removed during an epilepsy treatment years earlier. That unforgettable experience solidified Tye’s interest in neuroscience. “I wanted more satisfying answers -- what actually happens in the brain when we learn something or want something?”
But did she really want a life in academic research, or was that just all that she knew? What if she should be a writer? To find out, she deferred admission to University of California, San Francisco and went to Australia to live on a yoga ashram, then on an isolated farm, and then in a tent on a beach while teaching at an arts camp, all while trying (unsuccessfully) to write a novel. With that learning experience behind her, she entered UCSF, where her thesis advisor and mentor, Patricia Janak, taught her important lessons about self-motivation. “Good mentorship changed my life, and that’s the most important contribution I hope to make as a researcher here at MIT.”
Working in Janak’s lab in an addiction research center, Tye became interested in why so many people who suffer from addiction also suffer from anxiety and depression, and often experience anxiety and depression during withdrawal. Is it just a correlation due to common environmental or neurological triggers, or is there a causal relationship? It is thought that stress can cause anxiety and that long-term, chronic stress (mild but unpredictable stressors such as sleep deprivation or impending job loss) can cause depression. But do these emotional states make one more prone to addiction, or to relapse after kicking the habit?
Addiction is often described as a “hijacking” of the brain’s natural reward circuit that encodes positive emotional value to an experience and that motivates pleasure seeking or pain avoidance. Because drugs and alcohol trigger strong pleasure signals in this circuit, most addiction research is focused on positive reward learning and on the role of the brain chemical dopamine in motivating rewarding-seeking behavior. Tye’s doctoral and post-doctoral research, however, highlighted several underappreciated contributions to addiction of a brain region called the amygdala, normally associated with fear and anxiety, and also of dopamine’s role in anxiety and depression.
“I want to know at what point the brain assigns a positive or negative emotional association to an environmental cue, and where the first divergence point is for neural circuits encoding positive and negative valence.” she explains. She developed an innovative approach, looking at the first few hours of reward learning in rats and what happens in the amygdala, the first brain region to assign negative emotional value to an experience. Indeed, she found that the amygdala was also important for reward-related learning in much the same way it was important for fear-related learning.
She realized there must be subcircuits in the amygdala with different functions and that might provide a neural link from depression and anxiety to addiction. To investigate that possibility, Tye pursued post-doctoral studies at UCSF with Antonello Bonci to learn more refined electrophysiology techniques and then joined Karl Deisseroth’s lab at Stanford to learn optogenetics, a technology developed there in 2005 that can control brain activity with light. Specifically, she could switch discrete populations of dopamine neurons on and off in transgenic rats and mice. Using that system, she discovered that activating dopamine neurons could rescue stress-induced depression-related behavior. “It makes sense, because so much of depression is a loss of motivation and an inability to experience pleasure. You don’t want to even get out of bed.”
She plans to continue using optogenetics and electrophysiology at the Picower Institute to determine the intersections and interactions of circuits underlying reward learning, anxiety and mood disorders, and compulsive drug-seeking behavior. “The two primary challenges in reducing the prevalence of drug addiction are preventing the development of addiction and the relapse to addiction,” she told the Picower faculty last year, and we cannot meet those challenges without understanding the impact of depression and anxiety on drug addiction. She hopes her research here will provide the solid evidence needed for developing novel treatments for these common and devastating brain disorders.
In the 1983 movie “A Man with Two Brains,” Steve Martin kept his second brain in a jar. In reality, he had two brains inside his own skull—as we all do, one on the left and one on the right... more
In the 1983 movie “A Man with Two Brains,” Steve Martin kept his second brain in a jar. In reality, he had two brains inside his own skull—as we all do, one on the left and one on the right hemisphere. When it comes to seeing the world around us, each of our two brains works independently and each has its own bottleneck for working memory.
Normally, it takes years or decades after a brand new discovery about the brain for any practical implications to emerge. But this study by MIT neuroscientists could be put to immediate use in designing more effective cognitive therapy, smarter brain games, better “heads up displays,” and much more. The study appears in the 6/20/11 issue of the Proceedings of the National Academy of Sciences.
Researchers have known for over a hundred years that we can only hold about four things in our minds at once. This capacity limitation of our working memory (our mental sketchpad) varies somewhat among individuals, and the more you can hold in mind at once, the more complex your thoughts and the higher your IQ tends to be. But although this limitation is a fundamental feature of cognition and intelligence, researchers knew nothing about its neural basis.
Monkeys, amazingly, have the same working memory capacity as humans, so Earl Miller, the Picower Professor of Neuroscience in MIT’s Picower Institute for Learning and Memory, and Timothy Buschman, a post doctoral researcher in his lab, investigated the neural basis of this capacity limitation in two monkeys performing the same test used to explore working memory in humans. First the researchers displayed an array of two to five colored squares, then a blank screen, and then the same array in which one of the squares changed colored. The task was to detect this change and look at the changed square.
As the monkeys performed this task, Buschman recorded simultaneously from neurons in two brain areas related to encoding visual perceptions (the parietal cortex) and holding them in mind (the prefrontal cortex). As expected, the more squares in the array, the worse the performance.
“But surprisingly, we found that monkeys, and by extension humans, do not have a general capacity in the brain,” says Miller. “Rather, they have two independent, smaller capacities in the right and left halves of the visual space. It was as if two separate brains—the two cerebral hemispheres—were looking at different halves of visual space.”
In other words, monkeys, and by extension humans, do not have a capacity of four objects, but of two plus two. If the object to remember appears on the right side of the visual space, it does not matter how many objects are on the left side. The left may contain five objects, but as long as the right side contains only two, monkeys easily remember it. Conversely, if the right side contains three objects and the left side only one, their capacity for remembering the key object on the right is exceeded and so they may forget it.
This study resolves two long-standing debates in the field. Does our working memory function like slots, and after our four slots are filled with object we cannot take in any more; or does it function like a pool that can accept more than four objects, but as the pool fills the information about each object gets thinner? And is the capacity limit a failure of perception, or of memory?
“Our study shows that both the slot and pool models are true,” says Miller. “The two hemispheres of the visual brain work like slots, but within each slot, it’s a pool. We also found that the bottleneck is not in the remembering, it is in the perceiving.” That is, when the capacity for each slot is exceeded, the information does not get encoded very well. The neural recordings showed information about the objects being lost even as the monkeys were viewing them, not later as they were remembering what they had seen.
This effect in visual working memory may not hold for other forms of memory, but visual perceptions is one of the primary ways that humans process the world, so its impact is both far reaching in terms of understanding the brain and human consciousness and in practical terms.
“The fact that we have different capacities in each hemisphere implies that we should present information in a way that does not overtax one hemisphere while under-taxing the other,” explains Buschman. “For example, heads-up displays (transparent projections of information that a driver or pilot would normally need to look down at the dashboard to see) show a lot of data. Our results suggest that you want to put that information evenly on both sides of the visual field to maximize the amount of information that gets into the brain.”
Likewise, cognitive therapies for improving working memory (and in brain games designed to keep it young and nimble) should present information in a way that trains each hemisphere separately. Biomedical monitors that currently have one column of information should balance it in right and left columns, and security personnel could take in more information if displays scrolled vertically rather than horizontally, which wastes the independent capacities on the right and left. The researchers are forming collaborations to develop many of these ideas.
Their next basic research project is to discover why this perceptual bottleneck occurs in the first place, Miller says. “That would give us a deep understanding of how the brain represents information and would give us the first real insights into consciousness.”
This research was funded by the National Institutes of Health and the National Institute of Mental Health.
The healthy brain has balance of excitatory and inhibitory signals that stimulate activity but also keep it under control. Some brain diseases, like autism and Down’s syndrome, have too much... more
The healthy brain has balance of excitatory and inhibitory signals that stimulate activity but also keep it under control. Some brain diseases, like autism and Down’s syndrome, have too much inhibition, which impairs cognitive functions. Reducing inhibition appears to improve cognition, and it can restore juvenile plasticity in the adult brain, making it more adaptable. Scientists want to recapture this plasticity to enhance recovery from stroke or brain injury and to treat people suffering from developmental or degenerative brain disorders. Now, a new MIT study using a common antidepressant that coincidentally reduces neural inhibition shows how this “disinhibition” works in ways that might be used therapeutically.
“It was previously known that the antidepressant fluoxetine, or Prozac, can improve plasticity and also reduce neural inhibition, but how this worked was unclear. We found that fluoxetine-mediated disinhibition permits neuronal rewiring, but it must be accompanied by an instructional cue for how the neurons should rewire themselves in a constructive, meaningful manner,” said Elly Nedivi, associate professor of neurobiology at the Picower Institute for Learning and Memory and senior author of the study in the 4/10/11 issue of Nature Neuroscience.
In normal development, the maturation of the inhibitory circuitry closes the “critical period” when the brain most easily rewires itself. The adult brain can still learn from experience, but more slowly. Scientists thought that ongoing learning does not rewire the brain structurally but only unmasks or re-weights existing connections. But 5 years ago, Nedivi and colleagues showed that locally connecting neurons, called interneurons, actually do structurally remodel themselves on a daily basis, even in the adult brain.
“Interneurons are the primary inhibitory neurons in the cortex, so we thought that this structural rearrangement of the inhibitory circuit could be a mechanism for experience-dependent functional plasticity in the adult brain,” she said.
For the current study, Nedivi and colleagues used a standard visual manipulation—closing one eye—to induce plasticity in adult mice. Such monocular deprivation forces neurons to shift their allegiance from the closed to the open eye. This shift happens more slowly in adults than in juveniles, for reasons this study now explains.
The team used imaging technology developed by Peter T. So, professor of mechanical engineering and biological engineering at MIT, to obtain time-lapse 3-D reconstructions of entire interneurons, including the branching arbors of dendrites that relay signals from other neurons to the cell body.
In experiments led by Jerry Chen, a former graduate student in Nedivi’s lab, they saw the dendritic trees in the deprived zone almost quadruple their remodeling in response to visual deprivation.
This structural remodeling occurred in two phases. During the first few days, the inhibitory interneurons retracted their dendrites away from other neurons. This retraction reduced the inhibition of excitatory neurons, which then become more active. Later, the interneurons’ dendrites also grew outwards, forming new connections with neurons receiving input from the functioning eye -- literally rewiring the circuitry.
The need to first retract before forming new connections explains the slow adaptation of the adult brain. “We realized we could speed up the constructive remodeling phase by artificially reducing inhibition with fluoxetine,” said Chen.
They found that giving the mice fluoxetine allowed the neurons to bypass the retraction phase and go right to the constructive phase. But this constructive remodeling had to occur at the same time as visual stimulation—an instructive clue—from the functioning eye.
“We think this finding could have clinical relevance,” Nedivi said. For example, during stroke rehabilitation, providing instructive activities with fluoxetine might accelerate a brain region’s adoption of a function previously performed by a damaged region.
This research was funded by the National Eye Institute and the Stanley Center for Psychiatric Research.
