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Stanley Center & Poitras Center Joint Translational Neuroscience Seminar Series: Dr. Steven Hyman

Anne Trafton |

Abstract:

The genetic analysis of schizophrenia, bipolar disorder, and autism spectrum disorders has achieved early success. Much work remains: increasing the size and diversity of cohorts, fine mapping GWAS loci, and improving tools to implicate variants too rare to allow statistical certainty. However, the greater challenges lie in transforming gene lists into biological insights and therapies. The genetic architecture of neuropsychiatric disorders creates special difficulties for biology including polygenicity, low penetrance alleles and sharing across multiple disorders. These difficulties are heightened by the challenges posed by the human brain, with its diversity of cells and circuits, its inaccessibility in life, and by recent evolutionary changes that often limits the utility of animal models. I will review progress in genetics and discuss why the Stanley Center is pursing genetic analysis to “diminishing returns”. I will then argue that to exploit genetics we must (1) significantly humanize our model systems and commit to using the “right” cell types; (2) enhance molecular tools to interrogate human neurons and glia at the single cell level; (3) eschew overreliance on approaches that have worked for the investigation of highly penetrant alleles; and (4) develop ethical and practical frameworks so that compounds, once shown to be safe, can be studied in patients without attempting to gain false reassurance of efficacy from animal behavior.

How the brain keeps time

Anne Trafton |

Keeping track of time is critical for many tasks, such as playing the piano, swinging a tennis racket, or holding a conversation. Neuroscientists at MIT and Columbia University have now figured out how neurons in one part of the brain measure time intervals and accurately reproduce them.

The researchers found the lateral intraparietal cortex (LIP), which plays a role in sensorimotor function, represents elapsed time, as animals measure and then reproduce a time interval. They also demonstrated how the firing patterns of population of neurons in the LIP could coordinate sensory and motor aspects of timing.

LIP is likely just one node in a circuit that measures time, says Mehrdad Jazayeri, the lead author of a paper describing the work in the Oct. 8 issue of Current Biology.

“I would not conclude that the parietal cortex is the timer,” says Jazayeri, an assistant professor of brain and cognitive sciences at MIT and a member of the McGovern Institute for Brain Research. “What we are doing is discovering computational principles that explain how neurons’ firing rates evolve with time, and how that relates to the animals’ behavior in single trials. We can explain mathematically what’s going on.”

The paper’s senior author is Michael Shadlen, a professor of neuroscience and member of the Mortimer B. Zuckerman Mind Brain Behavior Institute at Columbia University.

As time goes by

Jazayeri, who joined the MIT faculty in 2013, began studying timing in the brain several years ago while a postdoc at the University of Washington. He began by testing humans’ ability to measure and reproduce time using a task called “ready, set, go.” In this experiment, the subject measures the time between two flashes (“ready” and “set”) and then presses a button (“go”) at the appropriate time — that is, after the same amount of time that separated the “ready” and “set.”

From these studies, he discovered that people do not simply measure an interval and then reproduce it. Rather, after measuring an interval they combine that measurement, which is imprecise, with their prior knowledge of what the interval could have been. This prior knowledge, which builds up as they repeat the task many times, allows people to reproduce the interval more accurately.

“When people reproduce time, they don’t seem to use a timer,” Jazayeri says. “It’s an active act of probabilistic inference that goes on.”

To find out what happens in the brain during this process, Jazayeri recorded neuronal activity in the LIP of monkeys trained to perform the same task. In these recordings, he found distinctive patterns in the measurement phase (the interval between “ready” and “set”), and the production phase (the interval between “set” and “go”).

During the measurement phase, neuron activity increases, but not linearly. Instead, the slope of activity begins as a steep curve that gradually flattens out as time goes by, until the “set” signal is given. This is key because the slope at the end of the measurement interval predicts the slope of activity in the production phase.

When the interval is short, the slope during the second phase is steep. This allows the activity to increase quickly so that the animal can produce a short interval. When the interval is longer, the slope is gentler and it takes longer to reach the time of response.

“As time goes by during the measurement, the animal knows that the interval that it has to produce is longer and therefore requires a shallower slope,” Jazayeri says.

Using this data, the researchers could correctly predict, based on the slope at the end of the measurement phase, when the animal would produce the “go” signal.

“Previous research has shown that some neurons exhibit a ramping up of their firing rate that culminates with the onset of a timed motor response. This research is exciting because it provides the first hint as to what may control the slope of this ‘neural ramping,’ specifically that the slope of the ramp may be determined by the firing rate at the beginning of the timed interval,” says Dean Buonomano, a professor of behavioral neuroscience at the University of California at Los Angeles who was not involved in the research.

“A highly distributed problem”

All cognitive and motor functions rely on time to some extent. While LIP represents time during interval reproduction, Jazayeri believes that tracking time occurs throughout brain circuits that connect subcortical structures such as the thalamus, basal ganglia, and cerebellum to the cortex.

“Timing is going to be a highly distributed problem for the brain. There’s not going to be one place in the brain that does timing,” he says.

His lab is now pursuing several questions raised by this study. In one follow-up, the researchers are investigating how animals’ behavior and brain activity change based on their expectations for how long the first interval will last.

In another experiment, they are training animals to reproduce an interval that they get to measure twice. Preliminary results suggest that during the second interval, the animals refine the measurement they took during the first interval, allowing them to perform better than when they make just one measurement.

How the brain recognizes objects

Anne Trafton |

When the eyes are open, visual information flows from the retina through the optic nerve and into the brain, which assembles this raw information into objects and scenes.

Scientists have previously hypothesized that objects are distinguished in the inferior temporal (IT) cortex, which is near the end of this flow of information, also called the ventral stream. A new study from MIT neuroscientists offers evidence that this is indeed the case.

Using data from both humans and nonhuman primates, the researchers found that neuron firing patterns in the IT cortex correlate strongly with success in object-recognition tasks.

“While we knew from prior work that neuronal population activity in inferior temporal cortex was likely to underlie visual object recognition, we did not have a predictive map that could accurately link that neural activity to object perception and behavior. The results from this study demonstrate that a particular map from particular aspects of IT population activity to behavior is highly accurate over all types of objects that were tested,” says James DiCarlo, head of MIT’s Department of Brain and Cognitive Sciences, a member of the McGovern Institute for Brain Research, and senior author of the study, which appears in the Journal of Neuroscience.

The paper’s lead author is Najib Majaj, a former postdoc in DiCarlo’s lab who is now at New York University. Other authors are former MIT graduate student Ha Hong and former MIT undergraduate Ethan Solomon.

Distinguishing objects

Earlier stops along the ventral stream are believed to process basic visual elements such as brightness and orientation. More complex functions take place farther along the stream, with object recognition believed to occur in the IT cortex.

To investigate this theory, the researchers first asked human subjects to perform 64 object-recognition tasks. Some of these tasks were “trivially easy,” Majaj says, such as distinguishing an apple from a car. Others — such as discriminating between two very similar faces — were so difficult that the subjects were correct only about 50 percent of the time.

After measuring human performance on these tasks, the researchers then showed the same set of nearly 6,000 images to nonhuman primates as they recorded electrical activity in neurons of the inferior temporal cortex and another visual region known as V4.

Each of the 168 IT neurons and 128 V4 neurons fired in response to some objects but not others, creating a firing pattern that served as a distinctive signature for each object. By comparing these signatures, the researchers could analyze whether they correlated to humans’ ability to distinguish between two objects.

The researchers found that the firing patterns of IT neurons, but not V4 neurons, perfectly predicted the human performances they had seen. That is, when humans had trouble distinguishing two objects, the neural signatures for those objects were so similar as to be indistinguishable, and for pairs where humans succeeded, the patterns were very different.

“On the easy stimuli, IT did as well as humans, and on the difficult stimuli, IT also failed,” Majaj says. “We had a nice correlation between behavior and neural responses.”

The findings support the hypothesis that patterns of neural activity in the IT cortex can encode object representations detailed enough to allow the brain to distinguish different objects, the researchers say.

Nikolaus Kriegeskorte, a principal investigator at the Medical Research Council Cognition and Brain Sciences Unit in Cambridge, U.K., agrees that the study offers “crucial evidence supporting the idea that inferior temporal cortex contains the neuronal representations underlying human visual object recognition.”

“This study is exemplary for its original and rigorous method of establishing links between brain representations and human behavioral performance,” adds Kriegeskorte, who was not part of the research team.

Model performance

The researchers also tested more than 10,000 other possible models for how the brain might encode object representations. These models varied based on location in the brain, the number of neurons required, and the time window for neural activity.

Some of these models, including some that relied on V4, were eliminated because they performed better than humans on some tasks and worse on others.

“We wanted the performance of the neurons to perfectly match the performance of the humans in terms of the pattern, so the easy tasks would be easy for the neural population and the hard tasks would be hard for the neural population,” Majaj says.

The research team now aims to gather even more data to ask if this model or similar models can predict the behavioral difficulty of object recognition on each and every visual image — an even higher bar than the one tested thus far. That might require additional factors to be included in the model that were not needed in this study, and thus could expose important gaps in scientists’ current understanding of neural representations of objects.

They also plan to expand the model so they can predict responses in IT based on input from earlier parts of the visual stream.

“We can start building a cascade of computational operations that take you from an image on the retina slowly through V1, V2, V4, until we’re able to predict the population in IT,” Majaj says.

Feng Zhang describes new system for genome engineering

Anne Trafton |

A team including the scientist who first harnessed the CRISPR-Cas9 system for mammalian genome editing has now identified a different CRISPR system with the potential for even simpler and more precise genome engineering.

In a study published today in Cell, Feng Zhang and his colleagues at the Broad Institute of MIT and Harvard and the McGovern Institute for Brain Research at MIT, with co-authors Eugene Koonin at the National Institutes of Health, Aviv Regev of the Broad Institute and the MIT Department of Biology, and John van der Oost at Wageningen University, describe the unexpected biological features of this new system and demonstrate that it can be engineered to edit the genomes of human cells.

“This has dramatic potential to advance genetic engineering,” says Eric Lander, director of the Broad Institute. “The paper not only reveals the function of a previously uncharacterized CRISPR system, but also shows that Cpf1 can be harnessed for human genome editing and has remarkable and powerful features. The Cpf1 system represents a new generation of genome editing technology.”

CRISPR sequences were first described in 1987, and their natural biological function was initially described in 2010 and 2011. The application of the CRISPR-Cas9 system for mammalian genome editing was first reported in 2013, by Zhang and separately by George Church at Harvard University.

In the new study, Zhang and his collaborators searched through hundreds of CRISPR systems in different types of bacteria, searching for enzymes with useful properties that could be engineered for use in human cells. Two promising candidates were the Cpf1 enzymes from bacterial species Acidaminococcus and Lachnospiraceae, which Zhang and his colleagues then showed can target genomic loci in human cells.

“We were thrilled to discover completely different CRISPR enzymes that can be harnessed for advancing research and human health,” says Zhang, the W.M. Keck Assistant Professor in Biomedical Engineering in MIT’s Department of Brain and Cognitive Sciences.

The newly described Cpf1 system differs in several important ways from the previously described Cas9, with significant implications for research and therapeutics, as well as for business and intellectual property:

  • First: In its natural form, the DNA-cutting enzyme Cas9 forms a complex with two small RNAs, both of which are required for the cutting activity. The Cpf1 system is simpler in that it requires only a single RNA. The Cpf1 enzyme is also smaller than the standard SpCas9, making it easier to deliver into cells and tissues.
  • Second, and perhaps most significantly: Cpf1 cuts DNA in a different manner than Cas9. When the Cas9 complex cuts DNA, it cuts both strands at the same place, leaving “blunt ends” that often undergo mutations as they are rejoined. With the Cpf1 complex the cuts in the two strands are offset, leaving short overhangs on the exposed ends. This is expected to help with precise insertion, allowing researchers to integrate a piece of DNA more efficiently and accurately.
  • Third: Cpf1 cuts far away from the recognition site, meaning that even if the targeted gene becomes mutated at the cut site, it can likely still be recut, allowing multiple opportunities for correct editing to occur.
  • Fourth: The Cpf1 system provides new flexibility in choosing target sites. Like Cas9, the Cpf1 complex must first attach to a short sequence known as a PAM, and targets must be chosen that are adjacent to naturally occurring PAM sequences. The Cpf1 complex recognizes very different PAM sequences from those of Cas9. This could be an advantage in targeting some genomes, such as in the malaria parasite as well as in humans.

“The unexpected properties of Cpf1 and more precise editing open the door to all sorts of applications, including in cancer research,” says Levi Garraway, an institute member of the Broad Institute, and the inaugural director of the Joint Center for Cancer Precision Medicine at the Dana-Farber Cancer Institute, Brigham and Women’s Hospital, and the Broad Institute. Garraway was not involved in the research.

An open approach to empower research

Zhang, along with the Broad Institute and MIT, plan to share the Cpf1 system widely. As with earlier Cas9 tools, these groups will make this technology freely available for academic research via the Zhang lab’s page on the plasmid-sharing website Addgene, through which the Zhang lab has already shared Cas9 reagents more than 23,000 times with researchers worldwide to accelerate research. The Zhang lab also offers free online tools and resources for researchers through its website.

The Broad Institute and MIT plan to offer nonexclusive licenses to enable commercial tool and service providers to add this enzyme to their CRISPR pipeline and services, further ensuring availability of this new enzyme to empower research. These groups plan to offer licenses that best support rapid and safe development for appropriate and important therapeutic uses.

“We are committed to making the CRISPR-Cpf1 technology widely accessible,” Zhang says. “Our goal is to develop tools that can accelerate research and eventually lead to new therapeutic applications. We see much more to come, even beyond Cpf1 and Cas9, with other enzymes that may be repurposed for further genome editing advances.”

 

Neurotech 2015

Anne Trafton |

The Neurotech 2015 symposium presents talks by neurotechnology pioneers whose cutting-edge innovations are changing the face of neurobiological research from molecules to cognition. The symposium is open to the public, and registration is required, but seating is limited.

For more information and to register for this event, visit neurotech.mit.edu

Possible new weapon against PTSD

Anne Trafton |

About 8 million Americans suffer from nightmares and flashbacks to a traumatic event. This condition, known as post-traumatic stress disorder (PTSD), is particularly common among soldiers who have been in combat, though it can also be triggered by physical attack or natural disaster.

Studies have shown that trauma victims are more likely to develop PTSD if they have previously experienced chronic stress, and a new study from MIT may explain why. The researchers found that animals who underwent chronic stress prior to a traumatic experience engaged a distinctive brain pathway that encodes traumatic memories more strongly than in unstressed animals.

Blocking this type of memory formation may offer a new way to prevent PTSD, says Ki Goosens, the senior author of the study, which appears in the journal Biological Psychiatry.

“The idea is not to make people amnesic but to reduce the impact of the trauma in the brain by making the traumatic memory more like a ‘normal,’ unintrusive memory,” says Goosens, an assistant professor of neuroscience and investigator in MIT’s McGovern Institute for Brain Research.

The paper’s lead author is former MIT postdoc Michael Baratta.

Strong memories

Goosens’ lab has sought for several years to find out why chronic stress is so strongly linked with PTSD. “It’s a very potent risk factor, so it must have a profound change on the underlying biology of the brain,” she says.

To investigate this, the researchers focused on the amygdala, an almond-sized brain structure whose functions include encoding fearful memories. They found that in animals that developed PTSD symptoms following chronic stress and a traumatic event, serotonin promotes the process of memory consolidation. When the researchers blocked amygdala cells’ interactions with serotonin after trauma, the stressed animals did not develop PTSD symptoms. Blocking serotonin in unstressed animals after trauma had no effect.

“That was really surprising to us,” Baratta says. “It seems like stress is enabling a serotonergic memory consolidation process that is not present in an unstressed animal.”

Memory consolidation is the process by which short-term memories are converted into long-term memories and stored in the brain. Some memories are consolidated more strongly than others. For example, “flashbulb” memories, formed in response to a highly emotional experience, are usually much more vivid and easier to recall than typical memories.

Goosens and colleagues further discovered that chronic stress causes cells in the amygdala to express many more 5-HT2C receptors, which bind to serotonin. Then, when a traumatic experience occurs, this heightened sensitivity to serotonin causes the memory to be encoded more strongly, which Goosens believes contributes to the strong flashbacks that often occur in patients with PTSD.

“It’s strengthening the consolidation process so the memory that’s generated from a traumatic or fearful event is stronger than it would be if you don’t have this serotonergic consolidation engaged,” Baratta says.

“This study is a very nice dissection of the mechanism by which chronic stress seems to activate new pathways not seen in unstressed animals,” says Mireya Nadal-Vicens, medical director of the Center for Anxiety and Traumatic Stress Disorders at Massachusetts General Hospital, who was not part of the research team.

Drug intervention

This memory consolidation process can take hours to days to complete, but once a memory is consolidated, it is very difficult to erase. However, the findings suggest that it may be possible to either prevent traumatic memories from forming so strongly in the first place, or to weaken them after consolidation, using drugs that interfere with serotonin.

“The consolidation process gives us a window in which we can possibly intervene and prevent the development of PTSD. If you give a drug or intervention that can block fear memory consolidation, that’s a great way to think about treating PTSD,” Goosens says. “Such an intervention won’t cause people to forget the experience of the trauma, but they might not have the intrusive memory that is ultimately going to cause them to have nightmares or be afraid of things that are similar to the traumatic experience.”

The Food and Drug Administration has already approved a drug called agomelatine that blocks this type of serotonin receptor and is used as an antidepressant.

Such a drug might also be useful to treat patients who already suffer from PTSD. These patients’ traumatic memories are already consolidated, but some research has shown that when memories are recalled, there is a window of time during which they can be altered and reconsolidated. It may be possible to weaken these memories by using serotonin-blocking drugs to interfere with the reconsolidation process, says Goosens, who plans to begin testing that possibility in animals.

The findings also suggest that the antidepressant Prozac and other selective serotonin reuptake inhibitors (SSRIs), which are commonly given to PTSD patients, likely do not help and may actually worsen their symptoms. Prozac enhances the effects of serotonin by prolonging its exposure to brain cells. While this often helps those suffering from depression, “There’s no biological evidence to support the use of SSRIs for PTSD,” Goosens says.

“The consolidation of traumatic memories requires this serotonergic cascade and we want to block it, not enhance it,” she adds. “This study suggests we should rethink the use of SSRIs in PTSD and also be very careful about how they are used, particularly when somebody is recently traumatized and their memories are still being consolidated, or when a patient is undergoing cognitive behavior therapy where they’re recalling the memory of the trauma and the memory is going through the process of reconsolidation.”