Kavli Year in Review 2013

2013 was a remarkable year for the Kavli Institute for Neuroscience's investigators, who — armed with today’s most advanced neurotechnologies — are revealing how the brain works in unprecedented detail.

In the past year alone, the Institute’s activities have ranged from the deployment of new research tools to the establishment of collaborations at Yale and beyond its gates, and they have generated numerous publications, awards and honors.

“The Kavli Institute for Neuroscience continues to grow and foster interactions between the talented and diverse pool of neuroscientists at Yale,” said the Institute’s vice-director, David McCormick. “In the past year, our investigators have made striking progress toward understanding the normal and abnormal operation of the brain, owing to these collaborations.”

The year was bittersweet, however, because of the death of Fred Kavli, founder and chairman of The Kavli Foundation, in late November.

“It was very sad news, especially for those of us who had the privilege of knowing Fred,” said Pasko Rakic, director of the Kavli Institute and 2008 Kavli Laureate in Neuroscience. “Fred was an extraordinary man and we will strive to continue his legacy. He established the Kavli Institute at Yale to seek an understanding of the biological basis of human uniqueness, and our achievements in 2013 exemplify our progress toward these goals.”

It is impossible to capture all the achievements of Institute’s investigators and the hard-working members of their laboratories in 2013, but here is a sample:

Kavli Events

Neanderthal man: As if to underscore just how multidisciplinary neuroscience has become, the Institute welcomed Svante Paabo, director of the Max Planck Institute for Evolutionary Anthropology, in July, as its 2013 distinguished lecturer. Paabo is best known for sequencing the Neanderthal genome, but the question at the heart of his standing-room-only Yale lecture was distinctly human: What genetic changes fueled human brain development? Following his talk, Paabo joined the Institute's investigators for a working dinner to discuss how advances in genomics are altering the way scientists study the evolution of the human brain.

Boon to brain research: Kavli members also gathered to discuss the research opportunities created by President Obama's BRAIN Initiative, announced last April, the mission of which is closely aligned with the Institute’s. Several investigators, notably Michael Nitabach and David McCormick, were encouraged to apply for funding through the Initiative.

New Members

In 2013, the Kavli Institute welcomed several accomplished Yale researhers as new members: Michael Nitabach from the department of molecular and cellular physiology, Michael Crair from the department of neurobiology, and Susumu Tomita, associate professor in the department of cellular and molecular physiology.

The Nitabach Lab is working to understand the brain circuitry governing fundamental animal behaviors such as the sleep-wake cycle. The team unveiled ArcLight, a new tool for visualizing the activity of neural circuits in live animals, with Yale’s Vincent Pieribone and Lawrence Cohen, in the journal Cell in August. Termed a GEVI, for genetically encoded fluorescent voltage indicator, ArcLight represents a breakthrough in our ability to view the brain at work. Next, in a Kavli-funded collaboration with neurobiology’s Michael Higley and Pieribone, Nitabach is working to improve the technique’s resolution and optimize it for use in mammals.

The Crair Lab studies how genetic and environmental factors guide the development of the nervous system. In a study published in Neuron in September, Crair and his colleagues examined the role of a select group of brain cells connecting the thalamus, a relay center for sensory and motor information in the midbrain, and the cerebral cortex. They found that eliminating the activity of these cells caused fundamental changes to the structure and function of the sensory cortex. The Crair and Nitabach labs are currently collaborating on the use of voltage-sensitive dyes to monitor brain activity in mice.

The Tomita Lab is interested in the regulation of synapses, the junctions between neurons. In 2013, Tomita and his colleagues published a pair of papers in Neuron: The first shed light on the role of the vertebrate cornichon proteins in excitatory synaptic signaling; and, the second revealed the interplay between three classes of glutamate receptors in maintaining neuronal activity. In 2013, Tomita also began a collaboration with the Kavli’s Nenad Sestan.

Kavli Fellows

The Kavli Institute supports the training of graduate students in neuroscience through the Kavli Education Fund. Six Kavli Fellows were named in 2013: Colin Bond in Ralph DiLeone’s lab and Carole Gianessi in Jane Taylor’s lab, both in the department of psychiatry; in neurobiology, David Salkoff in David McCormick’s lab and Zhen Li in Nenad Sestan’s lab; Danielle Bolling, who is working at the Child Study Center with Kevin Pelphrey; and, Kathren Fink who is a member of William Cafferty’s lab in the department of neurology.

Kavli Collaborations

Kavli investigators continued to work together to address critical questions in brain research, including the underlying biology of autism and the genetic factors driving the evolution of human traits.

Autism’s biology: Writing in the journal Science in 2012, Nenad Sestan and geneticist Matt State, who is now at the University of California - San Francisco, outlined an approach to finding meaning in the genetic complexity of autism. Then, this past November, working with geneticist and Kavli member James Noonan and others, they used the approach to identify a network of genes active during early and mid-fetal development in a group of cortical neurons that are among the first to form connections with other brain cells. Their results suggest a potential target for treatment of the disorder.

Evolving limbs: A collaboration between James Noonan and Pasko Rakic takes advantage of know-how developed at the Institute to study human evolution at the genetic level — something that was out of reach just a few years ago. In the journal Cell last July, they published a list of genes and regulatory elements that may be involved in the development of primate-specific features such as bipedalism and the opposable thumb.

"It has been difficult to understand how such human traits evolved, because we didn't have any idea where the important genetic changes might be," Noonan told Yale News. "Now we do, and we have the experimental tools to determine what biological effects these changes may have. Our study also provides a roadmap for understanding other human-specific traits that arise during development, such as increased brain size and complexity."

This experimental approach may help reveal the genetic changes that support human’s extraordinary cognitive abilities.

Awards and Honors

Kavli researchers picked up several awards in 2013.

In December, Pasko Rakic received a Distinguished Scientist Award from the Child Mind Institute in New York, in recognition of his “groundbreaking work in developmental neuroscience.” Rakic will lecture at a scientific symposium in New York City on October 10, 2014, entitled, “On the Shoulder of the Giants” hosted by the Child Mind Institute, along with Nenad Sestan, his former graduate student and a current Kavli investigator.

In September, Amy Arnsten received a Pioneer Award from the National Institutes of Health to study why brain circuits in the association cortices, which have been implicated in Alzheimer’s and schizophrenia, are so vulnerable to disease compared with evolutionarily older parts of the brain.

In a paper published in the Proceedings of the National Academy of Sciences in July, her team found that the neurotransmitter acetylcholine, acting through the alpha-7 nicotinic receptor, is essential to working memory, the ability to temporarily store a mental representation of the world and ourselves. That process is impaired in schizophrenia, which has been linked to the alpha-7 nicotinic receptor gene.

Research Highlights

Cortical connections: The cerebral cortex is highly interconnected, which allows for the integration of sensory and motor information. But exactly how cortical recurrent pathways influence the processing of sensory information, or cortical activity, has been largely unknown. Now, Eddie Zagha, a postdoctoral fellow in the McCormick Lab, and his colleagues discovered the mechanisms by which activity in one area of the cerebral cortex can rapidly modulate the activity in another. The study, published in the journal Neuron, suggests how feedback pathways in the cortex may operate. “Revealing how context directs the flow of information in the neocortex on a moment-to-moment basis is key to our understanding of the operation of the brain,” said David McCormick.

Putting on the brakes: The Higley Lab is working to understand how neurons integrate the vast number of excitatory and inhibitory inputs they receive. In the journal Science in May, they combined optogenetics, a technique that uses light to stimulate brain cells, and two-photon fluorescence imaging to probe the impact of the inhibitory neurotransmitter GABA on pyramidal cell dendrites — the signal-receiving branches of neurons — in mice. The research helps illuminate the function of synaptic inhibition in the cerebral cortex. For Michael Higley, the paper represented, “An amazing convergence of approaches that we've done for a while as individual techniques.”

Seizure shutdown: In 2013, the Blumenfeld Lab, in the department of neurology, “continued to unravel the mystery of why seizures can cause impaired consciousness,” said Hal Blumenfeld. They found for the first time in an animal model of temporal lobe seizures, the most common form of focal, or partial, epilepsy, that arousal circuits in the brainstem are depressed during seizures, leading to a sleep-like state in the rest of the brain. This work was mainly conducted by Joshua Motelow, an MD/PhD student who recently defended his doctoral thesis in the lab. In 2013, another MD/PhD student, Jennifer Guo, completed her thesis demonstrating the fundamental mechanisms responsible for loss of consciousness in absence seizures.

Alzheimer’s clue: Stephen Strittmatter, from the departments of neurology and neurobiology, added to earlier work on the molecular underpinnings of Alzheimer’s disease (AD). Publishing in Neuron in September, his group showed that the mechanism by which amyloid-beta peptides, a hallmark of the disease, triggers damage in neurons is dependent on the membrane-straddling glutamate receptor mGluR5. In a mouse model of AD, blocking the mGluR receptor reversed memory deficits and the loss of synapses.

Risky decisions: Neurobiology’s Daeyeol Lee penned a review article on the implications of neuroeconomic research on decision-making for the fields of neurology and psychiatry. On the heels of that review, also in the journal Neuron, his group published a paper looking at the neural substrates of exploratory behavior in rhesus monkeys. They showed that the medial frontal cortex, a part of the cerebral cortex that is important for decision-making and memory, plays a special role in facilitating this strategic behavior. The finding has implications for reinforcement learning in which an animal uses past experience to make better choices.

Food drive: Ralph DiLeone’s group is exploring the brain mechanisms that regulate eating. In a paper in Nature Neuroscience, they identified a new brain circuit that drives food intake in mice. The circuit projects from a specific type of neuron in the prefrontal cortex, a part of the brain involved in higher-order decision-making in humans, to the amygdala. DiLeone, associate professor of psychiatry and neurobiology, says the involvement of the amygdala, an evolutionarily older brain structure that processes emotions and memory, “was a big surprise.” The work suggests that the interaction between these two very different brain areas may mediate eating behaviors.

In the News

Brain research featured prominently into the news cycle in 2014, largely because of the launch of the BRAIN Initiative. But a few Kavli researchers also made headlines:

The Huffington Post called on Daeyeol Lee to answer, “Can science show us secrets of making better decisions?”

In the Winter issue of Yale Medicine, psychology’s Marvin Chun weighs in on what functional magnetic resonance imaging (fMRI) can and can’t tell us about the mind. When asked how the technique has improved since he began using it in the mid 1990s, he said, “We’ve gone from launching a rocket to landing one on Mars. The machine hasn’t changed — we’re still recording the BOLD signal — but the computational tools we have at our disposal are mind blowing.”

Chun was also one of about a dozen faculty members chosen to lecture as part of the inauguration of Yale’s new president, Peter Salovey, in October.

In the same issue of Yale Medicine, Joerg Bewersdorf, assistant professor of cell biology and biomedical engineering, is featured for his work developing the next-generation of light microscopes to support biomedical research. In Nature Methods in May, Bewersdorf reported a breakthrough in microscopy: the development of a pointillist microscope that can be used to create high-resolution videos of fluorescently labeled cells.