The NIH BRAIN Initiative – a new 12-year research program launched last year by President Obama – recently awarded grants to 58 projects that will develop new technologies to capture individual brain cells and complex neural circuits in action.
A deeper understanding of the brain – made possible by these new tools – may ultimately lead to new treatments and cures for brain disorders such as depression, Parkinson’s, and autism.
“There’s a big gap between what we want to do in brain research and the technologies available to make exploration possible,” said NIH Director Francis S. Collins, MD, PhD. “This is just the beginning of an ambitious journey and we’re excited about the possibilities.”
Researchers at Columbia University Medical Center lead or co-lead three BRAIN Initiative projects, listed below. The Brain Activity Map proposal of Columbia neuroscientist Rafael Yuste, MD, PhD, professor of biological sciences and neuroscience and co-director of the Kavli Institute for Brain Science at Columbia University, was vital to the creation of the BRAIN Initiative.
How a Memory is Made
At night, the slow brain waves of sleep are intermittently broken with bursts of neuronal activity that sends brief but intense ripples through the brain’s memory center.
Far from being disruptive, these ripples are mental replays of the day’s activities and are believed to be crucial in turning some of our experiences into long-term memories.
Understanding how these ripples are produced is key to understanding why some experiences are remembered and some are forgotten, but for Attila Losonczy, MD, PhD, and colleagues at NYU, UC-Irvine, and Brandeis, the ripples also are a way to decode, for the first time, an entire brain circuit in a vertebrate.
Until now, only simple circuits in invertebrates have been mapped and decoded, and the proposal to decode a complete circuit in a mouse is bold.
“Integrating all the different techniques needed to fully understand a brain circuit that underlies a behavior has never been attempted on this scale in a mammal,” said Dr. Losonczy, assistant professor in the Department of Neuroscience at P&S, the Kavli Institute for Brain Science at Columbia University and Columbia’s Zuckerman Mind Brain Behavior Institute.
One challenge will be to simultaneously capture the activity of different parts of the circuit as a ripple is produced. Recording such data is impossible with traditional electrodes, but in Dr. Losonczy’s lab, the activity of hundreds of neurons in a living animal can be recorded at once with fluorescent, high-resolution microscopy that captures the flash of light each neuron gives off when firing.
By the end of the project, the team hopes to build a complete and accurate computer model of the brain circuit – accounting for every cell and synapse — that produces the ripples.
The results will “provide transformative insights into the mechanisms of episodic memory formation and storage in the mammalian brain and into the mechanism of network computation in vertebrates in general,” said Dr. Losonczy, in an interview with the Kavli Foundation.
(Read the entire interview with Dr. Losonczy at the Kavli Foundation website.)
The title of the project is “Towards a Complete Description of the Circuitry Underlying Memory Replay.”
Oliver Hobert, PhD
How Worm Neuroscience May Shine New Light on Complex Brains
With the flick of a switch, neuroscientists are now able to turn on specific types of neurons in the living brain with laser light to gain unprecedented insight into the function of each type of neuron.
The technique – called optogenetics – works when light-activated proteins are inserted into the neurons under investigation. But directing proteins to specific neuronal cell types has turned out to be a challenge.
“Right now, the ability to manipulate specific neurons in the brain is somewhat limited. Often times multiple types of cells are turned on by optogenetic tools, so it’s hard to interpret these experiments,” says neuroscientist Oliver Hobert. “What’s needed are tools to drive these proteins to very specific neurons – just the neurons you want to study.”
Dr. Hobert, a professor in the Department of Biochemistry & Molecular Biophysics at P&S, thinks tiny worms called C. elegans may have the answer.
For several years in his lab, the simple C. elegans worm has been used to understand how the astounding diversity of cell types in a nervous system are created. What became apparent by studies in both worms and vertebrates is that most genes in the nervous system are expressed in many different cell types in the nervous system. Developing tools to drive gene expression in very specific neuronal types seemed to pose a significant challenge.
Dr. Hobert looked instead into the regulatory DNA that lies outside the genes, the so-called dark matter of the genome, for regions that specified cell identity. He ultimately discovered that each cell type in the C. elegans nervous system has its own unique DNA bar code. This bar code is employed to turn on specific genes that create each cell’s unique features.
With his BRAIN Initiative grant, Dr. Hobert will look for the same type of regions in the mouse. If they exist, neuroscientists will then have a way to insert optogenetic proteins into very specific types of neurons in a complex vertebrate brain.
He says: “What works in worms should work in mice, and the end result will be a much more powerful tool for neuroscientists.”
The title of the grant is “Developing Drivers for Neuron Type-Specific Gene Expression.”
Richard Mann, PhD
Understanding Circuits for Locomotion with Walking Fruit Flies
For most, walking doesn’t seem to require much brainpower. But in reality, putting one foot in front of the other – or three feet if you’re a fly – only happens after a complex interplay between the nervous system’s motor circuits and its sensory circuits.
The rhythms needed to swing legs back and forth can be generated by motor circuits alone. More nuanced locomotion requires sensory circuits that allows an animal to alter its pace, direction, or gait in response to the environment.
How the brain integrates all the sensory information to guide locomotion is still unknown, but a better understanding could lead to insights into the movement disorders that occur in Parkinson’s, stroke, and spinal cord injury.
Fruit flies provide a good way to unravel these circuits, because it’s easy to manipulate their genes – to turn off sensory neurons in their six legs, for example. And new tools – including those developed by Richard Mann in the Department of Biochemistry & Molecular Biophysics – can now measure their ability to walk (and fly).
Dr. Mann, in collaboration with groups at Caltech, Harvard, and Princeton, will now use those techniques to identify all the neural circuits used by flies to locomote. With brain imaging, they will then watch these circuits in action in flies walking on treadmill or flying in a wind tunnel.
Ultimately the researchers plan to create a computer model of sensory-guided locomotion, which may aid in the development of robotic prosthetic limbs and devices that can replace damaged senses.
The title of the project is “Integrative Functional Mapping of Sensory-Motor Pathways.”
Other Columbia University researchers who received BRAIN initiative grants include Ken Shepard, PhD, in the Department of Electrical Engineering who will work with researchers at Caltech and Baylor College of Medicine to build arrays of miniature light- probes that can be implanted into brain tissue and record activity of each neuron within one millimeter of each probe (~100,000 neurons). It will ultimately permit simultaneous recording from millions of neurons at arbitrary positions and depths in the brain. The title of the project is “Modular Nanophotonic Probes for Dense Neural Recording at Single-Cell Resolution.”