Scientific Mission of the Institute
Information encoded by the brain’s myriad neural circuits hold the key to understanding cognitive functions such as perception, emotion, action, attention and memory and offers the promise of clarifying the causes of neurological and psychiatric disease. The Kavli Institute for Brain Science focuses on the development of novel experimental and computational strategies for analyzing and deciphering how signaling in neural circuits controls behavior.
Methods Highlights
Imaging Brain Activity and its Underlying Connectivivity: fMRI and DTI Techniques (Coming Soon)
Computer Modeling of Neural Processes
(Coming Soon)
Second Harmonic Generation Imaging
A Comparative Analysis of Behavior from Snails and Flies to Mice and Primates
To understand the molecular basis of behavior in humans, it is critical to augment cognitive psychological and neuroimaging methods performed in humans with rigorous experimental approaches in animals, where analysis of neural circuits can be carried out at a much finer spatial and temporal resolution. To delineate the basic building blocks underlying complex neuronal circuitry and neuronal plasticity, we will study flies and snails. In addition we will study mice, monkeys, and humans who share the general design of their nervous systems, and certain functional building blocks of behavior and cognition. The mouse, technically tractable for molecular techniques, has a valuable behavioral repertory, but it is not an ideal model for many higher human cognitive processes. We will therefore extend the molecular methods developed in the mouse to the analysis of neural circuits in the non-human primate. This will make possible neuropsychological studies in non-human primates with a new level of precision, and enable us to better understand the underpinnings of behaviors in humans.
Imaging and molecular manipulation of neural circuits
Many features of brain function can be appreciated only through the ability to visualize at high spatial resolution the functional circuits, their component neurons, and synaptic connections. We will develop cellular imaging techniques over a wide range of scales and resolution. Specific imaging priorities will include: (1) Electronmicroscopic and cellular imaging using genetically engineered optical probes that can report on the subcellular activation of signal transduction cascades important for neural plasticity; (2) Optical imaging of activity in well-defined neuronal populations such as those that represent the internal representation for vision, smell, or space; (3) Multi-unit electrophysiological recording in intact behaving mice, and non-human primates; (4) Improved MRI imaging of activity in large ensembles of neurons in mice, monkeys and people. Design of new genetic and pharmacological methods for probing signaling within functional neuronal circuits. We will take advantage of the compendium of information available on cell-specific gene expression in developing neurons and the ease of genetic manipulation in the mouse, to block or otherwise modify the function of highly restricted classes of neurons in the adult animal and assay resultant changes in the function of specific neuronal circuits. This will permit the functional ablation of predefined populations of neurons with a specificity unattainable by conventional lesioning methods. In addition, the development of transgenic mice methods for anterograde or retrograde transynaptic transport of foreign marker proteins will provide novel information on neuronal connectivity.
Remodeling of neural circuits through learning-related plasticity
The ability of neurons to modulate the strength of their synapses in response to extra- or intracellular cues, is thought to be fundamental for both the fine-tuning of synaptic connections during development, as well as for the growth of new connections with learning and memory in the adult organism. At present, virtually nothing is known about the molecular mechanisms that convert activity in neural circuits into structural changes. As a first step in exploring the molecular mechanisms and structural synaptic plasticity in these neural circuits, we will combine the following molecular, imaging and electrophysiological techniques: (1) time-lapse confocal imaging of the same fluorescently labeled synapses followed continuously over time, (2) the expression of fluorescent marker proteins specific to either the pre- or postsynaptic compartment, and (3) physiological recording of the labeled synaptic connections. In this fashion, we plan to follow individual structural changes at the same synapses over time so as to directly relate this remodeling of neural circuits to physiological function and memory storage.
Remodeling of neural circuits through adult neurogenesis
We will explore the possibility of creating novel neural circuits using endogenous as well as transplanted neurons derived from embryonic stem cells. These approaches will permit us to test circuit function and plasticity by conferring new properties on established neural circuits, as well as by constructing circuits de novo. Recent experiments at Columbia have demonstrated the feasibility of transplanting stem cell derived neurons into the embryonic CNS, and have shown that such neurons can integrate well into host neural circuits.
Manipulating neural circuits
To test hypotheses about the function of neural circuits it is essential to be able to manipulate them specifically. In a parallel effort, we will seek to develop techniques that enable us to specifically alter the activity of neural circuits. We envision creating research groups devoted to generating these new tools, on the one hand, and applying them to specific circuits, on the other. Specifically, we will pursue the creation of inactivation or activation strategies using engineering of potassium channels and their expression in particular types of nerve cells and the use of optical tools to turn cells on or off in desired spatiotemporal patterns.