Cooperative Agreements

 DESCRIPTION (provided by applicant): Electrical (voltage) signal is the primary substrate of information processing in the brain. Detecting and recording voltage changes from neurons in living animals remains the ultimate goal of experimental neuroscience to the present day. Standard glass and metal electrodes are hugely invasive and their use suffers from poor spatial resolution, limited coverage, and blindness to cellular identity.

 DESCRIPTION (provided by applicant): Anatomy defines the `reference' atlas for all of neuroscience. It is one of the most important markers of disease or damage to the brain, and constrains the circuitry of neural computation. However, brain maps are fundamentally incomplete. There remains an information and resolution gap at the mesoscale: whole brain maps visualized at micrometer resolution so that cell shapes, numbers, and positions along with their long range projections can be visualized in a single brain.

 DESCRIPTION (provided by applicant): The mammalian central nervous system (CNS) contains many hundreds of molecularly and functionally distinct cell types, which comprise the basic building blocks of neural circuitry. Individual cell types can be labeled and manipulated using transgenic and knock-in animals, but this approach, is slow, expensive, and limited in scope. Furthermore, it cannot be applied to higher primates or humans.

 DESCRIPTION (provided by applicant): This application will develop new genetic tools and advance current procedures for precise and rapid mapping of behavior specific memory engrams. The proposed studies also will provide unique insight into the role of cholinergic signaling in the integrated networks that underlie anxiety behaviors. Modulatory transmitters that fine tune circuit activity are essential, albeit somewhat cryptic, components of neural coding. Perhaps the least understood- and yet most broadly distributed- neuromodulator in the CNS is acetylcholine (ACh).

 DESCRIPTION (provided by applicant): The ability to examine the connectivity and functions of specific brain nuclei and specific neuron types is critical for understanding how the brain works at both microcircuit and mesoscale levels. Therefore tools that enable targeting of selected types of neurons and/or groups of neurons within the neural system, especially tools that are easily applicable and can be used in many different species (model organisms) are important for the neuroscience community.

 DESCRIPTION (provided by applicant): The goal of this application is to develop SYNPLA, a specific, selective and high-throughput method for marking experience-induced plasticity with single synapse resolution. SYNPLA exploits our understanding of the molecular mechanism of long-term potentiation, which is mediated by the insertion of a specific subtype of glutamate receptor at recently potentiated synapses. In Aim 1 we develop SYNPLA in cultured neurons.

 DESCRIPTION (provided by applicant): Developing and validating a toolkit for cell type specific gene manipulation PIs: Clandinin and Shah Neurons express complex arrays of genes that play crucial roles in determining neuronal function. As such, single-gene mutations can lead to neurodevelopmental, neurophysiological, and neurodegenerative diseases. However, the nervous system is made up of many different types of neurons, which differ both in the genes they express and the function those genes perform.

 DESCRIPTION (provided by applicant): Monosynaptic tracing using rabies virus has become a standard component of the systems neuroscience toolkit, allowing identification and manipulation of neurons directly presynaptic to any targeted neuronal population in the brain. However, while this retrograde monosynaptic tracing system is now well established, an anterograde counterpart, which would allow identification and manipulation of neurons directly postsynaptic to a target cell group, has never been constructed.

 DESCRIPTION (provided by applicant): The brain is a remarkably complex organ comprised of hundreds of unique cell types that are organized to form sophisticated neural circuits. Although we have made progress toward understanding brain function and development, it is clear there is still much to be learned. Currently, all genome-wide methods that could be brought to bear on functional studies of the brain are destructive, meaning that as a genomic analysis is performed on a population of cells, the cells are destroyed.

 DESCRIPTION (provided by applicant): Examining neural circuits crucially relies on the ability to activate or silence individual circuit components to subsequently assess their impact on other parts of the circuit and their influence on behavior. Recent refinements of viral tools for gene delivery have allowed optogenetic methods to target cells based on specific cell types, localization, and connectivity. The physiological dissection of targeted circuits has been extremely successful in the mouse brain, but remains of limited use in non-human primate brain.