Understanding Circuits

PROJECT SUMMARY In this proposal we aim to identify gene regulatory elements that permit the targeting and manipulation of brain circuit models of human brain function. Gaining genetic access to specific neuron populations in nontransgenic animals and humans would enable targeted circuit modulation for hypothesis testing and provide a means to evaluate the safety and efficacy of circuit modulation for the treatment of epilepsy and psychiatric disorders.

Project Summary The human brain contains an astonishing diversity of neuronal and glial cell types distributed across dozens of functional areas.

Adeno-Associated Viruses (AAVs) are potent gene delivery vectors for neuroscience studies and gene therapy applications. However, naturally occurring AAVs are not cell type specific: they must be combined with other technologies, such as transgenic animals, to achieve cell type specific gene expression.

ABSTRACT Depicting the specific neuronal identity and connectivity underlying particular brain function remains a central goal for neuroscience. For over a century, neuroanatomy has continued to play critical roles in referencing a neuron's synaptic contact, dendritic morphology and axonal projection to its connectivity. The advances of genetic probes, optical imaging modalities and computer technologies permit monitoring and manipulating neuronal activity in living animals with unprecedented precision and scale.

PROJECT SUMMARY Every part of the brain is composed of dense tangles of heavily-interconnected neurons of many different types, each playing completely different roles in the circuitry. Rabies viral vectors have become indispensable tools for revealing the organization of this otherwise generally indecipherable jumble, because they allow the identification of synaptically-connected networks of neurons within the tissue.

Project Summary The development of trans-synaptic viral tracers is an important component of the BRAIN Initiative. At present, the lack of viral-based anterograde monosynaptic tracing tools with high signal strength and low toxicity is a gap in neuroscience.

Project Summary/Abstract ! Most genetic recorders described so far utilize the CRISPR/Cas9 system to leave a unique genetic scar in each cell that can be traced in daughter cells. However, since these systems are largely deletion based, there is a finite number of events and lineages that they can be used to trace. Hence all these recorders are fundamentally restricted in the number of lineages they can trace since development in mammals is a prolonged process, with radial glia in the brain dividing greater than 50 times.

PROJECT SUMMARY  A major goal of the BRAIN initiative is to understand neuronal connectivity and plasticity in the context of  animal behavior. The functions and connectivity 

Abstract Synaptic transmission is mainly mediated by classical neurotransmitters such as glutamate and g-amino butyric acid (GABA) which transduce fast information flow in the brain. This process is tightly regulated by neuromodu- lators including monoamines and neuropeptides.

PROJECT SUMMARY/ABSTRACT It is estimated that the human brain contains an overwhelming 1015 synapses, structures essential for the normal functioning of neural circuits. Our knowledge of the connections that form these critical signaling sites, in even the simplest vertebrate nervous systems, is sorely lacking.