Understanding Circuits

 DESCRIPTION (provided by applicant): Understanding the computations that take place in brain circuits will require identifying the wiring diagrams of those circuits. In recent years seveal new methods have been developed to identify the brain's wiring diagrams. Each of these methods have some strengths and limitations. Importantly, there is no available anterograde monosynaptic tracer that can be used to regulate gene expression of synaptically connected neurons in species ranging from drosophila to mice.

Project Summary/Abstract Synaptic plasticity is thought to be a basis of learning and memory of the brain. Signaling mechanisms underlying synaptic and behavioral plasticity have been extensively studied with the aid of pharmacological and genetic manipulation of signaling. However, it has been difficult to assess the spatiotemporal aspects of signaling activity particularly.

Project Summary Neuropeptides are essential neuromodulators in the brain. They are released into the extrasynaptic space, where they diffuse over long distances and signal through G protein coupled neuropeptide receptors. Neuropeptides control cognition, sensorimotor processing, and energetics through changes in vascular tone and blood flow in the nervous system. Pharmacological and molecular genetic studies have implicated alterations in neuropeptide signaling as a contributor to brain dysfunctions, including migraines, addiction, motivation and stress.

Project Summary/Abstract The mammalian brain is a highly diverse structure in which large numbers of cell types, grouped into broad functional areas, serve defined functions according to their developmental origin, shape and connectivity, transcriptional program and intrinsic biophysical properties. A mechanistic understanding of how the brain works, and how dysfunctions lead to neurological disorders, will require a systematic characterization of neural cell types.

PROJECT SUMMARY We will use high throughput techniques to produce a set of viral vectors that will allow selective expression of transgenes in specific populations of neurons in the brain. Along with many other applications, this will allow optogenetic control, recording, and genomic modification of targeted neuronal populations without the need for production of transgenic or knock-out lines.

Project Summary Cell signaling pathways in the brain are an essential part of a complex system regulating the activity and coordination of neuronal circuits. During learning and memory synaptic plasticity processes regulate the strength of synaptic connections and modify neuronal circuits. Intracellular signaling pathways play critical roles in regulating synaptic strength and are an important part of the molecular mechanisms underlying learning and memory.

Project Summary/Abstract: The emerging field of optogenetics — using light to engage biological systems — holds tremendous promise for dissection of neural circuits, cellular signaling and manipulating neurophysiological systems in awake, behaving animals.

Deciphering neural coding will require deconstructing the complex and intertwined signaling mechanisms that drive cellular excitability, synaptic plasticity, and circuit dynamics in the brain. This fundamental objective has been extremely challenging because unraveling the temporal and spatial interactions of multiple signaling pathways requires coordinated observation of multiple networks within individual cells and multiple neurons within intact circuits.

Project Summary:    Fundamental  to  furthering  our  understanding  of  the  brain  is  the  ability  to  longitudinally  track  changes  in  gene  expression  over  time  in  different  contexts  (e.g.  development  or  learning) (Aim 1) and to develop methods to target and manipulate specific neuronal cell  types regardless of species (Aim 2). &nb

Summary A central challenge in neuroscience is to develop methods to manipulate specific cell types within the mammalian brain. Recent developments in optogenetics have revolutionized our ability to control the activity of both neurons and non-neuronal cells. However, this approach suffers from one drawback, the difficulty in delivery light stimulus to target cells that are located deep within the brain or the body. The Chalasani lab has recently demonstrated a noninvasive method to control the activity of neurons.