Understanding Circuits

Neural circuits encode animal behaviors, and neuroplasticity induces long-lasting changes in neural circuits and animal behaviors. Neural circuits are formed by billions of neurons, which communicate mostly through synapses. Neuroplasticity occurs at the synapse, as neuronal activity modulates synaptic strength through a process known as synaptic plasticity. However, there is no tool to modulate synaptic transmission mimicking synaptic plasticity in vivo. The lack of such a tool makes it difficult to study long-lasting plastic changes in animal behaviors.

Summary/Abstract The ability to control protein function with light provides excellent temporal and spatial resolution for precise investigation in situ, and thus is having significant impact on neuroscience. There are two major barriers imposed by existing optogenetic methods: one being that they cannot be readily applied on any protein of choice, and the other being lack of high specificity and flexibility in site selection for photo-modulation. These limitations significantly restrain the scope, precision, and depth of investigations on neuronal processes.

Project Summary: Our limited ability to genetically access specific cell types within the nervous system constitutes a fundamental impediment in our efforts to probe brain function and intervene therapeutically, particularly in species lacking the well-developed genetic resources available in the mouse. Targeted payload delivery using recombinant viral approaches possesses a number of potential advantages, including anatomical specificity, ease of experimental implementation, and utility in a broad range of mammalian species.

PROJECT SUMMARY Deciphering the complex underpinning of brain structure and function requires a complete understanding of how molecular contacts between cells in the brain are regulated. Currently, there are a lack of tools to measure these intercellular protein-protein interactions (PPIs) with requisite sensitivity, precluding a complete understanding of endogenous regulatory mechanisms. Moreover, as intercellular contacts are guided by thousands of diverse PPIs, it is critical to be able to study multiple interactions simultaneously, which is presently not possible.

PROJECT DESCRIPTION Synapses are formed, broken and reformed dynamically both during development, normal function and in response to activity. Although this general principle is well-established, the way in which this is manifested in specific subtypes of neurons across a complex network, and how altered patterns of synaptic input will determine network function, have not been quantitatively investigated.

ABSTRACT Recording the electrical impulses of individual neurons in intact brain circuits in real time has been a longstanding goal in neuroscience. One potentially widely applicable use of voltage recording would be to test postsynaptic responses upon physiological or optogenetic activation of presynaptic partners. Recording a neuron while its inputs are controlled would enable a detailed understanding of how individual neurons process information. This understanding becomes important when circuity is altered in disease, e.g.

Project Summary Mammalian brain is composed of vast numbers of intricately interconnected neurons with various molecular, anatomical and physiological identities. To understand the roles of these individual building blocks of the brain, it will be critical to develop spatio-temporally precise tools that will allow neuronal subtype specific single cell level analysis.

PROJECT SUMMARY/ABSTRACT Identifying the diversity of cell types in the nervous system will allow for their selective manipulation and reveal their functional contributions in health and disease. However, this is not a trivial undertaking and is hindered by the lack of consensus on which properties to use for classification. Characteristics like anatomical location, connectivity, morphology, molecular profile, and electrophysiological properties have been used as classification systems, but singly, none provide a combined view of all these characteristics.

PROJECT SUMMARY How the brain performs its computational task is a great unsolved problem in biology, but this answer is vital for us to understand and combat disorders of brain function like autism, schizophrenia, and Alzheimer’s. One appealing strategy towards solving this problem is to deconstruct the brain into the component parts—the cell types—and to determine their respective key features and dissect which physiological functions are sub served by each distinct type.

Project Summary/Abstract The long-term goal of these investigations is to develop methods based on high- throughput DNA sequencing for determining neuronal circuitry. Neurons transmit information to distant brain regions via long-range axonal projections. In some cases, functionally distinct populations of neurons are intermingled within a small region. Disruptions of connectivity may underlie many neuropsychiatric disorders including autism and schizophrenia. At present, neuroanatomical techniques—particularly those with single neuron resolution—are expensive and labor intensive.