Understanding Circuits

PROJECT SUMMARY Understanding information flow in cortical circuits requires understanding both the anatomical connectivity between neurons and the way in which inputs to a neuron are integrated to generate a spiking output. Many techniques are now available to study connectivity across cells and brain areas, but the dendritic integration of these inputs is challenging to observe because we lack access to the complex electrical signals in fine dendrites.

Project Summary: Whether to laugh at a joke or to engage in a lively debate, we flexibly modify our vocalizations based upon social contexts. Such adaptive behavior requires real-time adjustments of motor outputs in response to rapidly changing sensory inputs. How does the brain accomplish this sensorimotor feat? Pioneering studies have characterized the brain areas responsible for sound production in many species (e.g., drosophila, zebra finches, marmosets, mice), but the neural circuits that generate vocal flexibility remain poorly understood.

Abstract The hippocampus has a well-established role in the initial formation and storage of memory. However, little is understood about brain mechanisms that support the re-organization and transfer of memories into longer-term cortical storage. A detailed understanding of hippocampal- to-cortical consolidation is critical to shed light on the regulation of long-term memories, and how they may become too transient (as in Alzheimer’s, Parkinson’s, Traumatic Brain Injury) or too persistent (as in PTSD).

SUMMARY High-throughput connectomics is needed to generate the TB-, PB- and EB-scale wiring diagrams of mammalian brains, but is limited to the few research institutes (e.g., Janelia, Allen, Max Planck) with sufficient infrastructure. As resource-rich as these institutes are, none are able to do a whole brain at nanometer scale on their own. The failure to broaden participation to a larger community is an obstacle to scaling connectomics. We propose a new and more affordable imaging strategy that will allow many more teams to engage in connectomics.

Project Summary Mapping the brain-wide connections of neurons provides a foundation for understanding the structure and functions of a brain. Neuroanatomical techniques based on light-microscopy or electron microscopy have advanced tremendously in throughput and cost in recent years, but it remains challenging to scale them up to systematically interrogate large non-human primate (NHP) brains.

SUMMARY This ambitious proposal will establish an integrated experimental-computational platform to create the first comprehensive brain-wide mesoscale connectivity map in a non-human primate, the common marmoset (Callithrix jacchus),. It will do so by tracing axonal projections of RNA barcode-identified neurons brain-wide in the marmoset, utilizing a sequencing-based imaging method that also permits simultaneous transcriptomic cell typing of the identified neurons.

PROJECT SUMMARY To understand complex neural pathways and networks and their remarkable ability to generate human behaviors, it is critical to precisely map brain connectomics in vivo. We propose to make significant advances in such brain mapping by founding the Center for Mesoscale Connectomics (CMC). We will first map the mesoscale connections between the frontal and parietal cortices. These connections likely subserve higher-order functions such as attention, decision-making, prospection, and executive control.

Project Summary/Abstract (30 lines of text limit) The ~1 billion neurons that form the human brainstem are organized at multiple scales, ranging from their cell type-specific patterns of dendritic arborization, to local circuits embedded within large-scale projection systems spanning the brainstem, and a complex nuclear architecture.

Project Summary/Abstract The proposed project will demonstrate the feasibility of generating a complete synapse-level brain map (connectome) by developing a serial-section electron microscopy pipeline that could scale to a whole mouse brain. This work will image 10 cubic millimeters, itself an unprecedentedly large dataset that may exceed tens of petabytes. Yet the mouse brain is 50 times larger. Reaching this ambitious goal will require advances in whole-brain staining, imaging, image-processing, analysis, and dissemination tools.

Project Summary: Center for whole mouse brain connectomics using high-throughput integrated volumetric electron microscopy (HIVE) Two fundamental components of the structural basis of brain function are cell type composition and the wiring diagram between those cells. Over the past decade there has been paradigm-shifting progress in understanding cell type composition of the brain. Now it’s time to systematically uncover the brain’s wiring diagram and place it into the context of cell types. Knowledge about the complete connectomes in C.