The main interest of the Kim lab is to understand the cellular architecture of the nervous system and how it supports cognitive functions in the mammalian brain. We use mice as our main animal model. The unique challenge to understanding the governing principles of the mammalian brain is that microscopic structures (e.g., cell bodies, axons) interact with each other in a macroscopic network (e.g., whole brain) to generate behavior. To overcome this challenge, we develop and utilize high-resolution 3D brain mapping methods to examine cellular details in the entire mouse brain. Leveraging our novel methods, we focus on three discreet, yet inter-related research topics.
OT is a key neuropeptide regulating social behavior as well as other physiological functions. We are investigating a wiring diagram of OT and OT receptors (OTR) in developing and adult brains. Furthermore, we use a combination of viral tools, cell type specific transgenic mice, in vivo neural activity recording, and a sophisticated behavioral tracking system to gain comprehensive neural circuit mechanisms of the OT system in normal and pathological brains.
The brain relies on coordinated interplay between neurons, glia, and neurovasculature (collectively, called “neurovascular units”) to maintain energy homeostasis and remove metabolic waste. NVU dysfunction has been implicated in numerous cognitive disorders (e.g., stroke, Alzheimer’s disease). We utilize the latest 3D imaging technology (e.g., light sheet microscopy with tissue clearing, 3D immunolabeling) with sophisticated computational tools to finely map out NVU cell types throughout the normal and pathological aging process.
Anatomical atlases provide a framework to understand the spatial arrangement of target signals in the brain. However, significant discrepancies exist between commonly used mouse brain atlases. To resolve this issue, we are integrating independently created atlases into a common spatial framework. Furthermore, we are creating new 3D atlases with a series of neuroinformatics tools to map different brain cell types from developing mouse brains.
Anatomical atlas in standard coordinates plays a central role to integrate and interpret findings from different studies. Recently, Allen Brain Institute released the adult mouse brain common coordinate framework (CCF) with seamless 3D high resolution images. Yet, majority of the past and on-going research relies on another atlas, created by Franklin and Paxinos (FP). Allen and FP anatomical labels often use different boundaries and nomenclatures of similar brain regions, creating confusion in interpreting anatomical regions. Furthermore, areas such as dorsal striatum remain unsegmented in both labels due to lack of distinct cytoarchitecture features. To overcome the issues, we created FP based labels into the Allen CCF, creating two independent labels merged into a single atlas framework. We used cell type specific transgenic mice and a MRI atlas to adjust and validate our labels. Moreover, we added detailed segmentation in dorsal striatum based on topographical cortico-striatal projectome data. Lastly, we digitized our anatomical labels to be used a bioinformatics tool and provide comprehensive comparison between Allen and FP labels. Our new label in the CCF is freely available via our website, providing valuable resource to isolate and identify brain anatomical structures.
Atlas Project LinkOxytocin receptor (OTR) plays critical roles in the development and expression of social behavior. Previous studies suggested that OTR expression is developmentally regulated with peak cortical expression in early postnatal period. However, quantitative understanding of OTR expression changes across different brain regions remains largely unknown. Thus, we examined the expression patterns of OTR positive cells throughout the whole brain at postnatal (P) periods (P7, 10, 14, 18, 21, 28) and in adulthood (P56) using transgenic reporter mice (OTR-eGFP). We used serial two-photon tomography to image the entire brain at cellular resolution and quantified fluorescently labeled cells with newly generated 3D postnatal brain templates at P7, 14, 21, and 28. We found significant heterogeneity in temporal pattern of OTR expression in brain regions including cortex. We then identified that transient OTR expression is mainly driven by OTR downregulation, not by cell death, using OTR-Cre:Ai14 for cumulative labeling. Lastly, we found significant delay of cortical OTR peak at P21 in OTR heterozygote mice (OTRvenus/+). We created a website to share the high-resolution imaging data as community resource for further data mining. In summary, our result provides essential quantitative data to understand postnatal OTR expression in the mouse brain.
An intricate web of blood vessels in the mammalian brain provides essential oxygen and nutrients to power the energy demands of the brain. The structure of the brain’s microvasculature provides the extraordinary surface needed for a high level of energy exchange and clearance of metabolic wastes. Small vessel pathologies are involved in cognitive decline associated with aging and many brain disorders. Mounting evidence supports the idea that neuronal activity dynamically regulates diameter of small vessels to maintain energy homeostasis. Moreover, emerging evidence suggests that 3D distribution and function of small vessels, and their interaction with vasomotor neurons are heterogeneous in different brain regions. Interestingly, some brain regions are more susceptible than others to age related degeneration, which can be linked to many neurological conditions with brain region specific symptoms such as Alzheimer's disease. To understand the underlying neurovascular mechanisms affected in health and pathological conditions, we create a precise 3D map of micro vessels and cell types controlling vessel motility in the entire mammalian brain using the mouse as a model. Furthermore, we examine neurovascular changes during aging. This work will establish reference maps that are needed as a foundation for the further study of neurovascular architectures supporting normal cognitive function and their changes in various neuropathologies.