Yongsoo Kim

• PhD
• Professor (Assistant) at Penn State Hershey Medical Center and Penn State College of Medicine

Large-scale, international collaborative efforts by members of the BRAIN Initiative Cell Census Network (BICCN) consortium are aggregating the most comprehensive reference database to date for diverse cell type profiling of the mouse brain, which encompasses over 40 different multi-modal profiling techniques from more than 30 research groups. One c...

This chapter is divided into several sections that follow the chronological development of the mammalian brain and its structural manifestation (Goffinet and Rakic, 2012). First, the specification of future neural tissue and the early types of signaling that contribute to the regionalization of the central nervous system (CNS) will be discussed (E5...

Morphology is a cardinal feature of a neuron that mediates its functions, but profiling neuronal morphologies at scale remains a formidable challenge. Here we describe a generalizable pipeline for large-scale brainwide study of dendritic morphology of genetically-defined single neurons in the mouse brain. We generated a dataset of 3,762 3D-reconstr...

3D brain atlases are key resources to understand the brain’s spatial organization and promote interoperability across different studies. However, unlike the adult mouse brain, the lack of developing mouse brain 3D reference atlases hinders advancements in understanding brain development. Here, we present a 3D developmental common coordinate framewo...

The dorsal endopiriform nucleus (EPd) is an enigmatic cortical subplate structure located inside the piriform cortex that shares a similar developmental origin with the claustrum. Although the EPd has been previously implicated in epilepsy and olfactory processing, its anatomical organization, connectivity patterns, and function remain largely uncl...

Aging is frequently associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods and in vivo imaging to determine detailed changes in aged murine cerebrovascular networks. Whole-brai...

Precision mapping techniques coupled with high resolution image acquisition of the mouse brain permit the study of the spatial organization of gene expression and their mutual interaction for a comprehensive view of salient structural/functional relationships. Such research is facilitated by standardized anatomical coordinate systems, such as the w...

This paper explicates a solution to building correspondences between molecular-scale transcriptomics and tissue-scale atlases. This problem arises in atlas construction and cross-specimen/technology alignment where specimens per emerging technology remain sparse and conventional image representations cannot efficiently model the high dimensions fro...

The precise anatomical degree of brain X chromosome inactivation (XCI) that is sufficient to alter X-linked disorders in females is unclear. Here, we quantify whole-brain XCI at single-cell resolution to discover a prevalent activation ratio of maternal to paternal X at 60:40 across all divisions of the adult brain. This modest, non-random XCI infl...

The gradual loss of cerebral white matter contributes to cognitive decline during aging. However, microvascular networks that support the metabolic demands of white matter remain poorly defined. We used in vivo deep multi-photon imaging to characterize microvascular networks that perfuse cortical layer 6 and corpus callosum, a highly studied region...

The gradual loss of cerebral white matter contributes to cognitive decline during aging. However, microvascular networks that support the metabolic demands of white matter remain poorly defined. We used in vivo deep multi-photon imaging to characterize microvascular networks that perfuse cortical layer 6 and corpus callosum, a highly studied region...

During development, brain regions follow encoded growth trajectories. Compared to classical brain growth charts, high-definition growth charts could quantify regional volumetric growth and constituent cell types, improving our understanding of typical and pathological brain development. Here, we create high-resolution 3D atlases of the early postna...

Introduction: Cerebrovascular dysfunction has been implicated in age-related cognitive decline and dementia, but the underlying vascular mechanisms are not well understood. An improved understanding of the nature of normal cerebrovascular aging is needed to help to establish the role that vascular dysfunction might play in cognitive decline and dem...

3D standard reference brains serve as key resources to understand the spatial organization of the brain and promote interoperability across different studies. However, unlike the adult mouse brain, the lack of standard 3D reference atlases for developing mouse brains has hindered advancement of our understanding of brain development. Here, we prese...

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BR...

Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and ligh...

This paper explicates a solution to the problem of building correspondences between molecular-scale transcriptomics and tissue-scale atlases. The central model represents spatial transcriptomics as generalized functions encoding molecular position and high-dimensional transcriptomic-based (gene, cell type) identity. We map onto low-dimensional atla...

Here, we present a protocol using serial two-photon tomography (STPT) to quantitatively map genetically defined cell types and cerebrovasculature at single-cell resolution across the entire adult mouse brain. We describe the preparation of brain tissue and sample embedding for cell type and vascular STPT imaging and image processing using MATLAB co...

Characterizing cellular diversity at different levels of biological organization across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also required to manipulate cell types in controlled ways, and to understand their variation and vulnerability in brain disorders. The BRAIN...

The hypothalamic neuropeptide, oxytocin (Oxt), has been the focus of research for decades due to its effects on body physiology, neural circuits, and various behaviors. Oxt elicits a multitude of actions mainly through its receptor, the Oxt receptor (OxtR). Despite past research to understand the central projections of Oxt neurons and OxtR- coupled...

The cerebrovasculature and its mural cells must meet brain regional energy demands, but how their spatial relationship with different neuronal cell types varies across the brain remains largely unknown. Here we apply brain-wide mapping methods to comprehensively define the quantitative relationships between the cerebrovasculature, capillary pericyt...

Oxytocin (Oxt) neurons regulate diverse physiological responses via direct connections with different neural circuits. However, the lack of comprehensive input-output wiring diagrams of Oxt neurons and their quantitative relationship with Oxt receptor (Oxtr) expression presents challenges to understanding circuit-specific Oxt functions. Here, we es...

Significance The cerebrovasculature has become increasingly recognized as a major player in overall brain health and many brain disorders. Although there have been several landmark studies to understand details of these crucially important structures in an anatomically defined area, brain-wide examination of the whole cerebrovasculature, including...

The brain is composed of diverse neuronal and non-neuronal cell types with complex regional connectivity patterns that create the anatomical infrastructure underlying cognition. Remarkable advances in neuroscience techniques enable labeling and imaging of these individual cell types and their interactions throughout intact mammalian brains at a cel...

An essential step toward understanding brain function is to establish a structural framework with cellular resolution on which multi-scale datasets spanning molecules, cells, circuits and systems can be integrated and interpreted¹. Here, as part of the collaborative Brain Initiative Cell Census Network (BICCN), we derive a comprehensive cell type-b...

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not kno...

The pericyte is a perivascular cell type that encapsulates the microvasculature of the brain and spinal cord. Pericytes play a crucial role in the development and maintenance of the blood-brain barrier (BBB) and have a multitude of important functions in the brain. Recent evidence indicates that pericyte impairment has been implicated in neurovascu...

In the mouse brain, olfactory information is transmitted to the olfactory cortex via olfactory bulb (OB) projection neurons known as mitral and tufted cells. Although mitral and tufted cells share many cellular characteristics, these cell types are distinct in their somata location and in their axonal and dendritic projection patterns. Moreover, mi...

An essential step toward understanding brain function is to establish a cellular-resolution structural framework upon which multi-scale and multi-modal information spanning molecules, cells, circuits and systems can be integrated and interpreted. Here, through a collaborative effort from the Brain Initiative Cell Census Network (BICCN), we derive a...

The classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not kno...

Chronic stress represents a vulnerability factor for anxiety and depressive disorders and has been widely used to model aspects of these disorders in rodents. Disinhibition of somatostatin (SST)-positive GABAergic interneurons in mice by deletion of γ2 GABAA receptors selectively from these cells (SSTCre:γ2f/f mice) has been shown to result in beha...

The oxytocin receptor (OTR) plays critical roles in social behavior development. Despite its significance, brain-wide quantitative understanding of OTR expression remains limited in postnatally developing brains. Here, we develop postnatal 3D template brains to register whole brain images with cellular resolution to systematically quantify OTR cell...

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2+ neurons and ChAT+ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we le...

Anatomical atlases in standard coordinates are necessary for the interpretation and integration of research findings in a common spatial context. However, the two most-used mouse brain atlases, the Franklin-Paxinos (FP) and the common coordinate framework (CCF) from the Allen Institute for Brain Science, have accumulated inconsistencies in anatomic...

Oxytocin receptor (OTR) plays critical roles in social behavior development. Despite its significance, brain-wide quantitative understanding of OTR expression remains limited in postnatally developing brains. Here, we validated and utilized fluorescent reporter mice (OTR venus/+ ) to examine OTR cells across postnatal periods. We developed postnata...

Parkinson's disease (PD) is associated with olfactory defects in addition to dopaminergic degeneration. Dopaminergic signalling is necessary for subventricular zone (SVZ) proliferation and olfactory bulb (OB) neurogenesis. Alpha-synuclein (α-syn or Snca) modulates dopaminergic neurotransmission, and SNCA mutations cause familial PD, but how α-syn a...

Within the basal ganglia circuit, the external globus pallidus (GPe) is critically involved in motor control. Aside from Foxp2 ⁺ neurons and ChAT ⁺ neurons that have been established as unique neuron types, there is little consensus on the classification of GPe neurons. Properties of the remaining neuron types are poorly-defined. In this study, we...

Anatomical atlases in standard coordinates are necessary for the interpretation and integration of research findings in a common spatial context. However, the two most-used mouse brain atlases, the Franklin and Paxinos (FP) and the common coordinate framework (CCF) from the Allen Institute for Brain Science, have accumulated inconsistencies in anat...

Non-random (skewed) X chromosome inactivation (XCI) in the female brain can ameliorate X-linked phenotypes, though clinical studies typically consider 80-90% skewing favoring the healthy allele as necessary for this effect. Here we quantify for the first time whole-brain XCI at single-cell resolution and discover a preferential inactivation of pate...

X-chromosome inactivation (XCI) in females is vital for normal brain function and cognition, as many X-linked genetic mutations lead to mental retardation and autism spectrum disorders, such as the fragile X syndrome (FXS). However, the degree by which XCI regulates disease presentation has been poorly investigated. To study this regulation in the...

The circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of these organizations and their developmental relationships are unknown,...

The circuitry of the striatum is characterized by two organizational plans: the division into striosome and matrix compartments, thought to mediate evaluation and action, and the direct and indirect pathways, thought to promote or suppress behavior. The developmental origins of and relationships between these organizations are unknown, leaving a co...

The thalamus receives input from 3 distinct cortical layers, but input from only 2 of these has been well characterized. We therefore investigated whether the third input, derived from layer 6b, is more similar to the projections from layer 6a or layer 5. We studied the projections of a restricted population of deep layer 6 cells ("layer 6b cells")...

The stereotyped features of neuronal circuits are those most likely to explain the remarkable capacity of the brain to process information and govern behaviors, yet it has not been possible to comprehensively quantify neuronal distributions across animals or genders due to the size and complexity of the mammalian brain. Here we apply our quantitati...

Systematic genetic access to GABAergic cell types will facilitate studying the function and development of inhibitory circuitry. However, single gene-driven recombinase lines mark relatively broad and heterogeneous cell populations. Although intersectional approaches improve precision, it remains unclear whether they can capture cell types defined...

Some individuals are resilient, whereas others succumb to despair in repeated stressful situations. The neurobiological mechanisms underlying such divergent behavioral responses remain unclear. Here, we employed an automated method for mapping neuronal activity in search of signatures of stress responses in the entire mouse brain. We used serial tw...

A full list of brain areas showing differential activity in helpless versus resilient animals. Cortical areas include detailed layer information. Positive z scores indicate higher activity in resilient group than helpless group, whereas negative z scores (highlighted in red) indicate higher activity in helpless group than resilient group.

The full raw dataset for cfos-GFP+ cell counting in each mouse. Eleven pairs of mice, each containing one helpless and one resilient mice, were imaged and analyzed. The table contains the number of detected cFos-GFP+ cells in each anatomical area across the whole-brain.

Endogenous c-Fos expression in mice showing helpless or resilient behavior. (A) Representative images of c-Fos expression detected by immunohistochemistry from a helpless (left) and a resilient (middle) mouse (n = 5 mice for each group). PL, prelimbic area; ILA, infralimbic area; fa, corpus calossum anterior forceps. Right: higher magnification ima...

The motor cortex orchestrates simple to complex motor behaviors through its output projections to target areas. The primary (MOp) and secondary (MOs) motor cortices are known to produce specific output projections that are targeted to both similar and different target areas. These projections are further divided into layer 5 and 6 neuronal outputs,...

Central to the understanding of brain functions is insight into the distribution of neuronal activity that drives behavior. Local measurements of brain activity in behaving mice can be made with electrodes and fluorescent calcium indicators (Buzsáki, 2004 and Grewe and Helmchen, 2009), but such approaches provide information regarding only a very s...

Here we describe an automated method, named serial two-photon (STP) tomography, that achieves high-throughput fluorescence imaging of mouse brains by integrating two-photon microscopy and tissue sectioning. STP tomography generates high-resolution datasets that are free of distortions and can be readily warped in three dimensions, for example, for...

The adult brain subventricular zone (SVZ) produces neuroblasts that migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB) in a specialized niche. Galectin-3 (Gal-3) regulates proliferation and migration in cancer and is expressed by activated macrophages after brain injury. The function of Gal-3 in the normal brain is unknow...

Neuroblasts born in the adult subventricular zone (SVZ) migrate long distances in the rostral migratory stream (RMS) to the olfactory bulbs where they integrate into circuitry as functional interneurons. As very little was known about the dynamic parameters of SVZ neuroblast migration, we used two-photon time-lapse microscopy to analyze migration i...

Neuroblasts generated in the adult subventricular zone (SVZ) migrate through the rostral migratory stream (RMS) to the olfactory bulb (OB). Previous work uncovered motility ranging from straight to complex, but it was unclear if directional changes were stochastic or exhibited stereotypical patterns. Here, we provide the first in-depth two-photon t...

J. Neurochem. (2010) 114, 750–760. We investigated the expression and role of the dopamine receptor 3 (D3R) in postnatal mouse subventricular zone (SVZ). In situ hybridization detected selective D3R mRNA expression in the SVZ. Fluorescence activated cell sorting (FACS) of adult SVZ subtypes using hGFAP-GFP and Dcx-GFP mice showed that transit ampli...

Embryonic neuroepithelia and adult subventricular zone (SVZ) stem and progenitor cells express nestin. We characterized a transgenic line that expresses enhanced green fluorescent protein (eGFP) specified to neural tissue by the second intronic enhancer of the nestin promoter that had several novel features. During embryogenesis, the dorsal telence...

Movie from a Mash1-GFP+ slice at the elbow of the RMS. Note the visible chain migration because of GFP retention in migrating neuroblasts. Cells appear to be moving in multiple different directions in the ventral portion. (2.66 MB MOV)

Only neuroblasts migrate from the SVZ to the RMS. A: Schematic of CTO injection, A1: shows injection track into lateral ventricle, A2: shows diffusion of CTO to the contralateral lateral ventricle. B: Sagittal section showing CTO injection (red) in the LV of a Dcx-GFP+ mouse. C: Coronal section, the majority of CTO+ cells (red) were also Dcx-GFP+ (...

Gad65-GFP+ cells give rise to all three major periglomerular cell layer subtypes. Recent studies have shown that different parts of the SVZ generate different types of interneurons in the OB [41], [62]. We tested if Gad65-GFP+ cells belong to specific sublineages of OB cells, and found GFP+ cells that were tyrosine hydroxylase+ (TH)(A), calretinin+...

3D tracing of Movie 4. Blue and red trajectories correspond to migratory and exploratory cells shown with blue and red arrows in Fig. 5 and Movie 4. Note the difference between migratory (blue) and exploratory (red) motility patterns. (1.03 MB MOV)

Movie from a CSH-nestin-GFP slice in the RMS, note that bright GFP+ cells are stationary. Playing movie at high speeds allows optimal visualization of dim cell movement. Corresponds to Fig. 2E–F. Frame is 353×353×51 (x, y, z) µm. (1.57 MB MOV)

Mash1-GFP labels Mash1 progenitor cells and neuroblasts. A–B: Mash1 immunohistochemistry on Mash1-GFP mice in the SVZ (A) and the RMS (B). Note that some immunolabeled Mash1+ cells were Mash1-GFP+ (arrows) whereas other Mash1+ cells were not Mash1-GFP+ (arrowheads). C: Dcx immunohistochemistry in the RMS showed that most Mash1-GFP+ cells were coloc...

EGFr immunohistochemistry in the vertical limb of the RMS, DAPI counterstain. Confocal stack of 32 optical sections, each separated by 0.37 microns. Note the preponderance of EGFrhigh cells at the edge of the RMS, many of which appear to be clustered. Within the RMS, a range of high to weak EGFr immunofluorescence is detected in a pattern suggestin...

Movie from a Nestin-GFP slice in the RMS. Note individual cells move with different migratory patterns. Slice was fixed and immunostained for EGFr, shown in Fig. 5. Frame is 284×295×51 (x, y, z) µm. (0.72 MB MOV)

Two photon time lapse imaging of a Gad65-GFP slice before (pre-treatment) and during 10 ng/ml TGF-α treatment. The first hour of pretreatment and the last hour of TGF-α treatment is shown and were analyzed. One quarter of the field imaged and analyzed is shown for greater clarity. (Time stamp reset after pretreatment.) (0.57 MB MOV)

The adult subventricular zone (SVZ) contains stem and progenitor cells that generate neuroblasts throughout life. Although it is well accepted that SVZ neuroblasts are migratory, recent evidence suggests their progenitor cells may also exhibit motility. Since stem and progenitor cells are proliferative and multipotential, if they were also able to...

The mammalian subventricular zone (SVZ) has garnered a tremendous amount of attention as a potential source of replacement cells for neuronal injury. This zone is highly neurogenic, harbours stem cells and supports long-distance migration. The general pattern of activation includes increased proliferation, neurogenesis and emigration towards the in...

Neuroblasts migrate long distances in the postnatal subventricular zone (SVZ) and rostral migratory stream (RMS) to the olfactory bulbs. Many fundamental features of SVZ migration are still poorly understood, and we addressed several important questions using two-photon time-lapse microscopy of brain slices from postnatal and adult eGFP(+) transgen...