2009 — 2012 |
Kim, In-Jung |
K99Activity Code Description: To support the initial phase of a Career/Research Transition award program that provides 1-2 years of mentored support for highly motivated, advanced postdoctoral research scientists. R00Activity Code Description: To support the second phase of a Career/Research Transition award program that provides 1 -3 years of independent research support (R00) contingent on securing an independent research position. Award recipients will be expected to compete successfully for independent R01 support from the NIH during the R00 research transition award period. |
Molecular Specification of Direction Selectivity in the Visual System
DESCRIPTION (provided by applicant): Orderly neural circuits underlie processing of information in the nervous system: our perceptions, decisions and behaviors. A main goal of neurobiology is to understand how the circuits form. We use the retina to address this issue. Distinct types of retinal ganglion cells respond to different visual features, based on which inputs they receive from retinal interneurons. Several types are direction selective, responding best to objects moving in a particular direction. The mammalian retina contains at least 3 types of direction selective ganglion cells (DSGCs). However, the lack of molecular markers to selectively identify DSGCs has impeded analysis of their development, synaptic inputs in the retina, and targets in the brain. We have now found markers for 3 types of DSGCs and developed transgenic approaches to label each type in vivo. This method allows us to elucidate molecular mechanisms that regulate differentiation of these neurons, and to trace the neuronal circuits that initiate responses to moving objects. In specific aims 1-3, we will characterize mice in which each DSGC type is specifically labeled. We will analyze the morphological and functional development of each DSGC type, and seek roles of the subtype specific genes (an adhesion molecule, JAM-B and two secreted molecules, FSTL4 and SPIG1/FSTL5) in these processes. In specific aim 4, we will use transsynaptic tracers to define the connections of each DSGC type. Finally (specific aim 5), we will seek new molecules that regulate diverse aspects of DSGC development. Together, these studies will provide novel insights into the cellular basis of visual processing. Following the mentored period in the Center for Brain Science at Harvard University, I will start my own lab as an independent investigator at an academic institution. My long-term goal is to study how neural circuits are formed and modified by experience. I hope that my work will provide insights in studying how neural circuit fails in psychiatric diseases.
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0.97 |
2019 — 2020 |
Kim, In-Jung |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Molecular Mechanisms of Visual Circuit Formation Between Superior Colliculus and Thalamus
Orderly and specific patterns of neural wiring are critical for proper behavioral outcomes. Most studies on long- range neuronal connections have utilized invertebrate models or analyzed periphery-to-brain connectivity. Those studies have uncovered the basic mechanisms responsible for establishing long-range neuronal connections, such as axon pathfinding, topographic mapping and laminar-specific connectivity. However, our understanding of the other connectivity-based phenomena, e.g., axon-target nuclei selection, remains rather limited. Axon-target nuclei selection is the process, by which growing axons choose their final targets while avoiding the adjacent ones. However, how such selection is achieved within complex mammalian brain, is not well understood. In this application, we propose to examine mechanisms of axon-target matching, focusing on connections between superior colliculus (SC) and thalamus in the mammalian brain. SC is a midbrain center controlling head and eye movements in response to a sensory stimulation. SC also mediates visual cue- triggered defense responses, such as freezing and escaping. The superficial layer of SC (sSC) receives visual inputs from the retina and cortex and contains neurons that project to the deep layers of the SC and to the other subcortical areas. The sSC projections to thalamus modulate visual information to elicit appropriate behavioral responses to specific stimuli. Moreover, some studies have reported that projections to a specific thalamic nucleus comprise the second visual pathway that responds to sensory cues in the absence of the primary visual cortex. However, little is known about the molecular mechanisms that regulate the development of neuronal connections between sSC and thalamus. Recently, we discovered that expression of retinoid- related orphan receptor ? (Ror?) is highly enriched within sSC. Based on the layer-restricted expression of Ror?, we hypothesize that Ror?+ sSC neurons project axons to distinct thalamic nuclei. Using innovative genetic strategies, we will examine the role of Ror? in the development of specific sSC circuits. We will also define underlying molecular mechanisms that regulate axonal projections of Ror?+ neurons to distinct thalamic nuclei. This project will help us understand molecular basis of neuronal connections between sSC and thalamus that are involved in specific visual responses and fear-related behaviors. Proposed studies will also improve our understaninding of how long-range axon-target nuclei selection is regulated in mammalian brain. The novel genetic approach employed in this proposal should be broadly applicable for studying long-range projections throughout mammalian nervous system.
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0.97 |
2020 — 2021 |
Kim, In-Jung |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Genetics of Visual Circuit Assembly in the Developing Superior Colliculus
My long-term goal is to understand how neural circuits underlying specific brain functions are formed, modified by experience, and altered in neurological conditions. The goal of this proposal is to examine mechanisms that regulate formation of the long-range neuronal connections between the superior colliculus (SC) and specific subcortical brain areas. We chose to focus on the connections between superficial layer of SC (sSC) and the thalamus. The SC is a midbrain center that plays an important role in sensory and motor processing. The sSC receives visual inputs from the retina and cortex, and sSC-thalamic connections are known to mediate defensive responses to threating visual stimuli. As most of traditional studies have investigated organization of sensory inputs to sSC, little is known about mechanisms regulating development of sSC output pathways. Moreover, no study has described developmental regulation of sSC-thalamic circuits underlying visually-driven behavioral responses. In a screen for the markers labeling subsets of sSC neurons, we have identified several genes that are likely to control development of sSC neurons. Now, we propose to investigate the role of those molecules in sSC output circuit assembly. We have already demonstrated that a transcriptional factor, retinoid-related orphan receptor ? (Ror?), regulates sSC neuronal projections to specific thalamic nuclei. Here, we plan to examine downstream mechanisms of Ror?-dependent regulation by gain- and loss-of-function approaches. We will also investigate the role of another transcription factor, Brn3b, in the development of distinct sSC circuits and identify the downstream effectors of Brn3b. Given that sSC neurons, confined to specific sublayers, selectively project axons to distinct thalamic nuclei, and that Brn3b and Ror? are expressed in different sublayers of sSC, we hypothesize that Brn3b regulates axonal projections via Ror?-independent mechanisms. Manipulations of Ror? and Brn3b expression produce different patterns of altered axonal projections to the thalamic nucleus, known to govern visual-cue triggered behaviors. Based on these findings, we will test if Ror?- and Brn3b-dependent mechanisms of circuit assembly are required for appropriate behavioral responses to visual threat. The success of the proposed project will improve our understanding of the molecular basis for establishing the long-range connections between sSC and thalamic areas. It will also provide novel mechanistic insights into developmental assmebly of subcortical visual circuits regulating responses to the threatening stimuli.
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0.97 |
2021 |
Kim, In-Jung |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Specific Retinal Circuits For Behavioral Responses to Threat
Project Summary Understanding the relationship between function of distinct cell types and behavior is a major challenge of modern neuroscience and is being extensively investigated in various model systems. The concept of functionally distinct cell types has been relatively well defined in the early visual system, especially in the mammalian retina. However, our understanding of the contribution of different retinal neurons responsible for the initial visual processing to specific behavioral responses remains rather limited. Here we propose to identify looming stimulus-sensitive retinal circuits using specific behaviors as readouts. Threatening visual inputs, such as approaching objects, trigger universal defensive behaviors in animals and humans. Recently, several brain circuits that respond to the looming stimulus have been identified using optogenetic techniques. Nevertheless, we still have a very limited knowledge about specific retinal circuits important for defensive behaviors and on their potential contribution to such behavioral outputs. To identify circuits for looming-triggered behaviors, we will focus on the retinal ganglion cells (RGCs) that receive visual inputs from interneurons and send axons to the brain. Each RGC type is supposed to respond to specific visual features, and it has been suggested that there are ~46 distinct RGC types in the mouse retina. Several studies, including our own, have generated multiple transgenic mouse lines that label specific RGC types and characterized them using morphological and physiological methods. Specific RGC types in those transgenics were marked by expression of either fluorescent proteins or DNA-modifying recombinase (e.g., Cre) allowing further genetic manipulations. To define which types of RGCs specialize in detecting approaching objects, we will selectively express a genetically encoded toxin or optogenetic regulators in specific RGC types and examine behavioral consequences of such manipulations. Based on previous findings from the looming-trigged behavioral paradigms and our preliminary data, we will start our analysis focusing on the candidate RGC types (i.e., W3 and OFF alpha RGCs) later extending to other RGCs. Our study will identify distinct RGC types that are necessary and sufficient for the defensive behaviors to approaching objects. Identification and characterization of specific retinal neurons regulating visual-threat related behaviors should allow us to deconstruct the circuitry involved in detection and interpretation of fearful stimuli. It will also help us understand an overall structure and functional properties of fear-related circuits. Moreover, the genetic methods utilized in this proposal could be expanded further to investigate the roles of a wide range of cell types in multiple behavioral outcomes.
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