Chi-Hon Lee - US grants
Affiliations: | LGRD | National Institute of Child Health and Human Development, Bethesda, MD, United States |
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The funding information displayed below comes from the NIH Research Portfolio Online Reporting Tools and the NSF Award Database.The grant data on this page is limited to grants awarded in the United States and is thus partial. It can nonetheless be used to understand how funding patterns influence mentorship networks and vice-versa, which has deep implications on how research is done.
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High-probability grants
According to our matching algorithm, Chi-Hon Lee is the likely recipient of the following grants.Years | Recipients | Code | Title / Keywords | Matching score |
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2002 — 2011 | Lee, Chi-Hon | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Cellular and Molecular Mechanism of R7 Target Selection @ Child Health and Human Development In both vertebrates and invertebrates, the interneuronal connections are often organized into columns and layers, which facilitate information processing and propagating. We use the Drosophila visual system as a model to study circuit assembly and focus on the mechanisms guiding R7 axons into specific layers and columns during development. In a large genetic screen based on a R7-dependent behavior, we identified two loci, baboon and importin-alpha3, which are required for the establishment of a precise R7 retinotopic map. Baboon encodes for a type I Activin receptor and importin-alpha3 for a component of nuclear import machinery. Removing Baboon or Importin-alpha3 in single R7s resulted in their axons invading neighboring columns, indicating that Baboon and Importin-alpha3 are required cell-autonomously in R7s to restrict their growth cones to retinotopically appropriate columns. In addition, the synaptic boutons of baboon or importin-alph3 mutant R7s appeared to be smaller and more irregular than those of the wild-type, suggesting that these two gene products are involved in synaptogenesis. Examining other known components of the Activin pathways, including the ligand Activin, the downstream transcription factor Smad2, revealed that the canonical Activin signaling pathway is required for restricting R7 growth cones to their retinotopically appropriate columns. Interestingly, Activin is functionally required in R7s, suggesting that Activin serves as an autocrine ligand it is secreted from and act on R7 growth cones.[unreadable] Several lines of evidence indicate that Importin-alph3 is a new component of the Activin signaling pathway. First, Smad2 and Importin-alph3 form a physical complex in the growth cones and axons. Second, nuclear accumulation of Smad2 depends on Importin-alpha3. Most importantly, these observations raise the intriguing possibility that Importin-alph3 plays a role in the retrograde axonal transport of Smad2. A similar role for Importins in transporting transcription factors from axons/dendrites to nuclei has been recently proposed in vertebrate neurons, suggesting this function of Importins is conserved in both flies and vertebrates. In summary, our results support a novel model for Activin signaling in R7s: Autocrine Activin activates Baboon on R7 growth cones and results in the phosphorylation of the downstream transcription factor Smad2, which together with Importin-alpha3 is transported from the growth cones back to the nuclei to regulate transcription. This model is further supported by our observation that blocking retrograde axonal transport in R7s phenocopied baboon/importin-alpha3 phenotypes. [unreadable] Removing Importin-alpha3 or Baboon resulted in incomplete penetrance of R7 phenotypes: only 12-30% of mutant R7 axons invaded their neighboring columns. This suggests the existence of an additional mechanism that functions redundantly to the Activin signaling pathway in restricting R7 growth cones to their retinotopically appropriate columns. To test whether repulsive interactions among neighboring R7s play a role to restrict R7 termini in appropriate columns, we genetically ablated most of the R7s and examined the targeting of the remaining R7s. We found that wild-type R7 axons form normal synaptic boutons in retinotopically correct columns even in a largely empty R7 terminal field. By contrast, removing neighboring R7s greatly increased the tendency of importin-alpha3 or baboon mutant R7s to invade adjacent columns. These results suggest that importin-alpha3 and baboon mutant R7 are still responsive to repulsion by neighboring R7s and these repulsive interactions account for their incomplete penetrance of phenotype. To determine the molecular nature of the R7-R7 interactions, we examined a number of candidate genes, whose products are known to mediate repulsive interactions. Among these, we identified the protocadherin Flamingo. Removing Flamingo alone in single R7s did not cause any obvious phenotype but the invasiveness of baboon mutant R7s was greatly enhanced by the removal of Flamingo in the neighboring R7s. In summary, at least two redundant mechanisms restrict R7 termini to the correct columns: (i) an intrinsic mechanism mediated by autocrine Activin signaling; and (ii) an extrinsic mechanism by Flamingo-mediated repulsion among R7s. |
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2006 — 2018 | Lee, Chi-Hon | Z01Activity Code Description: Undocumented code - click on the grant title for more information. ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Genetic Dissection of Color-Vision Circuits @ Child Health and Human Development Color vision, which differentiates spectral compositions independent of brightness, provides animals, from insects to primates, great power for object recognition and memory registration and retrieval. Using a combination of genetic, histological, electrophysiological and behavioral approaches, we study how the visual system processes chromatic information to guide behaviors in Drosophila. Using color preference and color learning assays, we demonstrated that flies innately prefer short wavelengths of light but they can be trained to select specific wavelengths of light by Pavlovian conditioning, indicating that flies, like honeybee and human, have true color vision. Using both light and electron microscope, we mapped the synaptic circuits of the chromatic photoreceptors, R7s and R8s, and their synaptic target neurons in the medulla ganglion of the peripheral visual system. We focused on the amacrine neurons, which interconnect medulla columns and the medulla projection (Tm) neurons, which are thought to serve functions analogous to those of vertebrate retinal ganglion cells by processing and relaying photoreceptor information to higher visual center. We found that the chromatic photoreceptors, R7 (UV-sensing) and R8 (blue/green-sensing), provide inputs to a subset of first-order interneurons. The first-order interneurons Tm5a/b receive direct synaptic inputs from R7s while Tm9, Tm20 and Tm5c receive direct synaptic inputs from R8s. In addition, these Tm neurons receive indirect inputs from R1-6 via L3. These Tm neurons relay spectral information from the medulla to the higher visual center, the lobula. In addition to the direct pathways from photoreceptors to Tm neurons, the amacrine neuron Dm8 receives input from multiple R7s and provides input for Tm5a/b/c. To relate neural connectivity to functions, we assigned components of synaptic machinery to specific connections. To directly probe the usage of neurotransmitters and receptors which determine the polarity and dynamic of signal transmission, we developed a method to profile transcripts in single neurons. We used highly specific promoter-Gal4 constructs to label single types of neurons with GFP and to isolated these GFP-labeled neurons from adult fly brains and profiled their gene expression patterns by RT-PCR. Using this method, we determined that a large percentage of the first/second-order interneurons in the chromatic circuits express the vesicular glutamate transporter indicating that they are glutamatergic while the remaining chromatic circuits express choline acetyltransferase and therefore are likely cholinergic. This contrasts with the motion detection pathway, which is mostly cholinergic. By inactivating specific neurons and examining behavioral consequences, we previously found that the amacrine Dm8 neurons, which receive UV-sensing R7 photoreceptor inputs, are both required and sufficient for animals' innate spectral preference to UV light. RNAi-knock-down of vesicular glutamate transporter in the Dm8 neurons significantly reduced UV preference, suggesting that glutamatergic output of Dm8 is critical for its functions. While Dm8 provides inputs for three types of transmedulla neurons, Tm5a/b/c, inactivating Tm5c alone abolished UV preference, indicating that Tm5c is the key downstream targets for this behavior. Furthermore, RNAi-knockdown of Kainate-type iGluR in Tm5c, thus inhibiting its ability to receive glutamatergic Dm8 inputs, significantly reduced UV preference. Using a modified GRASP (GFP-reconstitution across synaptic partners) method, which allows single-cell analysis of bona fide synaptic connections, we demonstrated that Dm8 receives 16 R7 inputs and provides inputs for 1-2 Tm5c neurons in the center of Dm8's receptive field. Thus, the R7s->Dm8->Tm5c connections constitute a hard-wired pooling circuit for detecting dim UV light. To map the circuits that transform photoreceptor signals into color percepts, we developed a novel aversive operant conditioning assay for intensity-independent color discrimination. Single flying flies were magnetically tethered in an arena surrounded by blue/green LEDs and the flies are then conditioned to discriminate between equiluminant blue or green stimuli. Wild-type flies can be trained in this paradigm to avoid either blue or green while mutant lacking functional R7 and R8 photoreceptors can not, indicating that the color entrainment requires the function of the narrow-spectrum photoreceptors R7s and/or R8s. Genetically inactivating four classes of first-order interneurons, Tm5a/b/c and Tm20, abolishes color learning. However, inactivating subsets of these neurons is insufficient to block color learning, suggesting that true color vision is mediated by multiple redundant pathways. The apparent redundancy in learned color discrimination sharply contrasts with innate spectral preference, which is dominated by a single pathway. Using a similar strategy, we mapped the visual motion pathways in Drosophila. Previous studies revealed that two types of lobula plate neurons, T4 and T5, signal small-field direction-selective motion responses and are downstream of the first-order neurons, L1 and L2, or the ON- and OFF-channel neurons, respectively. Serial-EM reconstruction revealed that T5 receives direct synaptic inputs from four types of transmedulla neurons, Tm1, Tm2, Tm4, and Tm9. Our transcript profiling and immunohistochemistry revealed that these Tm neurons express choline acetyltransferase and therefore are likely cholinergic. Furthermore, we found that T5 expresses both nicotinic and muscarinic acetylcholine receptors. The Tm2 and Tm9 input synapses are spatially segregated on T5s dendritic arbor, thus providing candidate anatomical substrates for the two arms of elementary motion detector circuits. Based on the synaptic circuit and receptor expression profiles, we hypothesize that T5 computes small-field motion signals by integrating multiple cholinergic Tm inputs using nicotinic and muscarinic cholinoceptors. |
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2011 — 2018 | Lee, Chi-Hon | ZIAActivity Code Description: Undocumented code - click on the grant title for more information. |
Dendrite Development of Medulla Tm Neurons @ Child Health and Human Development We propose to use the Drosophila medulla neurons as a model to study dendritic development in CNS. Like vertebrate cortex and retina, the medulla neuropil is organized in columns and layers, suggesting that the fly medulla neurons and vertebrate cortex neurons confront similar challenges in routing their dendrites to specific layers and columns. In addition, the fly visual system has several unique advantages: (i) the medulla neurons extend dendritic arbors in a three-dimensional lattice structure, facilitating morphometric analysis;(ii) the presynaptic targets for many medulla neuron types are known from our anatomical studies;(iii) genetic tools for labeling specific classes of medulla neurons and determining their connectivity have been developed. We have developed novel techniques to analyze dendritic structures in 3D and to exploit the unique advantages of this system. First, to image reliably the slender dendrites of medulla neurons, we developed a dual imaging technique that generates isotropic 3D-images of dendrites. Second, we developed an image registration technique that makes uses of the regular array structures of the optic lobe to standardize dendritic branching patterns. This, in combination with a series of statistical methods we established, allows us to analyze dendritic patterns in three-dimension space. Third, we have established an imaging technique (GRASP) to detect synaptic contacts at light-microscopic level. We used these techniques to generate a data set of three types of medulla neurons. Our preliminary analyses suggested (i) that the medulla neurons exhibit stereotypic dendritic arbors but the detailed branching pattern and topology are not conserved;(ii) that the synaptic partnership between axons and dendrites are robust and specific. Based on these results, we hypothesize that dendritic development in the optic lobe neurons proceed in two distinct processes: (i) routing dendrites in type-specific fashion, which, at least in part, serves to maximize the possibility of finding appropriate synaptic partners;(ii) matching different sections of dendrites with specific afferents, which likely requires specific interactions between axons and dendrites to ensure synaptic specificity. The mechanisms governing these processes are the focuses of the following two specific aims. |
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