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Principal Investigator: YONGLING ZHU
Organization: NORTHWESTERN UNIVERSITY AT CHICAGO
Fiscal Year: 2024
Award: $400,000
Funding agency: National Eye Institute
Project Summary/Abstract
The long-term goal of this research is to understand visual processing in the inner plexiform
layer of the retina. More immediately, the research serves to provide genetic access to distinct
glycinergic amacrine cell types for functional characterization and to understand how they shape
the response properties of retinal ganglion cells (RGCs). Amacrine cells (ACs) are the most
diverse neurons in the retina, with at least 60 types of ACs identified through single-cell RNA
sequencing in the mouse retina, along with the 40-50 AC types described in morphological
studies. It is believed that each AC type has a distinct functional role in visual processing, yet
the correspondence is only known for fewer than 20 types. Within the 60 identified AC types,
approximately 13 are characterized as glycinergic ACs with small dendrites spanning multiple
vertical layers. Our understanding of the functions of glycinergic ACs is limited to only about 5 of
these types. For most of the remaining glycinergic ACs, we are constrained from assigning
precise functions to these genetically and morphologically defined cell types. We propose to use
mouse intersectional genetics, combined with functional imaging and electrophysiology
recording, to dissect AC circuits in three separate Aims. In Aim 1, we will create Cre/tTA and
Cre/Flp intersectional strategies to discover new glycinergic AC types and to minimize the
labeling to the fewest possible types. In Aim 2, we will investigate how visual responses are
generated and organized across the laminar depth of the dendrites of the newly discovered
glycinergic AC types. In Aim 3, we will identify the postsynaptic RGCs of the glycinergic AC
types with intersectional ChR2 activation. We will further examine their functional roles with
chemogenetic inactivation. We will begin with COMS-AC, a newly identified glycinergic
amacrine cell and map its synaptic connectivity with multiple co-stratifying RGCs, followed by
testing the hypotheses that it plays a multitasking role in different RGC circuits with selective
inactivation. We will use both hypotheses driven and discovery-based approaches to gain
insights into the circuit functions of glycinergic ACs. This research will enhance our
comprehension of visual processing in the inner retina, and the technologies developed will
represent significant advancements compared to existing methods for studying amacrine cells,
with potential applicability to other brain circuits. Moreover, this project will offer valuable
insights into the pathophysiological neuronal mechanisms underlying retinal diseases,
contributing to the development of improved therapeutic strategies.
Terms: <2-photon><Amacrine Cells><Anatomic Sites><Anatomic structures><Anatomy><Brain><Brain Nervous System><Brain region><Cell Communication and Signaling><Cell Signaling><Comprehension><Connector Neuron><Dedications><Dendrites><Detection><Development><Electrophysiology><Electrophysiology (science)><Encephalon><Exhibits><Functional Imaging><Funding><Genetic><Goals><Image><Inhibitory Synapse><Inner Plexiform Layer><Intercalary Neuron><Intercalated Neurons><Interneurons><Internuncial Cell><Internuncial Neuron><Intracellular Communication and Signaling><Investigation><Label><Light><Maps><Methods><Mice><Mice Mammals><Microscope><Modeling><Morphology><Murine><Mus><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Neurophysiology / Electrophysiology><Pattern><Photoradiation><Physiologic Imaging><Play><Property><Publishing><Research><Retina><Retinal Diseases><Retinal Disorder><Retinal Ganglion Cells><Role><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Synapses><Synaptic><Techniques><Technology><Testing><Therapeutic><Viral><Visual><biological signal transduction><cell type><design><designing><developmental><electrophysiological><experiment><experimental research><experimental study><experiments><gangliocyte><ganglion cell><imaging><improved><insight><interest><mouse genetics><multi-task><multitask><neuronal><object motion><optic imaging><optical imaging><optogenetics><physiological imaging><postsynaptic><receptive field><response><retina disease><retina disorder><retinal ganglion><retinopathy><scRNA-seq><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spatiotemporal><synapse><two-photon><visual process><visual processing>