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Principal Investigator: Xinyi Jenny He
Organization: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
Fiscal Year: 2024
Award: $74,080
Funding agency: National Institute of Mental Health
Project Summary
Neuromodulators control the state of an animal’s brain and thus behavior through the activation of G protein-
coupled receptors (GPCRs). Although the role of neuromodulation has been appreciated for decades, the
chemical logic of neuromodulation has remained elusive due to inadequate tools to study it. Recent advances
in single-cell transcriptomics make it now clear that individual neurons co-express a huge diversity of
neuromodulatory GPCRs, yet GPCRs transduce signaling primarily by coupling to only three classes of G-
protein. This poses the question - does a neuron ‘know’ which of its many co-expressed receptors was
activated? And if so, how? I hypothesize that individual neurons are able to distinguish this chemical diversity,
even through shared signaling pathways, by utilizing spatiotemporal differences in GPCR signaling. To test
this, I will first determine which receptors are functionally co-expressed in primary hippocampal neuron
cultures, through a spatial-transcriptomic and functional screen. Then, I will compare response properties
focusing on Gs-coupled receptors by taking advantage of a powerful palette of biosensors to interrogate their
intracellular signaling with high spatial and temporal resolution. Finally, I will ask how these receptors are
utilized in intact circuits by using spatial-transcriptomics and live imaging of cellular activity in acute brain
slices. These findings will motivate my long term research goal of developing a subcellular understanding of
neuromodulation, which is key to understanding neural circuits in both healthy and diseased states. In addition,
this proposal includes a rigorous training plan and a team of collaborators that will bridge my research from
molecular to systems neuroscience. It includes training in quantitative and computational methods that will both
assist in my research aims and facilitate my development as a scientist. Through the excellence in research
and postdoctoral support at UCSF, the training environment in the von Zastrow lab, and the planned activities
listed in this proposal, this fellowship will prepare me for a career as an independent scientist invested in the
priorities of the BRAIN Initiative.
Terms: <2-photon><21+ years old><3'5'-cyclic ester of AMP><Acute><Address><Adenosine Cyclic 3',5'-Monophosphate><Adenosine Cyclic Monophosphate><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Adenosine, cyclic 3',5'-(hydrogen phosphate)><Adult><Adult Human><Ammon Horn><Animals><Area><Assay><BRAIN initiative><Behavior><Binding><Bioassay><Biologic Models><Biological Assay><Biological Models><Biosensor><Brain><Brain Mapping><Brain Nervous System><Brain Research through Advancing Innovative Neurotechnologies initiative><Catalogs><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chemicals><Code><Coding System><Communication><Computing Methodologies><Cornu Ammonis><Coupled><Coupling><Cyclic AMP><Cyclic AMP-Dependent Protein Kinases><Data><Degenerative Neurologic Disorders><Development><Disease><Disorder><Encephalon><Environment><Feedback><Fellowship><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G Protein-Coupled Receptor Signaling><G-Protein-Coupled Receptors><G-Proteins><GPCR><GPCR Signaling><GTP-Binding Proteins><GTP-Regulatory Proteins><Genetic><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Health><Hippocampus><Human><Image><Individual><Intracellular Communication and Signaling><Investments><Ligands><Logic><Maps><Mice><Mice Mammals><Microscopy><Model System><Modeling><Modern Man><Modernization><Molecular><Molecular Interaction><Murine><Mus><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Nervous System Degenerative Diseases><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><Neuromodulator><Neuronal Transmission><Neurons><Neurosciences><Output><PKA><Pathology><Pattern><Physiologic><Physiological><Population><Postdoc><Postdoctoral Fellow><Property><Protein Kinase A><Receptor Protein><Receptor Signaling><Research><Research Associate><Role><Scientist><Shapes><Sight><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Slice><Specificity><Survey Instrument><Surveys><Synapses><Synaptic><System><Techniques><Testing><Time><Training><Translating><Vision><adenosine 3'5' monophosphate><adulthood><axon signaling><axon-glial signaling><axonal signaling><biological sensor><biological signal transduction><brain tissue><cAMP><cAMP-Dependent Protein Kinases><career><catalog><cell type><combinatorial><computational methodology><computational methods><computer based method><computer methods><computing method><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><experiment><experimental research><experimental study><experiments><glia signaling><glial signaling><hippocampal><imaging><insight><live cell image><live cell imaging><live cellular image><live cellular imaging><nerve signaling><neural circuit><neural circuitry><neural control><neural imaging><neural regulation><neural signaling><neuro-imaging><neurocircuitry><neurodegenerative illness><neuroimaging><neurological imaging><neuromodulation><neuromodulatory><neuronal><neuronal excitability><neuronal signaling><neuropsychiatric disease><neuropsychiatric disorder><neuroregulation><neurotransmission><post-doc><post-doctoral><post-doctoral trainee><receptor><receptor function><research associates><response><sensor><social role><spatiotemporal><synapse><synaptic circuit><synaptic circuitry><temporal measurement><temporal resolution><time measurement><tool><transcriptomics><two-photon><visual function>