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Interdisciplinary Initiatives Program Seed Grant: Synthetic Signaling Pathways for Anterograde Tracing of Neural Circuits in the Mammalian Brain

Seed Grants
Awarded in 2018

Interdisciplinary Initiatives Program Round 9 - 2018

Alice Ting, Genetics and Biology
Nirao Shah, Psychiatry & Behavioral Sciences and Neurobiology

A central question in neuroscience is how hormones, such as estrogen, regulate animal behavior at the level of synapses and circuits. The Shah lab has recently identified hormone-responsive neuronal populations in the hypothalamus that mediate distinct social behaviors between the sexes. We and others are keenly interested in identifying the downstream, postsynaptic targets of these neurons, so that we can discover the mechanisms by which these neurons guide sexually dimorphic social behaviors such as territorial aggression and reproductive displays. However, existing tools for discovering synaptically connected neurons work reliably only in the retrograde, upstream direction; and even these are associated with toxicity and miss known connections. We and the larger community of neuroscientists are urgently in need of new technologies for reliable, non-toxic transsynaptic tracing especially in the anterograde direction, so that we can discover downstream targets of functionally important neuronal populations. To address this unmet need, the Ting and Shah labs are collaborating to combine their respective expertise in chemical biology and protein engineering with mouse genetics and molecular systems neuroscience. The Ting lab will develop a collection of genetically-encoded tools for anterograde transsynaptic tracing. The tools will utilize designer proteins (that are not found endogenously) that are experimentally introduced into potential “sender” neurons and potential “receiver” neurons in distinct regions of the mammalian brain. Receiver neurons that form direct synaptic contacts with sender neurons then activate a modular responder program that enables their identification by fluorescence microscopy, functional optogenetic manipulation to assay for behavioral salience, and unbiased molecular fingerprinting for future studies. These tools will be utilized by the Shah lab to identify the downstream, anterograde targets of hypothalamic neurons to understand how these neurons regulate sex differences in social behaviors at the circuit level. If we are successful, the outcome of this project should be two-fold: (1) a transformative toolkit of genetically-encoded reagents for transsynaptic tracing in the mammalian brain; and (2) discovery of new circuit elements in the mammalian brain that enable shared neurons to mediate distinct behaviors in the two sexes.