Abstract
Chemogenetic and optogenetic tools have transformed the field of neuroscience by facilitating the examination and manipulation of existing circuits. Yet, the field lacks tools that enable rational rewiring of circuits via the creation or modification of synaptic relationships. Here we report the development of HySyn, a system designed to reconnect neural circuits in vivo by reconstituting synthetic modulatory neurotransmission. We demonstrate that genetically targeted expression of the two HySyn components, a Hydra-derived neuropeptide and its receptor, creates de novo neuromodulatory transmission in a mammalian neuronal tissue culture model and functionally rewires a behavioral circuit in vivo in the nematode Caenorhabditis elegans. HySyn can interface with existing optogenetic, chemogenetic and pharmacological approaches to functionally probe synaptic transmission, dissect neuropeptide signaling, or achieve targeted modulation of specific neural circuits and behaviors.
Highlights
Chemogenetic and optogenetic tools have transformed the field of neuroscience by facilitating the examination and manipulation of existing circuits
Because neuromodulation is a powerful way of re-configuring neural circuits to produce distinct behavioral outcomes, because neuromodulation is not constrained by the architecture of the nervous system, and because the role of neuromodulators and their long-range effects remains largely unexplored[9,10], we focused our efforts on a system that enables reconstitution of synthetic modulatory chemical synaptic connectivity
Transport and release mechanisms[14] and postsynaptic calcium signaling are conserved throughout evolution[16,17,18], expression of this neuropeptide ligand-receptor pair, while orthogonal, would still harness fundamental and conserved signaling mechanisms in the desired cells
Summary
Chemogenetic and optogenetic tools have transformed the field of neuroscience by facilitating the examination and manipulation of existing circuits. No existing technology enables the purposeful creation of new, synthetic and manipulatable chemical synaptic connections for re-configuring neural networks in diverse organisms For these reasons, we developed a system that allows the engineering of synthetic relationships between neurons through the targeted reconstitution of modulatory neurotransmission between selected partners, eliciting orthogonal circuit control over neuromodulatory connectivity. We prioritized the design of a system that would be (1) versatile to function in a wide range of cell types and organisms, (2) modular to allow independent genetic targeting of pre- and postsynaptic components, (3) specific to modulate only the intended target cells while being inert to endogenous neurotransmission, (4) robust by targeting conserved intracellular signaling cascades, and (5) synergistic to interface with existing optogenetic and chemogenetic technologies Informed by these goals, we engineered “HySyn”, a Hydraderived, two-component system that creates synthetic neuromodulatory connections to manipulate intracellular calcium within in vivo neural circuits (Fig. 1a, left)
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