Optical control of deep synaptic signaling

The mammalian brain has up to 100 trillion synapses, representing an immense potential reservoir for information storage. Most theories of memory storage in the brain assume that memories are stored by changes in synaptic strength but, despite decades of work on synaptic plasticity and neuromodulation, and tantalizing progress the best understood mechanisms that change synaptic strength have yet been shown to underlie memory storage in the intact brain. A key reason is the challenge of measuring and manipulating synaptic strength at identified synapses at the population scale during learning. These challenges can now be addressed by new technologies for imaging and manipulating synaptic function at scale during behavior. We propose here to make a major advance in synaptic manipulation. Optogenetics has revolutionized neural circuit analysis by enabling stimulation or inhibition of action potential firing in select neurons. Chemical optogenetics has extended optical control to the synapse by enabling light- activation and ilght-block of the receptors that mediate synaptic transmission, plasticity and neuromodulation. Synthetic photoswitches have been developed to control ionotropic receptors for fast signaling and G protein coupled receptors for neuromodulation. The number of receptors has expanded greatly in the past 5 years, and there has been great success in using these in the brain of awake behaving animals from flies to fish to mouse. We propose to make a quantum leap in the precision of synapse control through new schemes for targeting optical control of receptors to specific synaptic compartments and specific classes of synaptic connections. Each neurotransmitter has multiple receptors, creating great complexity. The difficulty for analysis is increased by the fact the same receptor may be found on multiple cells in a circuit and, in fact, in more than one location in a particular cell, with distinct function at each location. Our method enables us to selectively control receptors in a genetically selected manner. We now add the ability to restrict control to one compartment in the cell: say the presynaptic site, where transmitter release is regulated, or the postsynaptic site, where the response to transmitter is regulated. We add to this, methods for enhancing penetration of control light through brain tissue— a key step to reduce invasiveness of implanted fiber optics and to ease the transition of the application to larger brains. The project is made possible by an inter-disciplinary collaboration between molecular and cell biologist Isacoff and synthetic chemist Trauner, who co-developed chemical optogenetics have collaborated extensively since, physical chemist Cohen, a pioneer in upconverting nanoparticles that turn IR light into visible light, and circuit neuroscientist Lammel, an expert in optogenetic and behavioral analysis. Project Number: 1R01MH142405-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Mental Health (NIMH) | Principal Investigator: Ehud Isacoff | Institution: UNIVERSITY OF CALIFORNIA BERKELEY, BERKELEY, CA | Award Amount: $1,170,843 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 NV-J (50)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11281027