Grant: Discovery Grants Program - Individual

The principal challenge for neuroscience is to understand how our thoughts, memories, feelings and even our sense of self can be created from the biological workings of the brain. Our ability to investigate these questions has improved dramatically in recent years. This is due, in part, to the introduction of sophisticated new neuroscience tools such as optogenetics, which uses light to precisely manipulate activity in genetically defined neuron populations. In addition, advances in our fundamental understanding of the nervous system have come from the study of neurodevelopmental disorders such as autism, where the loss of certain synaptic proteins can cause dramatic effects on development and behavior. The proposed research program uses these the natural logic of synapses to as the basis for engineering and design principles to make new neuroscience tools. Ideally, we can create new tools that can "snap into place" within the nervous system, allowing researchers to manipulate neural activity using the same fundamental building blocks as the nervous system itself. We have found that synapses will shuttle different information depending on what synaptic proteins are present. For example, a pair of proteins, Elfn1 and mGluR7, create a stable link across the synapse that changes synaptic communication onto somatostatin type interneurons, altering the flow of information through these synapses. By creating optogenetic tools that are selectively located on subsets of synapses, we can provide greater experimental control of neural activity. In the following proposal, we aim to use the interaction between Elfn1 and mGluR7 to place optogenetic tools at connections between genetically defined cell types. In doing so, we mimic the circuit logic of the nervous system and can provide precise control of neural activity. To start, we will generate inhibitory tools that will target themselves to somatostatin interneuron synapses and explore how somatostatin neurons influence feeding behavior. A second series of modifications should allow us to target any synapses that are made between two defined cell types by using one tool in the presynaptic cell population, and another in the target cell population. Finally, we will expand these principles to a whole suite of excitatory and inhibitory tools to provide precise control of synaptic activity. By directly manipulating activity at defined synaptic connections, we can grant neuroscientists direct control over the fundamental building blocks of the nervous system.