A Paradigm Shift in Neurological Science
We are advancing the understanding and treatment of CNS disorders based on a paradigm shift in neuroscience, including:
- Significant technological leaps in brain imaging and spatial gene expression profiling are revealing relationships between regional circuit activity and symptoms
- Optogenetics allows us to identify changes in the activity of specific neural circuits that are responsible for disease symptoms
The Three Pillars to the MapLight Platform
High level platform rationale
Optogenetics enables the real-time manipulation of neural circuits that are responsible for the clinical manifestations of CNS disorders. Neural circuits are prioritized for in-depth optogenetic analysis based on existing disease-relevant human functional neuroanatomy (fMRI), human functional neurosurgery (DBS), and rodent optogenetic literature.
Optogenetics is a transformative technology that allows us to turn neurons “on” or “off” in animal models with the flick of a light switch. We start with opsin proteins that can be activated or deactivated with light– excitatory ion channels like ChR2 that trigger action potential firing or inhibitory Cl– pumps like NpHR that silence neural activity. We then use genetically targeted viruses to specify which cells contain the light sensitive opsins, so that only cells in the circuit of interest will be responsive to the light. This process provides highly precise identification and control of the exact circuits and brain cells responsible for triggering pathological disease symptoms.
Circuit function is systematically tested across multiple nodes in a network, and parameters are adjusted to define the full range of symptoms controlled by individual circuits.
With STARmap technology, hundreds of gene transcripts can be assayed in situ, preserving the spatial integrity and anatomical architecture of the intact brain circuit. This allows us to efficiently locate drug target candidates within key neural circuits and combine this information with functional (e.g. immediate early gene expression) and anatomical (e.g. projection pathway) readouts.
The architecture and genetic composition of circuits can be confirmed across species to prioritize targets most likely to effectively translate from preclinical models into clinical patient populations
To identify unique molecular targets in a circuit of interest, gene expression profiling is used to identify gene products capable of modulating different circuit elements and the disease symptoms they mediate. Genes that have high specificity for the circuit of interest are evaluated as potential targets so that drugs can be developed with enhanced efficacy and fewer side effects.
MapLight’s proprietary cell atlas contains gene expression data from millions of single cells across the central and peripheral nervous systems. This rich resource is used to fuel the identification of novel cell types and targets to rank candidates by specificity to the circuit of interest, and to predict synergistic drug combinations.