How are behavioral control circuits altered in animal models of neuropsychiatric disorders?
Genetic mouse models of neuropsychiatric disease provide a unique opportunity to understand how genetic insults translate into behavioral abnormalities. What circuit and synaptic dysfunctions explain deficits in behavioral control observed in mouse models of autism, OCD and schizophrenia? Do common physiological abnormalities exist both within and across disease models? How do environmental factors and genetic modifiers interact to modulate disease-relevant circuitry?
To address these questions we use all means of genetic manipulation in mice, including conventional knockouts, conditional "floxed" alleles, CRISPR-Cas9 mediated genome targeting and viral expression of shRNAs. These tools allow us to study physiological changes to behaviorally relevant cell-types and synaptic connections, a key step in creating a "circuit understanding" of how alterations in an organisms genetic code finally impact upon its behaviors.
Methodology for probing circuit-specific alterations in synaptic transmission in genetic mouse models of neuropsychiatric disease. (Left) Expression of Channelrhodopsin in projection neurons of the OFC leads to expression in the axon terminals of projections into the dorsal striatum. 473nm laser stimulation can evoke synaptic release from these afferent neurons, allowing for analyses of presynaptic and postsynaptic function (right).