Jason Wester

Research Description:

A key challenge in neuroscience is to unravel the logic of cortical microcircuit organization, a necessary step towards a mechanistic understanding of how the cortex works. A crucial observation is that the cortex contains repeated microcircuit motifs, which implement canonical computations necessary for proper cortical function. Assembling these microcircuits during development requires the mutual recognition and interaction among specific neuronal subtypes, whose identities are largely genetically predetermined during embryonic neuronal differentiation. Thus, developmental disruption of even one type of neuron can have a ripple effect on cortical architecture and wiring, and contribute to disorders such as autism or schizophrenia. The goal of the Wester lab is to discover fundamental cortical microcircuit motifs, the details of their synaptic physiology, and the developmental algorithms that guide their assembly from early neuronal differentiation to postnatal maturation.

To accomplish this, we are using molecular genetic techniques available in mice, including multiple transgenic lines and in vivo stereotaxic injections of viral vectors, to target and manipulate specific subtypes of excitatory pyramidal cells and inhibitory interneurons in the neocortex and hippocampus. We are knocking out key genes that determine neuronal identity, to fate-switch a cell from one subtype to another during embryonic development, and then investigating how this impacts circuit development in mature mice. Furthermore, we are knocking out genes hypothesized to play important roles in cell-to-cell signaling during circuit assembly. We then use paired whole-cell recordings and optogenetics in acute slices to map local circuits and study their synaptic physiology under normal and mutant conditions. Additionally, techniques such as single cell RNA-sequencing allow us to investigate cell- and non-cell-autonomous changes in molecular expression. These datasets can then be applied to build biophysical models of circuit motif computations and to test in vivo hypotheses of cortical circuit function.