Molecular Regulators of Neuronal Interfaces

Major current neuron research questions:

How do neurons develop and maintain selective resiliency in the context of disease?

Do neurons display local plasticity in neuromodulator production, and if so, how? 

How do neurons target the correct brain areas to form relevant circuits?

Reprograming neural identity to restore circuit function.  Neuron subtype specification is generally thought to occur at birth when progenitor cells give rise to fate committed neuron subtypes. These features were once thought to be static. However, recent data points to a new type of circuit flexibility called neurotransmitter switching. In this form of plasticity, fate committed neurons can replace one neurotransmitter with another, resulting in changes to circuit function and behavior.  In these projects, we identify molecular pathways responsible for this switching and assess how and why they work. These results suggests the capacity to modulate circuits post-mitotically by reprograming which neurotransmitters neurons make.

Mapping and restoring human neuron connectivity. In these projects, we address a critical problem: how can we restore neuron connectivity to improve therapeutics? IIn particular, we focus on how a critical visual cell type,  retinal ganglion cells, wire and rewire with distinct retinorecipient regions with the long-term goal of enabling axon regrowth and connectivity in humans. We use three novel approaches: generation of chambered multifluidic devices to direct human pluripotent stem cell (hPSC)-derived RGCs to undergo directed axon growth, analysis of pro-survival neural cues to promote neural resiliency, and paired cell surface proteomics.

Identification of Neural and Synaptic integrity Genes by High Throughput screening (INSiGHT). Synapses are the cellular structures through which all neurons communicate. We have demonstrated synapse partnerships are not static, even in adulthood. Rather, adult neurons can alter their partner choice. These observations are critical because they suggests that neural wiring or identity can be selectively reprogrammed, representing an opportunity for therapeutic intervention. To uncover synapse reprograming pathways our lab has developed a pipeline for the Identification of Neural and Synaptic integrity Genes by High Throughput retinal screening. Several candidates we discovered are associated with human disease and affect synapse. In ongoing work, we are identifying the mechanisms that govern who, when, and why neurons form synapses to enable direct manipulation of this conversation.