Research

The System

The striatum is the primary input to the basal ganglia, a group of brain nuclei interconnected by looped circuitry that influences diverse neural processes. Our lab focuses on how multicellular activity is sculpted in space and time in striatum and how this process becomes altered in the context of disease.

We specifically focus on the two principle striatal projection neuron types: D1- and D2- dopamine receptor expressing spiny projection neurons (SPNs). Activity in these neurons has a striking spatiotemporal organization that appears to be important for normal striatum-dependent behaviors.

The relative levels and patterns of D1- and D2-SPN activity can change as a function of normal experience, but can also become altered in models of neurological or psychiatric disease. We are interested in what factors constrain these striatal dynamics and whether we can exploit those factors to restore normal function in brain disorders where basal ganglia dysfunction is implicated.

The Approach

We perform large-scale recordings of striatal activity using miniaturized fluorescence microscopes and two-photon microscopy in transgenic mice to selectively record from genetically defined neuronal subpopulations.

We combine these tools with viral genetic and pharmacological manipulations in healthy animals and animal models of neuropsychiatric diseases to better understand both normal and aberrant striatal function.

        Miniaturized fluorescence microscopy        Two-photon fluorescence microscopy

                   

Using these tools, we have found that D1- and D2-SPNs encode different movement types via spatially clustered co-activation.  Moreover, there is SPN-type specific deficits in spatially clustered activity in animal models of Parkinson’s disease and L-DOPA-induced dyskinesia.

Environmental stimuli can also alter the relative levels and spatiotemporal structure of D1- and D2-SPN activity. Moreover, evidence suggests these dynamics are impacted by learning. Therefore, coordinated striatal activity likely plays roles other than encoding movement, which is consistent with proposed striatal involvement in a wide range of neuropsychiatric diseases.

The Questions

Ongoing and future projects in the lab can be encompassed in three broad categories:

1. How are the levels and spatiotemporal dynamics of D1-SPNs and D2-SPNs altered during striatum dependent behaviors (e.g., learning)?
2. Are these dynamics also altered in animal models of other neuropsychiatric diseases? If so, can they be corrected by mainstay or novel treatments?
3. What are the molecular and circuit-level factors responsible for sculpting these patterns of striatal activity?