Striatal Microcircuit Dynamics

Summary / Abstract
The dorsal striatum (DS) is an important brain structure for normal sensorimotor control, including
decisions about how vigorously to move. As one example, loss of the dopamine input to DS is responsible for
bradykinesia in Parkinson's Disease. Yet how DS circuits processes information, and how this information
processing is modulated by dopamine, are not well understood.
DS circuits include sparse populations of interneurons - most commonly expressing either parvalbumin
(PV+), somatostatin (SST+) or acetylcholine (ChAT+). Interneurons appear to coordinate the activity of striatal
spiny projection neurons (SPNs), and alterations in striatal interneurons are found in human Tourette
Syndrome and rodent models of dystonia. Studies in brain slices have found many ways in which striatal
interneurons can affect SPNs and each other, via direct connections and by modulation of dopamine release.
However it has been challenging to connect these various results together into a coherent vision of DS
microcircuit function. Progress has been hampered by the lack of critical data about the joint activity patterns of
DS interneurons, SPNs, and local dopamine fluctuations, at precise moments during well-controlled behavioral
tasks.
To overcome this obstacle, this proposal uses an innovative, technically-advanced combination of
behavioral electrophysiology, optogenetics and optical dopamine sensors. We will perform real-time
measurements and manipulations of DS interneurons and dopamine, as freely-moving rats respond to cues.
The response times depend on rats' reward expectation for the selected action. Taking advantage of the
computational framework of reinforcement learning to derive trial-by-trial estimates of internal decision-
variables, we will test specific hypotheses about how the activity of distinct interneuron types is shaped by
recent choice and reward history.
Aim 1 will characterize the activity of DS PV+, SST+ and ChAT+ interneurons as actions are initiated. In
both dorsolateral and dorsomedial striatum we will record bulk calcium signals from each subpopulation, or the
spiking of identified interneurons, simultaneously with dopamine signals. Aim 2 will examine how, and when,
transient suppression of interneurons affects movement initiation and the activity of nearby SPN ensembles.
Aim 3 will determine how loss of DS dopamine jointly affects interneuron activity and behavior.
The long-term goals of this research program are to determine the fundamental operational principles
of striatal circuits. This knowledge would be of immense value in designing improved therapies for a wide
range of human neurological disorders.

Grant Number: 5R01NS123516-05
NIH Institute/Center: NIH
Principal Investigator: JOSHUA BERKE