Project Summary/Abstract
Compulsive motor behaviors (i.e. repetitive stereotyped, insuppressible behaviors) are a common motor
symptom found in a wide range of neurodegenerative, neurodevelopmental and neuropsychiatric disorders.
These motor symptoms interfere with the daily functioning, productivity and quality of life of over 1% of the
population, yet treatment options are limited and often ineffective, due to insufficient understanding of the
underlying brain circuits and lack of therapeutic targets. The striatum (caudate/putamen), the major input
nucleus of the basal ganglia, is a key mediator of compulsive motor behaviors in both humans and rodents.
Compulsive motor behaviors commonly co-occur with anxiety disorders, and psychophysical models have
proposed that the two are mechanistically linked, suggesting the corresponding brain circuitries may overlap.
How limbic-associated inputs converge on the motor portions of the striatum, however, is unclear. The
objective of this proposal is to determine how synaptic inputs from the basal and lateral nuclei of the amygdala
(BLA) influence dorsolateral striatum function, and if pathological synaptic integration of BLA inputs by the
dorsolateral striatum exacerbates compulsive motor behaviors. The dorsolateral striatum contains two types of
functionally opposing spiny projection neurons (SPNs), which predominantly receive synaptic inputs from the
sensorimotor cortex and thalamus, and ultimately promote or suppress action initiation. A leading hypothesis is
that compulsive motor behaviors are due to imbalanced activation of SPN populations, pathologically
promoting action initiation. The proposed research will determine how SPNs pathologically integrate synaptic
inputs from the BLA in complementary mouse models of compulsive motor behavior (genetically induced by
deletion of Slitrk5 or Sapap3, or experimentally induced by repetitive over-activation of BLA inputs to the
dorsolateral striatum). This approach will reveal common, model-independent circuit pathologies. Guided by
strong preliminary data and cutting edge techniques (2-photon laser scanning microscopy, dendritic calcium
imaging, slice electrophysiology, mutant mouse lines containing fluorescently tagged SPN-subtypes, and
spatially localized optogenetics in ex vivo slices and in vivo), the proposed research will 1) determine how the
dendritic excitability of dorsolateral striatum SPN populations is altered in Slitrk5 and Sapap3 knockout mice, 2)
functionally map how SPN dendrites are engaged by the BLA, and how this impacts synaptic integration in
mutant mice, and 3) determine the role of repetitive in vivo activation of BLA inputs to the dorsolateral striatum
in inducing behavior and circuit pathologies overlapping with and exacerbating those found in mutant mice, and
identify the common circuit pathologies corrected by the behaviorally therapeutic (in mice, but only a subset of
patients) serotonin reuptake inhibitor fluoxetine. The results from this proposal are expected to reveal both
novel pathological loci and the underlying mechanisms of a widely used but imperfect treatment for compulsive
motor behaviors, aiding in the development of improved therapies for this common and debilitating symptom.