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.

Public Health Relevance

The proposed research is designed to identify precise, targetable brain circuit alterations that underlie pathological compulsive motor behaviors, making the outcomes relevant to public health. Successful testing of the hypotheses in this proposal will improve our fundamental understanding of how motor brain circuits are modulated by the amygdala to induce pathological compulsive motor behaviors, a symptom of numerous neurodegenerative, neurodevelopmental and neuropsychiatric disorders. This knowledge will help develop improved therapies to enhance the quality of life for a broad spectrum of patients, making the proposed research relevant to the NIH's mission.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Pathophysiological Basis of Mental Disorders and Addictions Study Section (PMDA)
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Morris, Jill A
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State University New York Stony Brook
Schools of Medicine
Stony Brook
United States
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