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Mechanisms of Synapse Formation and Regulation in the Development and Function of the Basal Ganglia

Research Summary

Bernardo Sabatini studies the neural processes by which an animal picks its next action. He focuses on the circuitry of the basal ganglia, an evolutionary conserved brain structure fundamental to motor action and selection, and seeks to understand how the regulation of synapses in this structure modify animal behavior. Furthermore, he examines how perturbations of these processes contribute to neuropsychiatric disease. His laboratory utilizes and develops novel molecular, optical, and electrophysiological approaches for these studies.

Each animal must use information about past experience, its sensory environment, and its internal motivation state to decide what action to carry out. Specialized brain circuits in the basal ganglia are fundamental to this process of "action selection." The basal ganglia are highly conserved across phylogeny, including humans, and are fundamental to controlling day-to-day activity of all vertebrates. Perturbations of basal ganglia directly cause severe human neuropsychiatric disorders such as Parkinson's and Huntington's disease, and contribute to obsessive-compulsive disorder, Tourette's syndrome, and schizophrenia. Furthermore, mimicry of signaling in the basal ganglia is the mechanism of addiction of all drugs of abuse.

The goals of the laboratory are to understand how the circuitry of the basal ganglia mediates the process of action selection and how its perturbation contributes to neuropsychiatric disease. We begin our studies from a synapse and circuit centric point of view, using a variety of approaches to examine the following questions:

1. How is the circuitry of the basal ganglia established and how are these processes shaped by early life experience?

2. How do neurotransmitters such as dopamine and opioids, known powerful modulators of animal behavior, alter basal ganglia circuitry to exert their behavioral effects?

3. What are the dynamic interactions among nuclei of the basal ganglia and with other brain structures that mediate the selection and triggering of a motor action?

4. What are the mechanisms of circuit plasticity and synapse regulation by which an animal learns to string together a sequence of motor actions to accomplish a goal?

In order to accomplish these goals, we study the brains of mice, whose basal ganglia have high homology to those of humans. We utilize in vitro, ex vivo, and in vivo optical, electrophysiological, and molecular approaches to manipulate and read-out synapse and circuit function in the basal ganglia.

This work is supported in part by grants from the National Institutes of Health (NIMH and NINDS), the Nancy Lurie Marks Family Foundation, and the Simons Foundation.

As of December 3, 2013

Scientist Profile

Investigator
Harvard Medical School
Biophysics, Neuroscience