CRCNS: Rhythm Generation and Propagation by a Pallidostrialtal Circuit of the Basal Ganglia

Carnegie Mellon University, Pittsburgh PA

Investigators

Abstract

In specialized brain areas called the basal ganglia, neurons generate certain rhythmic activity patterns during particular stages of motor processing. This rhythmicity becomes enhanced in disorders such as Parkinson's disease (PD), where pathological activity patterns include pronounced oscillations within certain frequency bands, increased synchrony, and phasic bursting. These patterns of amplified rhythmicity are thought to compromise functionality of basal ganglia networks and to contribute to motor impairments. The overarching goal of this work is to understand how cellular and synaptic changes that occur in PD render neural circuits in the basal ganglia more susceptible to rhythmic activity in disease. Specifically, this research will focus on an understudied neural circuit that is well positioned to influence rhythmicity throughout the basal ganglia and will help to identify potential cellular targets to disrupt pathological network activity in disease. A combination of in vivo and in vitro physiological approaches together with computational model development, simulation, and analysis will be used to identify biological features of this circuit that can generate and maintain rhythmicity and to explain how this network contributes to runaway rhythmicity in PD. The external segment of the globus pallidus (GPe) is a central nucleus within the basal ganglia that has been strongly implicated in the onset and maintenance of rhythmic activity. Under normal conditions, neurons in the GPe fire tonically and independently, at rates of 10-80 Hz; after dopamine depletion, GPe neurons become highly synchronized and fire in rhythmic bursts. The GPe interacts with other basal ganglia nuclei through multiple circuits, one of which, a pallidostriatal circuit linking GPe with the striatum, has only recently been identified as a natural contributor to basal ganglia rhythmicity. A major goal of this work is the identification of features within the pallidostriatal circuit that generate and maintain rhythmicity and may underlie runaway rhythmicity in pathological conditions. Achievement of this aim will help in the location of targets that can be modulated to disrupt the pathological amplification or propagation of basal ganglia rhythmicity. These results will be achieved through an approach that integrates in vivo and in vitro physiological experiments with computational model development, simulation, and analysis.