University of North Carolina at Chapel Hill Graduate School
Doi
Abstract
The striatum serves as the major input nucleus of the basal ganglia circuitry, important for its varied roles in cognition, motivation, and sensorimotor function. Despite decades of study, fundamental features of the striatum’s functional organization and broader role(s) within the basal ganglia circuitry remain contentious and/or poorly defined. Given the diverse and critical roles of striatal activity in normal brain function and a multitude of disease states (including neurodegenerative and psychiatric disorders), a better understanding of this nucleus’ functional organization is imperative. The use of electrophysiological tools, which predominate the field, allow for in-depth characterizations of discrete, pre-selected brain regions, but are not appropriate for delineating functional neural circuit interactions on large spatial scales in an unbiased manner. A complementary approach to these studies is the use of functional magnetic resonance imaging (fMRI), which provides global, unbiased measures of functional neural circuit and network connectivity. In the first two studies described herein (Chapters 2 and 3), we used fMRI to map the functional response patterns to electrical DBS of the rat nucleus accumbens (NAc; ventral striatum), as well as the dual striatal outputs: external globus pallidus (GPe), and substantia nigra pars reticulata. Notable findings included the presence of negative fMRI signals in striatum during stimulation of each nuclei, robust prefrontal cortical modulation by NAc- and GPe-DBS, and marked functional connectivity changes by high frequency DBS. We next used optogenetic tools to more selectively map the brain-wide responses to stimulation of GPe neurons in healthy and Parkinson’s disease model rats (Chapter 4), as well as dorsal striatal neurons and their motor cortical inputs (Chapter 5). Optogenetic stimulation of each nuclei elicited an intriguing dorsal striatal negative fMRI signal, observed during direct striatal stimulation as well as putative recruitment of both excitatory both inhibitory striatal inputs, and thus suggestive of neurovascular uncoupling. Additionally, results from our GPe experiments revealed that this signal may be compromised in certain neurological disease states (e.g., Parkinson’s disease). Collectively, the studies described in this dissertation have exploited fMRI tools to reveal novel features of striatal connectivity, which may shed light on striatal function in health and disease.Doctor of Philosoph
