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theses

The basal ganglia are a system of subcortical nuclei whose functions include regulating the motivation for voluntary actions. One key aspect of this function is to assist in action selection, often referred to popularly as decision making, by keeping track of past results and utilizing this information to produce ideal decisions and by signaling the motivational significance of environmental events. Two types of basal ganglia neurons have been most extensively studied in terms of their role in these functions: the dopaminergic neurons of the substantia nigra pars compacta and the tonically active cholinergic interneurons of the neostriatum. Both have stereotypic responses to motivationally salient stimuli, and it is assumed that this information is used in choosing the most beneficial response. The focus of my thesis work was to investigate how the responses of neostriatal cholinergic interneurons to motivationally salient stimuli (commonly termed the pause response) are translated into downstream effects in projection neurons. My underlying hypothesis was that if these signals are to participate in the translation of a temporally brief and important environmental event into changes in behavior, that there must be a fast and temporally precise effect on the projection neuron output to other brain structures. Although striatal projection neurons express receptors for acetylcholine, they are of the slow acting muscarinic type, not the fast acting nicotinic type. Therefore, fast cholinergic regulation of projection neurons is assumed to be mediated by changes in synaptic input. We utilized technologies including optogenetics, transgenic mice and molecular biology to experimentally recapitulate the pause response of cholinergic interneurons in acute murine brain slice preparations, which preserve much of the intrinsic neostriatal circuitry, as well in behaving mice. We were then able to simultaneously record neostriatal neurons using in vitro whole-cell intracellular and in vivo extracellular electrophysiological recordings. These experiments revealed a novel neostriatal cholinergic-GABAergic circuit involving a recently described GABAergic interneuron similar to cortical neurogliaform GABAergic interneurons, which translate the pause response of cholinergic interneurons into fast and powerful inhibition of projection neurons. In addition to uncovering an unknown and unpredicted mechanism of action of acetylcholine in the neostriatum, these results demonstrate the power of combining traditional electrophysiological recording methods with current optogenetic, transgenic

ETD_4076

http://hdl.rutgers.edu/1782.1/rucore10002600001.ETD.000065031

Ph.D.

Includes bibliographical references

Includes vita

by Daniel F. English

doi:10.7282/T3D50KW7

ETD doctoral

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