An Optogenetic Investigation into the Roles of Striatum, Dopamine, and Collateral Behavior During Interval Timing
- Author(s): Strassmann, Patrick;
- Advisor(s): Jin, Xin;
- Kristan, William
- et al.
Time is a fundamental dimension of decision-making. When to perform an action is often as important as what action to take, and thus our sense of time is essential for guiding everyday behavior. Our perception of time allows us to form temporal associations between events and to detect irregularities in our environment; it allows us to optimize our choices and anticipate future consequences. However, unlike other sensory modalities, our sense of time appears to be entirely self-generated, as if our brain possesses—as some researchers have supposed—an “internal clock.” We clearly have a sense of time, yet how time is tracked and encoded by the brain remains mysterious. Animal behavior demonstrates features of timing across many timescales, from milliseconds to months. This dissertation focuses on timing on the scale of seconds-to-minutes, most commonly known as interval timing. Basal ganglia circuits are essential for motor control, action selection, and reinforcement learning. However, numerous lines of evidence also suggest that the basal ganglia –in particular the dorsal striatum and nigrostriatal dopamine – play a central role in interval timing. Does the basal ganglia serve a motor-independent function during interval timing, or is its role in timing fundamentally intertwined with action? In animal models of interval timing, researchers widely observe the development of non-instrumental, collateral behaviors as animals learn to time under operant conditioning. This dissertation explores the idea that these collateral behaviors can act as a functional mechanism to support timekeeping. We suggest that the basal ganglia’s role in interval timing may indeed be tied to these collateral behaviors. Chapter 1 reviews modern conceptions of how interval timing can be categorized, as well as the lines of evidence suggesting a role for motor-related brain regions in interval timing. In Chapter 2, I discuss the peak-interval operant task used throughout our experiments, I provide an analysis of the emergent behavior, and finally suggest a metric by which to assess timing accuracy on a trial-by-trial basis. In Chapter 3, I describe our optogenetic methodology for disrupting collateral behavior by disrupting striatal activity, and I demonstrate how these behavioral disruptions subsequently affect temporal decisions. In Chapter 4, I disrupt collateral pressing behavior by optogenetically manipulating a brainstem motor output nucleus. I demonstrate that the effects of disrupting action in the brainstem result in similar timing deficits as does disrupting action via the dorsal striatum. In Chapter 5, I assess how stimulating dopamine neurons in the SNc affects timing performance, and validate our methodology and nigrostriatal dopamine release using fast-scan cyclic voltammetry. I demonstrate that dopaminergic stimulation in these experiments only affects timing behavior insofar as collateral pressing behavior is also disrupted.