<p>Finding and consuming food and water are among the most critical functions for an animal's survival. Food seeking (e.g., exploration and approach) and consummatory (e.g., licking, chewing, swallowing) behaviors are usually highly controlled, resulting in stable food intake, body mass, and fat stores in humans and laboratory animals. These variables are thought to be governed by homeostatic control systems that closely regulate many aspects of feeding behavior. However, the homeostatic mechanisms underlying these processes are often disrupted in humans, resulting in either hyperphagia or hypophagia. Despite many decades of investigations into the regulatory circuits of animals and humans, the neural circuits that underlie voluntary feeding are unclear. There have been considerable advances into understanding how the brain is able to broadly regulate food consumption (e.g., the role of circulating hormones on food intake and body weight). As much work has focused on hypothalamic mechanisms, relatively little is known about how other neural systems contribute to specific aspects of food seeking and consumption. </p><p> The basal ganglia have been implicated in many aspects of motivated behavior including appetitive and consummatory processes. However, the precise role that basal ganglia pathways play in these motivated behaviors remain largely unknown. One reason for this is that the basal ganglia are functionally and anatomically heterogeneous, with distinct functional circuit elements being embedded within overlapping tissue. Until recently, tools permitting identification and manipulation of molecularly defined neuron populations were unavailable. </p><p> The following experiments were designed to assess the role of the basal ganglia in regulating appetitive and consummatory behavior in mice. The first experiment (Chapter 2) examines the relationship between neural activity in the substantia nigra¬, a¬ major output nucleus of the basal ganglia, and an animal's motivational state. Both dopaminergic and GABAergic neurons show bursts of action potentials in response to a cue that predicts a food reward in hungry mice. The magnitude of this burst response is bidirectionally modulated by the animal's motivational state. When mice are sated prior to testing, or when no pellets can be consumed, both motivational state and bidirectional modulation of the cue response are unchanging. </p><p> The second set of experiments (Chapter 3 and 4) utilizes a mouse model of hyperdopaminergia: Dopamine transporter knockout mice. These mice have persistently elevated synaptic dopamine. Consistent with a role of dopamine in motivation, hyperdopaminergic mice exhibit enhanced food seeking behavior that is dissociable from general hyperactivity. Lentiviral restoration of the dopamine transporter into either the dorsolateral striatum or the nucleus accumbens, but not the dorsomedial striatum, is sufficient to selectively reduce excessive food seeking. The dopamine transporter knockout model of hyperdopaminergia was then used to test the role of dopamine in consummatory processes, specifically, licking for sucrose solution. Hyperdopaminergic mice have higher rates of licking, which was due to increased perseveration of licking in a bout. By contrast, they have increased individual lick durations, and reduced inter-lick-intervals. During extinction, both knockout and control mice transiently increase variability in lick pattern generation while reducing licking rate. Yet they show very different behavioral patterns. Control mice gradually increase lick duration as well as variability in extinction. By contrast, dopamine transporter knockout mice exhibited more immediate (within 10 licks) adjustments--an immediate increase in lick duration variability, as well as more rapid extinction. These results suggest that the level of dopamine can modulate the persistence and pattern generation of a highly stereotyped consummatory behavior like licking, as well as new learning in response to changes in environmental feedback. </p><p> The final set of experiments was designed to test the relationship between consummatory behavior and the activity of GABAergic basal ganglia output neurons projecting from the substantia nigra pars reticulata to the superior colliculus, an area that has been implicated in regulating orofacial behavior. Electrophysiological recording from mice during voluntary drinking showed that activity of GABAergic output neurons of the substantia nigra pars reticulata reflect the microstructure of consummatory licking. These neurons exhibit oscillatory bursts of activity, which are usually in phase with the lick cycle, peaking near the time of tongue protrusion. Dopaminergic neurons, in contrast, did not reflect lick microstructure, but instead signaled the boundaries of a bout of licking. Neurons located in the lateral part of the superior colliculus, a region that receives direct input from GABAergic projection neurons in the substantia nigra pars reticulata, also reflected the microstructure of licking with rhythmic oscillations. These neurons, however, showed a generally opposing pattern of activity relative to the substantia nigra neurons, pausing their firing when the tongue is extended. To test whether perturbation of the nigrotectal pathway could influence licking behavior, channelrhodopsin-2 was selectively expressed in GABAergic neurons of the substantia nigra and the axon terminals within the superior colliculus were targeted with optic fibers. Activation of nigrotectal neurons disrupted licking in a frequency-dependent manner. Using optrode recordings, I demonstrate that nigrotectal activation inhibits neurons in the superior colliculus to disrupt the pattern of licking. </p><p> Taken together, these results demonstrate that the basal ganglia are involved in both appetitive and consummatory behaviors. The present data argue for a role of striatonigral dopamine in regulating general appetitive responding: persistence of food-seeking. Nigraltectal GABA neurons appear to be critical for consummatory orofacial motor output.</p> / Dissertation
| Identifer | oai:union.ndltd.org:DUKE/oai:dukespace.lib.duke.edu:10161/9857 |
| Date | January 2015 |
| Creators | Rossi, Mark Allen |
| Contributors | Yin, Henry H. |
| Source Sets | Duke University |
| Detected Language | English |
| Type | Dissertation |
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