<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

本研究操弄受試的食物剝奪程度以及鋰鹽（LiCl）去價值程序，觀察此兩種實驗操弄對於大白鼠舔舐行為的影響，以探討飢餓驅力調節完結行為的機制。實驗一連續觀察8天大白鼠舔舐15%蔗糖液的表現，結果顯示初期兩天剝奪受試和自由吃食受試的舔舐表現並沒有顯著差異，第三天起剝奪組才顯著高於自由吃食組。實驗二待大白鼠習於食物剝奪狀態下舔舐15%蔗糖液之後，進行僅舔舐空管的消除情境測試。實驗結果顯示將剝奪狀態改為自由吃食，不論有無接受誘因學習都不能降低受試舔舐空管的表現。實驗三則待大白鼠習於食物剝奪狀態下舔舐25%蔗糖液之後，接受空管測試（實驗三A、B、C）與舔水消除情境測試（實驗三B、C）。實驗三結果如同實驗二，將剝奪狀態改為自由吃食，不論有無接受誘因學習都不能降低受試舔舐空管或舔水的表現。實驗四使用柳橙香料配加蔗糖液（20%）進行舔舐訓練，以僅含柳橙香料水進行消除情境測試。實驗結果顯示受試不論是由剝奪狀態轉為自由吃食，或由自由吃食轉為剝奪，都顯示出當驅力高舔舐表現高或驅力低表現低的現象。實驗五進行鋰鹽去價值實驗，大白鼠先擁有舔飲柳橙香料糖精液（實驗五A）或草莓香料食鹽水（實驗五B）的經驗後，再進行鋰鹽去價值程序。實驗結果顯示大白鼠唯有舔舐香料糖精液或香料食鹽水後接受鋰鹽注射才能降低其舔舐香料水的表現；糖精－鋰鹽配對、糖精－鋰鹽配對後再舔飲一次糖精液，以及香料水－鋰鹽配對都無法降低受試舔飲香料水的表現。糖精或食鹽水只要和鋰鹽配對過，便能產生味覺嫌惡。本研究結論如下：（1）飢餓驅力調節舔舐行為的能力只顯現在舔飲蔗糖液以及舔舐柳橙香料水的消除情境測試中；（2）香料與糖精或香料與食鹽必須同時呈現與鋰鹽配對才能降低香料引發舔舐行為的能力。 / The effects of food deprivation and lithium chloride (LiCl)-induced devaluation on licking behavior were studied for the regulatory mechanism of hunger drive on licking behavior. The first experiment for measuring the licking of 15% sucrose solution for 8 days and found that deprived subjects did not lick more than non-deprived ones until the third day. In the second experiment, the rats trained to lick 15% sucrose in a food-deprivation state were shifted to a non-deprivation state and tested under extinction procedure by using the empty tube. This shift in deprivation did not suppress licking in empty tube test for subjects with or without incentive learning experiences. In the third experiment, the rats trained to lick 25% sucrose in a food-deprivation state were shifted to a non-deprivation state and tested in empty tube (Exp. 3A, B, C) or water-licking test (Exp. 3B, C) conditions. Independent of incentive learning, the shift in deprivation did not suppress licking in these two kinds of extinction conditions although the concentration of sucrose was increased. In the fourth experiment, rats were trained to lick 20% sucrose mixed with orange flavor and tested in orange flavor water-licking test condition. Deprived rats licked more than non-deprived ones in the test condition whether they were trained under deprivation or non-deprivation. In the fifth experiment, rats were trained to lick orange flavor saccharin solution (Exp. 5A) or strawberry flavor sodium chloride (NaCl) solution (Exp. 5B) and then tested by the LiCl devaluation procedure. Flavored saccharin or flavored NaCl paired with LiCl suppressed rats to lick flavored water. But none of saccharin paired with LiCl, incentive learning after saccharin devaluation, and flavored water paired with LiCl had any significant effect. Saccharin or NaCl paired with LiCl could induce taste aversion. In conclusion, hunger drive modulating licking behavior was only found in licking sucrose or the flavored water-licking test condition. Further, only flavored saccharin or flavored NaCl solutions paired with LiCl could suppress licking flavored water.