The role of the VTA NMDA receptors, VTA DA cells and the VTA terminal regions in reward-related learning.

摘要

Reward-related learning occurs when an initially neutral stimulus acquires the capacity to elicit responses similar to an unconditioned stimulus (US) with which it is associated, in which case the stimulus now functions as a conditioned stimulus (CS). The mechanisms whereby stimuli come to function as CSs are not fully understood and comprise the theme of this dissertation. We have previously proposed that coincident signals from an unconditioned and the eventual conditioned stimulus (US and CS) signals on dopamine (DA) cells of the ventral tegmental area (VTA) leads to strengthening of CS synapses, allowing the CS to acquire the ability to activate VTA DA cells on its own and elicit conditioned approach, thereby functioning as a CS. Furthermore, we proposed that this type of learning is VTA NMDA receptor dependent. This dissertation was designed to test this model by specifically testing the following hypotheses: (1) A food US will activate VTA DA cells; (2) A food-associated CS will activate VTA DA cells and cause conditioned approach; (3) Blockade of NMDA receptors in the VTA will prevent a food-associated stimulus from acquiring the capacity to function as a CS (i.e., cause conditioned approach) and to cause conditioned activation of the mesocorticolimbic DA system.;To test the hypothesis that a US, in this case food, activates VTA DA cells, male rats were maintained at 85% of their free feeding weights for the duration of this study. Rats were exposed to an eating protocol in which the rats were able to eat or not eat food. Rat brains were then removed and immunostained for c-Fos followed by tyrosine hydroxylase (TH) to examine VTA DA cell activation. As expected, rats that ate the food demonstrated a significantly greater number of VTA DA (TH-labeled) cells expressing c-Fos than rats that did not receive food. To test the hypothesis that a CS, in this case a food-associated light, activates VTA DA cells, male rats were maintained at 85% of their free feeding weights for the duration of this study. Rats were trained to retrieve a food pellet after a light presentation (the CS) and then tested for the expression of the food checking response with only CS presentations. As expected, a light functioning as a CS caused a significantly greater number of VTA DA cells to express c-Fos than a light not functioning as a CS.;We also hypothesized that VTA NMDA receptor stimulation is necessary for a food-associated stimulus (CS; also a food-associated light) to elicit conditioned approach via conditioned activation of VTA DA cell terminal regions (mesocorticolimbic DA terminal regions). Rats were prepared with indwelling cannulae positioned so as to allow bilateral microinjections of AP-5 (a NMDA receptor antagonist) in the VTA and were maintained at 85% of their free feeding weights. Male rats were exposed to an acquisition or expression of learning protocol. Subsequently, all rat brains were processed for c-Fos labeling to examine activation of mesocorticolimbic DA terminal regions. As expected, AP-5 significantly impaired the acquisition of conditioned approach and significantly reduced the amount of c-Fos expressed in the cells in the mesocorticolimbic DA terminal regions in response to the CS. Also, AP-5 did not impair the expression of the already learned conditioned approach response.;All together, the results support the model - that a CS acquires, via the VTA NMDA receptor, the capacity to cause conditioned activation of VTA DA cells and mesocorticolimbic DA terminal regions therefore eliciting conditioned approach in a manner similar to a US.