Adjusting motivation in proportion to the desirability of an outcome drives most normal behavior. The intensity or vigor of the behavior can be used to infer the value of the current behavioral context, for example, the value of a reward predicted by a visual stimulus. We study motivation in monkeys in a reward schedule task. In this task monkeys must detect when a target spot turns from red-to-green, to obtain a drop of juice. In one set of tasks, a visual stimulus, a cue, indicates how much discomfort must be endured, e.g., the number of trials to be worked, to obtain the reward. The monkeys learn about the cues quickly, often after just a few trials. We assess motivational intensity by measuring both an operant response (releasing the bar when the red point turned green) and a Pavlovian response (lipping, a spontaneous appetitive movement of the lips) that animals display both at the cue and at the time of the bar release. The number of bar release errors decreased as monkeys progressed through the schedules and approached the reward, suggesting that monkeys are more motivated when the cost for obtaining the reward decreases. Similarly, the Pavlovian lipping response at the bar release was greater in rewarded trials compared to unrewarded trials, in line with the idea that releasing the bar is more valuable in rewarded trials. In contrast, the Pavlovian response to the cues was most intense during the first trials of a schedule, indicating that the first cues of a schedule are more valuable, presumably because they carry more information than subsequent ones. We investigated the roles of orbitofrontal (OFC) or rhinal (Rh) cortex in rhesus monkeys in assessing values of external stimuli associated with different rewards. It is known that bilateral symmetrical lesions of either OFC or Rh impair animals'ability to use cue-reward associations to adjust their motivation. To determine whether interaction of these structures is necessary for using reward-predicting cues to adjust motivation, we employed a disconnection design, testing monkeys (n=4) with crossed unilateral ablations of OFC and Rh in a task in which a visual stimulus indicated the amount of reinforcement available upon completion of an instrumental action. On each trial, animals earned a variable amount of water for releasing a lever after a change in the color of a visual target;trials began with a unique image that signaled the magnitude of the forthcoming reward. Consistent with previous results, we found that, during preoperative training, monkeys adjusted their performance as a function of both the current trials predicted reward size and their accumulated reward. Following the crossed unilateral ablation of OFC and Rh, monkeys committed significantly fewer errors in low reward trials;intermediate testing following the first stage ablation (two animals OFC first, two Rh first) revealed that this effect could not be explained by either unilateral lesion in isolation. This decreased sensitivity to different amounts of reward is qualitatively similar to the pattern of performance observed following bilateral OFC or Rh removal. To determine whether OFC and Rh interact primarily to form cue-reward associations or more generally in determining motivational state, we tested these monkeys as well as a set of control (n=3) and bilateral OFC animals (n=3) on a classic lever pressing task. In this task, reward size varied across blocks (25 trials per block), no visual cues predicted reward, and responding was no longer under visual instruction. Animals were free to press and release a lever at their own pace;they quickly learned that releases led to reinforcement. Both the control and bilateral OFC group showed sensitivity to reward size in this task, rapidly adjusting their response intervals after block transitions, with significantly faster responses during large reward blocks. Surprisingly, the crossed lesion group only began showing sensitivity to reward size very late in a block;averaging responses across all trials in a block revealed no effect of reward size on this groups'performance. These results suggest that interaction of OFC and Rh may be critical for more than simply forming cue-reward associations to guide behavior. Noradrenaline and dopamine are both thought important for normal motivation, but the specific contributions of each of these catecholaminergic systems is not established. We analyzed the activity of 75 SNc neurons (2 monkeys) and 63 LC neurons (2 other monkeys). Neurons in both areas showed a phasic activation at cue onset and right before the bar release, in line with the idea that they respond to salient events, here defined as those that evoke a Pavlovian response. In addition, both SNc and LC neurons showed a stronger response to cues in first trials, in parallel with the Pavlovian response. Around bar release, neuronal activity in the 2 regions differed markedly: in the SNc, firing was stronger in rewarded trials whereas in the LC firing was stronger in unrewarded trials. Thus, neuronal activity in the SNc displays the same pattern as the appetitive Pavlovian response to the cues and the bar release, in line with the idea that dopamine neurons encode the value of these salient events. The activity of LC neurons could be interpreted as reflecting the cost of an event, and the corresponding behavioral and cognitive investment that the animal must make to adjust its behavior accordingly. Because dopamine seems to play such an important role in motivation and the cognitive processing of sensory information, we are developing molecular tools to manipulate its efficacy in local brain regions of adult monkeys. Previous experiments using reversible dopamine receptor RNA interference by injecting DNA plasmids expressing antisense RNA into the rhinal cortex have shown that a 23% down-regulation of dopamine DRD2 receptors results in a failure of monkeys to make associations between stimuli and states in the reward schedule task (Liu et al. 2004, PNAS). To expand on these studies and to achieve better control and more efficient RNA interference, we are now taking a systematic approach to establishing a lentivirus based doxycycline inducible system for down-regulating dopamine receptors in the rhinal cortex of monkeys. Three steps are being taken now. First, using neuroblastoma cell culture, we are screening for Lentivirus expressed shRNA molecules that achieve efficient down-regulation of Dopamine DRD1 and DRD2 receptors. Second, we have shown that our Lentivirus vectors injected into the rhinal cortex are co-expressed with dopamine DRD1 and DRD2 receptors in the monkey rhinal cortex. Third, we are testing expression of a doxycycline inducible Lentiviral shRNA/XFP-reporter systems, which works in our neuroblastoma cell culture system, in the rhinal cortex of the rhesus monkey.

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Eldridge, M A G; Richmond, B J (2017) Resisting the Urge to Act: DREADDS Modifying Habits: (Trends in Neurosciences 40, 61-62; 2017). Trends Neurosci 40:324
Eldridge, Mark A G; Richmond, Barry J (2017) Resisting the Urge to Act: DREADDs Modifying Habits. Trends Neurosci 40:61-62
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