DNA targeting of rhinal cortex D2 receptor protein reversibly blocks learning of cues that predict reward

Abstract

When schedules of several operant trials must be successfully completed to obtain a reward, monkeys quickly learn to adjust their behavioral performance by using visual cues that signal how many trials have been completed and how many remain in the current schedule. Bilateral rhinal (perirhinal and entorhinal) cortex ablations irreversibly prevent this learning. Here, we apply a recombinant DNA technique to investigate the role of dopamine D2 receptor in rhinal cortex for this type of learning. Rhinal cortex was injected with a DNA construct that significantly decreased D2 receptor ligand binding and temporarily produced the same profound learning deficit seen after ablation. However, unlike after ablation, the D2 receptor-targeted, DNA-treated monkeys recovered cue-related learning after 11-19 weeks. Injecting a DNA construct that decreased N-methyl-D-aspartate but not D2 receptor ligand binding did not interfere with learning associations between the cues and the schedules. A second D2 receptor-targeted DNA treatment administered after either recovery from a first D2 receptor-targeted DNA treatment (one monkey), after N-methyl-D-aspartate receptor-targeted DNA treatment (two monkeys), or after a vector control treatment (one monkey) also induced a learning deficit of similar duration. These results suggest that the D2 receptor in primate rhinal cortex is essential for learning to relate the visual cues to the schedules. The specificity of the receptor manipulation reported here suggests that this approach could be generalized in this or other brain pathways to relate molecular mechanisms to cognitive functions.onkeys, as do humans, quickly learn to use visual cues to adjust their behavior based on how much work has been completed and how much remains (the relative workload) before reaching a goal or obtaining a reward (1-4). Because of its strong inputs from the ventral visual pathway and projections to the hippocampal formation (5-13), the rhinal (perirhinal and entorhinal) cortex has been heavily investigated for its role in visual recognition memory (14) and acquisition of stimulus-stimulus associations (15-18). In addition, we became interested in its role in reward-related learning because of its dense innervation by dopamine-rich fibers (19)(20)(21)(22), which presumably arise in the substantia nigra pars compacta͞ventral tegmental area complex (23). Using a behavioral task, visually cued reward schedules, in which the monkeys are required to perform multiple operant trials to obtain a reward at the end of a schedule, we previously demonstrated that bilateral rhinal cortex ablations prevent monkeys from learning to use visual cues to make the behavioral adjustments in the schedule task (2) and that responses of single neurons in monkey perirhinal cortex reflect a visual cue's relation to the progress through a schedule, i.e., relative workload (3). These latter two studies led us to conclude that monkey rhinal cortex has a critical role in establishing the associations between visual cues and this form o...

Divergent and nonuniform gene expression patterns in mouse brain

“…The abundance and nature of observed gene expression differences, generally reflecting changes in discrete cell populations, suggest that phenotypic differences may be driven combinatorially by many small differences in the spatial regulation of gene expression. Functional implications for variations of expression patterns within structures noted in this study are suggested in reports that indicate a role for dopamine D2 receptor acting in entorhinal cortex during associative visual learning in nonhuman primates (17), as well as for variations in creativity correlated with receptor binding in the human thalamus (18). Furthermore, a recent study of striatopallidal neurons and dopaminergic regulation of GABAergic synaptic transmission highlights the functional relevance of the complex interplay of receptor expression, cell type, and circuitry within highly localized brain regions (19).…”

“…Therapeutics affecting the dopamine and serotonin systems are among the most commonly prescribed neuroactive drugs, covering a variety of indications ranging from depression and schizophrenia to movement disorders. The dopamine D2 receptor alone is a site of action for a number of therapeutics and has roles in locomotion, emotion, cognition, and drug abuse (17,20,21). Differences in individual responses to such drugs have been observed in humans (22) and previous studies have shown that C57 and DBA mice respond differently to drugs known to affect dopamine signaling (23).…”

Neuronal Signals in the Monkey Basolateral Amygdala during Reward Schedules

“…Fiducial markings as in Figure 4. cortex in which the D 2 receptor is crucial for learning the relation of the cue to the schedule states (Liu et al, , 2004. There is, however, a difficulty.…”

Prospective and retrospective temporal difference learning

“…Richmond and his colleagues Shidara and Richmond, 2002;Shidara et al, 1998;Sugase-Miyamoto and Richmond, 2005;Bowman et al, 1996;Liu et al, 2004;Ravel and Richmond, 2006;La Camera and Richmond, 2008) have investigated many behavioral and neural aspects of an appealingly simple problem for monkeys that they call the reward schedule task. The task is illustrated in figure 1A.…”