Till now, most of the research on learning at the molecular level or LTP/TLD has focused on classical conditioning paradigms. To my knowledge for the first time someone has started looking at whether , on the molecular level, classical conditioning , which works by associations between external stimuli, is differently encoded and implemented from operant learning , which depends on learning the reward contingencies of one’s spontaneously generated behavior.
Bjorn Brembs and colleagues have shown that the normal learning pathway implicated in classical conditioning, which involves Rugbata gene in fruit fly and works on adenylyl cyclase (AC) , is not involved in pure operant learning; rather pure operant learning is mediated by Protein Kinase C (PKC) pathways. This is not only a path breaking discovery , as it cleary shows the double dissociation showing genetically mutant flies, it is also a marvelous example fo how a beautiful experimental setup was convened to separate and remove the classical conditioning effects from normal operant learning and generate a pure operant learning procedure. You can read more about the procedure on Bjorn Brembs site and he also maintains a very good blog, so check that out too.
Here is the abstract of the article and the full article is available at the Bjorn Brembs site.
Learning about relationships between stimuli (i.e., classical conditioning ) and learning about consequences of one’s own behavior (i.e., operant conditioning ) constitute the major part of our predictive understanding of the world. Since these forms of learning were recognized as two separate types 80 years ago , a recurrent concern has been the
issue of whether one biological process can account for both of them . Today, we know the anatomical structures required for successful learning in several different paradigms, e.g., operant and classical processes can be localized to different brain regions in rodents  and an identified neuron in Aplysia shows opposite biophysical changes after operant and classical training, respectively. We also know to some detail the molecular mechanisms underlying some forms of learning and memory consolidation. However, it is not known whether operant and classical learning can be distinguished at the molecular level. Therefore, we investigated whether genetic manipulations could differentiate between operant and classical learning in dorsophila. We found a double dissociation of protein kinase C and adenylyl cyclase on operant and classical learning. Moreover, the two learning systems interacted hierarchically such that classical predictors were learned preferentially over operant predictors.
Do take a look at the paper and the experimental setup and lets hope that more focus on operant learning would be the focus from now on and would lead to a paradigmatic shift in molecular neuroscience with operant conditioning results more applicable to humans than classical conditioning results, in my opinion.
B BREMBS, W PLENDL (2008). Double Dissociation of PKC and AC Manipulations on Operant and Classical Learning in Drosophila Current Biology, 18 (15), 1168-1171 DOI: 10.1016/j.cub.2008.07.041