Animals and humans adapt to changes in the environment through the encoding and storage of previous experiences. Although associative learning involving a reinforcer has been the major focus in the field of cognition, other forms of learning are gaining popularity as they are likely more relevant and frequent in human daily choices. Indeed, associations between non-reinforcing stimuli represent the most evolutionarily advanced way to increase the chances of predicting future events and adapting individuals’ behavior. Animals are also able to form these higher-order conditioning processes, but more research is needed to understand how the brain encode and store these complex cognitive processes. The HighMemory project (Figure 1) proposes to study the role of hippocampo-cortical circuits in higherorder conditioning processes. These processes explain why individuals are very often repulsed or attracted by stimuli (persons, places, sounds), which do not have intrinsic repellent or appealing value and were never explicitly paired with negative or positive outcomes. A possible explanation of these “ungrounded” aversions or repulsions is that these stimuli were incidentally associated with other cues directly reinforced. This is called higher-order conditioning or mediated learning (ML). However, with increased number of incidental associations, the subjects acquire more information, allowing the separation between the real saliences of two different stimuli. Therefore, with the increase of training, ML evolves into what researchers define as “reality testing” (RT). Importantly, these behavioral processes involve the hippocampus, are characterized by defined and accessible phases and involve several brain regions, making them perfect models to study the tight regulation of behavior by hippocampo-cortical projections. By using cutting edge genetic (viral and chemogenetic techniques), Ca2+ imaging and mouse behavioral (sensory preconditioning) approaches, the aim of HighMemory is to dissect and characterize, at macro- (brain regions), meso- (cell sub-types) and micro-scale (activity changes), the causal involvement of hippocampo-cortical projections in higher-order cognitive processes, from the formation of ML, the transition to RT and the expression of these distinct mental states. Notably, HighMemory will provide important information to better understand and tackle the physiology of complex cognitive processes and mental disorders such as psychotic-like states.
