Training protocols with long intervals between sessions are known to lead to more robust memory formation as compared to training protocols characterized by the same number of sessions grouped in a short amount of time (massed training). This phenomenon, termed spaced training or distributed practice effect, has long been known by psychologists, and it is independent of the information to be processed. Memories are generally acquired through gains developing incrementally over multiple training sessions. With time, representations distribute over brain networks to constitute stable memories. We will exploit the ability of spaced training to enhance memory to identify cellular and circuit determinant of memory systems ruled by slower dynamics but longer lasting capacities.
Trial and error learning studies demonstrate that parallel corticostriatal loops are serially engaged to optimize memory with increasing trials. Exploring the notion that the same could occur also when optimization depends on spaced training, we have recently found that spatial memory acquired in a massed or a spaced training condition requires the activity of two distinct striatal domains. This result supports the overarching hypothesis of this proposal that the duration of off-line resting periods regulates memory stability by engaging different memory networks. Taking the striatum as a model system we will first define the biological features responsible for processing-based differences in the two striatal domains. Next, based on the greater memory stability observed in wild type mice after DLS stimulation, we propose to test the efficacy of this approach in ameliorating or even rescuing spatial memory deficits in mouse models of Alzheimer Disease (AD). To this purpose, by exploiting massed and spaced training, we will: 1. Define determinants - cell-types, and connections - of recruitment of discrete striatal domains in the acquisition of spatial memory through training with different timing rules; 2. Test the efficacy of acute and repeated optogenetic DLS stimulation in rescuing memory deficits in a well-established mouse model of AD (Tg2576), based on our preliminary results showing increased memory stability after DLS stimulation in wild type mice.
This proposal constitutes the first effort to identify cellular and circuit features of memory networks differentially responding to different training protocols. Defining the cell-types, connections, and neural activity responsible for circuit selection in the striatum will provide insight into the mechanisms determining increased memory persistence. Most importantly, this will offer a glimpse into circuit logic to drive refinement of current theoretical models of memory and to open unexplored avenues for targeted interventions to compensate memory loss in intellectually disabling conditions.