We typically use the concept of a 'blank slate' to describe an individual who is born without innate mental content, requiring them to accumulate all knowledge through experience. However, as we reach adulthood, we tend to learn new information by fitting it into our existing knowledge base, rather than learning in isolation. The framework of pre-existing knowledge, skills, or attitudes is referred to as 'schemas', a concept from cognitive psychology that explains how new information is integrated with previous experiences. However, unlike humans, rodents are laboratory animals that lack real-world knowledge. Therefore, it is crucial to establish a pre-existing knowledge framework in rodents. In this study, we used a Paired-Associates (PAs) behaviour paradigm that involves flavor-location pairs association, which enables the evaluation of memory encoding, consolidation, updating, and retrieval.

According to current perspectives, schemas extract features that are common across individuals and once formed, they influence memory retrieval strategies and facilitate associative learning. When new experiences are similar to schema predictions, learning can be accelerated as new content is readily assimilated into existing schemas. The interactions between the hippocampus (HPC) and medial prefrontal cortex (mPFC) play a crucial role in the formation and updating of memory schemas. However, in contrast to event-specific memory paradigms, the formation and lasting retention of schema memory representations in animal models have not been well-characterized. In this study, we utilized PAs behaviour paradigm, dynamically recorded calcium signals of CA1-ACC projection neurons and ACC neurons by fiber-photometry during the whole process of schema formation. Results showed that Calcium signals in CA1-ACC projecting neurons were robust when rats were newly exposed into schema learning, then generally diminished with continually training and close to static when rats had well developed schema memory. In contrast, ACC neurons showed mild activation at initial and later periods, while exhibited activation peak at middle. When rats accepted new information to update schema, both CA1-ACC projecting neurons and ACC neurons showed significantly activation. These results suggest that memory schema is initially located in CA1 and is gradually transferred to and stored in the ACC. Encoding of new associated information requires parallel activation in both brain areas.

As neuroscience research progresses, astrocytes have been found to play a greater role in the central nervous system than merely supporting neurons by providing homeostatic support or encapsulating synapses. Astrocytes are able to manipulate memory processes by both energy metabolism and neurotransmitter-specific effects and exhibit projection-specific effects depending on the input source or the output target of their neighbouring neurons. In this study, we used chemogenetic Gi pathway activation as a tool in astrocyte research, which allows real-time reversible manipulation of astrocytes in tandem with behavioural measurements. The recruitment of CA1-ACC network was investigated in each stage under CA1 astrocytes Gi pathway chemogenetic activation. Results showed that CA1 astrocytic Gi pathway activation before each training session will disrupt memory schema development, and rats will fail to assimilate new information. Then, this study divided schema formation process into three stages according to Calcium photometry feature. Gi pathway activation will impair schema establishment by reducing CA1-ACC projection neuron recruitment in initial stage and prevent both CA1-ACC projection neurons and ACC neuron excitation in the middle stage. CA1 astrocytes Gi markedly suppress new information assimilation into the established memory schema, but has less effect on original PAs memory retrieval. Moreover, modulation of astrocytes exhibits a certain degree of specificity. Gi pathway activation of CA1 astrocyte did not impact CA1-NAc projecting neurons’ recruitment, although they were slightly increasing during PAs training.

To summarize, schema is a mental representation of various associated episodes or memories. A dynamic interaction between HPC and ACC and transfer of the binding role from CA1 to the ACC are involved in establishing and expressing the features of long-term schematic memory. During novel experiences, the CA1 and ACC are functionally linked. An established associative memory network in the CA1 and ACC is essential for retrieval-mediated facilitation of new learning. Finally, CA1 astrocytes play a critical and projecting specifically role in modulating schematic learning, memory retrieval, and assimilation of new associative memory into existing memory schema.