It is a fundamental question how memories are represented in the brain. A prevailing hypothesis suggests that memory is encoded by a cooperative activity of specific subset group of neurons. However, identifying these neurons supporting a given memory is challenging because these neuronal ensembles are likely sparsely distributed within the brain. To circumvent this difficulty, we have previously developed a transgenic system in mice that allows us to manipulate neurons activated during a relevant behavior. In the system, the expression of a given transgene is regulated by neuronal activity via the promoter of c-fos gene, whose expression is rapidly and transiently induced in response to neuronal activity, and is also dependent on a tetracycline inducible expression system.
To establish the necessity and sufficiency of a subset of neurons activated during learning in memory engram, we have specifically stimulated or suppressed the activity of those sparsely activated neurons by chemical genetics such as DREADD (Designer Receptors Exclusively Activated by Designer Drug) system or tetanus toxin, and examined the subsequent results using a behavioral assay. The approach that specifically manipulate a small subset of functional neurons within a circuit would greatly facilitate to reveal the mystery how individual memories are represented in the brain and properly expressed.