Activity of CaMKII-expressing neurons in medial prefrontal cortex of male and female Long-Evans rats is necessary for encoding odor information and novelty recognition in an odor-based incidental memory test.

Incidental memories encoded through spontaneous interaction with stimuli in an environment contribute to higher cognitive functions. The spontaneous Identical (IST) and the Different Stimuli Tests (DST), with objects and odors, allow for incidental memory testing using variable memory loads in rats. Here, fiber photometry and chemogenetics were used to examine the necessity of CaMKII-expressing neurons in medial prefrontal cortex (mPFC) for novelty discrimination in the IST and DST with odors. Male and female Long Evans rats completed 6-odor IST and DST. No differences in total exploration times or stimuli visits were observed in either test or sex. During the sample phase of the DST, a heightened response and a sustained increase in mPFC neuronal activity occurred during the first stimulus interaction. A sustained increase in mPFC neuronal activity during interaction with the novel stimulus was also observed in the test phase of the DST, but not the IST. Activation of inhibitory DREADDs expressed in mPFC CaMKII-expressing neurons impaired novelty preference in the DST, but not IST, and significantly decreased c-Fos + cells in the mPFC. Taken together, we show increased activity in mPFC CaMKII-expressing neurons facilitates novelty recognition under higher memory loads in the DST.