Overexpression of the <i>Apoe</i> gene in the frontal cortex of mice causes sex-dependent changes in learning, attention, and anxiety-like behavior

Apolipoprotein E (ApoE) is a protein that is important for lipid storage, transport, and metabolism. <i>APOE</i> gene variants are associated with Alzheimer's disease, as well as attentional function in healthy humans. Previous research has shown that <i>Apoe</i> transcription is increased following stimulation of the pathway between the locus coeruleus (LC) and frontal cortex (FC) in mice. This result suggests that <i>Apoe</i> may affect attentional function by virtue of its expression in circuits that control attention. Does <i>Apoe</i> causally regulate attention, or is its expression simply a byproduct of neuronal activity in the LC and FC? To answer this question, we synthetically induced <i>Apoe</i> transcription in the FC of male and female mice, and subsequently tested their ability to learn a touchscreen-based rodent version of the continuous performance test of sustained attention (the rCPT). We found that increased <i>Apoe</i> transcription impaired performance when attentional demand was increased in male mice, while in female mice, increased <i>Apoe</i> transcription significantly accelerated rCPT learning. We further found that this increase in <i>Apoe</i> transcription affected one metric of the open field test, as well as cellular activity in the FC in a sex-dependent manner. The results of this study provide insight into how <i>Apoe</i> causally regulates translationally relevant behaviors in rodent models.