Overexpression of the Apoe 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. APOE gene variants are associated with Alzheimer’s disease (AD), as well as attentional function in healthy humans. Previous research has shown that Apoe transcription is increased following stimulation of the pathway between the locus coeruleus (LC) and frontal cortex (FC) in mice. This result suggests that Apoe may affect attentional function by virtue of its expression in circuits that control attention. Does Apoe 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 Apoe 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 Apoe transcription impaired performance when attentional demand was increased in male mice, while in female mice, increased Apoe transcription significantly accelerated rCPT learning. We further found that this increase in Apoe transcription affected subsequent anxiety-like behavior and cellular activity in the FC in a sex-dependent manner. The results of this study provide insight into how Apoe causally regulates translationally relevant behaviors in rodent models.