Overexpression of theApoegene in the frontal cortex of mice causes sex-dependent changes in learning, attention, and anxiety-like behavior

Abstract

AbstractApolipoprotein E (ApoE) is a protein that is important for lipid storage, transport, and metabolism.APOEgene variants are associated with Alzheimer’s disease (AD), as well as attentional function in healthy humans. Previous research has shown thatApoetranscription is increased following stimulation of the pathway between the locus coeruleus (LC) and frontal cortex (FC) in mice. This result suggests thatApoemay affect attentional function by virtue of its expression in circuits that control attention. DoesApoecausally regulate attention, or is its expression simply a byproduct of neuronal activity in the LC and FC? To answer this question, we synthetically inducedApoetranscription 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 increasedApoetranscription impaired performance when attentional demand was increased in male mice, while in female mice, increasedApoetranscription significantly accelerated rCPT learning. We further found that this increase inApoetranscription affected subsequent anxiety-like behavior and cellular activity in the FC in a sex-dependent manner. The results of this study provide insight into howApoecausally regulates translationally relevant behaviors in rodent models.