Stress Regulation of Sustained Attention and the Cholinergic Attention System

BACKGROUND: Stress exacerbates symptoms of schizophrenia and attention-deficit/hyperactivity disorder, which are characterized by impairments in sustained attention. Yet how stress regulates attention remains largely unexplored. We investigated whether a 6-day variable stressor altered sustained attention and the cholinergic attention system in male and female rats. METHODS: Sustained attention was tested with the sustained attention task. Successful performance on the sus-tained attention task relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nu-cleus basalis of Meynert (NBM). Thus, we evaluated whether variable stress (VS) altered the morphology of these neurons with a novel approach using a Cre-dependent virus in genetically modified ChAT::Cre rats, a species used for this manipulation only. Next, electrochemical recordings measured cortical ACh following VS. Finally, we used RNA sequencing to identify VS-induced transcriptional changes in the NBM. RESULTS: VS impaired attentional performance in the sustained attention task and increased the dendritic complexity of NBM cholinergic neurons in both sexes. NBM cholinergic neurons are mainly under inhibitory control, so this morphological change could increase inhibition on these neurons, reducing downstream ACh release to impair attention. Indeed, VS decreased ACh release in the prefrontal cortex of male rats. Quantification of global tran-scriptional changes revealed that although VS induced many sex-specific changes in gene expression, it increased several signaling molecules in both sexes. CONCLUSIONS: These studies suggest that VS impairs attention by inducing molecular and morphological changes in the NBM. Identifying mechanisms by which stress regulates attention may guide the development of novel treatments for psychiatric disorders with attention deficits.