Corticotropin releasing factor in the nucleus basalis of Meynert impairs attentional performance and reduces levels of glutamate and taurine in male and female rats.

Psychiatric disorders that are characterized by impairments in sustained attention, including attention deficit hyperactivity disorder (ADHD), post-traumatic stress disorder (PTSD), and major depression are also sensitive to exacerbation by stress. Sustained attention relies on cholinergic and non-cholinergic projections from the nucleus basalis of Meynert (NBM) in the basal forebrain to the medial prefrontal cortex (mPFC). We have previously shown that central administration of the stress neuropeptide corticotropin releasing factor (CRF) impairs performance on the sustained attention task (SAT) in adult male and female rats. The present study investigated whether this effect was mediated by CRF's action in the NBM. Rats were administered CRF in the NBM and subsequent SAT performance was measured. A high dose of CRF (100 ng) significantly impaired performance on non-signaled events across sex. Because performance on non-signaled events is believed to depend on non-cholinergic (i.e., GABA and glutamate) signaling, high performance liquid chromatography was used to quantify amino acid levels in the NBM and mPFC. We found females have higher levels of glutamate, glutamine, GABA glycine, and alanine in the NBM than males. Importantly, CRF in the NBM led to a local decrease of taurine and several amino acids involved in glutamate synthesis in males and females, changes which may mediate the CRF-induced SAT performance deficit. Together these studies suggest that CRF regulation of amino acids in the NMB contributes to stress-induced attention deficits.

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 sustained attention task relies on the release of acetylcholine (ACh) into the cortex from cholinergic neurons in the nucleus 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 transcriptional 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.

Method for testing sustained attention in touchscreen operant chambers in rats.

BACKGROUND: Sustained attention, the ability to detect rare and unpredictable events, is central to cognitive performance. This construct can be tested in rodents using a Sustained Attention Task (SAT), where rats are trained to detect an unpredictably occurring signal (a brief light presentation) from non-signal events. The traditional version of this task utilizes an operant chamber with a central panel light for the signal and two retractable response levers. Adaptation of SAT to the increasingly popular touchscreen operant chambers, which do not have levers or fixed lights, could enhance the versatility of the task. NEW METHOD: Here we developed a touchscreen version of SAT where the light signal is presented in the center of the touchscreen, followed by a tone to indicate the beginning of the response period. Rats indicate their choice during this period by touching their nose to one of two touchscreen response areas. The remaining parameters were kept similar to the traditional version. RESULTS: Rats acquired touchscreen SAT at a similar rate to the traditional version. As with the traditional version, shorter stimulus durations on the signaled trials reduced accuracy and the presence of a distractor (a flashing houselight) disrupted performance on the touchscreen version. COMPARISON TO EXISTING METHOD: Collectively, these data suggest that the touchscreen version is comparable to the traditional version of the SAT, and is an equally valid way of measuring sustained attention. CONCLUSIONS: Many researchers with touchscreen chambers could easily implement our modifications in order to study sustained attention.