Sustaining and recovering attentional performance requires interactions between the brain’s motivation and attention systems. The first experiment demonstrated that in rats performing a sustained attention task (SAT), presentation of a distractor (dSAT) augmented performance-associated increases in cholinergic neurotransmission in prefrontal cortex (PFC). Because stimulation of NMDA receptors in the shell of the nucleus accumbens (NAC) activates PFC cholinergic neurotransmission, a second experiment demonstrated that bilateral infusions of NMDA into the NAC shell, but not core, improved dSAT-performance to levels observed in the absence of a distractor. A third experiment demonstrated that removal of prefrontal or posterior parietal cholinergic inputs, by intra-cortical infusions of the cholinotoxin 192 IgG saporin, attenuated the beneficial effects of NMDA on dSAT perfomance. Mesolimbic activation of cholinergic projections to the cortex benefits the cognitive control of attentional performance by enhancing the detection of cues and the filtering of distractors.

Functional variation in the gene encoding the presynaptic choline transporter (CHT) has been linked to Attention-Deficit/Hyperactivity Disorder (ADHD). Here, we report that a heterozygous deletion in the CHT gene in mice (CHT+/−) limits the capacity of cholinergic neurons to sustain acetylcholine (ACh) release and attentional performance. Cortical microdialysis and amperometric methods revealed that whereas wildtype and CHT +/− animals support equivalent basal ACh release and choline clearance, CHT +/− animals exhibit a significant inability to elevate extracellular ACh following basal forebrain stimulation, in parallel with a diminished choline clearance capacity following cessation of stimulation. Consistent with these findings, the density of CHTs in cortical synaptosomal plasma membrane-enriched fractions from unstimulated CHT +/− animals matched those observed in wild-type animals despite reductions in CHT levels in total extracts, achieved via a redistribution of CHT from vesicle pools. As a consequence, in CHT +/− animals, basal forebrain stimulation was unable to mobilize wildtype quantities of CHT to the plasma membrane. In behavioral studies, CHT+/− mice were impaired in performing a sustained attention task known to depend on cortical cholinergic activity. In wild type, but not CHT +/− mice, attentional performance increased the density of CHTs in the synaptosomal membrane in the right frontal cortex. Basal CHT levels in vesicle-enriched membranes predicted the degree of CHT mobilization as well as individual variations in performance on the sustained attention task. Our findings demonstrate biochemical and physiological alterations that underlie cognitive impairments associated with genetically-imposed reductions in choline uptake capacity.

Advances in mouse genetic technology have spurred increasing interest in the development of cognitive tasks for mice. Here, we describe and discuss the modifications necessary to adapt a task for the assessment of sustained attention performance for use in mice, including for taxing the top-down control of such performance. The validity of the Sustained Attention Task (SAT), including the distractor version (dSAT), have previously been demonstrated in rats and humans. This task requires moveable or retractable operanda; insertion of operanda into the operant chambers cues animals to respond to a prior signal or non-signal event, reporting either a hit or a miss, or a correct rejection or false alarm, respectively. Retractable levers did not support sufficiently high and stable levels of performance in mice. Given the widespread use of static nose-poke devices for testing operant performance in mice, we therefore designed and fabricated a retractable nose-poke device. As this device extends into chambers, a hole for nose-poking is slowly opened and closed again as the device retracts (termed the “Michigan Controlled Access Response Port”; MICARP). Results describe the effects of variation of signal duration and event rate, trial outcome and trial type probability, effects of mice deprivation levels, and the reliability of SAT and dSAT performance. Mice perform the SAT and dSAT at levels comparable to those observed in rats. This task will be of assistance in expanding the translational usefulness of the SAT and dSAT.

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