Monitoring cholinergic activity during attentional performance in mice heterozygous for the choline transporter: A model of cholinergic capacity limits

Abstract

Reductions in the capacity of the human choline transporter (SLC5A7, CHT) have been hypothesized to diminish cortical cholinergic neurotransmission, leading to risk for cognitive and mood disorders. To determine the acetylcholine (ACh) release capacity of cortical cholinergic projections in a mouse model of cholinergic hypofunction, the CHT+/− mouse, we assessed extracellular ACh levels while mice performed an operant sustained attention task (SAT). We found that whereas SAT-performance-associated increases in extracellular ACh levels of CHT+/− mice were significantly attenuated relative to wildtype littermates, performance on the SAT was normal. Tetrodotoxin-induced blockade of neuronal excitability reduced both dialysate ACh levels and SAT performance similarly in both genotypes. Likewise, lesions of cholinergic neurons abolished SAT performance in both genotypes. However, cholinergic activation remained more vulnerable to the reverse-dialyzed muscarinic antagonist atropine in CHT+/− mice. Additionally, CHT+/− mice displayed greater SAT-disrupting effects of reverse dialysis of the nAChR antagonist mecamylamine. Receptor binding assays revealed a higher density of α4β2* nAChRs in the cortex of CHT+/− mice compared to controls. These findings reveal compensatory mechanisms that, in the context of moderate cognitive challenges, can overcome the performance deficits expected from the significantly reduced ACh capacity of CHT+/− cholinergic terminals. Further analyses of molecular and functional compensations in the CHT +/− model may provide insights into both risk and resiliency factors involved in cognitive and mood disorders.

Cholinergic capacity mediates prefrontal engagement during challenges to attention: evidence from imaging genetics

“…Gill et al, 2000; Himmelheber et al, 2000; St Peters et al, 2011)– do neither CHT +/− mice (Paolone et al, 2013; Parikh et al, 2013) nor the Ile89Val participants studied here show reliable performance deficits, especially in response to the distractor? This pattern seems especially perplexing in light of our previous findings (Berry et al, 2014) that Ile89Val carriers self-report greater mind-wandering and distractibility in everyday life, and also had greater performance decrements when faced with a salient, content-rich distractor (a laptop playing distracting videos) during another demanding sustained-attention task (the Continuous Temporal Expectancy Test, O'Connell et al, 2009).…”

“…; Demeter et al, 2011) and increases right medial PFC ACh release in rodents (Arnold et al, 2002; Kozak et al, 2006; St Peters et al, 2011). As described above, mice with genetically reduced CHT transporter expression (CHT +/−) release significantly less ACh during attentional performance than wild-type control mice (Paolone et al, 2013). We therefore hypothesized that during the more challenging dSAT condition, controls would significantly increase right BA 9 activation above that measured during standard SAT performance, but that this increase would be attenuated in Ile89Val participants.…”

“…Mice with a heterozygous deletion of the CHT gene show normal basal ACh release but a reduced cholinergic response to both task-induced attentional demands and direct basal forebrain stimulation (Paolone et al, 2013; Parikh et al, 2013). Somewhat surprisingly in light of the extensive previous evidence indicating the necessity of basal forebrain cholinergic modulation of prefrontal circuitry for attentional performance (see discussion above), CHT +/− animals had relatively preserved SAT performance and were not differentially impaired by the dSAT (Parikh et al, 2013).…”

“…Somewhat surprisingly in light of the extensive previous evidence indicating the necessity of basal forebrain cholinergic modulation of prefrontal circuitry for attentional performance (see discussion above), CHT +/− animals had relatively preserved SAT performance and were not differentially impaired by the dSAT (Parikh et al, 2013). In additional analyses, Paolone et al, (2013) found that these animals had higher cortical density of α 4α 2* nicotinic ACh receptors (nAChRs) and that their performance was more vulnerable to the detrimental effects of the nAChR antagonist mecamylamine, suggesting an increase in nACHRs as a possible compensatory mechanism.…”

The neuroscience of cognitive-motivational styles: Sign- and goal-trackers as animal models.

“…As such, the CHT is a major determinant of the capacity of cholinergic neurons to sustain elevated levels of cholinergic neuromodulation (Paolone, Angelakos, et al, 2013; Paolone, Mallory, et al, 2013). The capacity of the CHT to transport choline is largely controlled by translocation of intracellular CHTs into synaptosomal plasma membrane (Ferguson et al, 2003; Parikh et al, 2013; Pinthong et al, 2008; Ribeiro et al, 2003, 2006).…”