Abstract
Transgenic rodents expressing Cre recombinase cell specifically are used for exploring mechanisms regulating behavior, including those mediated by cholinergic signaling. However, it was recently reported that transgenic mice overexpressing a bacterial artificial chromosome containing choline acetyltransferase (ChAT) gene, for synthesizing the neurotransmitter acetylcholine, present with multiple vesicular acetylcholine transporter (VAChT) gene copies, resulting in altered cholinergic tone and accompanying behavioral abnormalities. Since ChAT::Cre+ rats, used increasingly for understanding the biological basis of CNS disorders, utilize the mouse ChAT promotor to control Cre recombinase expression, we assessed for similar genotypical and phenotypical differences in such rats compared to wild-type siblings. The rats were assessed for mouse VAChT copy number, VAChT protein expression levels and for sustained attention, response control and anxiety. Rats were also subjected to a contextual fear conditioning paradigm using an unconditional fear-inducing stimulus (electrical foot shocks), with blood samples taken at baseline, the fear acquisition phase and retention testing, for measuring blood plasma markers of hypothalamic–pituitary–adrenal gland (HPA)-axis activity. ChAT::Cre+ rats expressed multiple mouse VAChT gene copies, resulting in significantly higher VAChT protein expression, revealed anxiolytic behavior, hyperlocomotion and deficits in tasks requiring sustained attention. The HPA-axis was intact, with unaltered circulatory levels of acute stress-induced corticosterone, leptin and glucose. Our findings, therefore, reveal that in ChAT::Cre+ rats, VAChT overexpression associates with significant alterations of certain cognitive, motor and affective functions. Although highly useful as an experimental tool, it is essential to consider the potential effects of altered cholinergic transmission on baseline behavior in ChAT::Cre rats.
Highlights
Central cholinergic signaling is required for regulating aspects of memory, motivation and mood
The current findings show that, compared to their Wt siblings, Long-Evans choline acetyltransferase (ChAT)::Cre+ rats exhibit altered baseline behavior, affecting gross locomotor function, anxiety-related behavior as well as some aspects of sustained attention
The analysis revealed that these behavioral changes were paralleled by altered expression of vesicular acetylcholine transporter (VAChT) within the prefrontal cortex (PFC), at both a gene and protein level, with VAChT being a key molecular mechanism in the transport machinery of ACh from the cytoplasm to the lumen of synaptic vesicles, to release ACh into the synaptic cleft
Summary
Central cholinergic signaling is required for regulating aspects of memory, motivation and mood. Hyperactivity of brain cholinergic systems could underlie the cognitive disturbances observed in patients with affective disorders (Saricicek et al 2012; Mineur et al 2013), while additional evidence for this derives from clinical and preclinical studies which revealed that cholinergic receptor blockers can induce antidepressant-like responses (Furey and Drevets 2006). Despite the accumulating evidence in support of cholinergic perturbations as an etiological factor in several neuropsychiatric human diseases, patients remain mostly unresponsive to current cholinergicbased pharmacological therapies. This highlights a need for establishing appropriate mammalian models for understanding the cholinergic roots of these disorders and for in vivo validation of candidate therapeutics that are potentially more effective treatments, by correcting the relevant pathophysiological mechanisms
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