response to no stimulus on the 5-CSRTT (premature response), compared to the failure to withhold a response to a stimulus (false alarm) likely recruits different systems. Premature responses have been demonstrated to largely recruit the IL cortex (Chudasama et al. 2003). On the other hand, the failure to withhold a response to a stimulus, which incorporates the integration of stimulus contingencies, has not been demonstrated to recruit the IL cortex in the present thesis. False alarms on the rCPT may instead recruit the posterior portion of the ACC. Future experiments could lesion the more posterior portion of the ACC, targeting the postgenual ACC, like the work of Muir et al. (1996), which
demonstrated a role of this sub-region in response inhibition; based on evidence for a role of this sub- region in the inhibition of prepotent, inappropriate responding (Posner & Petersen 1990). Additionally, testing such postgenual ACC lesions under a probe on the rCPT which may tax inhibitory response control more so is of interest. For example, implementing a rodent version of the not-X CPT or reverse CPT used in humans (e.g. Conners et al. 1996; Conners et al. 2003). Not-X CPTs require subjects to respond during the presentation of any letter apart from ‘X’ (non-target trials) and to
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withhold responding during the infrequent presentation of the letter ‘X’ (target trials). This subset of CPTs requires the frequent execution of motor responses and as a result, the most common errors reported are false alarms during infrequent target trials; suggesting this probe as an important one to investigate the mechanisms underlying impulsive responding on the rCPT (Helton et al. 2009).
6.6 Development of a successful flanker distractor probe on the rCPT in rodents
The inhibition of behaviourally-irrelevant distraction when performing a goal-directed task is a key component for successful attentional performance, and requires greater attentional resources and activation of top-down control mechanisms to maintain or improve attentional performance (Gill et al. 2000). In the present thesis, in chapters 3 and 4, the rCPT was manipulated to produce a flanker distraction probe (see chapter 2 and appendix), and was found to impair attentional performance, particularly during incongruent trials (reduced hit rate and d’) but also during congruent trials (reduced hit rate); the latter being more impaired in rats with PL lesions. These findings suggest that rats are taking the congruence into account. For example, the key attention measure (d’) is reduced
selectively during incongruent trials, also, false alarms are reduced selectively during congruent trials. To my knowledge, this is the first successful demonstration of impaired attentional performance during conditions of visually salient flanker distraction in the rat. This is consistent with vigilance decrements reported in distraction conditions in a human version of the CPT, called the gradual-onset CPT; in which subjects were required to respond during male and not female faces, with urban and rural scenes presented around the faces during distraction trials (Rosenberg et al. 2013).
Distraction has previously been successfully demonstrated on the distractor condition of the SAT, in the form of a flashing house light (Gill et al. 2000; Himmelheber et al. 2000; McGaughy et al. 1996). This has also been shown to correlate with increased ACh efflux in the PFC (Gill et al. 2000; Sarter et al. 2006; Kozak et al. 2006). Distraction has also been attempted on the 5-CSRTT, mostly in the form of white noise immediately prior to stimulus presentation; however, impairments in choice accuracy have only been reported sometimes (Carli et al. 1983; Cole & Robbins 1992; Amitai & Markou 2011), with some studies reporting only increased correct response latencies and premature responses (likely due to rats habituating to the white noise) (Muir et al. 1996; Pezze et al. 2007). Although distraction has nicely been demonstrated in rodents on the SAT and 5-CSRTT (sometimes), the more complex visual discrimination, as well as complex forms of task relevant and irrelevant distraction used in the rCPT provides the opportunity for a more realistic measure of distraction in the context of human attention.
6.7 Conclusion
The present thesis has contributed to the understanding of the role of the prefrontal cortex and cholinergic modulation in two forms of attentional performance in rats. It has provided evidence for: 1) the relationship between cholinergic system activation and attentional performance to resemble an
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‘inverted-U’ shaped function in rCPT and 5-CSRTT performance; with respect to the ability of pro- cholinergic drugs to improve performance in cholinergically compromised subjects and to impair in non-cholinergically compromised subjects; 2) a double dissociation of mPFC sub-regions on attentional performance in the rCPT (role of the PL cortex) and 5-CSRTT (role of the ACC); with respect to the discrimination of temporally unpredictable targets compared with temporally predictable targets, respectively; 3) the role of ascending cholinergic projections from the nbM/SI to the dorsal mPFC, rather than the ventral mPFC, in 5-CSRTT performance. These findings contribute to the validation of the novel rCPT, and suggests this task as a useful and translational paradigm for the assessment of sustained attentional function, and to a lesser extent inhibitory response control, in an almost identical manner to CPTs in the clinic. Taken together, the findings highlight how the rCPT and 5-CSRTT measure different forms of attention and response control and recruit different brain
functions. They suggest that the rCPT may be a more appropriate paradigm for assessing focused or selective sustained attentional performance in a consistent manner with measuring attention in humans; and the 5-CSRTT a more appropriate paradigm for assessing inhibitory response control in a consistent manner with measuring motor impulsivity in humans. However, the different measures that can be obtained from the rCPT and 5-CSRTT likely complement one another, and therefore disorders in which deficits of attention and inhibitory response control are present, are likely to be better understood by using both tasks to highlight the differences and similarities in symptoms, and the mechanisms underlying these.
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