Validation of the role of prefrontal cortex in rCPT performance compared to findings with the 5-CSRTT

Chapter 4 described the effects of discrete excitotoxic lesions to sub-regions of the rat medial prefrontal cortex (mPFC) on the rCPT. It demonstrated functional dissociations of sub-regions of the

mPFCon attentional performance, supporting the role of the prefrontal cortex in rCPT performance. It

was observed that rats with lesions of the PL cortex demonstrated persistent attentional impairments under conditions of reduced SDs, high event rate and distraction. This suggests a role of the PL cortex in continuously maintaining focussed attention and blocking out irrelevant and competing stimuli, during attentional performance that requires the discrimination of temporally unpredictably presented signals. This finding is consistent with current evidence which suggests a central role of the PL cortex in a range of cognitive functions required for demanding problem solving, including

attention, working memory and response selection processes. For example, the PL cortex has been shown to be important for working memory (the short-term storage of a small amount of information for internal manipulation), predominantly with respect to attentional requirement and response selection mechanisms that underlie successful performance on working memory tasks (Granon et al. 1994; Ragozzino et al. 1999). Additionally, studies have reported a role of the PL cortex when attentional tasks require greater perceptual ability and not during more conditions of simple signal detection (e.g., on the 5-CSRTT) (Granon et al. 1998; Chudasama & Muir 2001).

In terms of homology of the PL cortex in rodents and the dorsolateral PFC in humans,while one can

only speculate in animals due to focal damage compared to more widespread damage in human disorders, anatomical evidence demonstrates some functional similarities. For example, as with the PL cortex in rats, the dorsolateral PFC in humans participates in a range of cognitive processes; one of the most well-established findings being its role in working memory performance, particularly with respect to attentional performance (directing and focusing attention to task-relevant objects and blocking out competing task-irrelevant information), rather than ‘memory’ (Funahashi & Kubota 1994; Fuster 1997; Seamans et al. 2008). Additionally, one study demonstrated humans with lesions of the dorsolateral PFC to be impaired on the X-CPT; which is consistent with the findings of impairments on

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the rCPT in PL-lesioned rats (Rueckert & Grafman 1996). These findings suggest, to some extent, a possibility for cross-species homology between the PL cortex in rats and the dorsolateral PFC in humans. However, this is not to say that the PL cortex does not interact with other mPFC sub-regions and networks, as well as subcortical regions to mediate cognitive processes (see Floresco et al. 1997; Granon & Poucet 2013).

This mPFC lesion experiment also suggests there may be a double dissociation within the mPFC on attentional performance on the rCPT (role of the PL cortex, as described above) compared to the 5- CSRTT (role of the ACC). In the present experiment, only transient attentional impairments early in behavioural testing were observed in rats with lesions of the ACC on the rCPT; suggesting less of a role of this region in rCPT performance. In contrast, on the 5-CSRTT, the ACC has been

demonstrated to play a role in choice accuracy; particularly with respect to the integration of

temporally sequenced behaviour, leading to preparatory readiness (Passetti et al. 2002; Chudasama et al. 2003). This double dissociation is likely based on predictable and paced stimulus presentation which can be timed in the 5-CSRTT (Young et al. 2013; Cope et al. 2016), compared with the discrimination of unpredictable stimulus presentation which cannot be timed in the rCPT.

Moving onto the role of the IL cortex and impulsivity, in the present experiment, rats with IL-lesions exhibited no effects on impulsivity measures on the rCPT (false alarm rate or premature/

perseverative responses). This suggests less of a role of the IL cortex on these particular forms of response inhibition in the rCPT. In contrast, in the 5-CSRTT, the IL cortex has been demonstrated to play a role in impulsive responding in the form of premature responses (Chudasama et al. 2003). The lack of parallel increases in impulsive responding on the rCPT and 5-CSRTT, is likely due to the high and variable event rate on the rCPT (ISI = 2/3s) which may not tax inhibitory response control to the same extent as the longer waiting period on the 5-CSRTT (ITI = 5s). This highlights the disparities in the form of impulsive responding tapped into by false alarms on the rCPT compared to premature responses on the 5-CSRTT (discussed more below in section 5ii).

Taken together, these findings suggest that the rCPT may be a more appropriate paradigm for the assessment of sustained attentional performance, with respect to focused attention, the discrimination of temporally unpredictable signals and blocking out competing stimuli. In contrast, the 5-CSRTT may be a more appropriate paradigm for the assessment of sustained attentional performance, with

respect tothe integration of temporally sequenced behaviour, leading to preparatory readiness.

Additionally, these findings highlight that there may also be a double dissociation of sub-regions of the mPFC on the different forms of impulsive responding on the rCPT and 5-CSRTT; which has not been elucidated in the present thesis and is of interest for future experiments.

Finally, the selective M4 PAM (VU0467154), and not the more generally acting donepezil, improved discrimination sensitivity in rats with a loss of neurons and signalling in the mPFC. This suggests an increased utility of this selective muscarinic compound to improve attentional performance in patients

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with a loss of such neurons and signalling, compared to limited efficacy reported with cholinesterase inhibitors in compromised rats (Muir et al. 1995; McGaughy et al. 1996; McGaughy & Sarter 1998). The locus of action of VU0467154 in the face of discrete mPFC lesions, was likely the primary visual cortex and posterior parietal cortex; which have been implicated in more complex task demands of detection and discrimination, response criterion and processing capacity (Lashley 1931; Schneider 1969; Muir et al. 1996; Riccio et al. 2002; Ogg et al. 2008; Petruno et al. 2013).