The relationship between cholinergic system activation and attentional performance may resemble an ‘inverted-U’ shaped function

In the present thesis, two lines of evidence support that the relationship between cholinergic system activation and attentional performance may resemble an ‘inverted-U’ shaped function (see chapter 3’s discussion for diagram). Firstly, the impairing effects of donepezil on attentional performance in non- compromised rats on the rCPT (and to a lesser extent, on the 5-CSRTT), and the improving effects in rat compromised by mecamylamine pretreatment on the 5-CSRTT (demonstrated in chapter 3). Secondly, the impairing effects of DREADD-mediated inhibition and excitation of ascending

cholinergic projections from the basal forebrain in non-compromised rats (demonstrated in chapter 5). Human evidence that the relationship between cholinergic system activation and attentional

performance may resemble an ‘inverted-U’ shaped function has been commonly reported in the human literature. For example, physostigmine and nicotine have been shown to increase relative ACh level and improve performance and fronto-parietal brain activity when this was low at baseline in AD (Beglinger et al. 2005; Bentley et al. 2008) and schizophrenic patients (Jacobsen et al. 2004) during taxing task conditions. In contrast, physostigmine perturbed the same activity in healthy controls who had a high pattern of activation at baseline (Ernst et al. 2001; Newhouse et al. 2004; Thiel et al. 2005; Beglinger et al. 2005; Bentley et al. 2008; Kumari et al. 2003; Bentley et al. 2004; Giessing et al. 2007; Furey et al. 2008). This suggests that the performance-enhancing effects of pro-cholinergic drugs are inversely correlated with baseline performance. Further support for the relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function is derived from differential effects of nicotine on performance dependent on smoking status of

subjects: in abstinent smokers experiencing performance and emotional disturbances, nicotine has been shown remediate impaired performance, while having the opposite effects in unimpaired non- smokers (Ernst et al. 2001; Rose et al. 2010; Azizian et al. 2010).

A neurobiological explanation to account for the relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function, consistent with current computational models of cholinergic function (Hasselmo & McGaughy 2004), comes from the ‘attentional effort hypothesis’ (Sarter et al. 2006). This hypothesis suggests that during challenges of

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attentional performance the endogenous increases in cholinergic stimulation cause diffuse modulatory increases within the fronto-parietal cortex. Consequently, exogenous increases in cholinergic

stimulation, via pro-cholinergic drugs, likely imitates this cholinergic modulation effect and therefore can only improve performance when neocortical activations are low at baseline. The relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function may be general to a number, or perhaps all, neurotransmitter systems, including dopamine (Williams & Castner 2006) and noradrenaline (Introini-Collison & McGaughy 1986); suggesting the ability of neuromodulators to optimise cognitive functions occurs within narrow

windows.

However, limitations of applying a putative inverted-U shaped function must be considered. In theory, inverted-U functions are suggestive of a product of competition between two processes: an up- process and a down-process. One potential caveat, is the regression of the mean phenomenon, in which low activations can only increase (up-process), and high activations can only decrease (down- process). Another potential caveat, is that the down-process may be a result of neurotoxicity, for example hallucinations, panic or palpitations, and as a result is not very informative. Whether the inverted-U shaped function is a result of the same set of receptors which change their function at higher levels of occupancy, or whether it is another set of receptors, elsewhere in the brain that have unfortunate neurotoxic side-effects associated with them, which is detrimental to the main effect and therefore causes an inverted-U function, requires further elucidation. One possibility is that these processes could be related to tonic versus phasic activity in the cholinergic system. A key study by Aston-Jones et al. (1999) investigated the role of the locus coeruleus and phasic and tonic

noradrenaline activity in sustained attention in monkeys. The general hypothesis was that phasic activity is optimal and tonic activity produces the downward process: enhanced selective attention is associated with locus coeruleus phasic activity, whereas reduced selective attention (enhanced distractibility) is associated with high tonic activity. To verify the inverted-U function in the context of the cholinergic system requires electrophysiological recording of neuronal activity in the basal forebrain/mPFC of rats, during performance on the rCPT/5-CSRTT under challenging conditions of reduced SD/distraction.

6.5(i) Equivalence of attentional measures of the rCPT and 5-CSRTT

The extent to which the key attentional measures of the rCPT (d’ and less so hit rate) and the 5- CSRTT (percent accuracy and less so percent correct) correspond to one another is complex and debatable (see chapter 2 for key measures formulae). Table 6.1 displays the findings from cholinergic pharmacological manipulations observed in chapter 3 and mPFC lesion manipulations observed in chapter 4, in an attempt to compare and contrast across the key measures of the tasks. Overall, there appears to be no direct 1-to-1 correspondence of attentional performance measures, likely due to these tasks being different, with different priorities, measuring different kinds of attention (also discussed in chapter 1). On the rCPT, the key attentional measure of d’ does not appear to overlap

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much with the key attentional measure of percent accuracy on the 5-CSRTT. Examples of this in the present thesis are the findings of:

1) Donepezil to impair attentional performance on the rCPT (reduced d’) in non-compromised rats, but

to have no effects on percent accuracy on the 5-CSRTT, likely due to the greater attentional resources required on the rCPT compared to the 5-CSRTT. This finding is consistent with greater attentional resources required for pro-cholinergic drugs to impair attentional performance in healthy humans (Kumari et al. 2003; Bentley et al. 2004; Thiel et al. 2005; Hahn et al. 2007). However, accuracy on the 5-CSRTT was more sensitive to a low-to-mid range dose of mecamylamine (1mg/kg), which has not previously been shown to impair performance on the 5-CSRTT in the current literature, compared to d’ on the rCPT which was more robust (Jones et al. 1995; Grottick & Higgins 2000; Stolerman et al. 2000; Hahn et al. 2016).