Modifications to the standard ASST allow exploration of additional phenomenon

In addition to experiments utilising the standard ASST, this thesis describes three new additional tasks to investigate responding based on irrelevant dimension stimuli. The adaptability and direct translatability of the rodent and human versions of the ASST to such modifications, is a primary strength it possesses over other assays, such as the WCST which are less amenable to stage substitutions and insertions. For example, the early modifications to the human ASST by Owen et al. (1993), which aimed to separate ED deficits arising from perseveration versus learned irrelevance, were directly translated into the rodent task by McGaughy et al. (2008). Within this thesis, the stimulus presentation of the Houses and Faces task designed for human testing (Hampshire and Owen, 2006), was partially back translated for use in rats, with the critical maximal separation between relevant and irrelevant stimuli across trials preserved, as well as the use of a novel panels-based ASST apparatus for testing. Additionally, the standard ASST, was amenable to the insertion of a blocking stage (Kamin, 1968; but see: Sharpe and Killcross, 2014), in the 6-stage simple-probe task. Both of these manipulations were implemented without requiring lengthy additional training of the rats overall, and did not hinder performance in control rats, while providing critical information on task performance in both mPFCin and neonatal- PCP-treated rats.

Despite the obvious benefits of the rodent ASST, it remains critically flawed due to the reliance on an observer’s subjective scoring of the rat’s choice (digging), as well as the labour involved in the observer also preparing and presenting the stimuli for each trial. The potential for human error and bias is considerable, and there is variability amongst labs not only in the non-organic components of testing (apparatus, stimuli used, testing procedure), but also in the training of observers. While the panels modification presents some advancement in testing, in that the scoring of a ‘pull’ is based on a specific length marked on the panel itself, the

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panels modification still remains susceptible to human error in stimulus preparations (such as too little or too much odour on the panels), and ultimately, the task needs to be automated. Unfortunately, thus far automation attempts have failed to generate a viable alternative. Implementation of a visual discrimination ASST, using an automated touchscreen, has been explored in mice. However, the task required several days (median of 13) for a single mouse to complete all stages of a single test (Brigman et al., 2005). Thus, to address the questions of set-formation and set-shifting, the researchers split the mice into two groups, one which performed an additional ID on the final day of testing, and one which performed an ED. Brigman et al., found no difference in performance for mice which were required to perform an ED shift compared to those performing an additional ID, thus there was no indication of set-formation. Similar results have been found with rats within the same visual discrimination touchscreen apparatus (Johan Alsiö personal communication) and thus far no studies have been published with either species showing viability of the method.

This ‘rock and a hard place’ scenario with subjectivity concerns regarding the bowl digging methods, and lack of evidence for attentional set-formation in the objective automated procedure, remains a primary concern for the future of the ASST paradigm. Ideally, an automated procedure utilising stimuli rats readily discriminate (i.e. odours and media), will be developed as a middle ground, however, this has yet to be successfully accomplished, and the Birrell and Brown (2000) ASST remains the most common measure of attentional set-shifting in rodents (Gilmour et al., 2012).

6.5 Relevance of findings for theories of attention

In Chapter 3, I introduced the conclusion that rather than performing ambiguous ‘higher order cognitive processes’, the role of the mPFC was to maintain a representation of the relevant information (e.g. the correct stimulus), and bias sensory processing (attention) and dopamine signalling, in favour of that information while ‘ignoring’ the irrelevant information. The consistent Bayesian

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derived evidence for irrelevant dimension-based responding, concurrent with the deficit in sensory gating reported for all three manipulations, supports the recent findings that individual error terms(Mackintosh, 1975) exist for stimuli presented in associative learning assays, rather than a single global error term (Rescorla and Wagner, 1972; Pearce and Hall, 1980). Indeed, the mPFC is likely the site of multisensory integration and abstract rule representation that reduces processing of the less predictive prediction errors, resulting in phenomena such as ‘Kamin blocking’.

One of the earliest descriptions of schizophrenia, described that at its core was “loosening of associations” (Bleuler, 1911). All three schizophrenia-related manipulations support this as a core deficit arising from ‘schizophrenia-related’ biology. Furthermore, the findings of this thesis and the recent evidence from animal behaviour experiments supporting individual prediction error terms (Haselgrove et al., 2010; Pearce et al., 2012; Sharpe and Killcross, 2014), indicates that earlier ASST manipulations designed to disentangle perseveration to the previously relevant dimension, compared to learned irrelevance in patients with frontal lobe damage (Owen et al., 1993), schizophrenia (Elliott et al., 1995), or in rats with deficient mPFC-noradrenergic signalling (McGaughy et al., 2008), may have failed to detect learned irrelevance contributions due to the lack of associative strength between the tested irrelevant dimension and reward feedback. In both the primate (where a novel dimension is introduced), and the rodent (which uses a never discriminable dimension), learned irrelevance modifications, the tested dimension would not have elicited individual prediction error signals, to the extent of the irrelevant dimension stimuli in the 4-stage, and 6-stage simple probe ASSTs. In the modifications in this thesis, the irrelevant dimension stimuli were either 50% predictive of reward during the standard discriminations, or 100% predictive or reward during the probe stages. Thus, further investigation into the nature of the ED deficit in patients with dlPFC damage, or schizophrenia, is warranted. Ideally, by taking advantage of the associative learning theories posits of individual prediction error terms.

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A recent implementation of a design which allowed individual prediction error to influence a learned irrelevance manipulation, re-examined perseveration versus learned irrelevance in Parkinson’s patients (Fallon et al., 2016). Using visual compound discriminations with two superimposed stimuli from three possible dimensions (e.g. fruit, houses, faces), the researchers found that Parkinson’s patients were impaired at stages that required responding to stimuli in a novel dimension presented in compound with stimuli from the previously relevant dimension, in addition to being impaired in responding to stimuli in previously irrelevant dimension compounded with a novel dimension. This was in contrast to a previous finding not using a design with an individual prediction error component (Owen et al., 1993). Thus, patients had both perseveration to the previously relevant dimension, in addition to enhanced learned irrelevance. Both schizophrenia and Parkinson’s disease induce dysfunctional dopamine signalling, and it is possible that if indeed individual prediction error signals contribute to the aberrant processing of irrelevant dimension stimuli, resulting in enhanced learned irrelevance, then similar findings may be found in patients with chronic schizophrenia. Indeed recent studies have returned to the dopaminergic dysfunction in schizophrenia as a target for remediation of the cognitive symptoms, with researchers focusing on agonism of D1Rs, as enhancement of this signalling pathway has been evidenced to improve working memory in monkeys (recently reviewed by: Arnsten et al., 2016). However, there is also potential for enhancement of D2Rs to enhance dlPFC function (Ott and Nieder, 2016). Given this yet mysterious relationship between D1/2Rs and working memory, and the extant efficacy of D2R antagonists for treatment of schizophrenia’s positive symptoms, it is possibly more pragmatic to pursue glutamatergic, GABAergic or other transmitter signalling pathways to improve cognition in patients already treated with atypical antipsychotics.

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6.6 General Conclusion

The major conclusion of this thesis is that dysfunctional sensory gating, arising from mPFC-hypofunction, is the mechanism by which ASST performance measures, primarily ED set-shifting, and potentially, reversal learning are derived. The ‘working memory’ function of the mPFC (and dlPFC in primates), is critically important in the regulation of attention through biasing of sensory processing to task relevant stimuli, and inhibiting processing of irrelevant stimuli. Indeed, this function of mPFC is likely an emergent property of its multisensory processing. The role of dopamine and individual prediction errors, in the irrelevant dimension- based responding evidenced in this thesis warrants further investigation. Future experiments can target dopamine projections to the mPFC and determine if inhibition of those synapses disrupts working memory, and sensory gating, resulting in irrelevant dimension-based responding in the ASST. Experiments in the mechanistic basis of ASST deficits provide additional neural circuit targets for remediation of the debilitating cognitive symptoms of neuropsychiatric disorders such as schizophrenia.

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