Table of Contents
Acknowledgements - - - - - - - - - - - - - - - - - - - - - - - ix
Abstract - - - - - - - - - - - - - - - - - - - - - - - - - - - x
Chapter 1. Introduction to Attentional Regulation and Schizophrenia - - - - - - - - 1
1.1 Overview - - - - - - - - - - - - - - - - - - - - - - - - - 2
1.2 Schizophrenia genetics and neurochemistry - - - - - - - - - - - - - - 3
1.2.1 Dopamine - - - - - - - - - - - - - - - - - - - - - - - 5
1.2.3 Glutamate - - - - - - - - - - - - - - - - - - - - - - - 7
1.2.4 GABA - - - - - - - - - - - - - - - - - - - - - - - - . 9
1.3 Schizophrenia neuroanatomy - - - - - - - - - - - - - - - - - - 10
1.4 Schizophrenia behavioural flexibility and attentional regulation - - - - - - - 13
1.4.1 Schizophrenia and the Wisconsin Card Sorting Test- - - - - - - - - - 14
1.4.2 Schizophrenia and the Attentional Set-Shifting Task - - - - - - - - - . 17
1.5 Tasks used to measure behavioural flexibility in rodents - - - - - - - - - . 21
1.6 Thesis rationale - - - - - - - - - - - - - - - - - - - - - - 25
Chapter 2. General Methods - - - - - - - - - - - - - - - - - - - - 27
2.1 ASST protocol - - - - - - - - - - - - - - - - - - - - - - - 28
2.1.1 Apparatus - - - - - - - - - - - - - - - - - - - - - - - 28
2.1.2 Training - - - - - - - - - - - - - - - - - - - - - - - 28
2.1.3 Standard 7-stage ASST testing - - - - - - - - - - - - - - - - 29
2.2 Histology - - - - - - - - - - - - - - - - - - - - - - - - 30
2.3 Statistical analysis - - - - - - - - - - - - - - - - - - - - - . 32
2.3.1 Frequentist approach: Null hypothesis testing - - - - - - - - - - - 32
2.3.2 Probability approach: Bayesian analysis - - - - - - - - - - - - - 32
Chapter 3. Investigation of Medial Prefrontal Cortex (mPFC) Mediated Attentional Set-
Shifting Deficits - - - - - - - - - - - - - - - - - - - - - - - - 41
3.1 Introduction to acute manipulations to induce ‘schizophrenia-related’ behaviour in
rodents - - - - - - - - - - - - - - - - - - - - - - - - - - 42
3.1.1 Adult sub-chronic/acute NMDA receptor antagonist manipulations - - - - . 42
3.1.2 Stress-induced perturbations - - - - - - - - - - - - - - - - . 44
3.1.3 Lesion experiments - - - - - - - - - - - - - - - - - - - - 45
3.1.4 Inactivation of the mPFC via designer receptors exclusively activated by designer
drugs (DREADDs) - - - - - - - - - - - - - - - - - - - - - - 47
3.2 Rationale - - - - - - - - - - - - - - - - - - - - - - - - 48
3.3 Methods and materials - - - - - - - - - - - - - - - - - - - - 49
3.3.1 Animals - - - - - - - - - - - - - - - - - - - - - - - 49
3.3.2 Pharmacogenetic manipulation - - - - - - - - - - - - - - - - 49
3.3.3 Behavioural Testing - - - - - - - - - - - - - - - - - - - . 50
3.4 Results - - - - - - - - - - - - - - - - - - - - - - - - - 54
3.4.1 mPFCin-rats have set-shifting deficits in the standard 7-stage ASST - - - - - 54
3.4.2 Behavioural pattern analysis reveals increased irrelevant dimension responding in
mPFCin-rats - - - - - - - - - - - - - - - - - - - - - - - - 56
3.4.3 mPFCin-rats attend to stimuli in the irrelevant dimension - - - - - - - - 58
3.5 Discussion - - - - - - - - - - - - - - - - - - - - - - - - 62
3.5.1 Irrelevant dimension responding during set-shifting inducing enhanced learned
irrelevance. - - - - - - - - - - - - - - - - - - - - - - - - 62
3.5.2 Model of neural mechanisms of the mPFC-inhibition on ASST performance. - - 64
3.5.3 Implications for theories of attention and associative learning - - - - - - 70
3.6 Histological Analysis of mPFC DREADDs - - - - - - - - - - - - - - - 73
Rationale - - - - - - - - - - - - - - - - - - - - - - - - - . 73
3.7 Methods and materials - - - - - - - - - - - - - - - - - - - - 73
3.8 Results - - - - - - - - - - - - - - - - - - - - - - - - - 74
3.8.1 All rats exhibited clear DREADDs expression within the mPFC - - - - - - 74
3.8.2 DREADDs are trafficked throughout the projections of the infected mPFC neurons.
- - - - - - - - - - - - - - - - - - - - - - - - - - - - 75
3.8.3 No difference in c-Fos immunoreactivity following clozapine-N-oxide
administration. - - - - - - - - - - - - - - - - - - - - - - - 77
3.9 Discussion - - - - - - - - - - - - - - - - - - - - - - - - 80
3.9.1 Analysis of DREADDs expression. - - - - - - - - - - - - - - - . 80
3.9.2 Infected projections are consistent with the pattern of mPFC neuronal projections
- - - - - - - - - - - - - - - - - - - - - - - - - - - - 80
3.9.3 Inhibitory DREADDs can be effective without reduction in activity at the cell body
- - - - - - - - - - - - - - - - - - - - - - - - - - - - 81
Chapter 4. Effects of Neonatal-Phencyclidine (PCP) Treatment on Attentional Regulation in
Set-Shifting and Novel Object Recognition - - - - - - - - - - - - - - - - 83
4.1 Introduction to neonatal-NMDAR antagonism rats - - - - - - - - - - - 84
4.1.1 Neurochemistry - - - - - - - - - - - - - - - - - - - - - 85
4.1.2 Brain structural abnormalities - - - - - - - - - - - - - - - - 87
4.1.3 Schizophrenia-related innate behaviour in neonatal-NMDAR blockaded rats - - 87
4.