ATTENTION REGULATION AND BEHAVIOURAL FLEXIBILITY IN RATS WITH RELEVANCE TO SCHIZOPHRENIA

By

Alonzo J. Whyte

Presented To

Department of Psychology

Abstract

Schizophrenia is a neuropsychological disorder in which the neural systems which regulate attention allocation, primarily the dorsolateral prefrontal cortex, are
dysfunctional, resulting in deficient gating of attention to irrelevant inputs from the environment. This sensory processing dysfunction hinders goal-directed behaviour to the extent that the subsequent cognitive deficits of schizophrenia prevent many chronic patients from leading normal lives. It is the onus of neuroscience to understand the nature of deficits induced by the disorder, thus providing target mechanisms for remediation of those deficits in patients. To accomplish this, manipulations in rats with relevance to schizophrenia are examined in assays with translation to human neurobiology and behaviour. In this thesis, three manipulations with relevance to schizophrenia, were examined for attentional regulation in the attentional set-shifting task, and similar assays, to determine how different forms of schizophrenia-related pathology influence attentional regulation and behavioural flexibility.
The foremost findings of the experiments herein were that manipulations inducing schizophrenia-related neurobiology, resulted in impaired performance in
extradimensional set-shifting and reversal learning. These deficits were found following: acute inhibition of the mPFC in adult rats, in adult rats who had been exposed to a glutamate receptor antagonist during the neonatal period of development, and/or in adult rats who had gestational disruption of neuron proliferation. Across all three manipulations, a clear behavioural pattern of deficient sensory gating, evidenced by responding to irrelevant stimuli during the set-shifting task was found.
These findings suggest that at the core of the cognitive deficits in schizophrenia is the 'loosening of associations' such that patients suffer the inability to regulate
attention, and limit sensory processing to relevant information. The subsequent aberrant learning about irrelevant information then impairs performance during goal-
directed behaviours.
Table of Contents 

Acknowledgements  - - - - - - - - - - - - - - - - - - - - - - -   ix 
Abstract  - - - - - - - - - - - - - - - - - - - - - - - - - - -   x 

Chapter 1 Introduction to Attentional Regulation and Schizophrenia - - - - - - - -   1 
11 Overview  - - - - - - - - - - - - - - - - - - - - - - - - -   2 
12 Schizophrenia genetics and neurochemistry  - - - - - - - - - - - - - -   3 
121 Dopamine  - - - - - - - - - - - - - - - - - - - - - - -   5 
123 Glutamate  - - - - - - - - - - - - - - - - - - - - - - -   7 
124 GABA  - - - - - - - - - - - - - - - - - - - - - - - -   9 
13 Schizophrenia neuroanatomy  - - - - - - - - - - - - - - - - - -   10 
14 Schizophrenia behavioural flexibility and attentional regulation  - - - - - - -   13 
141 Schizophrenia and the Wisconsin Card Sorting Test- - - - - - - - - -   14 
142 Schizophrenia and the Attentional Set-Shifting Task  - - - - - - - - -   17 
15 Tasks used to measure behavioural flexibility in rodents  - - - - - - - - -   21 
16 Thesis rationale  - - - - - - - - - - - - - - - - - - - - - -   25 

Chapter 2 General Methods  - - - - - - - - - - - - - - - - - - - -   27 
21 ASST protocol  - - - - - - - - - - - - - - - - - - - - - - -   28 
211 Apparatus  - - - - - - - - - - - - - - - - - - - - - - -   28 
212 Training - - - - - - - - - - - - - - - - - - - - - - -   28 
213 Standard 7-stage ASST testing  - - - - - - - - - - - - - - - -   29 
22 Histology - - - - - - - - - - - - - - - - - - - - - - - -   30 
23 Statistical analysis - - - - - - - - - - - - - - - - - - - - -   32 
231 Frequentist approach: Null hypothesis testing  - - - - - - - - - - -   32 
232 Probability approach: Bayesian analysis  - - - - - - - - - - - - -   32 

Chapter 3 Investigation of Medial Prefrontal Cortex (mPFC) Mediated Attentional Set-
Shifting Deficits - - - - - - - - - - - - - - - - - - - - - - - -   41 
31 Introduction to acute manipulations to induce ‘schizophrenia-related’ behaviour in 
rodents  - - - - - - - - - - - - - - - - - - - - - - - - - -   42 
311 Adult sub-chronic/acute NMDA receptor antagonist manipulations  - - - -   42 
312 Stress-induced perturbations - - - - - - - - - - - - - - - -   44 
313 Lesion experiments  - - - - - - - - - - - - - - - - - - - -   45 
314 Inactivation of the mPFC via designer receptors exclusively activated by designer 
drugs (DREADDs)  - - - - - - - - - - - - - - - - - - - - - -   47 
32 Rationale  - - - - - - - - - - - - - - - - - - - - - - - -   48
33 Methods and materials  - - - - - - - - - - - - - - - - - - - -   49 
33 1 Animals - - - - - - - - - - - - - - - - - - - - - - -   49 
332 Pharmacogenetic manipulation  - - - - - - - - - - - - - - - -   49 
333 Behavioural Testing - - - - - - - - - - - - - - - - - - -   50 
34 Results  - - - - - - - - - - - - - - - - - - - - - - - - -   54 
341 mPFCin-rats have set-shifting deficits in the standard 7-stage ASST - - - - -   54 
342 Behavioural pattern analysis reveals increased irrelevant dimension responding in 
mPFCin-rats  - - - - - - - - - - - - - - - - - - - - - - - -   56 
343 mPFCin-rats attend to stimuli in the irrelevant dimension - - - - - - - -   58 
35 Discussion  - - - - - - - - - - - - - - - - - - - - - - - -   62 
351 Irrelevant dimension responding during set-shifting inducing enhanced learned 
irrelevance - - - - - - - - - - - - - - - - - - - - - - - -   62 
352 Model of neural mechanisms of the mPFC-inhibition on ASST performance - -   64 
353 Implications for theories of attention and associative learning  - - - - - -   70 
36 Histological Analysis of mPFC DREADDs - - - - - - - - - - - - - - -   73 
Rationale  - - - - - - - - - - - - - - - - - - - - - - - - -   73 
37 Methods and materials  - - - - - - - - - - - - - - - - - - - -   73 
38 Results  - - - - - - - - - - - - - - - - - - - - - - - - -   74 
381 All rats exhibited clear DREADDs expression within the mPFC - - - - - -   74 
382 DREADDs are trafficked throughout the projections of the infected mPFC neurons
 - - - - - - - - - - - - - - - - - - - - - - - - - - - -   75 
383 No difference in c-Fos immunoreactivity following clozapine-N-oxide 
administration  - - - - - - - - - - - - - - - - - - - - - - -   77 
39 Discussion  - - - - - - - - - - - - - - - - - - - - - - - -   80 
391 Analysis of DREADDs expression  - - - - - - - - - - - - - - -   80 
392 Infected projections are consistent with the pattern of mPFC neuronal projections
 - - - - - - - - - - - - - - - - - - - - - - - - - - - -   80 
393 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 
41 Introduction to neonatal-NMDAR antagonism rats  - - - - - - - - - - -   84 
411 Neurochemistry - - - - - - - - - - - - - - - - - - - - -   85 
412 Brain structural abnormalities  - - - - - - - - - - - - - - - -   87 
413 Schizophrenia-related innate behaviour in neonatal-NMDAR blockaded rats  - -   87
414 Schizophrenia-related attentional set-shifting behaviour in neonatal-PCP-treated 
rats  - - - - - - - - - - - - - - - - - - - - - - - - - -   89 
42 Rationale  - - - - - - - - - - - - - - - - - - - - - - - -   90 
43 Methods and materials  - - - - - - - - - - - - - - - - - - - -   90 
431 Animals - - - - - - - - - - - - - - - - - - - - - - -   90 
432 Behavioural Testing - - - - - - - - - - - - - - - - - - -   91 
44 Results  - - - - - - - - - - - - - - - - - - - - - - - - -   94 
441 Neonatal-PCP-treated rats show no clear deficits in the ASST  - - - - - -   94 
442 Neonatal-PCP-treated rats have an ED deficit in the ASST-MSS  - - - - - -   98 
443 Young neonatal-PCP-treated rats show deficits in the short delay novel object 
discrimination, however this deficit is not present in adult neonatal-PCP rats - - -   101 
444 Adult neonatal-PCP-treated rats show deficits in the 24 hour delay novel object 
discrimination - - - - - - - - - - - - - - - - - - - - - - -   102 
45 Discussion  - - - - - - - - - - - - - - - - - - - - - - - -   102 
451 Failure to replicate the ASST deficits in neonatal-PCP-treated rats - - - -   102 
452 The ASST-MSS task revealed an ED deficit in neonatal-PCP-treated rats  - - -   104 
453 Developmental period dependent effects in neonatal-PCP-treated rats in the 
novel object recognition task - - - - - - - - - - - - - - - - - -   106 
454 Reproducibility of set-shifting results  - - - - - - - - - - - - - -   107 
46 Histological analysis of neonatal-PCP-treated rats  - - - - - - - - - - -   110 
Rationale  - - - - - - - - - - - - - - - - - - - - - - - - -   110 
47 Methods and materials  - - - - - - - - - - - - - - - - - - -   110 
48 Results  - - - - - - - - - - - - - - - - - - - - - - - - -   110 
481 Neonatal-PCP-treated rats exhibit a deficit in weight gain and post-mortem brain 
weight - - - - - - - - - - - - - - - - - - - - - - - - -   110 
482 Neonatal-PCP-treated rats have less parvalbumin-expression within the mPFC    112 
491 Successful replication of neonatal-PCP induced anatomical disruption  - - -   114 
492 Role of the mPFC disruption in the novel object recognition deficits  - - - -   114 

Chapter 5 Effects of Gestational Methylazoxymethanol Acetate (MAM)-treatment on 
Attentional Set-Shifting Task Performance  - - - - - - - - - - - - - - -   116 
51 Introduction to the MAM manipulation - - - - - - - - - - - - - -   117 
511 MAM-treated rats anatomical and histological abnormalities  - - - - - -   117 
512 Neurotransmitter & electrophysiological abnormalities in MAM-treated rats  -   119 
513 Innate and behavioural flexibility deficits in MAM-treated rats - - - - -   121 
514 MAM-based translational evidence for schizophrenia treatments  - - - - -   122 
52 Rationale  - - - - - - - - - - - - - - - - - - - - - - - -   123 
53 Methods and materials  - - - - - - - - - - - - - - - - - - -   125 
531 Animals - - - - - - - - - - - - - - - - - - - - - - -   125 
532 Baseline 7-Stage ASST testing  - - - - - - - - - - - - - - - -   125 
533 ORG49209 ASST testing  - - - - - - - - - - - - - - - - - -   126 
534 4-ID testing  - - - - - - - - - - - - - - - - - - - - - -   126 
54 Results  - - - - - - - - - - - - - - - - - - - - - - - - -   127 
541 MAM-treated rats have a deficit at REV 1 of the standard ASST- - - - -   127 
542 MAM-treated have increased evidence for irrelevant dimension-based responding
 - - - - - - - - - - - - - - - - - - - - - - - - - - -   128 
543 No evidence of a MAM-induced ED deficit in the 4 ID task  - - - - - - -   130 
544 ORG49209 effect on REV 1 performance in controls and MAM-treated rats -   131 
55 Discussion  - - - - - - - - - - - - - - - - - - - - - - - -   132 
551 Reversal learning impairment in MAM-treated rats - - - - - - - - -   132 
552 Irrelevant dimension responding and perseveration in MAM-treated rats  - -   132 
553 Protocol based explanations for failures to replicate  - - - - - - - - -   133 
554 ORG49209 failed to improve REV 1 performance in MAM-treated rats  - - -   134 
56 Histological analysis of MAM-treated rats  - - - - - - - - - - - - - -   135 
Rationale  - - - - - - - - - - - - - - - - - - - - - - - - -   135 
57 Methods and materials  - - - - - - - - - - - - - - - - - - -   135 
58 Results  - - - - - - - - - - - - - - - - - - - - - - - - -   136 
581 MAM-treated rats exhibit abnormal brain and body weights  - - - - - -   136 
582 Gross observation reveals schizophrenia-related anatomy in MAM-treated rats
 - - - - - - - - - - - - - - - - - - - - - - - - - - -   137 
583 Parvalbumin expression is altered in the hippocampus but not mPFC of MAM-
treated rats  - - - - - - - - - - - - - - - - - - - - - - -   141 
59 Discussion  - - - - - - - - - - - - - - - - - - - - - - - -   144 
591 Failure to replicate reduced parvalbumin expression within the PFC  - - - -   144 
592 MAM treatment primarily affects the hippocampus  - - - - - - - - -   145 

Chapter 6 General Discussion and Conclusions - - - - - - - - - - - - - -   148 
61 Experimental summary  - - - - - - - - - - - - - - - - - - -   149 
62 Reliability of acute versus developmental manipulations and the relevance to 
schizophrenia  - - - - - - - - - - - - - - - - - - - - - - - -   150 
63 Utility of the Bayesian analysis for characterisation of behavioural pattern - - -   152 
64 Modifications to the standard ASST allow exploration of additional phenomenon-   154
65 Relevance of findings for theories of attention  - - - - - - - - - - - -   155 
66 General Conclusion  - - - - - - - - - - - - - - - - - - - - -   158 
References  - - - - - - - - - - - - - - - - - - - - - - - - -   159

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