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Role of Prefrontal Cortex and Cholinergic Modulation in Attentional Role of prefrontal cortex and cholinergic modulation in attentional performance in rats Beth Mary Fisher Department of Psychology Downing College University of Cambridge September 2017 This dissertation is submitted for the degree of Doctor of Philosophy Declaration This dissertation is the result of my own work and includes nothing which is the outcome of work done in collaboration except as declared in the Preface and specified in the text. It is not substantially the same as any that I have submitted, or, is being concurrently submitted for a degree or diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. I further state that no substantial part of my dissertation has already been submitted, or, is being concurrently submitted for any such degree, diploma or other qualification at the University of Cambridge or any other University or similar institution except as declared in the Preface and specified in the text. It does not exceed the prescribed word limit of the degree committee for the faculty of biology of 60,000 words. i2 Acknowledgements Firstly, I would like to thank my supervisor Tim Bussey and advisor Trevor Robbins for their invaluable support, guidance and encouragement throughout my PhD. Their insightful scientific discussions, passion for the field and praise of me, have shaped me to become a scientist I am proud of, and given me an unknown confidence. Not only are they experts in the field, but they are down to earth, kind and fun. I feel lucky to have worked alongside them both. I would like to thank all of the past and present translation cognitive neuroscience lab members for their support, advice and friendship. Particularly, I would like to thank the PIs: Tim Bussey and Lisa Saksida, for creating a lab full of great science, motivated people and fun lab meetings. Johan Alsio, for his supervision and support, particularly with the DREADDs project in chapter 5; Johan’s dedication to many projects was inspiring to see. Adam Mar, for introducing me to the rodent continuous performance task. Ben Phillips, for being a great friend and office buddy, always there for daily discussion on projects and what we were having for dinner each evening, both being big foodies! Chris Heath, for being a great energy, always enthusiastic and happy to discuss data and give advice. Jon Hailwood and Laura Lopez-Cruz, for being great and supportive office mates alongside Ben. Colin McKenzie, for his training and assistance in the wetlab. Julie Gautry and the rest of the combined animal facility staff for taking great care of my animals. To all of my students who assisted with some of the projects in the present thesis: Hajar Al Sayed, Zoe Morris, Shaista Madad, Bhavna Ramachandran, Theo Wethered, Sarah Weeks, Sam Pressling, Juli Tkotz and Minji Kim. Thank you to the BBSRC who provided me with funding and made me feel part of a community throughout my PhD. Also, to Boehringer Ingelheim, who provided me with funding for the final year of my experiments. Particularly, thanks to Janet Nicholson, Angelo Ceci and Serena Deiana for their support and discussions on projects. Thank you to my incredibly supportive and caring family. Particularly my Mum, Dad and sister, Amy, who have truly been by my side every step of my journey, feeling every bump along the way with me. I feel extremely lucky to have had their unconditional love and support. My Grandma, for constantly telling me how proud she is of me, and telling every person she meets she has a granddaughter undertaking a PhD at Cambridge. Also, to my Grandma and Grandad Fisher, who I know would have been equally as proud. My amazing friends, for their love, laughter and support, as well as understanding all the times I couldn’t attend their birthday parties due to being with the rats! Lastly, I would like to thank my fiancé and best friend, Alex, who has been my rock. Thank you for the unconditional love, support, kindness and patience; including the endless 8-hour round trips from Manchester to visit me. Thank you for always putting a smile on my face, even when p>.05. Roll on our wedding in August next year! ii3 Summary The present thesis investigates the role of the prefrontal cortex and cholinergic modulation in attentional performance, and to a lesser extent, inhibitory response control, in rats. A greater understanding of these functions is important for the effective treatment of attentional and impulsive control deficits, present in a range of neuropsychiatric disorders. For this field to progress, the assessment of attentional performance in a similar manner across humans and animals is crucial. In the present thesis, attentional performance was assessed on the novel, touchscreen-based rodent continuous performance task (rCPT), which assesses sustained, focused attention in essentially an identical manner to CPTs commonly used in the clinic. Findings were compared to performance on the well-characterised 5-choice serial reaction time task (5-CSRTT), which assesses sustained, spatial divided attention and shares some, but not all characteristics of CPTs. The series of experiments described in this thesis contributes to the understanding of the role of the prefrontal cortex and cholinergic modulation in attentional performance; they also highlight differences between the two tasks in behaviour, brain functions and networks. Excitotoxic lesions of the medial prefrontal cortex (mPFC) and a range of cholinergic systemic pharmacology validated the role of the prefrontal cortex and cholinergic modulation in rCPT performance. A chemogenetic study also validated the role of the ascending cholinergic basal forebrain system in 5-CSRTT performance. These findings support 1. the idea of the relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function; 2. a double dissociation of mPFC sub-regions on attentional performance, in which the prelimbic cortex (PL) appears to play a role in rCPT performance, compared with a role of the anterior cingulate cortex (ACC) in 5-CSRTT performance; and 3. a role of ascending cholinergic projections from the basal forebrain to the ACC in 5-CSRTT performance. These findings also establish the development of a successful flanker distractor probe in rodents on the rCPT. This thesis concludes with an important comparison of the attentional and impulsivity measures in the rCPT compared to the 5-CSRTT, to help provide guidelines as to which task is most appropriate to use for particular research questions. iii4 Table of contents Declaration i Acknowledgements ii Summary iii Table of contents iv List of figures and tables ix Abbreviations xii Publications and conference proceedings xiv Chapter 1: General introduction 1 1.1 Attentional performance and when it goes wrong 1 1.2 Measuring attentional performance in humans: continuous performance tasks (CPTs) 2 1.3 Measuring attentional performance in animals 3 1.3.1 Five-choice serial reaction time task (5-CSRTT) 3 1.3.2 Five–choice continuous performance task (5C-CPT) 5 1.3.3 Sustained attention task (SAT) 6 1.4 Touchscreen-based methods of cognitive assessment in rodents 6 1.5 Rodent continuous performance task (rCPT) 8 1.6 Neurochemistry and neuropsychology of attention performance 10 1.6.1 The prefrontal cortex and attentional performance 10 1.6.2 The basal forebrain cortical cholinergic system and attentional performance 11 1.6.3 The cholinergic hypothesis of Alzheimer’s disease 14 1.6.4 Cholinergic pharmacological manipulations on attentional performance 14 1.6.5 Monoamines/catecholamines and attentional performance 15 1.7 Neurochemistry and neuropsychology of inhibitory response control 16 1.8 Thesis outline 17 Chapter 2: General methods 19 2.1 Subjects 19 2.2 Rodent Continuous performance task (rCPT) 19 2.2.1 Behavioural apparatus 19 2.2.2 Behavioural training 20 2.2.3 Probes 23 2.2.4 Variable measurements 25 2.3 5-Choice Serial Reaction Time Task (5-CSRTT) 26 2.3.1 Behavioural apparatus 26 2.3.2 Behavioural training 26 2.3.3 Probes 29 2.3.4 Variable measurements 30 iv5 2.3.5 Non-touchscreen verses touchscreen 5-CSRTT 30 Chapter 3: Effects of pharmacological manipulations of the cholinergic system on 32 attentional performance 3.1 Introduction 33 3.1.1 Nicotinic (nAChRs) and muscarinic (mAChRs) acetylcholine receptors 33 3.1.2 Effects of cholinesterase inhibitors on attentional performance 33 3.1.3 Effects of non-selective agonism and antagonism of nAChRs on attentional 35 performance 3.1.4 Effects of selective agonism and antagonism at α4β2 and α7 nAChRs on 42 attentional performance 3.1.5 Summary and hypotheses 44 3.2 Effects of donepezil alone and following mecamylamine pre-treatment on the rCPT 46 and 5-CSRTT under conditions of reduced SD 3.2.1 Methods 46 3.2.1.1 Subjects 46 3.2.1.2 Apparatus 46 3.2.1.3 Drugs 46 3.2.1.4 Statistical analysis 47 3.2.2 Results 48 3.2.2.1 Effects of donepezil alone and following mecamylamine pre-treatment on 48 the rCPT, with conditions of reduced SD 3.2.2.2 Effects of donepezil alone and following mecamylamine pre-treatment on 48 the 5-CSRTT, with conditions of reduced SD 3.3 Effects of nicotine on the rCPT under conditions of SD and distraction 53 3.3.1 Methods 53 3.3.1.1 Subjects 53 3.3.1.2 Apparatus 54 3.3.1.3 Drug 54 3.3.1.4 Statistical analysis 54 3.3.2 Results 55 3.3.2.1 Effects of nicotine on the rCPT, under conditions of reduced SD 55 3.3.2.2 Effects of nicotine on the rCPT, with
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