This electronic thesis or dissertation has been downloaded from the King’s Research Portal at https://kclpure.kcl.ac.uk/portal/ Investigating the role of excitatory circuitry in the orbitofrontal cortex in social cognition Bennett, Sophie Heloise Awarding institution: King's College London The copyright of this thesis rests with the author and no quotation from it or information derived from it may be published without proper acknowledgement. END USER LICENCE AGREEMENT Unless another licence is stated on the immediately following page this work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International licence. https://creativecommons.org/licenses/by-nc-nd/4.0/ You are free to copy, distribute and transmit the work Under the following conditions: Attribution: You must attribute the work in the manner specified by the author (but not in any way that suggests that they endorse you or your use of the work). Non Commercial: You may not use this work for commercial purposes. No Derivative Works - You may not alter, transform, or build upon this work. Any of these conditions can be waived if you receive permission from the author. Your fair dealings and other rights are in no way affected by the above. Take down policy If you believe that this document breaches copyright please contact [email protected] providing details, and we will remove access to the work immediately and investigate your claim. Download date: 27. Sep. 2021 INVESTIGATING THE ROLE OF EXCITATORY CIRCUITRY IN THE ORBITOFRONTAL CORTEX IN SOCIAL COGNITION Sophie Héloïse Bennett INSTITUTE OF PSYCHIATRY, PSYCHOLOGY & NEUROSCIENCE KINGS COLLEGE LONDON Submitted for the PhD in Neuroscience 1 Abstract Impaired social cognition is a common component of many neurodevelopmental conditions. These impairments impair quality of life. However, the factors shaping social development and accompanying neural circuitry are not well understood. The brain regions that contribute to social cognition are called the “social brain”. The orbitofrontal cortex is one of the brain regions that constitute the “social brain”. Damage to the orbitofrontal cortex causes profound deficits in social cognition, including disinhibition and aggression. Dysfunctional circuitry in the orbitofrontal cortex may contribute to impaired social cognition in neurodevelopmental disorders. However, the role played by neuronal circuitry in the orbitofrontal cortex to social cognition is unclear. I sought to examine the role of excitatory circuitry within the orbitofrontal cortex in social cognition. I first explored the contribution of excitatory circuitry in the orbitofrontal cortex to impaired social behaviour in Nrxn1α KO mice. These mice carry a genetic microdeletion that is a risk factor for multiple neurodevelopmental disorders, including autism and schizophrenia. Previous experiments have demonstrated that these mice display impaired social behaviour. I found that impaired social behaviour in Nrxn1α KO mice was accompanied by a reduction in short-term facilitation of pyramidal synapses. The second aim of my thesis was to investigate the role of sensory experience in shaping the development of social cognition and accompanying “social brain” circuitry. This was achieved by depriving rodents of whisker input during a sensitive period of social development. I found that a short period of whisker deprivation led to long-lasting changes in rodent play behaviour. However, this was not accompanied by changes in excitatory circuitry in the orbitofrontal cortex. 2 Table of Contents Abstract .................................................................................................................................................. 2 Table of Contents .................................................................................................................................. 3 Table of Figures ................................................................................................................................... 11 Table of Tables .................................................................................................................................... 14 Acknowledgements ............................................................................................................................. 16 Statement of contribution ................................................................................................................... 17 1 Introduction ................................................................................................................................. 18 1.1 An introduction to social cognition ........................................................................... 18 1.1.1 What is social cognition? ................................................................................... 18 1.1.2 The relationship between social and non-social cognition ................................ 22 1.1.3 Social cognition in psychiatric and neurological disorders ............................... 24 1.2 Social cognitive development ................................................................................... 30 1.2.1 Social cognitive development in typically-developing children ........................ 30 1.2.2 Social cognitive development in atypical development..................................... 34 1.2.3 Domain-specificity and domain-generality during development ...................... 35 1.3 The “social brain”...................................................................................................... 38 1.3.1 Human neuroimaging and neuropsychology studies ......................................... 38 1.3.2 Investigations of social brain circuitry in rodent and primate models ............... 42 3 1.3.3 Neuromodulatory systems ................................................................................. 45 1.3.4 Summary ............................................................................................................ 48 1.4 The orbitofrontal cortex and social cognition ........................................................... 48 1.4.1 The anatomy of the orbitofrontal cortex ............................................................ 48 1.4.2 Anatomical connections of the orbitofrontal cortex .......................................... 50 1.4.3 The orbitofrontal cortex and non-social cognition............................................. 52 1.4.4 The role of the orbitofrontal cortex in social cognition ..................................... 55 1.5 Excitatory circuitry and social cognition .................................................................. 57 1.5.1 Excitatory circuitry and neurodevelopmental disorders .................................... 57 1.5.2 Long and short-range brain connectivity and neurodevelopmental disorders ... 59 1.5.3 Maturation of excitatory circuitry and social cognition ..................................... 62 1.5.4 Long-range connectivity and social cognition ................................................... 63 1.6 Rodent models of neurodevelopmental disorders ..................................................... 64 1.6.1 What are rodent models good for? ..................................................................... 64 1.6.2 Rodent models of social cognition ..................................................................... 67 1.7 Aims .......................................................................................................................... 71 2 Abnormal social behaviour in the Nrxn1α KO mouse model of neurodevelopmental disorders .............................................................................................................................................. 72 2.1 Introduction ............................................................................................................... 72 2.1.1 Social cognition in neurodevelopmental disorders ............................................ 72 2.1.2 Cognitive deficits and neurodevelopmental disorders ....................................... 75 4 2.1.3 Genetics and neurodevelopmental disorders ..................................................... 77 2.1.4 Mouse models of social cognitive impairment .................................................. 80 2.1.5 The Neurexin genes ........................................................................................... 83 2.1.6 Neurexin1-α ....................................................................................................... 84 2.2 Methods ..................................................................................................................... 86 2.2.1 Animals and housing.......................................................................................... 86 2.2.2 Materials and procedures ................................................................................... 89 2.2.3 Statistical Analysis ........................................................................................... 104 2.3 Results ..................................................................................................................... 104 2.3.1 Nrxn1α KO mice display heightened anxiety .................................................. 104 2.3.2 Nrxn1α KO mice show abnormal social behaviour ......................................... 107 2.3.3 Nrxn1α microdeletion does not affect short-term object memory ................... 112 2.3.4 Short-term and long-term spatial memory is intact in Nrxn1α KO and HET mice