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Investigation of the Effects of Cannabidiol on Sleep-Like States and Memory-Associated Brain Events

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Investigation of the Effects of Cannabidiol on Sleep-Like States and Memory-Associated Brain Events DEGREE PROJECT IN MEDICAL ENGINEERING, SECOND CYCLE, 30 CREDITS STOCKHOLM, SWEDEN 2020 Investigation of the effects of Cannabidiol on sleep-like states and memory-associated brain events TUGDUAL ADAM KTH ROYAL INSTITUTE OF TECHNOLOGY SCHOOL OF ENGINEERING SCIENCES IN CHEMISTRY, BIOTECHNOLOGY AND HEALTH Investigation of the effects of Cannabidiol on sleep-like states and memory-associated brain events TUGDUAL ADAM Master in Medical Engineering Date: September 24, 2020 Supervisor: Lisa Genzel Examiner: Arvind Kumar School of Engineering Sciences in Chemistry, Biotechnology and Health Host company: Genzel Lab Swedish title: Undersökning av effekten av Cannabidiol på sömnliknande tillstånd och minnesassocierade hjärnhändelser iii Abstract A growing interest for Cannabidiol (CBD), a component of Cannabis Sativa, has occurred over the past years. The medical potential of the component is yet to be better characterized, as its effects on sleep, and in particular memory, are to date not well understood or consistently characterized. This master the- sis project focuses on analysing the effect of CBD on an anaesthesia-induced sleep-like state in rats, and its effects on the hippocampal sharp-wave-ripples, which have been shown to be associated with memory replay during sleep, and hence system consolidation. The hippocampus and prefrontal cortex, the two structures involved in memory consolidation, were recorded in 19 rats, split in two groups (CBD and vehicle). From these recordings, an automated sleep scorer using principal component analysis was developed to obtain the ani- mals’ hypnograms, which were analysed to study sleep-like structure. From the recordings of the hippocampal pyramidal layer, and an additionnal layer deeper under it, respectively ripples and sharp waves were detected in all an- imals, and characterized for each group. We observed and demonstrated that CBD changes the sleep-like structure by shortening both REM and NREM bouts, resulting in an increase in transitions between both states. Addition- ally, we observed that, although ripples are not significantly different between both groups, sharp waves tend to be smaller among CBD animals. Lastly we noticed that both sharp wave and ripple activity, after increasing upon transi- tion to NREM, decreases as the bout last. This finding suggests that vehicle animals, who have longer bouts and less transitions, would display less sharp wave and ripple activity, although we found no significant difference in the amount of both brain events. This paradox suggests that there is still more to characterize in order to understand if CBD enhances or not memory consol- idation. In sum, CBD changes anaesthesia-induced sleep by shortening the duration of both NREM and REM bouts, resulting in an increase in transitions between both state. As for sleep events, sharp waves appeared shorter among CBD animals, although the same difference was not observed for ripples. Fi- nally, sharp wave and ripple activity appear to peak upon transition from REM to NREM sleep, and decreases as the NREM bout lasts longer, however, no ef- fect of CBD on this observation was highlighted. iv Sammanfattning Under de senaste åren har det förekommit ett växande för intresse för Canna- bidiol (CBD), en del av textit Cannabis Sativa. Ämnets medicinska potential är ännu inte väl kartlagt, då dess effekter på sömn, och minne i synnerhet, hittills inte är väl förstått eller konsekvent karaktäriserade. Det här examens- arbetet fokuserar på att analysera effekten av CBD på ett anestesi-inducerad sömnliknande tillstånd hos råttor, och dess effekter på det hippocampala skarp- vågkrusningkomplex, som har visat sig vara förknippade med minnesuppspel- ning under sömn, och därmed systemkonsolidering. De två strukturerna invol- verade i minneskonsolidering, hippocampus och prefrontalcortex, registrera- des i 19 råttor, uppdelade i två grupper (CBD och kontroll). Från dessa re- gistreringar utvecklades ett automatiserat sömnbetyg med hjälp av principal- komponentanalys för att erhålla djurens hypnogram, som analyserades för att studera sömnliknande uppbyggnad. Från registreringarna av det hippocampala pyramidala lagret, och ett ytterligare lager djupare under det, upptäcktes krus- ningar och skarpa vågor hos alla djur och kännetecknades för varje grupp. Vi observerade och demonstrerade att CBD förändrar den sömnliknande struktu- ren genom att förkorta både REM- och NREM-anfall, vilket resulterade i ett utbrott i övergångar mellan dem båda tillstånden. Dessutom observerade vi att även om krusningar inte signifikant skiljer sig mellan båda grupperna, tende- rar skarpa vågor att vara mindre bland CBD-djur. Slutligen märkte vi att både skarp våg- och krusningsaktivitet, efter utbrott vid övergången till NREM, av- tar under anfallets gång. Denna upptäckt tyder på att kontrolldjur, som slår längre och har färre övergångar, skulle uppvisa mindre skarp våg- och krus- ningsaktivitet, även om vi inte hittade någon signifikant skillnad i mängden av båda hjärnhändelserna. Denna paradox antyder på att det fortfarande finns mer att karaktärisera för att förstå om CBD förbättrar minneskonsolidering el- ler inte. Sammanfattningsvis förändrar CBD anestesi-inducerad sömn genom att förkorta varaktigheten av både NREM- och REM-anfall, vilket resulterar i ett utbrott i övergångar mellan båda tillstånden. När det kommer till sömn- aktiviteter förefaller det att skarpa vågor är kortare bland CBD-djur, även om samma skillnad inte observerades för krusningar. Slutligen verkar skarp våg- och krusningsaktivitet toppas vid övergången från REM till NREM-sömn, och avta när NREM-anfallet varar längre, däremot framhävs ingen effekt av CBD i denna observation. Preface The following document constitutes my master research project as the conclu- sion of my Master in Medical Engineering at the Royal Institute of Technology (KTH), Stockholm, Sweden. The project was conducted at the Genzel Lab, Radboud University, Nijmegen, Netherlands, from the 2nd of february 2020 to the 30th of June 2020, and was supervised by Lisa Genzel, PI of the laboratory, as well as Adrian Aleman, junior researcher. I chose, during my studies, to specialize in various fields, among which was neuroscience. With the precious help of Arvind Kumar, responsible for the course DD2401 Neuroscience, I contacted Lisa and found a project about the neuroscience of sleep, for which I have always felt a strong interest. The following report presents my research project at the Genzel Lab, the meth- ods I developed for tackling the main issues, the results I obtained as well as a critical discussion regarding the latter. Tugdual Adam v Acknowledgement I would first of all like to thank Lisa Genzel, PI of the Genzel Lab, for mak- ing this project possible, and for being patient and of precious help, especially when it came to providing neuroscientific background to the data and results, as I arrived with only little knowledge about the specifics of sleep and memory neuroscience. I would then like to thank Arvind Kumar, professor at KTH, and also my own reviewer, who made all of this possible by giving me the contact of Lisa Gen- zel. I moreover learned a lot about neuroscience thank to him during the course at KTH DD2401 Neuroscience. He gave me the basics to start this master the- sis. I would also like to thank Adrian Aleman, junior researcher at Genzel Lab, who introduced me to the laboratory when I arrived, and was of precious help for the statistical aspect of the project, and Anumita Samanta, in charge of the project I am working on, for her enthusiasm and great help for the neuroscien- tific background of the project. More generally, I thank all of the researchers and students at the Genzel Lab for sharing their different experiences, back- grounds, for being of help and keeping each other distracted via our Slack platform during this covid-19 quarantine, which lasted most of my time in the Netherlands. Finally, a big thank to my family for being of moral support dur- ing my time away working from my student room as my workplace was closed due to the pandemic. vi Contents 1 Introduction 2 1.1 Comprehensive framework . .2 1.1.1 Role of sleep in memory consolidation . .2 1.1.2 Sleep disorders and cannabis . .4 1.2 Project objectives and hypotheses . .5 2 Material and methods 7 2.1 Material and experiments . .7 2.2 Channel selection . .9 2.3 Data preprocessing . 10 2.4 Sleep classification . 10 2.5 Automatic scoring assessment . 12 2.6 Event detection . 12 2.6.1 Ripples detection . 13 2.6.2 Sharp waves detection . 13 2.7 Statistical analysis . 13 2.7.1 Processing of the data . 13 2.7.2 Two sample Student’s test . 13 2.7.3 Repeated measure analysis of variance . 14 3 Results 15 3.1 Automated sleep scorer . 15 3.1.1 Analysis of the PCA weights . 17 3.1.2 Scorer accuracy . 17 3.2 Effect of cannabidiol on sleep . 19 3.3 The effect of cannabidiol on memory-associated events . 25 3.3.1 Sharp waves and ripples characterization . 25 3.3.2 Sleep events in long bouts . 30 4 Discussion 32 5 Conclusion 38 vii viii CONTENTS Bibliography 39 A Additional figures and tables 44 B Background chapter 51 Glossary and abbreviations BW - Brief wake • CBD - Cannabidiol • EEG - Electroencephalogram • EMG - Electromyogram • HPC - Hippocampus • LFP - Local field potential • NREM(S) - Non rapid eye movements (sleep) • OST - Object space task • PFC - Prefrontal cortex • PCA - Principal component analysis • PC1 (or PC2) - First (respectively second) principal component • (R)ANOVA - (Repeated measures) Analysis of variance • REM(S) - Rapid eye movements (sleep) • SW(s) - Sharp Wave(s) • SWR(s) - Sharp-wave-ripple(s) • SWS - Slow wave sleep • THC - D-9-tétrahydrocannabinol • VEH - Vehicle • 1 Chapter 1 Introduction 1.1 Comprehensive framework Sleep is a vital function that can be found in most animals on earth. Its func- tions are numerous and it plays a crucial role in cognition, immunity, brain waste clearance, performance and energy conservation [1]. Sleep goes back as far as the appearance of a central nervous system in evolution, and evidence even show that sleep may have existed prior to the emergence of brains [2].
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