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132

SummaryOur advanced cognitive abilities are generally considered as defining our humanity, yet what adaptations our brain has undergone to gain these faculties remains one of the central ques-tions in neuroscience. Traditionally, answers to this question have been sought in the anatomy of our brain, pointing at its large size and large number of neurons. Yet upon further exami-nation, our brain appears to have little exceptional or extra-ordinary features to which our outstanding cognitive abilities can be straightforwardly attributed. The question arises then, to what extent our advanced cognitive capacities may also be down to adaptations on a smaller scale, at the level of neurons and circuits. In this thesis, we explore the electrophysiological properties of human neurons and synapses in an effort to identify which features our neurons share with rodents, and in which they differ. To achieve this, we use whole-cell recordings from living human pyramidal neurons in slices of brain tissue resected during neurosurgery.

The first question addressed is how the dendritic arborisations of human neocortical pyra-midal neurons compare to those of other species and how they affect dendritic signal propa-gation. Reconstructing close to a hundred biocytin-filled human neurons provided the first quantitative dataset on full dendritic trees of human pyramidal neurons. Comparison of their dendritic morphologies to those of mice and macaques showed that human layer 2/3 pyra-midal neurons have almost three times as much dendrite and a distinct branching architec-ture. The effect of the distinct human dendritic arborisation on passive signal propagation was explored using computer modelling, which revealed strong attenuation of signals in human dendrites. This indicates that human neurons may rely heavily on local dendritic computation, but mechanisms may also exist to compensate this signal attenuation to some extent, such as a substantially lower specific membrane capacitance.

The extensive dendritic arborisations of human neurons support a vast amount of synapses, but little is known about their physiology; the properties of short-term plasticity and infor-mation transfer at human cortical synapses have never been studied directly. We therefore proceeded to characterise short-term plasticity at synapses between human layer 2/3 cortical pyramidal neurons. Human cortical synapses were found to all show short-term depression, similar to rodent synapses. In contrast to rodent synapses however, they recover much more rapidly from depression and are therefore capable of transferring much more information. Thus, when it comes to receiving information, human cortical pyramidal neurons not only receive an enormous volume of input, made possible by their large dendritic arborisations, but the inputs that they receive are also higher in information content, owing to fast recov-ering synapses. In order for human neurons to make use of all this information, they will have to be sensitive to the associated rapid fluctuations in synaptic inputs and be able to react quickly with their firing of action potentials. We tested how reliably human neurons can do so using an experimental paradigm called frequency tracking. Human neurons indeed turn out to be capable of encoding much more rapid fluctuations in inputs into the timing of their action potential than juvenile or adult mouse neurons, an ability supported by the faster onset kinetics of their action potentials.

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Summary

Information is stored in the brain by activity-dependent modifications in the strength of connections between neurons. An important form of such neuron-level information storage, called spike timing-dependent plasticity, has not been investigated directly at a cellular level in the human brain. In the second part of this thesis, we therefore set out to characterise the rules, mechanisms and modulation of spike timing-dependent plasticity at human cortical synapses. We find that human synapses can undergo bidirectional changes in strength throughout adulthood with a wider and reversed temporal window compared to that gener-ally found in juvenile rodents. Employing pharmacological and calcium imaging techniques, we found synaptic potentiation and depression at human synapses is gated by postsynaptic NMDA receptors and that dendritic L-type voltage-gated calcium channels recruited by back-propagating action potentials are important for synaptic strengthening.

Spike timing-dependent plasticity rules are not fixed, but plastic themselves and can be altered by the actions of neuromodulators such as acetylcholine. This thesis ends with an investiga-tion focussed on nicotinic acetylcholine receptors, which show a distinct layer and cell-type specific expression in the neocortex. We aimed to identify to what extent this layer-specific expression translates to layer-specific modulation of spike timing-dependent plasticity rules. Starting in mouse medial prefrontal cortex, we found that endogenous acetylcholine release augments long-term potentiation of glutamatergic synapses on layer 6 pyramidal neurons by activating dendritic nicotinic receptors which amplify back-propagating action potentials. This is in contrast to layer 5 where long-term potentiation was shown before to be supressed by nicotine and so points to layer-specific control over spike timing-dependent plasticity rules by the cholinergic system. Returning to the human neocortex, we found comparable mechanisms were in place there, with functional nicotinic receptors having a similar laminar distribution and cholinergic modulation of synaptic plasticity being opposite in superficial versus deep cortical layers.

The findings presented in this thesis show that many basic electrophysiological features are shared between human and rodent neurons, but importantly, we have also come to identify a number of morphological and physiological differences which may strongly impact the way these cells process and storage information. When considering the origins of the cognitive capacities of the human brain, one therefore cannot merely point to its size and numbers of neurons, but must also take into account an array of neuron-level adaptations that may have large implications for the computational power of the system as a whole.

134

Nederlandse samenvattingOnze intelligentie wordt doorgaans gezien als hetgeen wat ons mensen onderscheidt van andere dieren en wat ons mens-zijn definieert. Waar onze cognitieve vermogens vandaan komen blijft echter een van de grote vragen in de neurowetenschap. Vaak worden zij toege-schreven aan ons grote brein en de enorme hoeveelheid hersencellen, maar eigenlijk zijn er weinig anatomische aspecten van ons brein te noemen waarin wij werkelijk zo uniek zijn in vergelijking met andere dieren. De vraag is dus of onze intelligentie wellicht niet alleen uit een verschil in kwantiteit komt, maar ook een verschil in kwaliteit. Uiteindelijk worden al onze hersenfuncties ondersteund door hersencellen die met elektrische signaaltjes infor-matie uitwisselen in complex georganiseerde circuits. Zouden er op dit niveau wellicht eigen-schappen aan te wijzen zijn die onze intelligentie kunnen verklaren?

Op dit moment is er maar weinig bekend over de elektrische eigenschappen van de hersen-cellen in ons brein. De reden hiervoor is dat om deze te onderzoeken men levend hersenma-teriaal nodig heeft en dat is niet vaak voor handen. Gevolg is dat bijna al onze kennis over hoe hersencellen informatie verwerken en opslaan komt uit studies naar de hersenen van proefdieren, doorgaans ratten en muizen van een paar weken oud. Willen wij ons brein ooit helemaal begrijpen dan zullen we moeten toetsen in hoeverre de kennis opgedaan over het knaagdierenbrein van toepassing is op het onze. Ons laboratorium is een van de weinigen ter wereld met de kans dit te doen; zo nu en dan wordt er bij de neurochirurgie afdeling van het VU Medisch Centrum een stukje hersenweefsel weggesneden bij patiënten en dit weefsel kan, nadat het in dunne plakjes is gesneden, zo’n 12 uur in leven worden gehouden. Zo kunnen wij metingen doen aan levende menselijke hersencellen en hun elektrische eigenschappen eindelijk in detail bestuderen. Dit proefschrift presenteert het resultaat van 6 jaar onderzoek naar menselijke hersencellen dat met deze methode werd mogelijk gemaakt.

We beginnen met een heel basale vraag; hoe zien menselijke hersencellen er uit? Hersen-cellen hebben vanuit hun cellichaam grote uitlopers, de z.g. dendrieten, die functioneren als de ontvangstantennes van de cel. Hier komt informatie binnen van andere cellen via gespe-cialiseerde structuren die synapsen worden genoemd, die optreden waar de ene cel contact maakt met de ander. De dendrieten geven met hun vele vertakkingen de hersencel het kara-kteristieke uiterlijk van een ontwortelde boom, zoals ook op de voorkant van dit proefschrift is te zien. Verassend genoeg is er na meer dan 100 jaar neurowetenschap nog steeds geen duidelijk beeld van hoe deze er nu volledig uitzien. Het visualiseren van hersencellen in post-mortem materiaal gebeurt doorgaans in microscopisch dunne plakjes, veel dunner dan de spanwijdte van een hersencel, en geeft dus zelden een beeld van de complete dendritische ‘boom’. Ons preparaat laat cellen veel meer intact en zo hebben wij bijna honderd digitale 3D reconstructies weten te maken van haast complete menselijke hersencellen. Deze lieten zien dat menselijke hersencellen ongeveer drie keer zo groot zijn als die van een muis en zelfs andere apen soorten. Met hun veel grotere dendritische boom kunnen menselijke hersen-cellen dus veel meer informatie ontvangen dan de hersencellen van een muis.

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Vervolgens hebben we bestudeerd hoe menselijke hersencellen met elkaar communiceren. Door twee cellen tegelijk te meten met een electrode, kon onderzocht worden hoe efficiënt informatie van de ene naar de andere cel via de synaps kon worden overgedragen. In veel aspecten bleken mensen- en muizensynapsen vergelijkbare fysiologische eigenschappen te hebben, maar er was ook een belangrijk verschil. Synapsen raken bij herhaalde activiteit steeds verder uitgeput, maar het bleek dat menselijke synapsen zeer snel bijkomen hiervan. Met dit vergrootte uithoudingsvermogen kan een menselijke synaps in een korte tijd veel meer infor-matie doorgeven dan die van een muis.

De ‘informatie’ die cellen uitwisselen neemt de vorm aan van een klein stroom signaaltje. Het cellichaam is de plek waar al deze inkomende signaaltjes bij elkaar worden opgeteld en waar een beslissing gemaakt wordt of er iets moet worden doorgegeven aan andere cellen. Dit gebeurt wanneer de stroompjes bij elkaar optellen tot een bepaalde drempelwaarde, waarna een actiepotentiaal optreedt. Dit is een soort kettingreactie waarbij er een grote stroomstoot wordt gegenereerd die langs het axon naar andere cellen stroomafwaarts schiet. Het hebben van zo veel synapsen, die allen veel informatie over kunnen dragen, stelt het cellichaam behoorlijk op de proef. We hebben daarom gekeken naar hoe snel een menselijke hersencel kan reageren op zo’n snelle stroom van informatie. De actiepotentialen van menselijke hersen-cellen bleken veel sneller uit de startblokken schieten, waardoor zij op veel fijnere fluctuaties in elektrische signalen kunnen reageren. Menselijke hersencellen zijn dus uitgerust met actie-potentialen die snel genoeg zijn om met de grote hoeveelheid informatie die zij binnen krijgen om te gaan.

In het tweede gedeelte van dit proefschrift zijn wij ingegaan op de cellulaire mechanismen die ten grondslag liggen aan ons geheugenvermogen. Herinneringen kunnen in ons brein worden opgeslagen door relatief kleine groepjes hersencellen. Een karakteristieke eigenschap van zo’n cel populatie die voor een herinnering zorgt is dat hun onderlinge verbindingen sterker zijn. Het vormen van een versterkte onderlinge verbinding vindt plaats door de synapsen tussen deze cellen sterker te maken. Dit fenomeen heet synaptische plasticiteit en treedt op wanneer twee verbonden cellen herhaaldelijk samen actief zijn; de synaps tussen de twee cellen merkt dit en ondergaat dan een verandering in sterkte.

Synaptische plasticiteit speelt waarschijnlijk een cruciale rol in ons leer- en geheugenver-mogen, maar desondanks is dit proces tot op heden nog nauwelijks direct op celniveau in het menselijk brein onderzocht. Wij hebben daarom de activiteitspatronen die synaptische plasticiteit opwekken nagebootst in menselijke hersenplakjes, om zo de precieze voorwaarden voor synaptische plasticiteit en de onderliggende moleculaire mechanismen in detail uit te zoeken. Wij vonden dat synaptische plasticiteit in het menselijk brein in een aantal opzichten vergelijkbaar is met dat in knaagdieren. Met name de onderliggende mechanismen, zoals de betrokkenheid van bepaalde receptoren en ion kanalen (de NMDA receptoren en L-type calcium kanalen) waren identiek. Toch was de relatie tussen welke verandering in synaptische sterkte optrad bij welk activiteitspatroon erg verschillend en in sommige opzichten zelfs compleet tegenovergesteld. Wat dit precies betekent is vooralsnog onduidelijk en zal in de toekomst met computer modellen moeten worden uitgezocht. Interessant is wel dat daar waar synaptische plasticiteit in veel dieren lijkt af te nemen bij volwassenwording, de synapsen in ons brein ons hele volwassen leven door sterker en zwakker gemaakt kunnen worden. Dit suggereert, wellicht geruststellend, dat je nooit te oud bent om iets te leren.

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Hoe het wordt bepaald waar herinneringen worden opgeslagen, dus welke cellen sterker of zwakker met elkaar worden verbonden, is onderwerp van veel neurowetenschappelijk onder-zoek. Neuromodulatoren zoals bijvoorbeeld dopamine, serotonine en acetylcholine kunnen hier wellicht een rol in spelen. Wanneer deze stoffen in ons brein worden afgegeven kunnen zij het gedrag van hersencellen heel specifiek beïnvloeden en bepalen of synapsen worden versterkt of niet. Wij waren geïnteresseerd in hoe specifiek acetylcholine synaptische plastic-iteit in de menselijke hersenschors kan beïnvloeden. Acetylcholine activeert de nicotinerge acetylcholine receptor; deze heet zo omdat de nicotine in tabaksrook toevallig ook deze receptor activeert. Uit muizen onderzoek is bekend dat de nicotine receptor een heel specifiek verspreidingspatroon heeft over de verschillende cellagen van de hersenschors. In het laatste onderdeel van dit proefschrift laten wij zien dat dit verspreidingspatroon tot op zekere hoogte ook in mensen aanwezig is. Activatie van deze nicotine receptoren blijkt een cellaag-specifiek effect te hebben op synaptische plasticiteit; in de bovenste cellagen remmen zij de verster-king van synapsen, terwijl zij het in de diepste cellagen juist bevorderen. Acetylcholine heeft dus een cellaag-specifieke controle over welke synapsen wanneer versterken en kan zo het proces van geheugenopslag en het aanpassen van circuits in verschillende cel populaties van ons brein dirigeren.

Dit proefschrift laat zien dat er tussen mens en muis veel overeenkomsten, maar ook belan-grijke verschillen bestaan in de elektrische eigenschappen van hun hersencellen. Deze verschillen hebben een directe invloed op hoe informatie door de hersencellen van ons brein wordt verwerkt en opgeslagen. Om deze verschillen werkelijk op waarde te kunnen schatten is meer onderzoek nodig, met name naar de hersencellen van dieren die evolutionair, qua hersengrootte of qua intelligentie dichter bij de mens staan. Toch kunnen we nu al stellen dat er in de zoektocht naar de oorsprong van menselijke intelligentie niet alleen naar groot-schalige anatomische aspecten van ons brein gekeken moet worden; er bestaat namelijk een heel palet aan kleine adaptaties op celniveau die grote consequenties kunnen hebben voor de rekencapaciteit van ons brein in zijn geheel.

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Dankwoord Dit proefschrift is het resultaat van inmiddels bijna zes jaar werken aan de VU. In deze tijd heb ik het voorrecht gehad om met veel bijzondere mensen samen te werken. Graag wil ik hier een aantal in het bijzonder bedanken voor hun rol in de totstandkoming van dit proefschrift.

Beste Huib, bedankt dat ik zo lang deel uit heb mogen maken van je lab. Ik heb er over de jaren echt een geweldige tijd gehad en veel geleerd. Ik weet nog goed hoe ik je voor het eerst ontmoette toen ik als bachelor student je kantoor instapte om een interview te doen met ‘een echte wetenschapper’. Ik was natuurlijk zenuwachtig, maar je ontspannen houding sloeg al snel op mij over. Die ‘no worries’ mentaliteit heb ik later ook altijd erg op prijs gesteld als dingen vast leken te zitten. Verder dank ik je ook voor alle kansen die ik heb gekregen om aan leuke projecten mee te doen. Met name het werken aan humaan hersenweefsel heeft mij vele spannende dagen en nachten vol adrenaline gegeven waar ik erg van heb genoten. In bredere zin ben ik misschien nog het meest dankbaar voor de vrijheid die ik kreeg in het onderzoek en het vertrouwen om mij mijn gang te laten gaan, ondanks dat het waarschijnlijk niet altijd even duidelijk geweest zal zijn waar ik nu precies mee bezig was.

Beste Hans, ik weet werkelijk niet wat ik zonder jouw hulp, ervaring en encyclopedische kennis over de praktijk van de electrofysiologie had moeten doen. De zes maanden dat ik in Oxford stage liep zonder jou waren erg moeilijk, met experimenten die maar niet wilden lukken. Het was treffend dat jij na drie zinnen al wist wat het probleem was en hoe het opgelost had kunnen worden (cesium-gluconaat i.p.v. cesium-chloride! Aargh…). Jouw aanwezigheid was dan ook een sterke reden om voor het INF te kiezen als promotieplek en ik ben blij dat ik dat heb gedaan; ik heb zo ontzettend veel van je geleerd de afgelopen jaren. Van je verhalen over de oude methoden heb ik altijd gesmuld, het was leuk om die te horen van iemand die er vanaf het eerste uur bij is geweest. Ik vind het daarom ook bijzonder passend dat mijn laatste experiment in het lab er een was met jou en een van die oude technieken, de nucleated patch. Hans, doe mij een plezier en zet je brein op papier; “A practical guide for the electrophysiolo-gist: techniques, tricks and troubleshooting” lijkt mij wel een aardige titel. Of begin anders ’s werelds eerste electrofysiologie museum met al je oude meetapparatuur, hand-gedreven slicers en prehistorische pipet-trekkers! Ik lig voor de deur te slapen.

Dear members of the INF, past and present; over the many years I’ve spent in the lab it has been a pleasure to meet and work with such an interesting and colourful array of people. All of you have helped shape my PhD years into what have certainly been some of the most fulfilling years of my life. Not once have I felt reluctant to go to work, or have I felt bored while on the job. I put this down to the unique INF feeling you all help create. Yes, other departments may sometimes jokingly refer to us as the autists when we don’t show up for drinks, but within our world I believe we are having an equally rich social experience as any other. The many endless behind-the-patch-rig discussions about experiments, the state of present-day science, global politics or nothing at all, the shameless nerd-talk over beers and raw cauliflower, and of course the ‘human nights’ with their one-of-a-kind atmosphere... These things will stay with me forever and I will miss them always. It is now, thinking back of all those years, that I come to realise how much precious memories have been made in that one corridor of the Earth and Life Sciences Faculty. It saddens me to think I’m leaving this behind, but I go with the feeling of having been part of something special. Thank you all.

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Ten slotte wil ik nog één speciaal persoon bedanken, mijn lieve vriendin Siri. Lieve Sier, ik ben zo dankbaar dat ik jou heb. Jouw liefde, passie en levenslust herinneren mij er altijd aan hoe mooi het leven is en hoeveel er is te ontdekken in de wereld buiten het lab. De onvoorwaardelijke steun die je me geeft houdt mij altijd op de been en zeker in de laatste jaren van mijn PhD, waarin ik besef dat ik een groot beroep heb gedaan op je begrip, is die onmisbaar geweest. Ik had het echt niet zonder jou kunnen doen. De tien jaar die wij nu samen zijn hebben mij als mens gevormd en zijn de meest waardevolle jaren van mijn leven, ik kan dan ook niet wachten op wat onze toekomst zal brengen! Ik hou van je.

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List of publicationsTesta-Silva, G., Verhoog, M.B., Goriounova, N.A., Loebel, A., Hjorth, J.J.J., Baayen, J.C., de Kock, C.P.J., and Mansvelder, H.D. (2010). Human synapses show a wide temporal window for spike-timing-dependent plasticity. Frontiers in Synaptic Neuroscience.

Verhoog, M.B., and Mansvelder, H.D. (2011). Presynaptic ionotropic receptors controlling and modulating the rules for spike timing-dependent plasticity. Neural Plasticity. 2011.

Poorthuis, R.B., Bloem, B., Verhoog, M.B., and Mansvelder, H.D. (2013). Layer-specific interfer-ence with cholinergic signalling in the prefrontal cortex by smoking concentrations of nicotine. The Journal of Neuroscience. 33, 4843–4853.

Verhoog, M.B.*, Goriounova, N.A.*, Obermayer, J., Stroeder, J., Hjorth, J.J.J., Testa-Silva, G., Baayen, J.C., de Kock, C.P.J., Meredith, R.M., and Mansvelder, H.D. (2013). Mechanisms under-lying the rules for associative plasticity at adult human neocortical synapses. The Journal of Neuroscience. 33, 17197–17208.

Testa-Silva, G., Verhoog, M.B., Linaro, D., de Kock, C.P.J., Baayen, J.C., Meredith, R.M., De Zeeuw, C.I., Giugliano, M., and Mansvelder, H.D. (2014). High bandwidth synaptic communica-tion and frequency tracking in human neocortex. PLoS Biology. 12, e1002007.

Mohan, H.*, Verhoog, M.B.*, Doreswamy, K.K., Eyal, G., Aardse, R., Lodder, B.N., Goriounova, N.A., Asamoah, B., Brakspear, A.B.C., Groot, C., van der Sluis, S., Testa-Silva, G., Obermayer, J., Boudewijns, Z.S.R.M., Narayanan, R.T., Baayen, J.C., Segev, I., Mansvelder, H.D. and de Kock, C.P.J. (2015). Dendritic and axonal architecture of individual pyramidal neurons across layers of adult human neocortex. Cerebral Cortex 25, 4839–4853.

Verhoog, M.B., Obermayer, J*, Kortleven, C.A.*, Wilbers, R., Wester, J., Baayen, J.C., De Kock, C.P.J., Meredith, R.M., and Mansvelder, H.D. Layer-specific cholinergic control of human and mouse cortical synaptic plasticity by pre- and postsynaptic nicotinic acetylcholine receptors. Under revision.

Eyal, G., Verhoog, M.B., Testa-Silva, G., Deitcher, Y., Lodder, J., Benavides-Piccione, R., Morales, J., DeFelipe, J., de Kock, C.P.J., Mansvelder, H.D., and Segev, I. Human L2/3 pyramidal cells possess unique membrane and dendritic properties with augmented computational capabili-ties. Manuscript in preparation.

* equal contribution