Bevriezen of vluchten: wat zou je doen?

Dani
Lemmon

Stel dat je een kleine, nieuwsgierige muis bent die op zoek is naar zijn avondeten. Plots gaat een donkere schaduw over je heen en voel je een roofdier boven je hoofd, een havik die misschien ook op zoek is naar eten. Je brein van 0,4 g ondergaat instinctief tientallen berekeningen in een fractie van een seconde. Valt de havik aan of komt hij langs? Moet je bevriezen om te voorkomen dat je wordt opgemerkt of proberen te ontsnappen?

Wat gebeurt er in de hersenen tijdens aangeboren gedrag?

Wanneer een muis instinctief verstart of wegrent voor een roofdier, lichten zijn hersenen op met activiteit die complexe, kronkelige netwerken overspant. Een primaire speler in deze netwerken is een structuur in de hersenen van zoogdieren (inclusief mensen) die de superieure colliculus wordt genoemd. De superieure colliculus combineert visuele, auditieve en tactiele informatie van sensorische organen en stuurt signalen door de hersenen om beweging naar of weg van stimuli te oriënteren en te sturen. Wat er gebeurt in de hersengebieden stroomafwaarts van de superieure colliculus is niet goed begrepen; dit project ontrafelt een stukje van dat mysterie.

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Figuur 1: Hersennetwerken beïnvloeden het aangeboren gedrag bij muizen

Is aangeboren gedrag bij muizen relevant voor ziekten bij de mens?

Ja, absoluut. Bij mensen spelen de netwerken van de superieure colliculus een belangrijke rol bij het verwerken van angst en zijn ze betrokken bij aandoeningen zoals autisme, angst en posttraumatische stressstoornis (PTSD). Begrijpen hoe de hersenen van muizen reageren op bedreigende prikkels is noodzakelijk voor het ontrafelen en uiteindelijk behandelen van ziekten bij de mens waarbij soortgelijke circuits betrokken zijn.

Onderzoek naar de bijdrage van een specifiek hersengebied aan aangeboren gedrag

Het Farrow-lab van Neuro-electronics Research Flanders (NERF) heeft onlangs ontdekt dat activatie van specifieke cellen, genaamd NTSR-neuronen, in de superieure colliculus muizen plotseling 1-2 seconden laat stoppen. Door deze snelle verschuiving in aandacht en de plotselinge locomotieve stilstand kan de muis stoppen en de omgeving onderzoeken. Het team gebruikte vervolgens functionele beeldvorming van het hele brein, waarbij hersenactiviteit wordt gemeten op basis van veranderingen in het bloedvolume, om na te gaan welke andere delen van de hersenen actief waren toen NTSR-cellen werden gestimuleerd. Ze waren verrast om activiteit te vinden in een hersengebied dat nooit is gekoppeld aan aangeboren gedragingen die worden aangedreven door de superieure colliculus. Dit kleine hersengebied, de posterieure paralaminaire kernen van de thalamus (PPnT), is minder intimiderend dan de naam klinkt! Eerder onderzoek heeft de PPnT in verband gebracht met auditieve angstconditionering, waarbij een knaagdier leert om een geluid te associëren met een onaangename ervaring zoals een voetschok. In dit project onderzoeken we de rol van de PPnT in aangeboren stopgedrag door de PPnT bij muizen uit te schakelen tijdens gelijktijdige activatie van NTSR-cellen. Verandert het stopgedrag van muizen wanneer de PPnT wordt gedempt? Dit was de vraag die we wilden beantwoorden.

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Figuur 2: Schematisch diagram van experimenteel ontwerp

Optogenetica en chemogenetica: krachtige tools om deze onderzoeksvraag te beantwoorden

Als optogenetica en chemogenetica klinken alsof ze rechtstreeks uit een sci-fi-roman komen, blijf dan rustig zitten en wacht tot je hoort hoe ze worden gebruikt om dierlijk gedrag nauwkeurig te kunnen manipuleren door lichte of kleine chemicaliën te gebruiken. Optogenetica is gebaseerd op genetische manipulatie van hersencellen, zodat ze reageren op een specifieke golflengte van licht. In ons geval hebben we chirurgisch een kleine optische vezel geïmplanteerd (ja, denk aan een minuscule streng van een LED lamp met lichtgevende vezels) net boven de superieure colliculus van muizen met NTSR-cellen die genetisch zijn gemanipuleerd om te worden geactiveerd door blauw laserlicht. De optische vezel in de hersenen van de muis was via een kabel aan de laser bevestigd, zodat bij handmatige activatie van de laser, een pulstrein van blauw licht van 1 seconde rechtstreeks naar de superieure colliculus werd gestuurd; dit activeerde NTSR-neuronen en resulteerde in plotseling stopgedrag.

Vervolgens hebben we chemogenetica gebruikt om de PPnT af te sluiten. We injecteerden een genetisch gemodificeerd virus rechtstreeks in de PPnT van muizen, waardoor de cellen daar tijdelijk werden gedeactiveerd. Dit gebeurde enkel als we een medicijn genaamd clozapine-N-oxide toedienden vóór de gedragstesten. Tijdens de test mochten muizen gedurende 20 minuten vrij rondlopen in een open veld, een houten kist. We hebben de laser geactiveerd toen de muis het centrum passeerde, ongeveer 15-20 keer, en we vergeleken het stopgedrag tussen muizen met een geremde PPnT en controlemuizen waarin de PPnT normaal functioneerde.

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Figuur 3: Testopstelling in open veld

Het remmen van de PPnT verhoogt de gewenning aan activering van NTSR-neuronen

We ontdekten dat controlemuizen gedurende de hele test van 20 minuten consequent stopten bij elke laser activatie om NTSR-neuronen te activeren. Daarentegen waren muizen met een geremde PPnT gewend aan de laserstimulatie, wat betekent dat hun stopreactie geleidelijk afnam na herhaalde stimulaties. Dit betekende dat deze muizen geleidelijk hogere snelheden vertoonden tijdens laserstimulaties en significant lagere kansen om te stoppen in vergelijking met controles. Onze resultaten toonden aan dat het remmen van de PPnT de gewenning aan activering van NTSR-neuronen verhoogt.

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Figuur 4: Percentage muizen dat is gestopt vanwege laserstimulatie

Een nieuwe rol voor de PPnT: waarom is dit van belang?

Deze resultaten suggereren een nieuwe rol voor de PPnT; het bemiddelt aangeboren gedrag door gedragsaanpassing bij herhaalde stimulus te voorkomen. Evolutionair gezien is dit erg belangrijk voor een muis, aangezien het negeren van herhaalde maar relevante, mogelijk dreigende signalen, dodelijk kan zijn. De PPnT laat een verrassende prikkel niet onopgemerkt voorbijgaan. Deze resultaten kunnen met name relevant zijn voor de behandeling van PTSD, waarbij sprake is van overactiviteit in het angstreactiesysteem. Vooruitkijkend, zou het circuit dat we in onze studie hebben gemanipuleerd, erop kunnen worden gericht om patiënten met PTSD te helpen wennen aan niet-bedreigende stimuli.

Laten we een mentale sprong naar jou maken, onze kleine muis die over het veld rent met de havik boven ons. Mede dankzij de bijdrage van de PPnT aan de netwerken die aangeboren gedrag bepalen, stop je instinctief, vliegt de havik boven je hoofd en kun je in alle rust verder foerageren voor je diner.

 

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Universiteit of Hogeschool
Universiteit Antwerpen
Thesis jaar
2020
Promotor(en)
Dr. Karl Farrow