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Neuroscience: our relationship with intelligence

Vivid memories: looking deep into the pre-wired brain

James Bowers, Chief editor at Polytechnique Insights
On February 18th, 2021 |
3 min reading time
Emmanuel Beaurepaire
Emmanuel Beaurepaire
CNRS Research Director at the Laboratory of Optics and Biosciences of the École Polytechnique (IP Paris)*  
Key takeaways
  • Research shows that neurones in the hippocampus region of the brain are organised very early in life to provide a basis for memory.
  • Expert in multiphoton microscopy, Dr. Emmanuel Beaurepaire and his colleagues aim to study this process in a European-funded project, HOPE.
  • Researchers will first label neurones with colours in a technique developed in 2007 by a team at Harvard University, referred to as ‘brainbow’.
  • Then, they can use three-photon microscopy to study the neurones and their projections in the hippocampus as they develop over the lifetime of a mouse.

Are our brains hard­wired at birth? At least, par­tial­ly, says science. 

Over the past few years, stud­ies in the brain region respon­si­ble for mem­o­ry, the hip­pocam­pus, sug­gests that the neu­rones there seem to be pre-wired dur­ing devel­op­ment 1.  This leads to the con­clu­sions that groups of neu­rones deter­mined by very ear­ly events may form the ele­men­tary build­ing blocks of our mem­o­ry. To under­stand how these build­ing blocks emerge dur­ing devel­op­ment, new advances in microscopy offer a way to see into the brain, allow­ing researchers to watch how the hip­pocam­pus changes as new expe­ri­ences occur. 

Paint­ing neurones

Back in 2007, a team based at Har­vard Uni­ver­si­ty devel­oped a tech­nique that allows researchers to colour neu­rones in a devel­op­ing brain – which they apt­ly dubbed brain­bow. As a result, when sci­en­tists look at them under a micro­scope, they see the brain as a strik­ing col­lec­tion of mul­ti-coloured neur­al cells. Oth­er than cre­at­ing images that seem more like art than sci­ence, the tech­nique allows researchers to point out spe­cif­ic neu­rones, pre­cise­ly locat­ing the tra­jec­to­ries of their spindly axons. 

Brain­bow: Researchers can label mouse cor­ti­cal tis­sue with colour and image it using a tech­nique known as chro­mat­ic mul­ti­pho­ton (ChroMS) microscopy. (Cred­it: Adapt­ed from Abde­ladim et al, Nat. Com­mun. 2019)

Using colour labels in this way enables researchers to probe neu­ro­ge­n­e­sis, the process where­by the brain pro­duces new neu­rones. As such, each cell is essen­tial­ly a clone of a par­ent cell so, when labelled using brain­bow, each will car­ry the same colour as their ances­tor, pro­vid­ing a way to fol­low the lin­eage of brain cells. 

Where there is HOPE…

If colour­ing neur­al cells is the first step, the sec­ond is being able to see them in high res­o­lu­tion. After all, the brain is com­posed of dense bun­dles of inter­twined neu­rones – not so easy to pick out the detail. In a new Euro­pean project, HOPE, set to take place from next year, Emmanuel Beau­re­paire and his team at Insti­tut Poly­tech­nique de Paris are using three-pho­ton microscopy to peer deep into the hippocampus. 

Pre­vi­ous work from Pr. Rosa Cos­sart at Aix-Mar­seille Uni­ver­si­ty, a col­lab­o­ra­tor of HOPE, describes the process of pre-wiring of the hip­pocam­pus and the changes that come when new mem­o­ries occur. The project will rely on three-pho­ton microscopy to look at coloured neu­rones, specif­i­cal­ly fol­low­ing changes in the hip­pocam­pus from birth in mice. 

The team, which also includes Jean Livet from Insti­tut de la Vision, plans to pro­duce exten­sive maps of neu­ronal pro­jec­tions and study hip­pocam­pal struc­ture to see how the cells con­nect with one anoth­er: a project which will require both human- and com­put­er-pow­er using deep learning. 

“We want to see the way brain cir­cuits are put in place dur­ing devel­op­ment and how that can be linked to expe­ri­ence in the adult brain,” says Emmanuel Beau­re­paire. “Of course, as always with the brain, we are restrict­ed by our abil­i­ty to look inside it. Using three-pho­ton microscopy – which we’ve been work­ing on for the past four years – we can look about a mil­lime­tre deep into tis­sue of a live mouse.” 

Pow­er­ful lasers are used to stim­u­late the flu­o­res­cent mate­ri­als, mean­ing the colour­ful neu­rones can be seen with high pre­ci­sion. Not only can the tech­nique look deep­er than oth­er microscopy meth­ods, but its high sen­si­tiv­i­ty also allows researchers to see detail to the point of indi­vid­ual synaps­es. It might not seem like much, but 1 mm is cer­tain­ly enough to take a good look around. “Our mul­ti-pho­ton microscopy is ide­al for the hip­pocam­pus – of mice. The tech­nique is too inva­sive for a larg­er brain like a human and, for now, we wouldn’t be able to go deep enough,” he states. 

Going beyond the visual 

“Neu­ro­science is the main appli­ca­tion of mul­ti­pho­ton microscopy, but it will go hand-in-hand with oth­er tech­niques,” he adds. “Fur­ther down the line, we also plan to use opto­ge­net­ics, a tech­nique which lets us stim­u­late or block spe­cif­ic neu­rons using light to observe the effects.” 

“At the moment we are see­ing a huge leap for­ward in our under­stand­ing of neu­ro­science – in terms of mem­o­ry, con­scious­ness and learn­ing – which will no doubt lead to new solu­tions in a range of domains,” says Emmanuel Beaurepaire. 

Prob­lems that can occur in the devel­op­ing hip­pocam­pus are known to be involved in a range of health prob­lems that can per­sist through­out life: epilep­sy and autism, to name a few. But going back to the orig­i­nal ques­tions at the begin­ning of this arti­cle, the answer is one of fun­da­men­tal sci­ence. “It is about first under­stand­ing how the brain works. Lat­er, per­haps, they can be built upon for med­ical or psy­chi­atric treatments.”


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