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Lazarini et al. (2014), Adult neurogenesis restores dopaminergic neuronal loss in the olfactory bulb. J Neurosci. 34(43): 14430-42.
Learning and memory: the role of new-neurons revealed
Researchers at the Institut Pasteur and the CNRS have recently identified in mice the role played by neo-neurons formed in the adult brain. By using selective stimulation the researchers were able to show that these neo-neurons increase the ability to learn and memorize difficult cognitive tasks. This newly discovered characteristic of neo-neurons to assimilate complex information could open up new avenues in the treatment of some neurodegenerative diseases. This publication is available online on the Nature Neuroscience journal’s website.
The discovery that new neurons could be formed in the adult brain created quite a stir in 2003 by debunking the age-old belief that a person is born with a set number of neurons and that any loss of neurons is irreversible. This discovery was all the more incredible considering that the function of these new neurons remained undetermined. That is, until today.
Using mice models the team working under Pierre-Marie Lledo, head of the Laboratory for Perception and Memory (Institut Pasteur/CNRS) recently revealed the role of these neo-neurons formed in the adult brain with respect to learning and memory. With the help of an experimental approach using optogenetics*, developed by this very same team and published in December 2010, the researchers were able to show that when stimulated by a brief flash of light these neo-neurons facilitate both learning and the memorization of complex tasks. This resulted in mice models that were able to memorize information given during the learning activity more quickly and remember exercises even 50 days after experimentation had ended. The study also shows that neo-neurons generated just after birth hold no added advantages as relates to either learning or memory. In this respect it is only the neurons produced by the adult brain that have any considerable significance.
“This study shows that the activity of just a few neurons produced in the adult brain can still have considerable effects on cognitive processes and behavior. Moreover, this work helps to illustrate how the brain assimilates new stimulations seeing as normally electrical activity (which we mimic using flashes of light) is produced within the brain’s attention centers”, explains the study’s director Pierre-Marie Lledo.
Beyond simply discovering the functional contribution of these neo-neurons, the study has also reaffirmed the clear link between “mood” (defined here by a specific pattern of stimulation) and cerebral activity. It has been shown that curiosity, attentiveness and pleasure all promote the formation of neo-neurons and consequently the acquisition of new cognitive abilities. Conversely, a state of depression is detrimental to the production of new neurons and triggers a vicious cycle which prolongs this state of despondency. These results, and the optogenetics technologies that enabled this study, may prove very useful for devising therapeutic protocols which aim to counter the development of neurologic or psychiatric diseases.
Activation of adult-born neurons facilitates learning and memory, published online on the Nature Neuroscience website, May 13, 2012
Mariana Alonso1, 2, Gabriel Lepousez1, 2, Sebastien Wagner1, 2, Cedric Bardy1, 2, Marie-Madeleine Gabellec1, 2, Nicolas Torquet1, 2 and Pierre-Marie Lledo1, 2
1 Institut Pasteur, Laboratory for Perception and Memory, F-75015 Paris, France.
2 French National Center for Scientific Research (CNRS), Associated Research Unit (URA2182),
F-75015 Paris, France.
The brain: light-controlled neo-neurons
We have shown, in an experimental model, that newly formed neurons in the adult brain can be stimulated by light. A novel technique associating optical and genetic tools allows neurobiologists to render neo-neurons photo-excitable. For the first time we have observed, and specifically recorded the activity of these new nerve cells in the olfactory system. Using this technique the group has revealed the nature of signals emitted from new neurons across neuronal circuits in the brain. This work represents an essential step towards better understanding the role of new nerve cells and in developing therapeutic applications, most notably in the realm of neurodegenerative diseases.
By introducing and inducing expression of photo-sensitive proteins in new neurons, we have been able to control their activity with the use of luminescent flashes. Using this technique, we been able to observe, stimulate, and specifically record the activity of new nerve cells. We have brought proof that new neurons formed in the olfactory bulb of the adult brain are integrated into preexisting nervous circuits. We have also shown that, against all expectations, the number of contacts between young cells and their target cells greatly increased over several months.
This work constitutes an essential step in characterizing the functions fulfilled by new neurons. It opens new avenues to investigation for understanding the connectivity between “newly formed” neurons and their host circuits. This is a crucial step on the way to foreseeing the use of stem cells within the framework of new therapeutic protocols for repairing brain damage, notably in the realm of neurodegenerative diseases.
How, when and where new inhibitory neurons release neurotransmitters in the adult olfactory bulb, Journal of Neuroscience, December 15, 2010.
Cedric Bardy1,2, Mariana Alonso1,2, Walid Bouthour1,2 and Pierre-Marie Lledo1,2 1 Institut Pasteur, Perception and Memory unit, 2 CNRS, URA 2182, 25 rue du Dr. Roux, F-75724 Paris Cedex 15, France.
Adult neurogenesis promotes synaptic plasticity in the olfactory bulb
Neurogenesis continues throughout adulthood in the mammalian olfactory bulb (OB), suggesting that newly-generated, adult-born neurons contribute to neural plasticity and learning. It has been described that recently-generated adult-born hippocampal excitatory granule neurons have a lower threshold for initiating action potentials and longt-term potentiation (LTP) than more mature neurons. In the OB, it is still unknown whether newborn neurons (which are GABAergic, rather than glutamatergic, interneurons) display distinct synaptic properties from their mature counterparts. We provide such information in a recent study (Nature Neuroscience, in press).
To explore the functional consequences of adult neurogenesis in the OB circuit, we examined whether glutamatergic synapses on olfactory GABAergic interneurons display synaptic plasticity. We find that, shortly after they differentiate and synaptically integrate, adult-born olfactory interneurons exhibit long-term synaptic plasticity. Remarkably, the degree of synaptic plasticity fades with maturation of the newborn neurons. In contrast, when recording pre-existing interneurons, we never observed LTP, indicating that recently-generated adult-born interneurons play a distinct role in olfactory processing than more mature counterparts. These results demonstrate that recently-generated adult-born olfactory interneurons and older, preexisting interneurons undergo contrasting experience-dependent synaptic modifications and support the hypothesis that adult-born neurons are involved in olfactory learning.
In addition, we go further than simply describing the acquisition of LTP by the newcomers. When studying the locus of synaptic plasticity, to our surprise, we found that the enhanced glutamatergic synaptic transmission results from presynaptic changes. Thus, the arrival of newborn interneurons in the OB triggers long-lasting changes of glutamatergic terminals of the adult OB that lead to higher probability of glutamate release. We need to precise now how arrival of the newcomers changes the probability of glutamate release from pre-existing glutamatergic fibers.
Nissant, A. et al. Adult neurogenesis promotes synaptic plasticity in the olfactory bulb. Nat Neurosci. 2009, 12(6):728-30.
Regeneration of dopaminergic neurons:
To examine how adult neurogenesis in the olfactory bulb contributes to regeneration after circuit injury, we performed acute DAergic neuronal loss by injecting 6-hydroxydopamine (6-OHDA). We found that a 6-OHDA treatment strongly decreases the number of neurons expressing the enzyme tyrosine hydroxylase (TH) nearby the injected site in the olfactory bulb. Despite this neuronal loss, the number of TH+ interneurons was restored two months later. This rescue resulted at least in part from enhanced recruitment of immature neurons in the lesioned glomerular layer area, but not elsewhere. During this period of circuit restoration, we found that the integration of lentivirus-labeled adult-born neuron was biased: newly-formed neurons were preferentially incorporated into glomerular circuits of the lesioned area at the expense of other areas. Remarkably, the restoration of glomerular circuits was also accompanied by behavioral rehabilitation. While acute 6-OHDA treated mice transiently lost innate responses towards social and non-social olfactory cues, mice exhibited unchanged innate responses two months later. Adult neurogenesis not only replenished the population of TH+ neurons in the glomerular layer after chemical DA depletion, but it also restored olfactory sensory processing. Thus, this study reports a critical role for adult neurogenesis in behavioral recovery after brain injury.
Updated on 27/10/2014
Perception and Memory Laboratory
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