DS0407 - Exploration du système nerveux dans son fonctionnement normal et pathologique

Functional circuit dissection of reward encoding in the olfactory system – SmellBrain

The extreme plasticity of the olfactory system


Unique functional properties for newborn neurons

In nearly all mammals, including humans, neurons are produced and incorporated in certain brain regions throughout life (a process known as adult neurogenesis). The study of the continuous production of new neurons in adults has two important purposes. For one, it allows us to understand how and why the adult brain responds to the demands of the surrounding environment or to changes in internal physiological parameters by recruiting new neurons in some neural circuits. In addition, neurogenesis provides a model study for the identification of the molecular and cellular mechanisms that underlie the integration of newborn neurons, a crucial first step toward their potential use in therapeutic ends.<br />One of the major targets of neuronal production in adults is the olfactory bulb, the first relay center of the olfactory system that connects the nose to the brain. The goal of the SmellBrain project is to predict the emotional and cognitive aspects of an olfactory experience by deciphering how the emotional content of olfactory representation is encoded and modulated in the healthy and diseased brain. This project has produced a large number of original results published in high-profile international journals. We have also identified cellular components of functional plasticity of the olfactory system in the olfactory bulb.

Our multidisciplinary approach to the study of olfactory system plasticity unites cellular biology, optogenetics, in vivo imaging, neurophysiology, and behavioral studies in order to elucidate the role of neurogenesis in olfactory circuits and develop new therapeutic strategies. These strategies would be based on the reprogramming of olfactory memories and their emotional content in the context of certain behavioral disorders such as mood disorders or post-traumatic stress disorder.
Recent innovations in imaging and functional analyses have surfaced in the field of neuroscience. We employ two of them: optogenetics and two-photon in vivo imaging. The first technique allows us to control neurons with light. This new research method has transformed our technological approach by allowing us to optically manipulate neuronal circuits in order to study their role in sensory perception and cognitive function.
The second approach consists of increasingly ingenious developments in microscopy that have improved imaging conditions such as visual range, resolution and acquisition speed. A particular optical microscopy technique we have used is multi-photon imaging, based on non-linear optic concepts that allow us to image deep inside the brain without harming the neurons or circuits under observation. The combination of these two techniques at multiple scales has informed our recent findings on the neural basis of learning and the attribution of pleasure to our sensory experiences.

Conclusive evidence for adult neurogenesis naturally led to speculation on the functional contribution of this phenomenon. A classic strategy to parse the functions of a biological phenomenon is to prevent its occurrence. Thus different methods have been used to date to prevent the production of new neurons in the adult brain: the use of pharmacological agents, genetic ablation to prevent the division of neural progenitor cells, and the irradiation of neurogenic zones. Many studies have shown contradictory results due to the diversity of methods and behavioral tasks used. We have chosen a more specific approach by making newborn neurons light-sensitive. Thanks to this novel approach, we have been able to attribute several new functions to the production of new neurons in the olfactory bulb. For one, we have discovered that new neurons escaped inhibitory control, which rendered them more excitable and easily active in the circuits in which they were incorporated (Mazo et al. 2016). Second, we have shown that their recruitment provided synaptic plasticity unparalleled by preexisting neurons (Sailor et al. 2017). On the whole, a high degree of excitability and capacity to form new connections have conferred newborn neurons a privileged function in the adaptation of a subject to olfactory changes in its environment. Finally, we have discovered that newborn neurons were particularly efficient detectors of coincidence between olfactory messages and the internal state of each subject - a function that appears essential for the attribution of affective valence to olfactory stimuli (Grelat et coll., 2018).

This study shows that the first relay of the olfactory system permanently receives neo-neurones whose characteristic is to be extremely malleable, as shown by the percentage of synaptic contact renewal that is about 10 to 20 times higher than that measured in other regions of the brain. Future work will have to determine the origin of this unique property of neo-neurons.

Katsimpardi L & Lledo P-M (2018). Regulation of neurogenesis in the adult and aging brain. Current Opinion in Neurobiology 53, 131–138.

We review the functional properties of neural stem cells (NSCs). Ranging between quiescence, activation and intermediary subtypes, NSCs choose their fate through their developmental inheritance, regional positioning within the niche, as well as dynamic transcriptional and metabolic states.

Grelat A, Benoit L, Wagner S, Moigneu C, Lledo P-M* & Alonso M* (2018). Adult-born neurons boost odor-reward association. Proc. Natl. Acad. Sci. 115, 2514-2519 (*co-senior authors).

Using behavioral analysis when light was delivered into the olfactory bulb, we found that the mere activation of adult-born neurons is sufficient to trigger appropriate behavior.

Sailor KA, Schinder AF & Lledo P-M (2017). Adult neurogenesis beyond the niche: its potential for driving brain plasticity. Curr. Opin. Neurobiol. 42, 111-117.

Here we discuss the fact that adult neurogenesis demands massive structural remodeling of preexisting network. We conclude that adult neurogenesis may have more far-reaching role in general brain plasticity.

Mazo C, Lepousez G, Nissant A, Valley MT & Lledo P-M (2016). GABAb receptors tune cortical feedback to the olfactory bulb. J Neurosci. 36(32), 8289–8304.

This study demonstrates how olfactory cortical feedbacks are crucial for generating beta but not gamma oscillatory activity.

Sailor KA, Valley MT, Wiechert MT, Riecke H, Sun GJ, Ming G-L, Song H & Lledo P-M (2016). Persistent structural plasticity optimizes sensory information processing in the olfactory bulb. Neuron 91, 1-13.

This study represents the first demonstration of a coordinated structural pre- and post-synaptic plasticity tracked over multiple months (i.e., up to 18 months). The report shows that both adult-born and pre-existing post-natal derived interneurons have matching, highly dynamic spines that persist throughout life.

In our everyday experiences we have a remarkable ability to rapidly determine, with great ease, whether we like or dislike a scent while also determining its identity and recovering its qualitative descriptors. In vertebrates, and more so in humans, the response to most odors is not innate, but instead adaptive, where these odor associations are acquired through learning and experience throughout life. For instance, learned odor associations can be bidirectional where rodents can learn an aversion to an odor by pairing the odor presentation with an electrical shock and conversely, giving a reward during odor presentation can cause a learned attraction. In humans, defined odor preferences and relative pleasantness can be culturally determined, again being learned through experience. Despite the strong effect that odor-driven learned behavioral responses have on humans, the circuits and mechanisms involved are unknown.
This still unsolved fundamental question calls for a better understanding of the mechanisms that allow sensory systems to be associated, either acutely or in the long term, with other functional brain areas controlling executive function such as motor commands, memory, and reward. In all sensory systems, the flow of information within the sensory processing hierarchy does not depend only on external sensory inputs, but also depends on the top-down inputs from higher-order brain structures that encode information about the outcome or past experience associated with the sensory stimulus. In various pathological conditions, impairment of top-down processes have been posited to cause the aberrant integration of external sensory information with the internal representation, thereby leading to altered perception and reward expectation. Interestingly, associative features about the reward outcome and the expectation following a previous stimulus-reward association learning task have been observed early in processing within the primary cortex of the gustatory, auditory, visual and olfactory system. These findings raise the question: “Why is the encoding of the reward outcome required at such early stages of sensory processing that occurs during associative learning?” In addition, this introduces the question: “How do top-down circuits convey high-order attributes of valence to the early sensory representation?”
Using the mouse olfactory system as a model, the SmellBrain project aims to delineate the top-down circuits involved in reward signal encoding that occurs in the first relay of the olfactory system, the main olfactory bulb (OB), and testing the role of this reward-related activity for driving adapted behaviors. Using an integrative approach involving cutting-edge techniques such as optogenetics, advanced in vivo imaging, neurophysiology and behavior assays, we will identify the still unknown synaptic properties, cellular mechanisms, and brain connections that associate reward values to odorants following associative learning.
This project is also a first attempt, at least in the olfactory system, to manipulate the synaptic plasticity of top-down projections by controlling in vivo the activity of multiple synaptic partners with high temporal precision, in a defined behavioral context. Such control of synaptic plasticity in long-range brain connections could engrave, or erase, associative features in early sensory circuits. Understanding this system could pave the way for new potential therapeutic approaches to treat pathological circuit dysfunction as possibly associated with autism, depression, addiction and schizophrenia.

Project coordinator

Monsieur Pierre-Marie Lledo (INSTITUT PASTEUR (BP))

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.



Help of the ANR 305,760 euros
Beginning and duration of the scientific project: September 2015 - 36 Months

Useful links

Explorez notre base de projets financés



ANR makes available its datasets on funded projects, click here to find more.

Sign up for the latest news:
Subscribe to our newsletter