The focus of my research is to understand the bi-directional relationship between vascular plasticity in the adult and developing brain and neuronal activity. We are seeking to know how an animal’s experience can shape the development of its neural and vascular networks on the one hand, and how plastic remodeling of those networks can shape behaviors on the other hand. The challenges to tackle such questions are many. The first of these challenges is that animals exhibit a wide range of individual variability, at the level of the fine organization of their cerebral networks (neuronal and vascular), but also in the expression of behaviors. The relationship between developmental processes and the expression of behavioral individuality is notoriously difficult to explore. In the mammalian brain, while elegant relationships between individual variations in behavior and the functional properties of neurons have been made, such explorations at the structural level remain daunting.
To help tackle these questions, I have developed and advanced in the past years the use of tissue clearing and light-sheet microscopy to map the cells and networks of the adult mouse brain with high throughput. These methodologies enable whole-brain unbiased mapping of functional networks (based on Fos expression), axonal projections, and the vascular network (Kirst et al., 2020; Renier et al., 2014, 2016; Topilko et al., 2022; Vieites-Prado and Renier, 2021). By combining 3D histological exploration with modern techniques allowing the visualization and manipulation of neuronal activity, our past work and projects cover a diverse set of goals and questions that aim to explore the relationship between development, plasticity and behaviors.
We are using a combination of targeted and unbiased methods for axon tracing in the adult and developing brain to explore the interaction between neuronal activity and axonal branch plasticity.
For this, we are developing novel assays and quantifications for axonal tracts in the whole brain using either high-density structural endogenous markers or more traditional viral-based approaches.We validated the existence of long-term structural and functional plasticity and identified some of the key regions to study, we are now investigating the connections between those regions using dual- or triple- viral tracings, as well as transcriptomic approaches to identify the identity of the affected neurons.
This line of research should allow a mechanistic exploration of how structural plasticity of axonal branches condition the expression of behavioral adaptations and variations.
We developed an advanced methodology for the mapping of the rodent cerebral vasculature using molecular labeling of intact brains (Kirst et al. 2020). This tool offers a novel way to explore the structure of the vascular network in normal and pathological conditions. We seek to establish the role of neuronal activity in shaping the topology of the vasculature in the adult brain. We hope to tackle 3 fundamental questions:
- What is the nature of vascular adaptations to long term changes in activity levels?
- Which cell types are involved and how do they communicate?
- What are the effects of vascular remodeling on neuronal function?
For this, we are generating the first 3D neuroanatomical developmental atlas based on cleared tissue and light sheet microscopy, as well as novel computational tools to characterize vascular topology. With these resources, we hope to understand the complexity of the factors that interact to shape the adult topology of the vascular network.
On top of studying the plasticity of axonal and vascular networks, the other major goal of my research is to assess whether these changes have any significant impact on brain function by looking at behavioral variability across individual and how it could relate to plasticity.
Interestingly, following on our recent publication (Topilko et al., 2022), we observed that individual performances in nest building differ widely in a cohort of isolated mice. Social behaviors have often been used to model mice individuality (such as social defeat or home-cage hierarchy) and their consequences on brain plasticity. Because of the variability in outcomes, ease of implementation, and non-obligatory nature of the task, nesting is an ideal model to study how brain circuits integrate many cues to freely engage in a complex task, but also how neuronal plasticity can introduce individual variations in the engagement in this behavior.
Since we have made significant headways in characterizing neurons distributed in the mouse brain whose activities correlate with the complexity of built nests, we can use the behavioral systems setup in the lab to answer the following questions:
- Find the neuronal substrate of nesting: how mice decide how much time and energy they spend to freely engage in a nest-building task in an unsupervised environment.
- Characterize whether developmental or adult brain plasticity contribute to the neuronal substrates of behavioral variability
Our ultimate goal would be to find a reliable model system to study then the molecular control of adult plasticity and link it with behavioral flexibility. These projects may shed a light on the molecular mechanisms controlling the stability or instability of axonal projections in the mature brain. These mechanisms could be at the origin of drifts in the organization of the neuronal networks that could further amplify the variations introduced during development or following environmental pressure. Understanding the role of specific molecular pathways on the onset of individuality through plasticity could be one of the keys to better target treatments for psychiatric disorders.
