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« Innovative and collaborative Research Grant » Category
Human cerebral organoids to unravel the role of meningeal macrophages in neurodevelopment
Our understanding of the intricate connection between immune cells and the central nervous system is a dynamically advancing realm of research. Progress in this field of study provides not only enhanced insights into brain development but also a more refined perspective on the relationship between immune cells and brain diseases. The meninges, which envelop the central nervous system, consist of thin protective layers teeming with immune cells, notably meningeal macrophages (MMs). While these immune cells are known to serve as key sentinels, safeguarding the brain during neuroinfections, our knowledge of their role during brain development remains limited. Our preliminary findings have revealed that neonatal MMs depletion in mice has an impact on neural stem cell proliferation in a neurogenic niche. These novel observations stimulate the need for a new project that aims at gaining a more comprehensive understanding of the role of MMs in neurodevelopment. To that end, we propose to use hiPSC-derived 3D human cerebral organoid (hCO) models, which mimick the human brain development. In this project, we will assess whether the MMs’ secretome can influence the development of hCOs. In parallel, we will develop an innovative chimeric model to integrate mouse meninges (wild-type or MMs depleted) in hCOs and characterize the impact on hCOs development. This research project will set up the basis of a new partnership between two laboratories and holds the potential to significantly expand our insights into the contribution of MMs to neurodevelopment.
3D NErve MOdel – NEMO
Two to three percent of physical trauma has an injured nerve. This is disabling and painful, physically, socially and psychologically. Studies have shown the value of transplanting stem cells to improve nerve regrowth in animals. However, their use in humans raises 2 difficulties: 1) either the stem cells come from the patient and the transplant is delayed because their purification and culture require time; 2) or the cells come from a donor and immunosuppressants must be used to prevent rejection. To overcome these obstacles, we have grafted the active principles of the stem cells, contained in the vesicles they secrete. This preclinical study proves the effectiveness of these vesicles in repairing peripheral nerves and improving locomotion in animals. On the basis of this evidence, we want to design a 3D-model in vitro of human peripheral nerve in order to study and understand the molecular mechanisms underlying nerves repair via vesicles. This nerve model could also serve as a screening platform for testing new drugs, as well as a platform for developing news models of neuromuscular pathologies such as amyotrophic lateral sclerosis.
Thalamic Contribution to the Hippocampal Positional System in the rat.
The aim of this project is to understand how brain structures, well known for their role in visual information processing, participate in the construction of spatial representation in rodents. Spatial representation is a central issue in cognition research. Nearly fifty years of neurophysiological research, based for the most part on the rodent model, have identified the brain structures essential to the construction of this spatial representation. The hippocampus is one of these structures. Electrophysiological studies aim to understand how a brain structure functions, by analyzing the activity of neurons in relation to the animal’s behavior. The main hippocampal cells are pyramidal neurons, which show intense activity when the animal is at a particular spatial location in a given environment. Collectively, these place cells enable the animal to know where it is and in which environment. We now know that the activation of these cells relies on multimodal information (e.g. olfactory, tactile, visual, etc.), providing the navigation system with strong adaptive potential. Nevertheless, the functional relationships between structures specialized in visual information processing and those specialized in spatial information processing remain largely unknown. The aim of this project is therefore to understand how the brain structures involved in memory and visual perception interact when animals explore new environments.
Setting up novel tools to gain mechanistic insights into the role of Tshz3 in autism-spectrum disorders
Autism-spectrum disorder (ASD) is a common neurodevelopmental condition characterized by impaired social interactions, language deficits and repetitive behaviors among many other clinical manifestations. Multiple genetic factors have been linked to ASD, including TSHZ3 gene. We have developed Tshz3 mouse models that reproduce the core behavioral abnormalities of ASD. Although our recent findings suggest that the dysfunction of distinct neuronal subsets due to Tshz3 deletion underlies different ASD symptoms, the specific role of Tshz3 among these different neuronal populations remains largely unknown. To address this issue, we seek to develop novel tools that, packed in viral vectors for in vivo delivery, will enable to thoroughly define the functions of Tshz3 in vivo and selectively delete it in cortical projection neurons and striatal cholinergic interneurons, which are key players in TSHZ3-linked ASD. Our aim is to provide preliminary data on the efficacy of these tools and test the behavioral and cellular consequences of targeted Tshz3 deletion.
Investigating the identity of the neurons that synchronize heart rate and blood pressure with breathing.
When stressed, anxious or scared, taking deep breaths is a universal relaxation technique that slows heart rate and decreases blood pressure. Indeed, the respiratory and cardiovascular functions are synchronized: heart rate and blood pressure increase and decrease in phase with respiratory activity, two phenomena called respiratory sinus arrhythmia (RSA) and Traube-Hering (TH) waves, respectively. A large RSA is physiologically and psychologically beneficial (calming effect), while a decreased RSA is linked to cardiovascular (heart failure, hypertension) and neuropsychiatric disorders (post-traumatic stress syndrome, chronic anxiety). Inversely, enlarged TH waves can cause the development of hypertension. Our project is aimed at investigating how the brain generates RSA and TH waves, and how it regulates their amplitudes. Our hypothesis is that a subgroup of inhibitory neurons, in a key area at the base of the brain that generates the respiratory rhythm, is involved. We will test this by modulating the activity of these inhibitory neurons while recording RSA and TH waves. We will also characterize the precise identity of these inhibitory neurons, in term of neurotransmitter used and anatomy. Altogether, this project should help resolve the intriguing question of the generation by the brain of the opposing physiological (amplification of RSA) vs. pathological (amplification of TH waves) effects associated with the respiratory modulation of cardiovascular activities.
Cancer neuroscience is an emerging area of research exploring the intricate relationship between the nervous system and tumors. Recent studies have shed light on the role of the peripheral nervous system in influencing tumor growth. This interplay involves a dynamic exchange of signals and substances between cancer cells and neurons, impacting the behavior of both. Our project focuses on a particularly aggressive cancer, pancreatic ductal adenocarcinoma (PDAC), where sensory neurons have been found to promote tumor growth. To delve deeper into these interactions, we aim to create innovative “innervated-tumor-on-chip” models. These models allow us to simulate and study neural networks in a controlled environment using microfluidic compartmentalized chips. What’s significant is that our research employs cutting-edge technology to produce these models without relying on animal testing. This ethical approach not only reduces the need for animal experimentation but also aligns with responsible research practices. Our project serves as a pathway to future research, enriching our understanding of the complex interactions between sensory neurons and cancer cells. By uncovering these interactions, we can develop new ways to fight cancer, leading to improved treatments and outcomes for patients .
Uncovering Behavioral Predictors of Cocaine Addiction Vulnerability in Social Rat Groups: Advancing, Understanding and Establishing a Versatile Machine Learning Based Behavioral Platform for Rats
This project aims to better understand why some rats are more likely to become addicted to cocaine than others. We will study their behavior and look for patterns that can predict their vulnerability to addiction. By analyzing how rats interact in social groups, we can gain valuable insights into their susceptibility to addiction. We will use advanced deep-learning tracking techniques: the Live Rat Tracker (LRT) and Motion Sequencing (MoSeq2), to study their behavior in detail. We will also include both male and female rats to see if there are any differences in how they develop addiction. The methods we use can be applied to other research areas, not just addiction. We are creating a new platform available to the NeuroMarseille community that will use the LRT system, which is a cutting-edge technology. This will be a significant step forward and put us at the forefront of research in this field.
Breathing dysfunctions in the Kcnq2 Thr274Met/+ mice: model of SUDEP
Epilepsy affects more than 65 million people worldwide, making it one of the most common chronic neurologic disorders. Although many antiepileptic drugs are available, one-third of people with epilepsy fail to achieve seizure control with pharmacotherapy. Moreover, patients with epilepsy have a higher risk of sudden death than control populations. Despite the challenges of collecting real-time physiologic data from an event that occurs so unpredictably, cases of sudden death that occurred while patients were being monitored in hospital and data collected from animal models indicate that sudden death are due to respiratory dysfunction more often than previously thought. In this project, we have several objectives: First, we will investigate the mechanisms underlying respiratory rhythmogenesis at the cellular and at the network level to understand the physiopathology of SUDEP, on an exclusive mouse model created in the laboratory. Second, we will use of specific channel blockers to decreased neuronal excitability and prevent SUDEP. Third, we will work in close collaboration with the hospital to find new genes involved in SUDEP. Fourth, we will use new methods used in epilepsy prediction in order to applied to respiratory rhythm abnormalities to find a physiological signature of SUDEP, which is a prediction. This project is based on previous work of the participants to explore a new hypothesis which postulate that sudden death in epilepsy relies on dysfunction of the central respiratory.
« Technical boost grant » category
Functional photoacoustic imaging in brain slices using fluorescent indicators
The measurement of the electrical activity of neurons in vivo is of great importance for understanding how the brain functions. Current optical microscopy (and mesoscopy) technologies enable cell-specific activity recording using fluorescent indicators sensitive to intracellular calcium concentration or membrane potential. However, the maximum recording depth achievable by optical techniques in the brain is less than a millimeter a fundamental limitation imposed by the diffusion light from the tissues. With this project we want to adopt photoacoustic imaging, a technique capable of measuring optical absorption several millimeters deep in the brain, for neuronal activity recording. Recent works have also demonstrated that it is possible to image neuronal activity by photoacoustics using fluorescent indicators sensitive to calcium or voltage, as these molecules are optical absorbers. However, this work used low-frequency piezoelectric sensors, which limited spatial resolution. In this project, we will be using a new-generation photoacoustic imager, developed by the start-up DeepColor, which achieves good spatial resolution (<100 μm) without impacting acquisition speed. DeepColor’s technology is based on optical interference measurement of the acoustic field, using a Fabry-Perot cavity. This method enables 3D volumes to be acquired at speeds compatible with the recording of functional signals. As a first step, we will record photoacoustic and epifluorescence simultaneously in brain slices, to validate the signals obtained with the former and their dynamics. Once the in vitro results validated, the project will move to the recording of neural activity in-vivo.