Periodic Reporting for period 1 - EXPLORATOME (Circuit mechanisms underlying sensory-evoked navigation)
Período documentado: 2022-01-01 hasta 2023-06-30
The EXPLORATOME project aims to identify the computations performed by descending commands neurons to generate locomotor sequence in a simple vertebrate model organisms by investigating circuits underlying behavior in larval zebrafish Danio rerio and other fish species (Danionella cerebrum, Astyanax mexicanus, Amphiprion ocellaris).
Our project has 3 aims:
Aim 1: Identifying sequences in navigation
Aim 2: Mapping the command neurons for triggering single motor actions
Aim 3: Analysis of circuits underlying motor sequences
Altogether our project is shedding light on how the brainstem computes motor commands in the vertebrate brain, a necessary step to design alternative strategies for functional recovery following neurological injury or diseases such as Parkinson's disease.
Our project has 3 aims:
Aim 1: Identifying sequences in navigation
Aim 2: Mapping the command neurons for triggering single motor actions
Aim 3: Analysis of circuits underlying motor sequences
Altogether our project is shedding light on how the brainstem computes motor commands in the vertebrate brain, a necessary step to design alternative strategies for functional recovery following neurological injury or diseases such as Parkinson's disease.
Aim 1: Identifying sequences in navigation
In Aim 1, we planned to analyze how freely-moving animals elicit locomotor sequences in response to dynamic changes in the chemosensory landscape the fish encounter. We performed experiments and developed a lexical model of behavior to describe that freely-swimming larval zebrafish repeat avoidance turns in response to acidic aversive gradients (Reddy et al., Plos Computational Biology 2022; https://pubmed.ncbi.nlm.nih.gov/35007275/). We showed that fish spontaneously repeat the same bout types, either forward or turn bouts. In response to aversive cues, they exhibit bouts with large tail beat frequencies, amplitudes and therefore higher speeds.
As a collaboration with Antonio Costa and Massimo Vergassola (Laboratory of Physics Statistics, ENS, Paris), we have conducted a subsequent analysis of long time scale patterns in the behavior that reveals very interesting motor states (Sridhar, Costa, Vergassola and Wyart, in preparation).
Via a collaboration implemented by Claire Wyart with the Okinawa Institute of Science and Technology (OIST, Japan), we have performed as well behavioral experiments on chemotaxis in larvae from coral reef fish, focusing on anemone fish Amphiprion ocellaris and Amphiprion clarkii (Wyart, Locke, Roux, Laudet, in preparation). Via a collaboration implemented by Gautam Sridhar with the Rétaux lab in the Neuropsi institute in Saclay, France, we are performing experiments on chemotaxis in cavefish Astyanax mexicanus. The diversity of species enables us to compare the navigation and corresponding neural circuits of command neurons and the organization of the brainstem in vertebrates.
Aim 2: Mapping the command neurons for triggering single motor actions
In Aim 2, we planned to elucidate the contribution of reticulospinal neurons (RSNs) to the generation of single locomotor actions called “bouts”. For this goal, we needed to map which vsx2-expressing RSNs called V2a RSNs are recruited to trigger the forward versus turn bouts. We did so by building a light sheet microscope to record from all V2a RSNs while the larval zebrafish is spontaneously swimming (Carbo-Tano, Lapoix et al., Nature Neuroscience in press). We showed that medial medullary V2a RSNs are recruited for forward bouts while rostral V2a RSNs in the pontine and retropontine regions of the hindbrain. We will now investigate the non V2a reticulospinal neurons in larval zebrafish (Carbo-Tano, Wyart, unpublished results).
In order to learn on the reticular formation from comparative studies in different fish species, we have implemented experiments of whole brain imaging and behavior in Danionella cerebrum in collaboration with the Del Bene lab in the Paris Vision Institute (Rajan et al., Cell Reports 2022; https://pubmed.ncbi.nlm.nih.gov/34558208/).
Aim 3: Analysis of circuits underlying motor sequences
In Aim 3, we planned to establish how descending command neurons dynamically integrate relevant sensory and spinal inputs to determine locomotor sequences. To tackle this question, we mapped the upstream region to the RSNs that triggers the forward locomotion and is referred to the Mesencephalic Locomotor Region (MLR) (Carbo-Tano, Lapoix et al., Nature Neuroscience in press). In addition, we established a novel methodology to infer transfer of information within neuronal networks recorded at the population level using calcium imaging (Chen, Ginoux et al., eLife 2023; https://pubmed.ncbi.nlm.nih.gov/36749019/ ) that also confirmed that MLR neurons drive the activity of motor-correlated medullary neurons in the reticular formation, most likely RSNs. We now investigate other higher motor centers than the MLR via a collaboration with the Portugues lab in TUM, Munich (Carbo-Tano, Younes, Portugues, Wyart, unpublished results).
We have published numerous reviews to communicate our work to a wide community of scientists:
- On the roles of interoception for locomotion, posture, innate immunity and morphogenesis:
o Wyart, eLife 2023 https://pubmed.ncbi.nlm.nih.gov/36961498/
o Wyart, Medecine Science Paris; https://pubmed.ncbi.nlm.nih.gov/37387662/
o Wyart et al., Neuroscience 2023; https://pubmed.ncbi.nlm.nih.gov/37419406/
o Wyart et al., Nature Reviews Neuroscience in press.
- On the roles of mechanosensory feedback for locomotion and posture:
o Dallmann et al., Integrative and Comparative Biology 2023; https://pubmed.ncbi.nlm.nih.gov/37419406/
o Wyart and Carbo-Tano, Current Opinion in Neurobiology in press.
In Aim 1, we planned to analyze how freely-moving animals elicit locomotor sequences in response to dynamic changes in the chemosensory landscape the fish encounter. We performed experiments and developed a lexical model of behavior to describe that freely-swimming larval zebrafish repeat avoidance turns in response to acidic aversive gradients (Reddy et al., Plos Computational Biology 2022; https://pubmed.ncbi.nlm.nih.gov/35007275/). We showed that fish spontaneously repeat the same bout types, either forward or turn bouts. In response to aversive cues, they exhibit bouts with large tail beat frequencies, amplitudes and therefore higher speeds.
As a collaboration with Antonio Costa and Massimo Vergassola (Laboratory of Physics Statistics, ENS, Paris), we have conducted a subsequent analysis of long time scale patterns in the behavior that reveals very interesting motor states (Sridhar, Costa, Vergassola and Wyart, in preparation).
Via a collaboration implemented by Claire Wyart with the Okinawa Institute of Science and Technology (OIST, Japan), we have performed as well behavioral experiments on chemotaxis in larvae from coral reef fish, focusing on anemone fish Amphiprion ocellaris and Amphiprion clarkii (Wyart, Locke, Roux, Laudet, in preparation). Via a collaboration implemented by Gautam Sridhar with the Rétaux lab in the Neuropsi institute in Saclay, France, we are performing experiments on chemotaxis in cavefish Astyanax mexicanus. The diversity of species enables us to compare the navigation and corresponding neural circuits of command neurons and the organization of the brainstem in vertebrates.
Aim 2: Mapping the command neurons for triggering single motor actions
In Aim 2, we planned to elucidate the contribution of reticulospinal neurons (RSNs) to the generation of single locomotor actions called “bouts”. For this goal, we needed to map which vsx2-expressing RSNs called V2a RSNs are recruited to trigger the forward versus turn bouts. We did so by building a light sheet microscope to record from all V2a RSNs while the larval zebrafish is spontaneously swimming (Carbo-Tano, Lapoix et al., Nature Neuroscience in press). We showed that medial medullary V2a RSNs are recruited for forward bouts while rostral V2a RSNs in the pontine and retropontine regions of the hindbrain. We will now investigate the non V2a reticulospinal neurons in larval zebrafish (Carbo-Tano, Wyart, unpublished results).
In order to learn on the reticular formation from comparative studies in different fish species, we have implemented experiments of whole brain imaging and behavior in Danionella cerebrum in collaboration with the Del Bene lab in the Paris Vision Institute (Rajan et al., Cell Reports 2022; https://pubmed.ncbi.nlm.nih.gov/34558208/).
Aim 3: Analysis of circuits underlying motor sequences
In Aim 3, we planned to establish how descending command neurons dynamically integrate relevant sensory and spinal inputs to determine locomotor sequences. To tackle this question, we mapped the upstream region to the RSNs that triggers the forward locomotion and is referred to the Mesencephalic Locomotor Region (MLR) (Carbo-Tano, Lapoix et al., Nature Neuroscience in press). In addition, we established a novel methodology to infer transfer of information within neuronal networks recorded at the population level using calcium imaging (Chen, Ginoux et al., eLife 2023; https://pubmed.ncbi.nlm.nih.gov/36749019/ ) that also confirmed that MLR neurons drive the activity of motor-correlated medullary neurons in the reticular formation, most likely RSNs. We now investigate other higher motor centers than the MLR via a collaboration with the Portugues lab in TUM, Munich (Carbo-Tano, Younes, Portugues, Wyart, unpublished results).
We have published numerous reviews to communicate our work to a wide community of scientists:
- On the roles of interoception for locomotion, posture, innate immunity and morphogenesis:
o Wyart, eLife 2023 https://pubmed.ncbi.nlm.nih.gov/36961498/
o Wyart, Medecine Science Paris; https://pubmed.ncbi.nlm.nih.gov/37387662/
o Wyart et al., Neuroscience 2023; https://pubmed.ncbi.nlm.nih.gov/37419406/
o Wyart et al., Nature Reviews Neuroscience in press.
- On the roles of mechanosensory feedback for locomotion and posture:
o Dallmann et al., Integrative and Comparative Biology 2023; https://pubmed.ncbi.nlm.nih.gov/37419406/
o Wyart and Carbo-Tano, Current Opinion in Neurobiology in press.
Beyond the state of the art: Neuromodulation
We have uncovered a very important modulatory role of noradrenergic nuclei and glial cells to stop locomotion upon sustained aversive cues (Orts-Del-Immagine et al., Glia 2022; https://pubmed.ncbi.nlm.nih.gov/34773299/).
Beyond the state of the art: Sensory integration during pathogen invasion
We have also uncovered that pathogen invasion in the central nervous system in a model of meningitis could recruit sensory neurons and modulate posture, explaining thereby the phenomenon of opisthotonos in humans suffering from severe meningitis (Prendergast et al., Current Biology 2023; https://pubmed.ncbi.nlm.nih.gov/36791723/).
Beyond the state of the art: Training the early career scientists
We have been active in transmitting our knowledge via training in schools in Europe (Cajal Interacting with Neural Circuits 2022, Cajal Connectomics 2023, Zenith European Training Network summer school in 2022, hackathon and final symposium 2023), in the United States of America (Summer School Neurophysics of locomotion 2022, KITP, UCSB, USA) and in Asia (Summer School Developing Neural Circuits, OIST, 2023).
Goals for the next period:
- Generalize our findings to other species (fish and mice)
- Dissect higher motor command centers and look for homologies and differences across vertebrate species
We have uncovered a very important modulatory role of noradrenergic nuclei and glial cells to stop locomotion upon sustained aversive cues (Orts-Del-Immagine et al., Glia 2022; https://pubmed.ncbi.nlm.nih.gov/34773299/).
Beyond the state of the art: Sensory integration during pathogen invasion
We have also uncovered that pathogen invasion in the central nervous system in a model of meningitis could recruit sensory neurons and modulate posture, explaining thereby the phenomenon of opisthotonos in humans suffering from severe meningitis (Prendergast et al., Current Biology 2023; https://pubmed.ncbi.nlm.nih.gov/36791723/).
Beyond the state of the art: Training the early career scientists
We have been active in transmitting our knowledge via training in schools in Europe (Cajal Interacting with Neural Circuits 2022, Cajal Connectomics 2023, Zenith European Training Network summer school in 2022, hackathon and final symposium 2023), in the United States of America (Summer School Neurophysics of locomotion 2022, KITP, UCSB, USA) and in Asia (Summer School Developing Neural Circuits, OIST, 2023).
Goals for the next period:
- Generalize our findings to other species (fish and mice)
- Dissect higher motor command centers and look for homologies and differences across vertebrate species