Periodic Reporting for period 4 - Spontaneous ZeBrain (Whole-brain dynamics underlying self-generated behaviour)
Reporting period: 2021-11-01 to 2023-10-31
Past and current studies that investigated the neuronal basis self-generated behaviours mainly focus on the readiness potential (RP) signal, a build-up ramping activity in the premotor cortex, occurring ~ 2 sec before the movement's onset. However, the neuronal mechanisms underlying the generation of self-generated behaviours (how RPs are generated), the involvement of other regions, and how the brain codes the impending movements (activity predictive of the onset and type of movement), still remain poorly understood.
In this project, we will address these open questions using the zebrafish larva model which enables monitoring whole-brain dynamics in an intact behaving vertebrate. Specifically, we will ask:
1) What is the brain representation and mechanisms underlying self-generated behaviours.
2) A comparison between the neuronal pathways underlying the initiation of self-generated and sensory
induced behaviours.
3) The internal and external modulation of self-generated behaviours.
In other words, we will shed light on how internal decisions are generated in the brain. What are the mechanisms that underlie the emergence of the the intrinsic brain activity predictive of a self-generated behaviour, and which information does this activity carry about the impeding motor behaviour.
This project concerns fundamental science. Therefore, in the short term it will have no practical applications. However, it will provide a lot of novel knowledge to the scientific community and the society in general.
A lot is known about the neural basis of decision making when the brain has to decide over several external sensory stimuli. However, this is not the case on how internal decision are generated.
In this project, we will address these open questions using the zebrafish larva model which enables monitoring whole-brain dynamics in an intact behaving vertebrate. Specifically, we will ask:
1) What is the brain representation and mechanisms underlying self-generated behaviours.
2) A comparison between the neuronal pathways underlying the initiation of self-generated and sensory
induced behaviours.
3) The internal and external modulation of self-generated behaviours.
In other words, we will shed light on how internal decisions are generated in the brain. What are the mechanisms that underlie the emergence of the the intrinsic brain activity predictive of a self-generated behaviour, and which information does this activity carry about the impeding motor behaviour.
This project concerns fundamental science. Therefore, in the short term it will have no practical applications. However, it will provide a lot of novel knowledge to the scientific community and the society in general.
A lot is known about the neural basis of decision making when the brain has to decide over several external sensory stimuli. However, this is not the case on how internal decision are generated.
In our first article we found that self-generated motor behaviour deviate the critical state of the brain to a more sub-critical one, momentarily reducing the entire repertoire of potential behaviours, thus allowing the zebrafish larva to engage in coherent motor behaviours. This is supported by the observation that consecutive movements are more likely to have a similar laterality if they were chained within less than 10 s than for longer inter-bout intervals.
Along the same lines, sensory interactions with the external environment limited the potential sensory responses to comply with the expectations about the detected stimulus.
Ponce-Alvarez, et al 2018 Neuron
In a second study, we took advantage of the auditory system of the zebrafish larva. In this study, we found a topographic and functional continuum of the sensorimotor representation, suggesting a gradual transformation of sensory information into motor patterns. In addition, we observed an increase in the duration of the auditory-induced calcium transients when a stimulus induced a motor behavior. We suggest that the sensorimotor transformations do not reflect a gating mechanism but rather the capacity of the circuit to integrate the auditory-induced neuronal response. This hypothesis is also supported by the long and variable latency of the induced tail movements. The increase in the duration of the calcium transients could be driven through recurrent connectivity to sufficiently amplify neural activity and reach the threshold required to activate the motor circuits. We suggest that thisn mechanism may help integrate auditory information to obtain reliable information about the detected stimulus to generate a relevant behavioral response.
This study was published in:
Privat, M et al 2019 Curr. Biol.
In a third article, we observed that both the optic tectum and the pretectum circuits responded to the square-wave gratings. However, only the pretectum responded specifically to the direction of the missing-fundamental signal. In addition, a group of neurons in the pretectum responded to the direction of the behavioral output (OKR), independently of the type of stimulus presented. Our results suggest that the optic tectum responds to the different features of the stimulus, but does not respond to the direction of motion if the motion information is not coherent . On the other hand, the pretectum mainly responds to the motion of the stimulus based on the Fourier energy.
Duchemin et alFront. in neural circuits 2021
For a fourth article, we used a unique fish model to study evolution (Astyanax mexicanus cavefish). The Mexican cavefish, Astyanax mexicanus , consists of eyed river-dwelling surface populations, and multiple independent cave populations which have converged on eye loss, providing the opportunity to examine the evolution of sensory circuits in response to environmental perturbation. Functional analysis across multiple transgenic populations expressing GCaMP6s showed that functional connectivity of the optic tectum largely did not differ between populations, except for the selective loss of negatively correlated activity within the cavefish tectum, suggesting positively correlated neural activity is resistant to an evolved loss of input from the retina. Further, analysis of surface-cave hybrid fish reveals that changes in the tectum are genetically distinct from those encoding eye-loss. Together, these findings uncover the independent evolution of multiple components of the visual system and establish the use of functional imaging in A. mexicanus to study neural circuit evolution.
Lloyd et al Current Biology 2022
Last year, we published our fifth study on the neuro-glia mechanisms underlying behavioural state transitions . In this article, we used optogenetics, ablations, and a genetically encoded norepinephrine sensor. We observed that RA synchronous Ca2+ events are mediated by the locus coeruleus (LC)-norepinephrine circuit. RA synchronization did not induce direct excitation or inhibition of tectal neurons. Nevertheless, it modulated the direction selectivity and the long-distance functional correlations among neurons. This mechanism supports freezing behavior following a switch to an alerted state. These results show that LC-mediated neuro-glial interactions modulate the visual system during transitions between behavioral states.
Uribe-Arias et al Neuron 2023
Our last and sixth research article has been submitted and is already in biorxiv (Privat et al 2024). Here, we took advantage of the Methyl-CpG-binding protein 2 (MeCP2) deficient zebrafish mutant, which displays perturbed tectal dynamics, to study the functional role of the attractor-like circuits in visual processing. In comparison to wild-type larvae, the mecp2-mutant showed reduced functional connectivity in the optic tectum. This abnormal connectivity significantly affected the visual response, and the ability to discriminate between visual stimuli. Finally, the mutant larvae where less efficient in hunting paramecia. We argue that the attractor dynamics of the tectal assemblies improve stimulus discrimination, visual resolution, and increase the sensitivity to behaviorally relevant visual stimuli.
Privat et al 2024 biorxiv
Along the same lines, sensory interactions with the external environment limited the potential sensory responses to comply with the expectations about the detected stimulus.
Ponce-Alvarez, et al 2018 Neuron
In a second study, we took advantage of the auditory system of the zebrafish larva. In this study, we found a topographic and functional continuum of the sensorimotor representation, suggesting a gradual transformation of sensory information into motor patterns. In addition, we observed an increase in the duration of the auditory-induced calcium transients when a stimulus induced a motor behavior. We suggest that the sensorimotor transformations do not reflect a gating mechanism but rather the capacity of the circuit to integrate the auditory-induced neuronal response. This hypothesis is also supported by the long and variable latency of the induced tail movements. The increase in the duration of the calcium transients could be driven through recurrent connectivity to sufficiently amplify neural activity and reach the threshold required to activate the motor circuits. We suggest that thisn mechanism may help integrate auditory information to obtain reliable information about the detected stimulus to generate a relevant behavioral response.
This study was published in:
Privat, M et al 2019 Curr. Biol.
In a third article, we observed that both the optic tectum and the pretectum circuits responded to the square-wave gratings. However, only the pretectum responded specifically to the direction of the missing-fundamental signal. In addition, a group of neurons in the pretectum responded to the direction of the behavioral output (OKR), independently of the type of stimulus presented. Our results suggest that the optic tectum responds to the different features of the stimulus, but does not respond to the direction of motion if the motion information is not coherent . On the other hand, the pretectum mainly responds to the motion of the stimulus based on the Fourier energy.
Duchemin et alFront. in neural circuits 2021
For a fourth article, we used a unique fish model to study evolution (Astyanax mexicanus cavefish). The Mexican cavefish, Astyanax mexicanus , consists of eyed river-dwelling surface populations, and multiple independent cave populations which have converged on eye loss, providing the opportunity to examine the evolution of sensory circuits in response to environmental perturbation. Functional analysis across multiple transgenic populations expressing GCaMP6s showed that functional connectivity of the optic tectum largely did not differ between populations, except for the selective loss of negatively correlated activity within the cavefish tectum, suggesting positively correlated neural activity is resistant to an evolved loss of input from the retina. Further, analysis of surface-cave hybrid fish reveals that changes in the tectum are genetically distinct from those encoding eye-loss. Together, these findings uncover the independent evolution of multiple components of the visual system and establish the use of functional imaging in A. mexicanus to study neural circuit evolution.
Lloyd et al Current Biology 2022
Last year, we published our fifth study on the neuro-glia mechanisms underlying behavioural state transitions . In this article, we used optogenetics, ablations, and a genetically encoded norepinephrine sensor. We observed that RA synchronous Ca2+ events are mediated by the locus coeruleus (LC)-norepinephrine circuit. RA synchronization did not induce direct excitation or inhibition of tectal neurons. Nevertheless, it modulated the direction selectivity and the long-distance functional correlations among neurons. This mechanism supports freezing behavior following a switch to an alerted state. These results show that LC-mediated neuro-glial interactions modulate the visual system during transitions between behavioral states.
Uribe-Arias et al Neuron 2023
Our last and sixth research article has been submitted and is already in biorxiv (Privat et al 2024). Here, we took advantage of the Methyl-CpG-binding protein 2 (MeCP2) deficient zebrafish mutant, which displays perturbed tectal dynamics, to study the functional role of the attractor-like circuits in visual processing. In comparison to wild-type larvae, the mecp2-mutant showed reduced functional connectivity in the optic tectum. This abnormal connectivity significantly affected the visual response, and the ability to discriminate between visual stimuli. Finally, the mutant larvae where less efficient in hunting paramecia. We argue that the attractor dynamics of the tectal assemblies improve stimulus discrimination, visual resolution, and increase the sensitivity to behaviorally relevant visual stimuli.
Privat et al 2024 biorxiv
We have succeeded in monitoring whole-brain dynamics with single-neuron resolution in an intact behaving vertebrate. We have improved our SPIM and we can now record the activity of 70-80% of the larva's ~100,000 neurons before the execution of self-generated behaviours.
Using immunochemistry, we are now capable of also identifying the cell type of each recorded neuron.
For data analysis we developed several software, and published 6 research articles, 2 reviews, and book chapter (in print)
Using immunochemistry, we are now capable of also identifying the cell type of each recorded neuron.
For data analysis we developed several software, and published 6 research articles, 2 reviews, and book chapter (in print)