Related presentation: Integrative neuroscience of Paramecium, a swimming neuron (at the Institute for Neural Computation, UCSD). See current offers for Master students.

Any animal behavior involves at least a sensory organ, a large part of the nervous system, the body (muscles, skeleton), and the environment. Conventional systems neuroscience typically picks a small part of the nervous system and looks at correlations between neural activity and stimuli or behavior, or at what happens when some neurons are activated in a given experimental situation. This means that most models in systems neuroscience are hybrid models that include abstract constructs such as “decoders” of neural activity. This is problematic because “codes” observed by the experimenter are generally not intrinsic to the biological system, but contextual to the particular experimental situation, and therefore cannot be considered as biological models (see my critique of neural codes and my epistemological work).

The alternative is integrative modeling at the organismal level, addressing all the elements of the system that are necessary to account for behavior. This is of course challenging, given that no modern nervous system is smaller than a few hundred neurons. I got interested in Paramecium,  a large (100-300 µm) unicellular eukaryote which swims in fresh water using its cilia. It is of course phylogenetically very distant from animals, but the last common ancestor of all eukaryotic life (roughly 1.5 billion years ago), including all animals, was a protist (swimming unicellular eukaryote) that displayed a large part of the cellular and molecular sophistication of modern cells.

When Paramecium hits an obstacle (see Paramecium bumping against a piece of my jumper), mechanosensitive channels open, depolarize the membrane and trigger a calcium-based action potential. In turn, the action potential triggers a reversal of the swimming direction, followed by a change of direction. This is called the “avoiding reaction”, illustrated in the figure below (A) from Jennings (1906, an amazing book on the behavior of microorganisms; I have collected a number of papers and books he wrote on the subject). Panel B shows the action potential with the ciliary reorientation (from Eckert & Naitoh, 1970). For this reason, Paramecium was in fact a model organism for neuroscience in the 1970s, which some authors called the “swimming neuron”. I wrote a detailed review on the integrative neuroscience of Paramecium (2) and I (occasionally) maintain a journal on Paramecium neuroscience.

Paramecium provides a unique opportunity to study and model an entire sensorimotor system, linking the biophysics of sensory transduction to ecologically relevant behaviors. Paramecium is also sensitive to chemicals, light, gravity, water currents, temperature. It displays adaptation, learning, behavior switching, intrinsic and developmental plasticity, collective behavior: it is in some sense a “proto-cognitive” system (2).

On this project, I collaborate with Alexis Prevost, Laetitia Pontani (Laboratoire Jean Perrin, a physics lab) and Eric Meyer (a geneticist of Paramecium). We have designed a simple microfluidic device to immobilize cells for electrophysiology (1). Thanks to this, we have developed a first quantitative model of the action potential coupled with motility, based on our electrophysiological and behavioral measurements (3). Here is a simulation of the resulting model:

We have also empirically characterized the avoiding reaction against obstacles, which is a combination of hydrodynamic interaction and physiological reaction (4).

We are pursuing this project in different directions:

1) Physiological control of motility. Our working hypothesis (resulting from our modeling analysis (3)) is that a differential calcium sensitivity of cilia leads to asynchronous reversal across the body during the action potential, resulting in turning. Proper experimental demonstration is tricky (calcium imaging, high-speed recording of ciliary movement, tracking of movement and orientation), but doable. For this, we are developing deep learning video analysis tools.

2) Genetics. We are looking for the molecular basis of sensory transduction (in particular the mechanoreceptors, which are unknown), using RNA interference (inhibiting gene expression by feeding) and behavioral screening of mutants. We are also trying to develop a genetically encoded calcium indicator.

3) Behavioral and physiological plasticity in ecological situations. We are exploring different situations where Paramecium exhibits some form of behavioral adaptation (see (2)). One is thermotaxis: Paramecium moves towards the temperature it has been previously adapted to. It also adapts to changes in extracellular ionic composition. Another one is the escape from confined regions: when confined in a capillary, it hits the dead end back and forth, repeatedly, until after a minute it escapes with long backward swimming. Yet another one is conditioning: Paramecium is trained to react to sounds by pairing them with electrical stimulation. In each case, we try to build integrative models of the phenomenon.

We are interested in prospective Master and PhD students (contact me). We are also welcoming collaborations. For example, we have lots of videos that we think are great material to train deep learning networks (to extract 3D orientation and 3D posture, cilia reversal, collision detection, etc).

Finally, we are happy to help anyone who wants to get started on Paramecium research in their own lab, including hosting visitors in our labs to learn experimental techniques. A good place to start is ParameciumDB, which is a genomics database but also hosts a wiki with experimental techniques. We have also shared movies of swimming paramecia as well as electrophysiological data and code for both the model and the analyses along with our modeling paper (3).

Relevant publications (chronological order):

1. Kulkarni A, Elices I, Escoubet N, Pontani L, Prevost AM, Brette R (2020). A simple device to immobilize protists for electrophysiology and microinjection.
2. Brette R (2021). Integrative Neuroscience of Paramecium, a “Swimming Neuron”.
3. Elices I, Kulkarni A, Escoubet N, Pontani LL, Prevost AM, Brette R (2022). An electrophysiological and kinematic model of Paramecium, the "swimming neuron".
4. Escoubet N, Brette R, Pontani LL, Prevost A (2023). Interaction of the mechanosensitive microswimmer Paramecium with obstacles.