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Draft:François Clarac

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François Clarac

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Introduction

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François Clarac
Known forRole of peripheral proprioceptors in crustacean reflex behaviors

Discovery of location of the rat lumbar spinal cord central pattern generator

Circuit organization of the central pattern generator

Synaptic mechanisms underlying entrainment of central pattern generator state

Electrophysiology
AwardsAcademy of Sciences Prize Academia Europea Prize
Scientific career
FieldsMotor neuroscience
InstitutionsAix-Marseille University, University of Montpellier

François Clarac is a neuroethologist and neuroscientist at Aix-Marseille University. Clarac’s research focuses on the cellular and molecular mechanisms in the central and peripheral nervous system governing the generation of locomotor behavior in crustaceans and rats. His lab’s work in crustaceans focused on the role of peripheral proprioceptors in reflex behaviors, the circuits connecting sensory neurons with the central pattern generator (CPG) in the thoracic ganglia, and the modulation of motor output by the CPG. His lab was also among the first to identify the location of the lumbar CPG of the rat spinal cord and the role of neuromodulators in driving rhythmic output firing.

Career and honors

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Clarac spent his career at Aix-Marseille University leading several labs and teaching neuroscience courses. He is a Member and Director Emeritus of the French National Centre for Scientific Research (CNRS) and a member of the Institut de Neurosciences des Systèmes at Aix-Marseille University.[1]. He has served as President of the Institute for Research on the Spinal Cord (IRME). He is also a member of the Academy of Sciences, Letters, and Arts of Marseille, where he has served as Secretary since 2018, Director in 2012 and 2014, and Chancellor in 2011[2]. He is currently retired and continues to teach at Aix-Marseille University and University of Montpellier[3].

He is the recipient of several honors, including the Academy of Sciences Prize and the Academia Europea Prize[3].

In addition to his research publications, he has authored two books with Jean-Pierre Ternaux. Encyclopédie Historique des Neurosciences (Historical Encyclopedia of Neuroscience) traces the historical development of neuroscience and the leaders whose discoveries have informed the modern understanding of brain function[4]. Le Bestiaire Cérébral (The Cerebral Bestiary) explores how the comparative study of animal nervous systems have informed the understanding of human brain function[5].

Research

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Clarac’s research studied the neural circuitry of peripheral proprioceptors and the central pattern generator of the spinal cord and how this circuitry generates locomotor behaviors. A majority of his lab’s research focused on crustaceans as simple model organisms whose neural circuitry could be dissected using electrophysiology, including rock lobsters (Jasus lalandii, Palinurus vulgaris), shore crabs (Carcinus mediterraenus, Carcinus maenas), and crayfish (Procambarus clarkii). His lab later translated their findings in crustaceans to more complex vertebrate species by studying the central pattern generator of newborn rats.

His lab’s research made several contributions to the understanding of how motor behavior is generated and regulated and can be categorized into four main areas of discoveries:

  1. Anatomy and connectivity of chordotonal organ proprioceptors involved in joint reflexes
  2. Sensory afferent innervation of thoracic ganglia and connectivity in reflex behaviors
  3. Bidirectional relationship between the central pattern generator and sensory afferents
  4. Neural and synaptic properties of central pattern generators

Anatomy and connectivity of chordotonal organ proprioceptors involved in joint reflexes

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Around the 1960’s, the field of motor neuroscience believed mechanisms in central nervous system (ie: brain and spinal cord) were the primary drivers of motor output. However, little attention had been paid to the peripheral sensing of motion and stance and how peripheral signaling can modify motor output[6]. To address this question, Clarac’s early research focused on mapping the neural anatomy and connectivity of crustacean chordotonal organs, multineuronal assemblies of bipolar cells embedded in the connective tissue of crustacean leg joints. As the principal proprioceptors of crustacean limbs, these sensory neurons act as stretch receptors that respond to changes in joint position and movement and encode this information during locomotor behaviors[7]. Clarac’s earliest research sought to describe the neuromuscular anatomy of crustacean joints. One study characterized the ischio-meropodite joint of Carcinus mediterraenus located at the base of the leg close to the thorax, revealing that the ischio-meropodite joint contained three chordotonal organs consisting of approximately 15-30 neurons[8]. Other studies also examined how different nerve roots emerging from the thoracic ganglia and their corresponding motor neurons innervate various muscles of the crab leg and the chordotonal organs of the joints[9].

Sensory afferent innervation of thoracic ganglia and connectivity in reflex behaviors

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Clarac’s lab was particularly interested in how afferent sensory neurons of the chordotonal organs influenced central motor neuron output. One of the primary functions of chordotonal organs is to induce stretch reflexes, automatic muscle responses triggered by stretching of sensory neurons that induce antagonistic muscle activity to resist force applied to a joint. Clarac’s research focused on how peripheral proprioceptors relay this information to induce changes in muscle function in both freely walking crustaceans and in vitro in intact chordotonal organs and thoracic ganglia using electrophysiology. His lab focused on three chordotonal organs and their role in mediating stretch reflexes in crustacean leg joints: the dactyl propriocepotor, the coxo-basipodite chordotonal organ, and the thoracic-coxal muscle chordotonal organ.

Dactyl proprioceptor modulation of muscle activity

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Focusing first on the dactyl, located at the tip of the crab leg, Dr. Clarac’s lab studied how induced strain on mechanoreceptors in the dactyl of Carcinus maenas influenced activity of muscles in the leg. Using electromyography to record the electrical activity in the mechanoreceptors and leg muscles of freely walking crabs, they demonstrated that the electrical activity in the depressor and extensor muscles within the trailing leg are coordinated in-phase with each other, while they are out of phase in the leading leg. Having established this sequence, they sought to understand how chronic strain on the dactyl mechanoreceptor influenced the activity and coordination of the other leg muscles. They found that dactyl strain led to alteration of several muscle group activities to favor lifting the leg, indicating that the activity from the dactyl mechanoreceptors were functionally connected across joints within the leg. They also found that imposing strain on the dactyl of one leg could alter activity of muscles in other legs, suggesting that the mechanoreceptor signals were relayed across thoracic segments by an undescribed central circuit[10]. These results demonstrated that stance and position information encoded by proprioceptor activity is relayed within and across legs to coordinate motor output.

Coxo-basipodite chordotonal organ synaptic connections with thoracic ganglia motor neurons

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In order to understand the neuronal basis of the relay they observed between leg proprioceptors and muscle groups within and across legs, Clarac’s lab went on to study the coxo-basipodite chordotonal organ and its involvement in the stretch reflex. The coxo-basipodite chordotonal organ is located near the base of the leg and is responsible for modulating activity of the muscles controlling leg lifting and depression. By tracing the axonal projections of the coxo-basipodite chordotonal organ sensory neurons, they demonstrated that these axons made direct contact to the motor neuron dendrites in the thoracic ganglia and that synaptic input from coxo-basipodite chordotonal organ sensory neurons could modify the motor output from these motor neurons onto specific muscle groups. Electrophysiology studies of these synaptic connections demonstrated that postsynaptic motor neurons form chemical monosynaptic and polysynaptic connections from up to eight different sensory neurons from the coxo-basipodite nerve fiber and that motor neurons received sequences of early and late excitatory post-synaptic potentials (EPSPs) as well as late inhibitory post-synaptic potentials (IPSPs). This study thus demonstrated that peripheral chordotonal organ input is integrated into motor neurons through multiple synaptic connections and that peripheral input can have varying effects on motor neuron activity[11].

Reversal of stretch reflex induced by the thoracic-coxal muscle chordotonal organ and coxo-basipodite chordotonal organ

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Clarac’s lab began to observe that the type of motor behavioral output triggered by chordotonal organ sensory input depended on the state of the thoracic ganglia. In their studies of the thoracic-coxal muscle chordotonal organ, located in the joint immediately exiting the thorax, they found that remotion (moving the limb backwards), modeled by stretching the thoracic-coxal muscle chordotonal organ, triggered promotor muscle activity in a typical resistance reflex (ie: inducing muscle activity against the applied force). However, in other experiments, remotion triggered remotor muscle activation in an assistance reflex (ie: inducing muscle activity to move in the same direction of the force). This apparent reversal of the stretch reflex suggested that the type of reflex triggered by chordotonal organ activation was mediated by the central state of the ganglia[12].

A similar finding was also observed in the coxo-basipodite chordotonal organ. El Manira et al. observed that the output reflex pattern (assistance or resistance) depended on whether the ganglion was tonically or rhythmically active. When the central state was tonically active (ie: firing constantly at a steady rate), stimulation of the coxo-basipodite chordotonal organ induced a resistance reflex, but when the central state was rhythmically active (ie: oscillating periods of high and low frequency firing), an assistance reflex was induced. They found that this change in reflex response was mediated, in part, by a centrally-derived action potential onto coxo-basipodite chordotonal organ sensory neurons that prevented their ability to generate an EPSP in a motor neuron[13]. These centrally-induced coxo-basipodite chordotonal organ afferent spikes, termed primary afferent depolarizations (PADs), were thus concluded to produce an inhibitory effect on the afferent sensory neuron, allowing the CPG to modify sensory neuron-driven reflex responses[14].

Bidirectional relationship between the central pattern generator and sensory afferents

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Clarac’s observation that the sign of stretch reflexes could be reversed led to further investigations of how central circuits in the thoracic ganglia of crustaceans and sensory afferents can affect each other’s function. These investigations revealed that the connections between the CPG and sensory afferents are bidirectional: the CPG can modify sensory input through presynaptic inhibition of sensory afferents and sensory inputs can modify rhythmic firing of CPG networks.

Presynaptic inhibition of afferents by the CPG

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Clarac’s lab demonstrated that the primary afferent depolarizations (PADs) generated by the CPG were mediated by GABAergic synapses formed by CPG-derived axons onto chordotonal organ sensory afferents. Electrophysiology studies showed that these GABAergic synapses increase chloride conductance and depolarize coxo-basipodite chordotonal organ sensory afferents, resulting in lower amplitude EPSPs in post-synaptic motor neurons of the CPG. Through this mechanism, chordotonal sensory neuron firing is decoupled from muscle activation, disrupting chordotonal organ reflex signaling[15][16]. Clarac’s lab proposed that the CPG uses this mechanism to prevent inappropriate automatic stretch reflexes from interfering with centrally-generated output motor programs.

Induction of oscillatory firing of CPG by sensory afferents

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Clarac’s lab also demonstrated that sensory afferent input from chordotonal organs regulates rhythmic activity of the CPG. By inducing rhythmic stretching of the thoracic-coxal muscle chordotonal organ in their in vitro preparation, chordotonal organ sensory input was found to enhance and entrain rhythmic firing of motor neurons in the proximal ganglion and adjacent ganglia[17][18]. His lab’s research would later seek to identify the precise synaptic mechanisms regulating rhythmic firing of thoracic ganglia CPGs.  

Neural and synaptic properties of central pattern generators

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As his lab began to reveal the reciprocal ability of sensory afferents and the CPG to influence each other, his research became focused on uncovering the mechanisms underlying the rhythmic properties of the CPG while also translating these findings into higher order mammalian species.

Role of cholinergic input and motor neuron properties in rhythmic activity of the crayfish CPG

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While Clarac’s previous studies showed that input from afferent sensory neurons of chordotonal organs can induce or enhance rhythmic activity of motor neurons of the thoracic ganglion CPG, the types of synaptic inputs into the central circuit were not known. His lab and others would go on to show that two factors drive rhythmic firing of the CPG: cholinergic input from sensory afferents and pacemaker properties of motor neurons. They found that when an isolated thoracic ganglion preparation was incubated with a cholinergic agonist, the motor neuron output from the thoracic ganglion shifted from tonic to rhythmic firing. When they monitored intracellular membrane potential of motor neurons in these same preparations, they found that motor neurons had regenerative, or oscillatory, firing properties in the presence of the cholinergic agonist[19]. They therefore concluded that cholinergic afferent input increases the excitability of central motor neurons, bringing motor neuron membrane potential to threshold for oscillatory firing. This observation was significant because it established motor neurons and their electrical properties as a main component of the CPG pacemaker.

Motor neuron coupling and interneurons in crayfish CPG

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Later studies revealed that oscillatory firing of the CPG was also supported by electrical coupling of CPG motor neurons via gap junctions. Clarac’s lab found that when one motor neuron of any nerve fiber was depolarized or hyperpolarized, the membrane potential of neighboring motor neurons changed by an equal magnitude. This indicated that motor neurons of the CPG are electronically coupled via gap junctions[20]. They also demonstrated that motor neurons of antagonistic muscles have an inhibitory connection mediated by interneurons. When the interneuron is at its normal membrane potential, antagonistic motor neurons can inhibit one another, but when the interneuron is depolarized and unable to fire action potentials, the inhibitory relationship between antagonistic motor neurons is abolished[20].

These studies were thus some of the first to identify key components of the crayfish CPG:

  1. Motor neurons positioned around the perimeter of the thoracic ganglion have intrinsic oscillatory properties that are enhanced by depolarizing sensory input.
  2. Electronic coupling of adjacent motor neurons through gap junctions coordinates the rhythmic output across the motor neuron population.
  3. Interneurons innervating the center of the thoracic ganglion mediate the inhibitory relationship between antagonistic motor neurons, allowing coordinated activation of muscles for the desired locomotor output.

Studies of oscillatory firing and the location of the rat lumbar CPG

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Clarac’s lab also sought to translate their findings in the crustacean CPG into more complex vertebrate species, focusing on rats. Similar to how cholinergic input drives oscillatory activity of the crayfish CPG, Clarac’s lab discovered that serotonin and excitatory amino acid neurotransmitters like NMDA can drive rhythmic firing in the rat spinal cord. Their studies showed that 5-HT can induce oscillatory firing of motor neurons in the ventral root through activation of 5-HT1 and 5-HT2 metabotropic receptors and subsequent activation of NMDA and AMPA receptors[21]. Thus, like the crayfish CPG, the rat lumbar spinal cord CPG was driven by depolarizing input that brought CPG motor neurons to threshold for oscillatory firing.

His lab was also the first to discover that the CPG of the rat lumbar spinal cord was located in the L1 and L2 segments. By insulating specific segments of the lumbar spinal cord and selectively applying NMDA and serotonin to these segments, Clarac’s lab found that oscillatory firing from all lumbar roots was only produced when L1 and L2 segments were incubated with NMDA and serotonin. In addition, when the spinal cord was divided longitudinally below L2, rhythmic motor output was still detected in the lower lumbar roots, indicating that the CPG in L1 and L2 forms parallel monosynaptic connections with motor neurons in the left and right lumbar roots[22]. This study thus demonstrated that CPG circuitry of the rat lumbar spinal cord is centered in L1 and L2 and forms parallel axonal projections to the lower lumbar roots.

Legacy and contribution to the field

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Clarac’s research helped open new lines of investigation that continue to provide insights into the complex mechanisms controlling motor behavior. Clarac’s discoveries of the intersegmental coordination of motor output in crayfish and the role of interneurons in CPG signaling have since been further refined by the discoveries of specific motor neuron and interneuron subpopulations that encode specific parameters of motor output, like strength, speed, and timing[23]. His discoveries of the role of neuromodulators in modulating the state of the CPG also helped establish the CPG as a useful model to study neural network organization and state in the field of network neuroscience. Neuromodulators continue to be recognized as crucial synaptic signaling mechanisms stabilizing and regulating the state of the CPG to encode specific motor behavior parameters[24]. Finally, since his lab’s discovery of the location and organization of the rat lumbar CPG, the field of motor neuroscience has begun to understand how human motor neuron populations in the lumbar segments develop and become active over the course of human lifespan and during motor behavior development[25]

References

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  1. ^ "Academy of Europe: Clarac François". www.ae-info.org. Retrieved 2024-12-01.
  2. ^ "CLARAC François Académie Marseille Sciences Lettres Arts". www.academie-sla-marseille.fr (in French). Retrieved 2024-12-01.
  3. ^ a b "François Clarac". De Boeck Supérieur (in French). 2022-10-12. Retrieved 2024-12-01.
  4. ^ Clarac, François; Ternaux, Jean-Pierre; Buser, Pierre (2008). Encyclopédie historique des neurosciences: du neurone à l'émergence de la pensée. Neurosciences et cognition. Bruxelles [Paris]: De Boeck. ISBN 978-2-8041-5898-9.
  5. ^ Clarac, François; Ternaux, Jean-Pierre (2012). Le bestiaire cérébral: des animaux pour comprendre le cerveau humain. Paris: CNRS éd. ISBN 978-2-271-07385-3.
  6. ^ CLARAC, F.; DANDO, M. R. (May 1973). "Tension Receptor Reflexes in the Walking Legs of the Crab Cancer pagurus". Nature. 243 (5402): 94–95. doi:10.1038/243094a0. ISSN 0028-0836. PMID 4706635.
  7. ^ El Manira, A.; DiCaprio, R. A.; Cattaert, D.; Clarac, F. (December 1991). "Monosynaptic Interjoint Reflexes and their Central Modulation During Fictive Locomotion in Crayfish". European Journal of Neuroscience. 3 (12): 1219–1231. doi:10.1111/j.1460-9568.1991.tb00056.x. ISSN 0953-816X. PMID 12106221.
  8. ^ Clarac, F. (1968). "Proprioceptor anatomy of the ischio-meropodite region in legs of the crab Carcinus mediterraneus C." Zeitschrift f�r Vergleichende Physiologie. 61 (2): 203–223. doi:10.1007/bf00341116. ISSN 0340-7594. {{cite journal}}: replacement character in |journal= at position 14 (help)
  9. ^ Bévengut, M.; Simmers, A. J.; Clarac, F. (December 1983). "Central neuronal projections and neuromuscular organization of the basal region of the shore crab leg". Journal of Comparative Neurology. 221 (2): 185–198. doi:10.1002/cne.902210207. ISSN 0021-9967. PMID 6655081.
  10. ^ Libersat, F.; Clarac, F.; Zill, S. (1987-05-01). "Force-sensitive mechanoreceptors of the dactyl of the crab: single-unit responses during walking and evaluation of function". Journal of Neurophysiology. 57 (5): 1618–1637. doi:10.1152/jn.1987.57.5.1618. ISSN 0022-3077. PMID 3585482.
  11. ^ El Manira, A.; Cattaert, D.; Clarac, F. (March 1991). "Monosynaptic connections mediate resistance reflex in crayfish (Procambarus clarkii) walking legs". Journal of Comparative Physiology A. 168 (3): 337–349. doi:10.1007/bf00198353. ISSN 0340-7594.
  12. ^ DiCaprio, R. A.; Clarac, F. (1981-02-01). "Reversal of a Walking Leg Reflex Elicited by a Muscle Receptor". Journal of Experimental Biology. 90 (1): 197–203. doi:10.1242/jeb.90.1.197. ISSN 0022-0949.
  13. ^ El Manira, A.; DiCaprio, R. A.; Cattaert, D.; Clarac, F. (December 1991). "Monosynaptic Interjoint Reflexes and their Central Modulation During Fictive Locomotion in Crayfish". European Journal of Neuroscience. 3 (12): 1219–1231. doi:10.1111/j.1460-9568.1991.tb00056.x. ISSN 0953-816X. PMID 12106221.
  14. ^ Cattaert, D.; ElManira, A.; Marchand, A.; Clarac, F. (January 1990). "Central control of the sensory afferent terminals from a leg chordotonal organ in crayfish in vitro preparation". Neuroscience Letters. 108 (1–2): 81–87. doi:10.1016/0304-3940(90)90710-q. ISSN 0304-3940. PMID 2304643.
  15. ^ Cattaert, D.; el Manira, A.; Clarac, F. (1992-03-01). "Direct evidence for presynaptic inhibitory mechanisms in crayfish sensory afferents". Journal of Neurophysiology. 67 (3): 610–624. doi:10.1152/jn.1992.67.3.610. ISSN 0022-3077. PMID 1578247.
  16. ^ El Manira, A.; Clarac, F. (December 1991). "GABA-Mediated Presynaptic Inhibition in Crayfish Primary Afferents by Non-A, Non-B GABA Receptors". European Journal of Neuroscience. 3 (12): 1208–1218. doi:10.1111/j.1460-9568.1991.tb00055.x. ISSN 0953-816X. PMID 12106220.
  17. ^ Sillar, Keith T.; Skorupski, Peter; Elson, Robert C.; Bush, Brian M. H. (October 1986). "Two identified afferent neurones entrain a central locomotor rhythm generator". Nature. 323 (6087): 440–443. doi:10.1038/323440a0. ISSN 0028-0836.
  18. ^ Sillar, Keith T.; Clarac, François; Bush, Brian M. H. (1987-09-01). "Intersegmental Coordination of Central Neural Oscillators for Rhythmic Movements of the Walking Legs in Crayfish, Pacifastacus Leniusculus". Journal of Experimental Biology. 131 (1): 245–264. doi:10.1242/jeb.131.1.245. ISSN 0022-0949.
  19. ^ Chrachri, A.; Clarac, F. (June 1987). "Induction of rhythmic activity in motoneurons of crayfish thoracic ganglia by cholinergic agonists". Neuroscience Letters. 77 (1): 49–54. doi:10.1016/0304-3940(87)90605-7. ISSN 0304-3940. PMID 3601216.
  20. ^ a b Chrachri, A.; Clarac, F. (1989-12-01). "Synaptic connections between motor neurons and interneurons in the fourth thoracic ganglion of the crayfish, Procambarus clarkii". Journal of Neurophysiology. 62 (6): 1237–1250. doi:10.1152/jn.1989.62.6.1237. ISSN 0022-3077. PMID 2600622.
  21. ^ Cazalets, J R; Sqalli-Houssaini, Y; Clarac, F (September 1992). "Activation of the central pattern generators for locomotion by serotonin and excitatory amino acids in neonatal rat". The Journal of Physiology. 455 (1): 187–204. doi:10.1113/jphysiol.1992.sp019296. ISSN 0022-3751. PMC 1175639. PMID 1362441.
  22. ^ Cazalets, JR; Borde, M; Clarac, F (1995-07-01). "Localization and organization of the central pattern generator for hindlimb locomotion in newborn rat". The Journal of Neuroscience. 15 (7): 4943–4951. doi:10.1523/jneurosci.15-07-04943.1995. ISSN 0270-6474. PMC 6577873. PMID 7623124.
  23. ^ Smarandache-Wellmann, Carmen; Grätsch, Swantje (2014-04-16). "Mechanisms of Coordination in Distributed Neural Circuits: Encoding Coordinating Information". The Journal of Neuroscience. 34 (16): 5627–5639. doi:10.1523/JNEUROSCI.2670-13.2014. ISSN 0270-6474. PMC 6608233. PMID 24741053.
  24. ^ Harris-Warrick, Ronald M (October 2011). "Neuromodulation and flexibility in Central Pattern Generator networks". Current Opinion in Neurobiology. 21 (5): 685–692. doi:10.1016/j.conb.2011.05.011. PMC 3171584. PMID 21646013.
  25. ^ Avaltroni, Priscilla; Cappellini, Germana; Sylos-Labini, Francesca; Ivanenko, Yury; Lacquaniti, Francesco (2024-07-23). "Spinal maps of motoneuron activity during human locomotion: neuromechanical considerations". Frontiers in Physiology. 15. doi:10.3389/fphys.2024.1389436. ISSN 1664-042X. PMC 11300930. PMID 39108539.
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