Object recognition in the visual cortex is based on a hierarchical architecture, in which specialized brain regions along the ventral pathway extract object features of increasing levels of complexity, accompanied by greater invariance in stimulus size, position, and orientation. Recent theoretical studies postulate a non-linear pooling function, such as the maximum (MAX) operation could be fundamental in achieving such invariance. In this paper, we are concerned with neurally plausible mechanisms that may be involved in realizing the MAX operation. Four canonical circuits are proposed, each based on neural mechanisms that have been previously discussed in the context of cortical processing. Through simulations and mathematical analysis, we examine the relative performance and robustness of these mechanisms. We derive experimentally verifiable predictions for each circuit and discuss their respective physiological considerations.

In the spinal cord, an intricate neural network generates and coordinates the patterning of limb movements during locomotion. This network, known as the locomotor central pattern generator (CPG), comprises of various cell populations that together orchestrate the output of motor neurons. Identification of CPG neurons through their specific gene expression is a valuable tool that can provide considerable insight to the character, intrinsic properties and role of a population, which represents a step toward understanding locomotor circuit function and correlating neural activity to behaviour. We selectively targeted two inhibitory CPG populations to investigate their molecular characteristics, circuitry and functional role; Renshaw cells (RCs) marked by their specific expression of the cholinergic nicotinic receptor α2 (Chrna2) and a subset of the dI6 population derived by their selective expression of the Doublesex and mab-3 related transcription factor 3 (Dmrt3). We found that RCs have hyperpolarisation-activated cation (Ih) and small calcium-activated potassium (ISK) modulatory currents that differentially regulate their excitation and firing properties, which influence the instantaneous feedback to motor neurons through the recurrent inhibition circuit. Due to previous difficulties isolating RCs from the surrounding locomotor circuits, their functional role remains poorly defined. For the first time, we selectively silenced RC inhibition and found that all aspects of motor behaviour, including coordination and gait were normal. The deletion of RC signalling instead altered the electrical and synaptic properties of the recurrent inhibitory circuit, suggesting that developmental plasticity compensates for the loss of RC inhibition. We reveal Dmrt3 neurons comprise a population of glycinergic inhibitory, spike-frequency adapting commissural interneurons active during locomotion. Conditional silencing of the Dmrt3 population resulted in considerable gait abnormalities in the neonatal and adult mouse. This manifested as an uncoordinated CPG output in vitro, impaired limb coordination in pups and increased fore- and hindlimb synchrony in adults that was exacerbated at faster locomotor speeds. Dmrt3 mediated inhibition subsequently impacts locomotion and suggests the Dmrt3 population contribute to coordinating speed dependent left-right limb alternation. This thesis provides cellular, circuit and behavioural insights into the Renshaw cell and Dmrt3 populations and enhances our knowledge regarding their probable function within the locomotor CPG.

Muscle fatigue is ubiquitous in every day life.Muscle fatigue might be considered as an altered state of motor behaviour, which impairs motor performance. By contrast, muscle fatigue could also be considered a positive phenomenon, which protects muscle tissue from damage that might be incurred to it by overuse. The principal aim of the thesis was to explore some of the mechanisms of muscle fatigue at the spinal level in animal models.The activation of multiple motor units of a single calf muscle may influence contractile properties of its neighbouring, otherwise inactive units, providing evidence for spatial spreading of fatigue between different muscle parts. The release of metabolites, their action on inactive muscle units and the effects of local hypoxia are the most likely causes. Fatigue-induced metabolite shift in the interstitium provokes excitation and/or sensitisation of high-threshold afferent fibers, with complex effects on the spinal premotoneuronal network involved in the modulation of motoneuronal output. This was examined by studing the intrasegmental lamellar distribution of the lumbar spinal interneurons following fatiguing contractions of the triceps surae muscle. Furthermore, fatigue of calf muscles enhanced the activity of fusimotor neurons to these muscles irrespective of the regime of muscle activity (isometric vs. lengthening) in conditions that simulate locomotion. Altered fusimotor activity, through increased or maintained muscle spindle afferent responsiveness may be advantageous, providing support to the skeletomotor activity and enhanced information about muscle periphery to higher nervous centres. The particular effects of interneuronal network at motor input (presynaptic inhibition system) and output (recurrent inhibition system) stages were then addressed. Fatigue of triceps surae muscle induced a suppression of the monosynaptic reflex. The intensity of presynaptic inhibition increased, while the intensity of recurrent inhibition decreased. Post fatigue-evoked changes in monosynaptic reflexes and presynaptic inhibition indicate the possibility that high-threshold afferents inhibit group Ia terminals pre-synaptically, which would allow fatigue-induced signals from the muscle to reduce the relevance of proprioceptive feedback. Besides intrasegmental, intersegmental spreading of nociceptive signals was explored. Activation of sensory afferents from dorsal neck muscles by capsaicin induces powerful activation of interneurons located in the cervical spinal cord, as well as a widespread activation of cells in lumbar spinal cord segments. The results confirm the pivotal role of small diameter muscle afferents in the orchestration of segmental responses to fatigue and show complex interactions that may lead to limited accuracy of motor output. They also depict processes that may be related to, and even become precursors of chronic muscle pain.

Movement is central for life, and all animals depend on accurate regulation of movement for purposeful behavior. There is great diversity of movements, ranging between simple and vital breathing movements to minute and subtle movements of the face used to communicate emotions. Consequently, motor neurons, which are the only route of central nervous system output, are essential for all motor behaviors. To control the many motor behaviors expressed by an animal, motor neurons are exposed to a large number and variety of modulating synaptic inputs and have evolved into subtypes with specific functions. In this thesis, motor neuron subtypes and the synaptic input to motor neurons from Renshaw cells and Ia afferents have been studied. Novel molecular markers that identify subtypes of motor neurons are described. Three markers, Chodl, Calca and ERRβ, have been used to study the degeneration of subtypes of motor neurons in a mouse model of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Another marker, 5-ht1d, has been used to record the electrophysiological character of gamma motor neurons. In mice that lack 5-ht1d, motor neurons develop with reduced proprioceptive input. Remarkably, these mice had fewer foot faults than control animals when challenged to cross a narrow beam suggesting that the amplitude of monosynaptic proprioceptive input to motor neurons is not essential for motor coordination. In a final set of experiments, genetic removal of vesicular transport of neurotransmitter from Renshaw cells suggest that Renshaw cells are not integral for motor circuit function or motor behaviors. However, they are involved in the development of motor circuits in the spinal cord. Together, this thesis provides novel molecular tools for studies of motor neuron subtypes and novel data regarding the development and function of spinal motor circuits.

No description available.

No description available.

Κύριος στόχος της εργασίας ήταν η συγκριτική μελέτη της παλίνδρομης αναστολής μεταξύ του ραχιαίου και του κοιλιακού πόλου του ιππόκαμπου αρουραίου. Χρησιμοποιήθηκε η μεθοδολογία της in vitro διατήρησης τομών ιππόκαμπου και εξωκυττάριων καταγραφών προκλητών δυναμικών πεδίου. Τα αποτελέσματά μας έδειξαν ότι η GABAA εξαρτώμενη παλίνδρομη αναστολή είναι ασθενέστερη, έχει μικρότερη διάρκεια και φθίνει πιο γρήγορα στον κοιλιακό σε σχέση με το ραχιαίο ιππόκαμπο. Χρησιμοποιώντας διάφορα φάρμακα που δρουν ενισχυτικά στον GABAA υποδοχέα δείξαμε ότι υπάρχει λειτουργική διαφοροποίηση του GABAA εξαρτώμενου ανασταλτικού μηχανισμού μεταξύ των δύο πόλων του ιππόκαμπου, ενισχύοντας την υπόθεση της λειτουργικής διαφοροποίησης στο επίπεδο του υποδοχέα μεταξύ των δύο πόλων. Στην in vivo μελέτη, χρησιμοποιώντας το μοντέλο επαγωγής επιληπτικών κρίσεων με χορήγηση πεντυλενοτετραζόλης, δείξαμε ότι η ενίσχυση της GABAA εξαρτώμενης αναστολής απο τα κατασταλτικά φάρμακα συσχετίζεται με το μέγεθος της αντιεπιληπτικής τους δράσης. Επιπλέον, η βιταμίνη D δεν παρουσίασε αντιεπιληπτική δράση στους C57BL/6J μύες, ούτε ενίσχυσε την αναστολή, κάτι που δείχνει ότι δεν έχει επίδραση στον GABAA υποδοχέα ή, τουλάχιστον, στους υπότυπούς του στον ιππόκαμπο. / The major aim of this work was the comparative study of recurrent inhibition between the dorsal and ventral pole of the rat hippocampus. We used the methodology of in vitro maintenance of hippocampal slices and recording of evoked field potentials. We showed that the GABAA mediated recurrent inhibition is weaker, lasts less and decays faster in ventral than in dorsal hippocampus. Using various drugs that act as positive allosteric modulators of the GABAA receptor, we showed that there is a functional differentiation of the GABAA inhibitory mechanism between the two hippocampal poles, strengthening the hypothesis of the functional differentiation at the level of the receptor between the two poles. In the in vivo study, using the pentylenetetrazole model for inducing epileptic seizures, we showed that the enhancement of the GABAA mediated recurrent inhibition correlates with the strength of antiepileptic action of the sedative drugs used. In addition vitamin D did not show antiepileptic action in C57BL/6J mice. Moreover it didn’t enhance recurrent inhibition, showing that it doesn’t have any action on the GABAA receptor or, at least, on its subtypes in hippocampus.

Συναπτική διέγερση και αναστολή βρίσκονται σε συνεχή δυναμική ισορροπία, απαραίτητη για την καλή λειτουργία του ΚΝΣ. Ένα από τα βασικά ανασταλτικά κυκλώματα του εγκεφάλου είναι αυτό της παλίνδρομης αναστολής. Το πιο χαρακτηριστικό, ίσως, παράδειγμα του κυκλώματος αυτού βρίσκεται στη CA1 περιοχή του ιππόκαμπου, η οποία προσφέρεται για ηλεκτροφυσιολογικές μελέτες in vitro, λόγω της στρωματοειδούς οργάνωσης των κυκλωμάτων ιππόκαμπου. Πρόσφατες έρευνες έχουν δείξει διαφορές στη δομή και λειτουργία των δύο πόλων του ιππόκαμπου, καθιστώντας αναγκαία τη συγκριτική τους μελέτη. Στην εργασία αυτή χρησιμοποιήθηκαν εξωκυττάριες καταγραφές από την πυραμιδική στοιβάδα σε συνδυασμό με το πρωτόκολλο διπλού ορθόδρομου ερεθισμού (περιορισμένα) και το πρωτόκολλο αντίδρομου-ορθόδρομου ερεθισμού (εκτενέστερα) για τη μελέτη του πλάτους και της διάρκειας της παλίνδρομης αναστολής σε τομές ραχιαίου και κοιλιακού ιππόκαμπου από αρσενικούς επίμυες, καθώς και της επίδρασης επί αυτής μιας σειράς καταπραϋντικών φαρμάκων που δρουν ως αλλοστερικοί ενισχυτές του GABAA υποδοχέα. Τα αποτελέσματα των πειραμάτων έδειξαν: Επαλήθευση της στρωματοειδούς οργάνωσης των κυκλωμάτων του ιππόκαμπου, με μεγαλύτερη κατευθυντικότητα των ανασταλτικών κυκλωμάτων στο ραχιαίο σε σχέση με τον κοιλιακό πόλο. Μεγαλύτερο πλάτος και διάρκεια και πιο αργή μείωση της παλίνδρομης αναστολής γενικά, και της GABAA συνιστώσας της ειδικότερα, στο ραχιαίο σε σχέση με τον κοιλιακό ιππόκαμπο. Ενίσχυση της παλίνδρομης αναστολής και στους δύο πόλους του ιππόκαμπου από διαζεπάμη, μιδαζολάμη, ζολπιδέμη, φαινοβαρβιτάλη, θειοπεντάλη, πεντοβαρβιτάλη, αλφαξαλόνη και προποφόλη. Συσχέτιση της αύξησης του πλάτους της αναστολής και της διάρκειας της ενίσχυσής της με την κλινική δράση της κάθε συγκέντρωσης φαρμάκου. Ενίσχυση της αποκλειστικά GABAA εξαρτώμενης αναστολής από υψηλές συγκεντρώσεις θειοπεντάλης και αλφαξαλόνης που δοκιμάστηκαν ενδεικτικά πολύ πέρα από τα φυσιολογικά χρονικά όριά της. Μεγαλύτερη διάρκεια ενίσχυσης της συναπτικής αναστολής από τις σχετικά υψηλότερες δόσεις φαρμάκων στο ραχιαίο σε σχέση με τον κοιλιακό πόλο. Έλλειψη δράσης του νευροστεροειδούς αλλοπρεγνανολόνη και των συνθετικών παραγώγων του στη συναπτική αναστολή. Περιορισμένος αριθμός in vivo πειραμάτων εκτίμησης της επίδρασης της αλλο-πρεγνανολόνης και των παραγώγων της στην αναστολή με το μοντέλο ελέγχου επιληπτικών κρίσεων που προκαλούνται από PTZ έδειξε πως, ενώ τα συνθετικά παράγωγα δεν είχαν καμία δράση, η αλλοπρεγνανολόνη είχε σημαντική θετική δράση / Synaptic excitation and inhibition are maintained in dynamic equilibrium, necessary for the proper function of the CNS. One of the basic inhibitory circuits of the brain is that of recurrent inhibition. The most distinctive example of recurrent inhibition occurs in the CA1 region of the hippocampus, a region particularly suited to in vitro electrophysiological investigations because of the unique lamellar organization of hippocampal circuits. Recent research has uncovered considerable differences in the structure and function of the two poles of the hippocampus necessitating a comparative study. In this study we used extracellular recordings from the pyramidal cell layer of dorsal and ventral rat hippocampal slices, in conjunction with limited use of the double orthodromic and more extensive use of the paired antidromic-orthodromic stimulation protocol in order to study the CA1 recurrent inhibition and the effects of a series of sedative drugs, with GABAA allosteric modulator properties, on it. The results of these experiments showed: A verification of the lamellar organization of hippocampal circuits. Dorsal pole inhibitory circuits showed a greater orientation specificity than ventral pole ones. A greater size and duration and a slower decay of recurrent inhibition in general, and of its GABAA-mediated component in particular, in dorsal compared to ventral hippocampus. An enhancement of recurrent inhibition in both hippocampal poles produced by diazepam, midazolam, zolpidem, phenobarbital, thiopental, pentobarbital, alfaxalone and propofol. A correlation between the enhancement of the size of recurrent inhibition or the duration of its enhancement and the clinical actions of every drug concentration tested. An enhancement of the exclusively GABAA-mediated recurrent inhibition by representative high concentrations of thiopental and alfaxalone well beyond its normal duration. A greater duration of recurrent inhibition enhancement by the relatively higher drug concentrations in dorsal compared to ventral hippocampus. A lack of action on synaptic inhibition by the neurosteroid allopregnanolone and its synthetic derivatives. A limited number of in vivo experiments assessing the effect of allopregnanolone and its derivatives on synaptic inhibition, measured as their ability to control epileptic seizures induced by acute injections of PTZ, showed that the synthetic derivatives had no effect whereas allopregnanolone had a significant positive effect.

Despite years of research, females continue to have a higher incidence of non-contact ACL injuries. One of the major findings of this research is that males and females perform certain tasks, such as, cutting, landing, and single-leg squatting, differently. In particular, females tend to move the knee into a more valgus position; a motion putting the ACL at risk for injury. Yet the underlying spinal control mechanisms modulating this motion are unknown. Additionally, the mechanisms regulating the ability to rapidly initiate and produce maximal torque are also unknown. Therefore, the purpose was to: 1) determine if the sexes modulate spinal control differently, 2) examine the contributions of spinal control mechanisms to valgus knee motion, and 3) identify contributions of spinal control to the ability to rapidly produce force. The spinal control variables were the first derivative of the Hoffmann (H)-reflex, the first derivative of extrinsic pre-synaptic inhibition (EPI), the first derivative of intrinsic pre-synaptic inhibition (IPI), recurrent inhibition (RI), and V-waves. To assess the neuromuscular system’s ability to rapidly activate, rate of torque development (RTD) and electromechanical delay (EMD) were measured. Lastly, valgus motion was determined by the frontal plane projection angle (FPPA). The results reveal males and females do modulate spinal control differently; specifically males had an increased RTD, which is the slope of the torque-time curve, and increased RI, which is a post-synaptic regulator of torque output. However, the spinal control mechanisms did not significantly contribute to FPPA at the knee. EMD which is the time lag from muscle activity to torque production was significantly predicted by the spinal control mechanisms. Specifically, EPI, a modulator of afferent inflow from peripheral and descending sources, IPI, a regulator of Ia afferent inflow, and sex significantly contributed to EMD. Lastly, the spinal control mechanisms significantly contributed to RTD. Specifically, IPI, sex, and V-waves, a measure of supraspinal drive, all significantly contributed to RTD. / Graduation date: 2009

L'objectif de ce travail de thèse est d'étudier d'une part les spécificités de la commande nerveuse lors de la contraction excentrique en explorant les mécanismes impliqués au niveau spinal et d'autre part d'examiner les mécanismes nerveux responsables de la plasticité du système neuromusculaire après un entraînement de force excentrique sous-maximal. A travers ce travail de thèse, nous mettons en évidence la contribution de l'inhibition récurrente à la réduction de l'activation musculaire classiquement observée lors de la contraction excentrique. Par ailleurs, nous montrons que l'inhibition récurrente est majorée lors des contractions sous-maximales indépendamment du mode de contraction. Ces résultats soulignent le rôle important de l'inhibition récurrente dans la spécificité de la commande nerveuse lors de la contraction excentrique. Nous confirmons que le pilotage nerveux de la contraction excentrique peut être modulé par l'entraînement de force excentrique même si les modulations de l'excitabilité spinale semblent dépendre des caractéristiques de l'entraînement. / The purpose of this PhD research is, on the one hand, to study the neural drive specificities during eccentric contractions by exploring the neural mechanisms involved at spinal level and, on the other hand, to examine the neural mechanisms responsible for the modulations of neuromuscular system following a strength submaximal eccentric training. Through this PhD research we highlight the contribution of recurrent inhibition by the Renshaw cell to the decrease of muscular activation typically observed during eccentric contraction. Furthermore, we show that recurrent inhibition is enhanced during submaximal contractions regardless of the contraction type. These results emphasize the important role of recurrent inhibition in the specificity of neural control during eccentric contractions. We confirm that the neural drive of the eccentric contraction may be modulated by eccentric strength training although modulations of spinal excitability seem to depend on the characteristics of training.