Nervous systems distinguish between self- and other-generated movements by monitoring discrepancies between planned and performed actions. To do so, when motor systems transmit motor commands to muscles, they simultaneously transmit motor copies, or corollary discharges, to sensory areas. There, corollary discharge signals are compared to sensory feedback arising from movements (reafference), which can result in gating of expected feedback. Curiously, in infant rats, twitches—which are self-generated movements produced exclusively and abundantly during active sleep (AS)—differ from wake-movements in that they trigger robust neural activity. Accordingly, we hypothesized that the gating actions of corollary discharge that predict wake reafference are suspended during twitching. In this dissertation, we first demonstrate that twitches, but not wake movements, robustly activate sensorimotor cortex as they do other brain areas. Next, we demonstrate that wake movements can activate the sensorimotor cortex under conditions involving presumed discrepancies between corollary discharge and reafference signals. Lastly, we reveal a neural mechanism in the brainstem that inhibits reafference, but only during wakefulness; this inhibitory mechanism is suppressed during active sleep. All together, our findings provide the first demonstration of a state-dependent neural comparator of planned and performed actions, one that permits the transmission of sensory feedback from self-generated twitches to the developing nervous system.

Developing animals primarily receive two kinds of somatosensory input. One arises from stimulation in the external environment (“exafference”) and the other arises from self-produced movements (“reafference”), especially those associated with the myoclonic twitches during active sleep. Neural recordings have shown that exafferent and reafferent neural signals activate sensorimotor structures throughout the brain, but it is not known whether twitches are accompanied by corollary discharge that inform the nervous system that twitches are self-generated. Recordings from the cerebellum in infant rats suggested that motor structures could be conveying twitch-related corollary discharge signals to the cerebellum. If true, one would expect to see evidence of corollary discharge in the precerebellar nuclei. We hypothesized that two precerebellar nuclei: the inferior olive (IO) and the lateral reticular nucleus (LRN), receive corollary discharge associated with the production of twitches. We tested the hypothesis by recording spontaneous activity of the IO and LRN during sleep and wake in infant rats. In the majority of IO units, and in a subset of LRN units, neural activity was particularly pronounced at the time of twitch onset. This activity was remarkably precise, reaching a peak in firing within ±10 ms of a twitch. This unique pattern suggested that, unlike sensory areas that receive reafference from twitches, these two structures receive corollary discharge associated with the production of twitches. Next, using anatomical tracing, immunohistochemistry, and neurophysiology, we identified non-overlapping premotor areas in the midbrain that send corollary discharge to the IO and LRN. Finally, using pharmacological inhibition, we identified that slow potassium channels are responsible for the sharp peak of twitch-related corollary discharge in the IO. Altogether, the current findings suggest that the infant brain has the capacity to distinguish between exafferent stimulation and twitch-related reafference. This capacity may underlie the developing infant’s burgeoning ability to distinguish between self- and other-generated movements.

<p>Auditory sensations can arise from objects in our environment or from our own actions, such as when we speak or make music. We must able to distinguish such sources of sounds, as well as form new associations between our actions and the sounds they produce. The brain is thought to accomplish this by conveying copies of the motor command, termed corollary discharge signals, to auditory processing brain regions, where they can suppress the auditory consequences of our own actions. Despite the importance of such transformations in health and disease, little is known about the mechanisms underlying corollary discharge in the mammalian auditory system. Using a range of techniques to identify, monitor, and manipulate neuronal circuits, I characterized a synaptic and circuit basis for corollary discharge in the mouse auditory cortex. The major contribution of my studies was to identify and characterize a long-range projection from motor cortex that is responsible for suppressing auditory cortical output during movements by activating local inhibitory interneurons. I used similar techniques to understand how this circuit is embedded within a broader neuromodulatory brain network important for learning and plasticity. These findings characterize the synaptic and circuit mechanisms underlying corollary discharge in mammalian auditory cortex, as well as uncover a broad network interaction potentially used to pattern neural associations between our actions and the sounds they produce.</p> / Dissertation

Considerable evidence indicates that visual sensitivity is reduced during saccadic eye movement. A central question has been whether saccadic suppression results from a non-visual central signal, or whether the obligate image motion that accompanies saccades is itself sufficient to mask vision. In the first of a series of experiments described here, the visual and non-visual effects of saccades were distinguished by measuring contrast sensitivity to luminance modulated low spatial frequency gratings, at 17 cd·m¯² and 0.17 cd·m¯², in saccade conditions and in conditions in which saccade-like image motion was produced by the rotation of a mirror but when observers’ eyes were kept still. The time course of suppression was examined by making measurements from well before image motion began until well after it had ended. A tenfold decrease in contrast sensitivity was found for luminance-modulated gratings with saccades, but little suppression was found with simulated saccades. Adding high contrast noise to the visual display increased the magnitude and the duration of the suppression during simulated saccades but had little effect on suppression produced by real saccades. At lower luminance, suppression was found to be reduced, and its course shallower than at higher luminance. Simulated saccades produced shallower suppression over a longer time course at both higher and lower luminance. In a second experiment the time course of contrast sensitivity to chromatically modulated gratings, at 17 cd·m¯², was examined. No suppression was found; rather there was some evidence of an enhancement of sensitivity, both before and after saccades, relative to fixation conditions. Differences in the effects of real and simulated saccades in the magnitude and time course of sensitivity loss with luminance modulated gratings suggest that saccadic suppression has an extraretinal component that acts on the magnocellular system; the pattern of enhancement found in the later experiment suggests a selective favouring of the parvocellular system both immediately prior to and immediately after saccades. The possibility that the degree of enhancement in sensitivity varies across the visual field was examined using spatially localized stimuli (either high spatial frequency chromatically modulated gratings or letter combinations). Sensitivity was found to decrease at the initial fixation point during the 75 ms prior to saccadic onset and simultaneously to improve at the saccadic target. In the immediate post-saccadic period, sensitivity at the saccadic target was found to exceed that which had been manifest at the initial fixation point prior to saccades, suggesting that post-saccadic enhancement may improve the temporal contrast between one fixation and the next. The final experiments investigated the possibility that our sense of continuity across saccades (as opposed to stability) is influenced by saccade-induced errors in locating events in time. The results of these experiments suggest that saccades can result in errors in judging (a) the time at which external events occur relative to saccadic onset, (b) the temporal order of visual events, and (c) the magnitude of temporal intervals. It is concluded that apparent time is generally foreshortened prior to saccades. This might be due to selective suppression of magnocellular activity and might function to hide saccades and their effects from our awareness. A speculative synthesis is presented based on the idea that recurrent feedback between the neocortical and cortical structures on the one hand, and the thalamic nuclei on the other, has special importance for perception around the time of saccades

The understanding of the subjective experience of a visually stable world despite the occurrence of an observer's eye movements has been the focus of extensive research for over 20 years. These studies have revealed fundamental mechanisms such as anticipatory receptive field (RF) shifts and the saccadic suppression of stimulus displacements, yet there currently exists no single explanatory framework for these observations. We show that a previously presented neuro-computational model of peri-saccadic mislocalization accounts for the phenomenon of predictive remapping and for the observation of saccadic suppression of displacement (SSD). This converging evidence allows us to identify the potential ingredients of perceptual stability that generalize beyond different data sets in a formal physiology-based model. In particular we propose that predictive remapping stabilizes the visual world across saccades by introducing a feedback loop and, as an emergent result, small displacements of stimuli are not noticed by the visual system. The model provides a link from neural dynamics, to neural mechanism and finally to behavior, and thus offers a testable comprehensive framework of visual stability.

The study of speciation is key to understanding the origins of biodiversity. Model organisms, with a host of genetic and molecular tools, are crucial to dissecting the genetics of speciation. Crosses between the recently-discovered Caenorhabditis sp. 9 and the well-known C. briggsae produce fertile F1 hybrid females, opening the door to genetic studies of speciation for the first time within the genus. I crossed eight different isogenic strains of C. briggsae reciprocally with six inbred lines of C. sp. 9 to investigate: Haldane’s rule, systematic asymmetries in hybrid viability, and whether genetic variation for hybrid viability segregates within each species. Results of these crosses confirm Haldane’s rule and demonstrate strong asymmetric parent-of-origin effects. Furthermore, I observed genotype-dependent differences in the number of F1 hybrid progeny. This provides evidence for genetic variation for hybrid viability within both species, allowing insights into the genetic forces driving the evolution of incompatibility loci.

The study of speciation is key to understanding the origins of biodiversity. Model organisms, with a host of genetic and molecular tools, are crucial to dissecting the genetics of speciation. Crosses between the recently-discovered Caenorhabditis sp. 9 and the well-known C. briggsae produce fertile F1 hybrid females, opening the door to genetic studies of speciation for the first time within the genus. I crossed eight different isogenic strains of C. briggsae reciprocally with six inbred lines of C. sp. 9 to investigate: Haldane’s rule, systematic asymmetries in hybrid viability, and whether genetic variation for hybrid viability segregates within each species. Results of these crosses confirm Haldane’s rule and demonstrate strong asymmetric parent-of-origin effects. Furthermore, I observed genotype-dependent differences in the number of F1 hybrid progeny. This provides evidence for genetic variation for hybrid viability within both species, allowing insights into the genetic forces driving the evolution of incompatibility loci.

A fundamental goal in neurobiology is to understand the development and organization of neural circuits that drive behavior. In the embryonic spinal cord, the first motor activity is a slow coiling of the trunk that is sensory-independent and therefore appears to be centrally driven. Embryos later become responsive to sensory stimuli and eventually locomote, behaviors that are shaped by the integration of central patterns and sensory feedback. In this thesis I used a simple vertebrate model, the zebrafish, to investigate in three manners how developing spinal networks control these earliest locomotor behaviors. For the first part of this thesis, I characterized the rapid transition of the spinal cord from a purely electrical circuit to a hybrid network that relies on both chemical and electrical synapses. Using genetics, lesions and pharmacology we identified a transient embryonic behavior preceding swimming, termed double coiling. I used electrophysiology to reveal that spinal motoneurons had glutamate-dependent activity patterns that correlated with double coiling as did a population of descending ipsilateral glutamatergic interneurons that also innervated motoneurons at this time. This work (Knogler et al., Journal of Neuroscience, 2014) suggests that double coiling is a discrete step in the transition of the motor network from an electrically coupled circuit that can only produce simple coils to a spinal network driven by descending chemical neurotransmission that can generate more complex behaviors. In the second part of my thesis, I studied how spinal networks filter sensory information during self-generated movement. In the zebrafish embryo, mechanosensitive sensory neurons fire in response to light touch and excite downstream commissural glutamatergic interneurons to produce a flexion response, but spontaneous coiling does not trigger this reflex. I performed electrophysiological recordings to show that these interneurons received glycinergic inputs during spontaneous fictive coiling that prevented them from firing action potentials. Glycinergic inhibition specifically of these interneurons and not other spinal neurons was due to the expression of a unique glycine receptor subtype that enhanced the inhibitory current. This work (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggests that glycinergic signaling onto sensory interneurons acts as a corollary discharge signal for reflex inhibition during movement. v In the final part of my thesis I describe work begun during my masters and completed during my doctoral degree studying how homeostatic plasticity is expressed in vivo at central synapses following chronic changes in network activity. I performed whole-cell recordings from spinal motoneurons to show that excitatory synaptic strength scaled up in response to decreased network activity, in accordance with previous in vitro studies. At the network level, I showed that homeostatic plasticity mechanisms were not necessary to maintain the timing of spinal circuits driving behavior, which appeared to be hardwired in the developing zebrafish. This study (Knogler et al., Journal of Neuroscience, 2010) provided for the first time important in vivo results showing that synaptic patterning is less plastic than synaptic strength during development in the intact animal. In conclusion, the findings presented in this thesis contribute widely to our understanding of the neural circuits underlying simple motor behaviors in the vertebrate spinal cord. / Un objectif important en neurobiologie est de comprendre le développement et l'organisation des circuits neuronaux qui entrainent les comportements. Chez l'embryon, la première activité motrice est une lente contraction spontanée qui est entrainée par l'activité intrinsèque des circuits spinaux. Ensuite, les embryons deviennent sensibles aux stimulations sensorielles et ils peuvent éventuellement nager, comportements qui sont façonnées par l'intégration de l'activité intrinsèque et le rétrocontrôle sensoriel. Pour cette thèse, j'ai utilisé un modèle vertébré simple, le poisson zèbre, afin d'étudier en trois temps comment les réseaux spinaux se développent et contrôlent les comportements locomoteurs embryonnaires. Pour la première partie de cette thèse j'ai caractérisé la transition rapide de la moelle épinière d'un circuit entièrement électrique à un réseau hybride qui utilise à la fois des synapses chimiques et électriques. Nos expériences ont révélé un comportement embryonnaire transitoire qui précède la natation et qu'on appelle « double coiling ». J'ai démontré que les motoneurones spinaux présentaient une activité dépendante du glutamate corrélée avec le « double coiling » comme l'a fait une population d'interneurones glutamatergiques ipsilatéraux qui innervent les motoneurones à cet âge. Ce travail (Knogler et al., Journal of Neuroscience, 2014) suggère que le « double coiling » est une étape distincte dans la transition du réseau moteur à partir d'un circuit électrique très simple à un réseau spinal entrainé par la neurotransmission chimique pour générer des comportements plus complexes. Pour la seconde partie de ma thèse, j'ai étudié comment les réseaux spinaux filtrent l'information sensorielle de mouvements auto-générés. Chez l'embryon, les neurones sensoriels mécanosensibles sont activés par un léger toucher et ils excitent en aval des interneurones sensoriels pour produire une réponse de flexion. Par contre, les contractions spontanées ne déclenchent pas ce réflexe même si les neurones sensoriels sont toujours activés. J'ai démontré que les interneurones sensoriels reçoivent des entrées glycinergiques pendant les contractions spontanées fictives qui les empêchaient de générer des potentiels d'action. L'inhibition glycinergique de ces interneurones, mais pas des autres neurones spinaux, est due à l'expression d'un sous-type de récepteur glycinergique unique qui augmente iii le courant inhibiteur. Ce travail (Knogler & Drapeau, Frontiers in Neural Circuits, 2014) suggère que la signalisation glycinergique chez les interneurones sensoriels agit comme un signal de décharge corolaire pour l'inhibition des réflexes pendant les mouvements auto- générés. Dans la dernière partie de ma thèse, je décris le travail commencé à la maîtrise et terminé au doctorat qui montre comment la plasticité homéostatique est exprimée in vivo aux synapses centrales à la suite des changements chroniques de l'activité du réseau. J'ai démontré que l'efficacité synaptique excitatrice de neurones moteurs spinaux est augmentée à la suite d’une diminution de l'activité du réseau, en accord avec des études in vitro précédentes. Par contre, au niveau du réseau j'ai démontré que la plasticité homéostatique n'était pas nécessaire pour maintenir la rythmicité des circuits spinaux qui entrainent les comportements embryonnaires. Cette étude (Knogler et al., Journal of Neuroscience, 2010) a révélé pour la première fois que l'organisation du circuit est moins plastique que l'efficacité synaptique au cours du développement chez l'embryon. En conclusion, les résultats présentés dans cette thèse contribuent à notre compréhension des circuits neuronaux de la moelle épinière qui sous-tendent les comportements moteurs simples de l'embryon.

Submitted by LUCAS AMARAL BATISTA LEITE null (leite.ri@gmail.com) on 2017-09-19T02:33:03Z No. of bitstreams: 1 LEITE_2017_REVISADA.pdf: 2464929 bytes, checksum: b0fa8613e387351b414b4366429661f6 (MD5) / Approved for entry into archive by Monique Sasaki (sayumi_sasaki@hotmail.com) on 2017-09-19T20:44:36Z (GMT) No. of bitstreams: 1 leite_lab_dr_mar.pdf: 2464929 bytes, checksum: b0fa8613e387351b414b4366429661f6 (MD5) / Made available in DSpace on 2017-09-19T20:44:36Z (GMT). No. of bitstreams: 1 leite_lab_dr_mar.pdf: 2464929 bytes, checksum: b0fa8613e387351b414b4366429661f6 (MD5) Previous issue date: 2017-08-21 / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / Esta tese de doutorado tem o objetivo de explicar a ascensão dos Estados Unidos no sistema internacional, por meio de análise os discursos presidenciais do State of the Union, no período correspondente aos anos de 1865 e 1912. Buscaremos compreender o papel da ideia de singularidade, especialmente presentes no chamado Destino Manifesto e nos marcos conhecidos como Doutrina Monroe e Corolário Roosevelt. Ademais, daremos ênfase às construções que relacionam a construção da identidade norte-americana em contraponto à do "Outro" a ser delimitada, como na adoção de uma leitura darwinista das relações sociais e dentre nações pelos presidentes norte-americanos. Igualmente, trabalharemos com a ideia de uma fronteira que se expande de acordo com a necessidade e os interesses do país dentro de um projeto de ordem e estabilidade hemisférica que corresponderia a um projeto similar de forma interna. Nossa análise será conduzida por referenciais teóricos considerados pós-estruturalistas, auxiliada particularmente pelas obras de autores como David Campbell (1992) e Robert Walker (1993), para os quais a linguagem é objeto de estudo na disciplina de Relações Internacionais. / This dissertation aims to illustrate the rise of the United States in the international system through presidential speeches of the State of the Union analysis, from 1865 to 1912. We seek to understand the role played by perceptions of singularity, especially in the so-called Manifest Destiny and the Roosevelt Corollary’s of Monroe Doctrine. Additionally, we emphasize the narratives that relate the construction of American identities as opposed to the "Other", usually approached under a Darwinian perception of social relations between the nations and the U.S. presidents, including the idea of a border that expands according to the needs and interests of the country - in an order and hemispheric stability that would correspond to a similar project internally. Our analysis will be conducted poststructuralist theory, mainly in the works of authors such as David Campbell (1992) and Robert Walker (1993), that consider the language as an subject of study in the discipline of International Relations. / Esta tesis de doctorado tiene el objetivo de analizar el ascenso de Estados Unidos en el sistema internacional a través de los discursos presidenciales del State of the Union en el período correspondiente a los años 1865 y 1912. Buscaremos comprender el papel de la idea de singularidad, especialmente presentes en el llamado "Destino Manifiesto" y en los hitos conocidos como "Doctrina Monroe" y "Corolario Roosevelt". Además, daremos énfasis a las construcciones que relacionan la construcción de la identidad norteamericana en contrapunto a la del "Otro" a ser delimitada, como en la adopción de una lectura darwinista de las relaciones sociales y entre las naciones por los presidentes norteamericanos, y la idea de Una frontera que se expande de acuerdo con la necesidad y los intereses del país, dentro de un proyecto de orden y estabilidad hemisférica que correspondería a un proyecto similar de forma interna. Nuestro análisis será conducido por referenciales teóricos considerados post-estructuralistas, auxiliada particularmente por las obras de autores como David Campbell (1992) y Robert Walker (1993) - los cuales colocan el lenguaje como objeto de estudio en la disciplina de Relaciones Internacionales. / FAPESP: 2013/00591-9

The understanding of the subjective experience of a visually stable world despite the occurrence of an observer's eye movements has been the focus of extensive research for over 20 years. These studies have revealed fundamental mechanisms such as anticipatory receptive field (RF) shifts and the saccadic suppression of stimulus displacements, yet there currently exists no single explanatory framework for these observations. We show that a previously presented neuro-computational model of peri-saccadic mislocalization accounts for the phenomenon of predictive remapping and for the observation of saccadic suppression of displacement (SSD). This converging evidence allows us to identify the potential ingredients of perceptual stability that generalize beyond different data sets in a formal physiology-based model. In particular we propose that predictive remapping stabilizes the visual world across saccades by introducing a feedback loop and, as an emergent result, small displacements of stimuli are not noticed by the visual system. The model provides a link from neural dynamics, to neural mechanism and finally to behavior, and thus offers a testable comprehensive framework of visual stability.