The motor nervous system is one of the main systems of the body and is our principle means ofbehavior. Some of the most debilitating and wide spread disorders are motor systempathologies. In particular the basal ganglia are complex networks of the brain that control someaspects of movement in all vertebrates. Although these networks have been extensively studied,lack of proper methods to study them on a system level has hindered the process ofunderstanding what they do and how they do it. In order to facilitate this process I have usedcomputational models as an approach that can faithfully take into account many aspects of ahigh dimensional multi faceted system.In order to minimize the complexity of the system, I first took agnathan fish and amphibians asmodeling animals. These animals have rather simple neuronal networks and have been wellstudied so that developing their biologically plausible models is more feasible. I developedmodels of sensory motor transformation centers that are capable of generating basic behaviorsof approach, avoidance and escape. The networks in these models used a similar layeredstructure having a sensory map in one layer and a motor map on other layers. The visualinformation was received as place coded information, but was converted into population codedand ultimately into rate coded signals usable for muscle contractions.In parallel to developing models of visuomotor centers, I developed a novel model of the basalganglia. The model suggests that a subsystem of the basal ganglia is in charge of resolvingconflicts between motor programs suggested by different motor centers in the nervous system.This subsystem that is composed of the subthalamic nucleus and pallidum is called thearbitration system. Another subsystem of the basal ganglia called the extension system which iscomposed of the striatum and pallidum can bias decisions made by an animal towards theactions leading to lower cost and higher outcome by learning to associate proper actions todifferent states. Such states are generally complex states and the novel hypothesis I developedsuggests that the extension system is capable of learning such complex states and linking themto appropriate actions. In this framework, striatal neurons play the role of conjunction (BooleanAND) neurons while pallidal neurons can be envisioned as disjunction (Boolean OR) neurons.In the next set of experiments I tried to take the idea of basal ganglia subsystems to a new levelby dividing the rodent arbitration system into two functional subunits. A rostral group of ratpallidal neurons form dense local inhibition among themselves and even send inhibitoryprojections to the caudal segment. The caudal segment does not project back to its rostralcounterpart, but both segments send inhibitory projections to the output nuclei of the rat basalganglia i.e. the entopeduncular nucleus and substantia nigra. The rostral subsystems is capableof precisely detecting one (or several) components of a rudimentary action and suppress othercomponents. The components that are reinforced are those which lead to rewarding stateswhereas those that are suppressed are those which do not. The hypothesis explains neuronalmechanisms involved in this process and suggests that this subsystem is a means of generatingsimple but precise movements (such as using a single digit) from innate crude actions that theanimal can perform even at birth (such as general movement of the whole limb). In this way, therostral subsystem may play important role in exploration based learning.In an attempt to more precisely describe the relation between the arbitration and extensionsystems, we investigated the effect of dynamic synapses between subthalamic, pallidal andstriatal neurons and output neurons of the basal ganglia. The results imply that output neuronsare sensitive to striatal bursts and pallidal irregular firing. They also suggest that few striatalneurons are enough to fully suppress output neurons. Finally the results show that the globuspallidus exerts its effect on output neurons by direct inhibition rather than indirect influence viathe subthalamic nucleus. / <p>QC 20131209</p>

Development of brain function is instructed by both genetically-determined processes (nature) and environmental stimuli (nurture). The relative importance of nature and nurture is a major question in developmental neurobiology. In this dissertation, I investigated the role of visual experience in the development and plasticity of the visual pathway. Each neuron that receives visual input responds to a specific area of the visual field- their receptive field (RF). Developmental refinement reduces RF size and underlies visual acuity, which is important for survival. By rearing Syrian hamsters (Mesocricetus auratus) in constant darkness (dark rearing, DR) from birth, I investigated the role of visual experience in RF refinement and plasticity. Previous work in this lab has shown that developmental refinement of RFs occurs in the absence of visual experience in the superior colliculus (SC), but that RFs unrefine and thus enlarge in adulthood during chronic DR. Using an in vivo electrophysiological approach, I show that, contrary to a widely held view, visual experience is not necessary for refinement of RFs in primary visual cortex (V1). In both SC and V1, RFs refine by postnatal day (P) 60, but enlarge by P90 with chronic DR. One week of visual experience was sufficient to prevent RF enlargement in SC and V1. How normal sensory experience prevents plasticity in mature circuits is not well understood. Using an in vitro electrophysiological approach, I demonstrated that GABAergic inhibition is reduced in DR SC, which in turn affects short-term (but not long-term) synaptic plasticity. The level of GABABR-mediated short-term synaptic depression (STD) that occurs during high-frequency afferent stimulation, such as occurs during vision, is reduced by DR. Using a computational model of RF size, I propose that, in addition to the effect of reduced inhibition, reduced STD of excitation could contribute to enlarged RFs. This work provides insight into mechanisms of development and plasticity of the nervous system. How plasticity is restricted in mature circuits is of fundamental importance in neuroscience and could instruct therapies to prevent maladaptive plasticity in disease and to enhance recovery of function in adults.

[Truncated abstract] The mammalian inner ear is innervated by the efferent olivocochlear system which is divided into medial and lateral systems. In anaesthetised animals, medial olivocochlear (MOC) axons can be electrically stimulated at the floor of the IVth ventricle. MOC stimulation suppresses the spontaneous activity and sound-evoked responses of primary afferents by its actions on outer hair cells. Effects of MOC stimulation have been also reported on responses of neurons in the cochlear nucleus, the first central auditory center receiving cochlear input. However, very little is known about the net results of MOC effects in higher order neurons. This issue was investigated by electrically stimulating MOC axons at the IVth ventricle and recording extracellular single unit activities in the central nucleus of the inferior colliculus (CNIC) of anaesthetised guinea pigs. For the first part of the study, anatomical and neurophysiological studies were carried out to establish that the focal midline MOC stimulation can selectively stimulate MOC axons without any current spread to adjacent ascending fibers. The MOC stimulation and CNIC recordings were then carried out in a series of experiments that included normal hearing animals, animals treated acutely with gentamicin (in which the acetylcholine-mediated peripheral suppression of the olivocochlear efferents is selectively eliminated) and partially deafened animals. ... However, in other CNIC neurons, effects could not be so explained, showing either additional suppression or even marked excitatory effects. (4) MOC stimulation also suppressed the spontaneous activity of CNIC neurons in normal hearing animals. When similar efferent stimulation was carried out in partially deafened animals, the abnormally high spontaneous activity of some CNIC neurons in the deafened frequency regions was also transiently suppressed by MOC shocks. The results from this study clearly demonstrate that the MOC system can modulate the responses of midbrain neurons in a more complex manner compared to the effects seen in the periphery. The more complex effects seen for responses to tones in quiet and in noisy background are likely to result from a complex interplay between altered afferent input in the cochlea and central circuitry. In addition, the ability of MOC efferents in suppressing the normal and abnormal spontaneous activity in the midbrain also could have implications for the role of the descending system in the pathophysiology and treatment of tinnitus.

Thesis (Ph.D.)--University of Western Australia, 2007.

Thesis (M.Sc.) - Carleton University, 2007. / Includes bibliographical references (p. 83-89). Also available in electronic format on the Internet.

Tierärztl. Hochsch., Diss., 2004--Hannover.

Techn. Universiẗat, Diss., 2004--Darmstadt.

No description available.

O colículo superior (CS) é conhecido por ser responsável pela detecção e orientação da cabeça e olhos em direção a estímulos visuais. Ainda o CS funciona na detecção e guia de respostas iniciais a objetos inesperados no campo visual e orientação da cabeça no sentido de estímulos apetitivos ou afastamento de estímulos potencialmente ameaçadores. Estudos prévios mostraram que a predação de insetos está associada à expressão da proteína Fos nas porções laterais do colículo superior (CSl) e ratos com lesões bilaterais de NMDA na região do CSl tipicamente falham em orientarem-se e caçarem insetos usando a sequência de movimentos estereotipados comumente vistos na caça predatória de insetos. Parece que as porções mediais do colículo superior (CSm) está envolvida com a organização de respostas defensivas, uma vez que estimulações nesse sítio elicia respostas de esquiva adicionadas de ajustes viscerais relacionados as respostas defensivas. Interessantemente, um aumento de imunorreatividade à proteína Fos foi observada no CSm enquanto ratos foram expostos ao predador natural (Comoli and Cedraz-Mercez, 2009). Um estudo sistemático com o rastreador neuronial FluoroGold realizado no nosso laboratório mostrou diferenças no padrão de conexões aferentes sugerindo que o CSm recebe informações principalmente de vários setores do córtex associativo que refletem uma maior integração de informações cognitivas referentes ao predador e do circuito hipotalâmico relacionado com a defesa, enquanto o CSl integra informações principalmente relacionadas ao sistema somatossensorial das vibrissas e da região orofacial que sabidamente são muito importantes para o comportamento de aproximação. Essas diferenças anatômicas podem ser importantes para influenciar o CS na modulação de respostas comportamentais aos estímulos relevantes biologicamente. Baseado no exposto acima sugerimos que haja uma distinção funcional entre o CSm e CSl de ratos. Nossos resultados mostraram que 100% dos ratos expostos ao predador natural ou as baratas e ao predador ao mesmo tempo desempenharam respostas de defesa e tiveram aumento da proteína Fos no CSm. A inativação do CSm com muscimol mostrou um aumento de comportamento exploratório e redução da resposta de congelamento motor quando esses animais foram expostos as baratas e ao predador natural ao mesmo tempo. Interessantemente na situação em que o rato encontra-se fisicamente ameaçado pela presença do predador e também fisiologicamente ameaçado por um déficit nutricional elevado (devido à privação alimentar) e defronta-se com presas observamos que 50% desses animais desempenham respostas defensivas e apresentam aumento da proteína Fos no CSm e setores do circuito de defesa; e 50% dos animais desempenham respostas predatórias e apresentam aumento de proteína Fos no CSl e pouca atividade no circuito de defesa. Sugerimos que o CSm é um sítio muito importante na integração de informações referentes à atenção voltada ao predador e que deve exercer um papel no processo de seleção comportamental ao nível dos gânglios da base. Ainda sugerimos que existe uma interação importante entre os sistema colicular e o sistema hipotalâmico de defesa. / The Superior Colliculus (SC) is well known to be responsible for detecting and orienting the head and eyes toward visual stimuli. Moreover SC works in the detection and guidance of initial responses to unexpected objects in the visual field, in addition to the orienting the head towards appetitive and away from potentially threatening stimuli. Previous studies have shown that insect predation in rats is associated with the expression of Fos protein at the lateral part of intermediate layer of Superior Colliculus (SCl) and rats with local bilateral NMDA lesions in the SCl typically fail to orient towards and chase the roaches with the series of stereotyped movements commonly seen in the predatory hunting of intact controls. It seems that the medial region of Superior Colliculus (SCm) is involved in the organization of defensive behavior once stimulation in this site elicits avoidance responses in addition to visceral adjustments related to defensive responses. Interestingly, an increase of Fos immunoreactivity was found in the medial region of SC (SCm) while rats were exposed to the cat (Comoli and Cedraz-Mercez, 2009). A systematic study with the retrograde tracer FluoroGold conducted in our laboratory showed the differences in the pattern of afferent connections suggesting that SCm mostly integrates inputs coming from associative cortical areas and key sites of the defensive circuitry while SCl integrates inputs from whiskers and orofacial-related somatosensory information which is important for approaching behaviors. These anatomical differences might be very important to influence SC in modulating behavioral responses to biologically relevant stimuli. Based on the mentioned above we propose that SCm and SCl could be functionally distinct. Our results showed that rats exposed to the natural predator or exposed to the roaches and the natural predator together performed fear responses and Fos upregulation at the SCm. Muscimol inactivation of SCm showed an increase of exploratory behaviors and reduction of freezing responses when the animals were exposed o both the roaches and the predator together. In a challenging experiment rats were food deprived and were exposed to both, the roaches and the natural predator and Fos protein was detected. Fifty percent of the rats showed predatory behavior and did not show the fear responses commonly seen when exposed to the natural predator. Moreover an increase of Fos protein levels was observed at the SCl of these rats. The other fifty percent of the rats showed fear responses and did not hunt the preys. In contrast an increase of Fos protein was detected at SCm and at the hypothalamic defensive circuitry of these rats. We suggest that SCm is very important for integration of information concerning the predator and might influence the behavioral selection process at the level of basal ganglia. We also suggest there is a relation between collicular and hypothalamic defensive circuits.

As reações incondicionadas de defesa observadas em mamíferos são organizadas pelo Sistema Encefálico de Aversão (SEA), composto, entre outras estruturas, pela substância cinzenta periaquedutal dorsal (SCPd) e o colículo inferior (CI). Tem sido proposto que o CI seja parte do circuito sensoriomotor para os estímulos auditivos de natureza aversiva e a SCPd como a principal via de saída (output) do SEA para a elaboração de comportamentos defensivos. Ambas as estruturas são reguladas tonicamente pelo neurotransmissor inibitório ácido gama-aminobutírico (GABA). Este trabalho aborda a mediação química GABA/Benzodiazepínica (BZD) do processamento da informação aversiva no CI e das respostas de medo elaboradas pela SCPd. Grupos independentes de animais submetidos ao implante de quimitrodos (eletrodos acoplados a cânulas-guia para injeção de drogas) foram usados para avaliar no CI e SCPd os efeitos de injeções locais de muscimol (agonista de receptores GABA-A), semicarbazida (inibidor da síntese da enzima precursora do GABA descarboxilase do ácido glutâmico) ou midazolam (agonista BZD). Foram registrados potenciais evocados auditivos (PEA) no CI como medida eletrofisiológica da ativação neuronial, além da determinação dos limiares de congelamento e fuga, com o procedimento de estimulação elétrica (EE), tanto do CI quanto da SCPd. A mesma abordagem farmacológica com injeções de drogas intra-CI foi empregada em animais submetidos ao teste do Labirinto em Cruz Elevado (LCE), um modelo animal tradicional de ansiedade. Adicionalmente, investigou-se a participação de ambas as estruturas na expressão do comportamento de desligar uma luz de intensidade aversiva em um novo teste de medo incondicionado (Light Switch Off Test; LSOT) recentemente proposto pelo nosso grupo. Encontramos uma clara segregação funcional entre a porção dorsal e ventral do CI, sendo a última envolvida nos comportamentos defensivos. Mecanismos GABAérgicos em ambas as estruturas influenciam a amplitude do PEA e o congelamento pós-fuga da EE, sugerindo uma relação funcional entre as duas estruturas. Já no LSOT, os resultados indicam o envolvimento de mecanismos GABAérgicos do vCI, mas não da SCPd, na modulação da resposta incondicionada à luz em ratos. Os resultados obtidos permitem ampliar o conhecimento atual sobre a neurobiologia dos estados de medo e ansiedade, em uma abordagem integrada dos mecanismos de processamento das informações sensoriais e da expressão de reações de defesa. / Unconditioned defense reactions observed in mammals are organized by the Brain Aversive System, comprising, among other structures, the dorsal periaqueductal gray matter (dPAG) and the inferior colliculus (IC). It has been proposed that the IC is part of the sensorimotor circuitry that processes aversive auditory information and the dPAG is considered the main neural substrate for the expression of defensive behaviors. Both structures are tonically regulated by the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). This work addresses the chemical mediation of GABA/Benzodiazepine (BZD) on aversive information processing in the IC and the elaboration of fear responses by dPAG. Independent groups of animals implanted with chemitrodes (electrodes attached to a guide cannula for drug injection) have been used to evaluate the IC and dPAG regarding the effects of local injections of GABAergic agents (muscimol, semicarbazide, and midazolam). Auditory evoked potentials (AEP) have been recorded in the IC as a measure of electrophysiological neuronal activation, in addition to determining the thresholds of defensive freezing and flight behaviors, using the electrical stimulation (EE) procedure in both IC and dPAG. The same pharmacological regimen of drug injections intra-dPAG and intra-CI have been applied to animals subjected to the elevated plus maze (EPM), a well-known animal model of anxiety, and also to a novel animal test for innate fear (Light Switch Off Test, LSOT) that has been developed and proposed by our group. We found a clear functional segregation between the dorsal and ventral portions of the IC, the latter being the specific collicular substrate of defensive behaviors. GABAergic mechanisms in both structures influence the amplitude of the AEP and post-stimulation freezing of EE, suggesting a functional link between the two structures. In the LSOT, our data indicate the involvement of GABAergic mechanisms of the ICv, but not the dPAG, in the modulation of the unconditioned response to light in rats. These original findings presented here contribute to broaden the current knowledge on the neurobiology of fear and anxiety, in an integrative approach of the mechanisms underlying sensory processing and the expression of defensive behaviors.