Frequency-modulated (FM) sweeps play a key role in species specific communication. Evidence from previous studies have shown that central auditory processing has been shown to vary based on the language spoken, which leads to the idea of experience-driven pitch encoding. Other studies have also shown that there is a decrease in this pitch encoding with aging. Using both iterated rippled noise (IRN) and frequency modulated amplitude modulation (FM/AM) methods to create complex pitch sweeps mimicking speech, allows for the processing of pitch to be determined. Neuromodulation using pharmacogenetics allows for the targeted inhibition of a specific neural pathway. Based on previous studies, the primary auditory cortex to inferior colliculus (A1/IC) pathway is hypothesized to be important in pitch encoding. However, there is a lack of evidence on specifically how the pitch information is encoded in the auditory system and how aging impacts the processing. To solve these issues, age-related changes in pitch encoding and maintaining pitch encoding through neuromodulation were characterized in the using behavioral and electrophysiology methods. Behavioral discrimination abilities, measured by modulation of the acoustic startle response, between pitch sweep direction and pitch sweep creation methods highlighted a reduced discrimination in aging and A1/IC inhibited rats. Electrophysiology changes was assessed using envelope-following responses (EFRs) and suggested a decreased initial frequency locking in aging and decrease in frequency locking overall with A1/IC pathway inhibition. Comparison of behavioral and electrophysiology to IRN and FM/AM stimuli show that the decrease in age-related processing as well as A1/IC pathway processing is larger in the behavioral pitch sweep discrimination than in the reduction in EFRs.

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.

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.

Damage to visual pathways can lead to irreversible blindness. Posterior visual pathways, located within a watershed area, are predisposed to hypoperfusion/reperfusion injury. In a novel rat model of bilateral common carotid artery occlusion (BCCAO), oxidative injury to the superior colliculus (SC), a major visual center within the watershed area was evaluated, in addition to its effects on retinal ganglion cells (RGCs). Nitrotyrosine, a footprint of peroxynitrite-mediated oxidative injury in the SC, and microtubule-associated protein 2, a dendrite marker in the retina, were assessed using immunofluorescence and confocal microscopy. Nitrotyrosine-immunoreactivity in the SC was increased 2 weeks after BCCAO compared to controls. Microtubule-associated protein 2-immunoreactivity in the central inner plexiform layer was reduced 3 weeks after BCCAO compared to controls. Global incomplete cerebral hypoperfusion/reperfusion induced oxidative injury in the SC and retrograde RGC dendritic changes. This suggests that cerebrovascular injury affecting the posterior visual pathways may contribute to vision loss in patients.

Damage to visual pathways can lead to irreversible blindness. Posterior visual pathways, located within a watershed area, are predisposed to hypoperfusion/reperfusion injury. In a novel rat model of bilateral common carotid artery occlusion (BCCAO), oxidative injury to the superior colliculus (SC), a major visual center within the watershed area was evaluated, in addition to its effects on retinal ganglion cells (RGCs). Nitrotyrosine, a footprint of peroxynitrite-mediated oxidative injury in the SC, and microtubule-associated protein 2, a dendrite marker in the retina, were assessed using immunofluorescence and confocal microscopy. Nitrotyrosine-immunoreactivity in the SC was increased 2 weeks after BCCAO compared to controls. Microtubule-associated protein 2-immunoreactivity in the central inner plexiform layer was reduced 3 weeks after BCCAO compared to controls. Global incomplete cerebral hypoperfusion/reperfusion induced oxidative injury in the SC and retrograde RGC dendritic changes. This suggests that cerebrovascular injury affecting the posterior visual pathways may contribute to vision loss in patients.

Thesis (Ph. D.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains x, 181 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 161-179).

Inhibition of return (IOR) is a cognitive phenomenon whereby reaction times (RTs) are slower to cued relative to uncued targets at cue-target onset asynchronies (CTOAs) greater than approximately 300 ms. One important theory of IOR proposes that there are two mutually exclusive forms of IOR, with an attentional/perceptual form arising when the oculomotor system is actively suppressed, and a motoric form arising when it is engaged (Taylor & Klein, 2000). Other theories propose that IOR is the result of multiple, additive neural mechanisms (Abrams & Dobkin, 1994). Here, we have performed computational simulations and empirical investigations in an attempt to reconcile these two competing theories. Using a dynamic neural field (DNF) model of the intermediate layers of the superior colliculus (iSC), we have modeled both a sensory adaptation mechanism of IOR, and a motoric mechanism resulting from the aftereffects of saccadic eye movements. Simulating these mechanisms, we replicated behavior and neurophysiology in a number of variations on the traditional cue-target paradigm (Posner, 1980). Predictions driven by these simulations have led to the proposal of many behavioral and neuroimaging experiments which further examine the plausibility of a 2-mechanisms theory of IOR. Contrary to our original predictions, we demonstrated that saccades are biased away from cued targets in a paired target saccade averaging paradigm, even at short CTOAs. In paradigms thought to recruit both sensory and motoric mechanisms, we robustly demonstrated that there are at least two independent, additive mechanisms of IOR when tasks require saccadic responses to targets. When similar paradigms were tested with manual responses to targets, additivity effects did not hold, implying that the motoric mechanism of IOR does not transfer from the oculomotor to skeletomotor systems. Furthermore, across numerous experiments using event-related potential (ERP) techniques, we have demonstrated that P1 component reductions are neither necessary, nor sufficient, for the behavioral exhibition of IOR. We propose that a comprehensive framework for behavioral IOR must include (at least) four independent neural mechanisms, differentially active depending on circumstances, including sensory adaptation, saccadic aftereffects, local inhibition, and cortical habituation.

Game theory outlines optimal response strategies during mixed-strategy competitions in which available actions are selected probabilistically. The neural processes involved in choosing individual strategic actions, however, remain poorly understood. Here, actions need to be selected (1) in the absence of sensory instruction or reward cues and (2) independent of previous events. This thesis examines the neural processes involved in action selection during mixed-strategy competition. To do so, we both measured and manipulated presaccadic activity in the primate superior colliculus (SC), a structure involved in the generation of orienting saccadic eye movements, during a strategic game. The first study tested whether the SC is involved in choosing saccades under strategic conditions. Monkeys were free to choose either of two saccade targets as they competed against a computer opponent during the mixed-strategy game ‘matching-pennies’. The accuracy with which pre-saccadic SC activity predicted upcoming choice gradually increased in the time leading up to the saccade. Probing the SC with supra-threshold stimulation demonstrated that these evolving signals were functionally involved in preparing strategic saccades. Finally, sub-threshold stimulation of the SC increased the likelihood that contralateral saccades were selected. In the second study, we compared the influence of previous actions and rewards on updating premotor activity in the SC in the strategic condition where eliciting stochastic responses was optimal and in a non-strategic condition where stochastic responses were also elicited but through explicit instruction. To avoid exploitation by opponents during mixed-strategy competitions one should select behaviors unpredictably, that is, independent of previous choices and their outcomes. The iterative updating of neural processes involved in selecting actions to produce mixed-strategy behaviors, however, remain poorly understood In both tasks, premotor activity and behavior were shaped by past actions and rewards with more recent events exerting the largest influence. Importantly, these sequential effects were attenuated under strategic conditions suggesting that updating of selection processes is not entirely automatic but can be tailored to different decision-making contexts. Together our results highlight the active role played by the brain in choosing strategic actions. / Thesis (Master, Neuroscience Studies) -- Queen's University, 2009-01-30 17:11:21.002

Neuroeconomic models take economic theory literally, interpreting hypothesized quantities as observables in the brain in order to provide insight into choice behaviour. This thesis develops a model of the neural decision process in strategic games with a unique mixed strategy equilibrium. In such games, players face both an incentive to best-respond to valuations and to act unpredictably. Similarly, we model choice as the result of the interaction between action value and the noise inherent in networks of spiking neurons. Our neural model generates any ratio of choices through the specification of action value, including the equilibrium ratio, and provides an explanation for why we observe equilibrium behaviour in some contexts and not others. The model generalizes to a random-utility model which gives a structural specification to the error term and makes action value observable in the spike rates of neurons. Action value is measured in the spike activity of the Superior Colliculus (SC) while monkeys play a saccade version of matching pennies. We find SC activity predicts upcoming choices and is influenced by the history of events in the game, correlating with a behaviourally-established model of learning, and choice simulations based on neural measures of value exhibit similar biases to our behavioural data. A neural measure of value yields a glimpse at how valuations are updated in response to new information and compared stochastically, providing us with unique insight into modelling choice in strategic games. / Thesis (Ph.D, Economics) -- Queen's University, 2011-06-14 14:48:36.226

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>