Neuropsychiatric disorders severely impact quality of life in millions of patients, contributing more Disease Affected Life Years (DALYs) than cancer or cardiovascular disease. The human brain is a complex system of 100 billion neurons connected by 100 trillion synapses, and human studies of neural disease focus on network-level circuit activity changes, rather than on cellular mechanisms. To probe for neural dynamics on the cellular level, animal models such as the nematode C. elegans have been used to investigate the biochemical and genetic factors contributing to neurological disease. C. elegans are ideal for neurophysiological studies due to their small nervous system, neurochemical homology to humans, and compatibility with non-invasive neural imaging. To better study the cellular mechanisms contributing to neurological disease, we developed automated analysis methods for characterizing the behaviors and associated neural activity during sleep and learning in C. elegans: two neural functions that involve a high degree of behavioral and neural plasticity. We developed two methods to study previously uncharacterized spontaneous adult sleep in C. elegans. A large microfluidic device facilitates population-wide assessment of long-term sleep behavior over 12 hours including effects of fluid flow, oxygen, feeding, odors, and genetic perturbations. Smaller devices allow simultaneous recording of sleep behavior and neuronal activity. Since the onset of adult sleep is stochastically timed, we developed a closed-loop sleep detection system that delivers chemical stimuli to individual animals during sleep and awake states to assess state-dependent changes to neural responses. Sleep increased the arousal threshold to aversive chemical stimulation, yet sensory neuron (ASH) and first-layer interneuron (AIB) responses were unchanged. This localizes adult sleep-dependent neuromodulation within interneurons presynaptic to the AVA premotor interneurons, rather than afferent sensory circuits. Traditionally, the study of learning in C. elegans observes taxis on agar plates which present variable environmental conditions that can lead to a reduction in test-to-test reproducibility. We also translated the butanone enhancement learning assay such that animals can be trained and tested all within the controlled environment of a microfluidic device. Using this system, we demonstrated that C. elegans are capable of associative learning by observing stimulus evoked behavioral responses, rather than taxis. This system allows for more reproducible results and can be used to seamlessly study stimulus-evoked neural plasticity associated with learning. Together, these systems provide platforms for studying the connections between behavioral plasticity and neural circuit modulation in sleep and learning. We can use these systems to further our understanding of the mechanisms underlying neural regulation, function, and disorder using human disease models in C. elegans.

Aims: We have established that neonatal treatment with quinpirole, a dopamine D2/D3 agonist, results in increases of dopamine D2 receptor sensitivity throughout the animal’s lifetime and has a number of consistencies with schizophrenia. Aim 1: Analyze the roles of α7 and α4β2 nicotinic receptors in nicotine sensitization in adolescent male and female rats neonatally treated with quinpirole. Aim 2: The roles of the α7 and α4β2 nicotinic receptors were analyzed in their effects on Brain-Derived Neurotrophic Factor (BDNF) and mammalian target of rapamycin (mTOR) in rats neonatally treated with quinpirole and sensitized to nicotine. Methods: Animals were neonatally treated with quinpirole or saline from postnatal days (P)1-21. Beginning on P33, animals were ip injected with nicotine (0.5 mg/kg free base) or saline and tested every second day from P33-49. Approximately 15-30 min before the nicotine or saline injection, animals were ip injected with either the α7 nicotinic receptor (nAChR) antagonist methllycacontine (MLA; 2 or 4 mgkg) or the α4β2 nAChR antagonist dihyro-β (DhβE; 1 or 2.5 mg/kg) erythrodine. Brain tissue was taken 24 h after the last day of testing. Results: Neonatal quinpirole enhanced nicotine sensitization and DhβE blocked nicotine sensitization regardless of neonatal treatment and was more effective in blocking sensitization in males versus females. MLA failed to block nicotine sensitization. Howeer, MLA blocked the acute hypoactive response to nicotine in males, and the higher dose of MLA reduced sensitization in males. Neonatal quinpirole sensitized the accumbal BDNF response to nicotine, but neonatal quinpirole resulted in a decrease of mTOR in both brain areas. Conclusions: The α4β2 receptor plays a critical role in adolescent nicotine sensitization. Interstingly, the α7 nAChR appears to be important in the acute response to nicotine and is more important in nicotine sensitization in males. Both nAChRs appear to be important in accumbal BDNF and their roles will be analyzed in the mTOR response.

This study analyzed the interaction of adolescent methylphenidate on the behavioral response to nicotine and the effects of these drug treatments on brain-derived neurotrophic factor in the nucleus accumbens and hippocampus in male and female Sprague-Dawley rats. Animals were intraperitoneal administered 1 mg/kg methylphenidate or saline using a “school day” regimen (five days on, two days off) beginning on postnatal day (P)28 and throughout behavioral testing. In Experiment 1, animals were intraperitoneal administered 0.5 mg/kg (free base) nicotine or saline every second day for 10 days from P45–P63 and tested after a three-day drug washout on the forced swim stress task on P67–P68. Results revealed that adolescent methylphenidate blunted nicotine behavioral sensitization. However, methylphenidate-treated rats given saline during sensitization demonstrated decreased latency to immobility and increased immobility time on the forced swim stress task in males that was reduced by nicotine. In Experiment 2, a different set of animals were conditioned to nicotine (0.6 mg/kg free base) or saline using the conditioned place preference behavioral paradigm from P44–P51, and given a preference test on P52. On P53, the nucleus accumbens and hippocampus were analyzed for brain-derived neurotrophic factor. Methylphenidate enhanced nicotine-conditioned place preference in females and nicotine produced conditioned place preference in males and females pre-exposed to saline in adolescence. In addition, methylphenidate and nicotine increased nucleus accumbens brain-derived neurotrophic factor in females and methylphenidate enhanced hippocampus brain-derived neurotrophic factor in males and females. Methylphenidate adolescent exposure using a clinically relevant dose and regimen results in changes in the behavioral and brain-derived neurotrophic factor responses to nicotine in adolescence that are sex-dependent.

This study examined the effects of bilateral and unilateral deafness by measuring cortical auditory evoked potential (CAEP) responses in children at initial stages of bilateral cochlear implant (CI) use. We recorded cortical responses evoked by right and left CI stimulation in 127 children with early onset (< 12 months) deafness, with 72 children receiving the two devices in the same surgery (simultaneously implanted) and 55 children receiving the devices in separate procedures (sequentially implanted). Three different types of responses were identified in children with bilateral CIs. No significant effects of duration of deafness, age at implantation, or duration of unilateral CI use were found on response latencies and amplitudes within each type of cortical response, but there were clear differences in responses types between groups and ears. In the context of these findings, the effects of bilateral and unilateral deafness to the auditory pathways were discussed.

This study examined the effects of bilateral and unilateral deafness by measuring cortical auditory evoked potential (CAEP) responses in children at initial stages of bilateral cochlear implant (CI) use. We recorded cortical responses evoked by right and left CI stimulation in 127 children with early onset (< 12 months) deafness, with 72 children receiving the two devices in the same surgery (simultaneously implanted) and 55 children receiving the devices in separate procedures (sequentially implanted). Three different types of responses were identified in children with bilateral CIs. No significant effects of duration of deafness, age at implantation, or duration of unilateral CI use were found on response latencies and amplitudes within each type of cortical response, but there were clear differences in responses types between groups and ears. In the context of these findings, the effects of bilateral and unilateral deafness to the auditory pathways were discussed.

The purpose of this thesis was to characterise the contribution that a specific molecule, CREB1, plays in the many facets of a developing addiction phenotype. Indeed, CREB1 is known to contribute to long term learning and memory, and present an altered activation profile upon exposure to reinforcing substances, in brain regions implicated in addiction. Together, these observations provide a prima facie driver to investigate the specific involvement of CREB1 in brain regions implicated in reinforcement and drug-seeking. / Initially, I investigated Sprague Dawley rats whom had undergone behavioural sensitization to the repeated administration of the psychostimulant d-Amphetamine. Detailed in Chapter 3, the aims of this study were to determine the impact that environmental drug-context associations and psychostimulant sensitization makes upon expression of the activated or phosphorylated form of CREB1 (pCREB1). The data presented in the study reveals that many brain nuclei relevant to the behavioural effects of drug exposure show expression of pCREB1 subsequent to enduring amphetamine abuse, as well as upon return to an environment previously paired with amphetamine. The profile of pCREB1 expression within brains was unique to each pattern of drug dosing and context exposure, suggesting that unique sub-circuits underlie these different behavioural repertoires. / Using the impetus from this study, I determined to further investigate the contribution of CREB1 from specific brain regions, and the impact of its deletion upon behaviours characteristic of addiction. Indeed, the aims of this section of the project were to firstly employ relevant detection systems and current genetic-engineering technologies in creating appropriate expression animal lines, emphasising reward and reinforcement pathways. In addition, I aimed to understand the signalling systems and pathways which are activated by neurotransmitters, culminating in the phosphorylation of CREB and subsequently altered gene expression and long-term cellular and neuronal adaptation, induced by ongoing exposure to drugs of abuse. / Detailed in Chapter 4, I created a novel mutant mouse which was deficient in CREB1 within the dorsal telencephalon. Mice 'floxed' for the Creb1 gene expressed loxP DNA sequence around an exon critical to CREB1 function. These mice were interbred with mice expressing the enzyme Cre recombinase in dorsal telencephalic brain regions. Thus, mice expressing Cre recombinase and floxed for Creb1 demonstrated the deletion of CREB1 protein in these brain regions, which is demonstrated through experiments presented in Chapter 4. / Further in vitro characterisation of this mutant mouse was carried out and presented in Chapter 5. As CREB1 is important in synaptic plasticity and growth, it was necessary to evaluate any impact upon ontogeny through stereological analysis of cell number and volume, for relevant brain nuclei. The experiments demonstrate that mutant CREB1 mice were no different to control mice, however, it was possible that this lack of phenotype was partly contributed though changes in the level of other CREB/ATF-1/CREM bZIP family members. To this end, I determined to assay for transcript changes in these and related genes, finding confirmation of the deletion of the Creb1 transcript in the cortex and hippocampus, whilst observing a concomitant increase in Crem transcript. These data suggested that compensatory changes in brain regions receiving a recombination of Creb1 were apparent, contributing to the lack of an obvious phenotype in these mice. / Having confirmed the specific deletion of CREB1 in the appropriate brain nuclei, I then moved to examine the impact of the deletion behaviourally, both in terms of general ethology, and in regard to drug-induced phenotypes. Presented in Chapter 6, experiments assaying general ethology of the CREB1 mutant revealed a spontaneous hypoactivity when placed in a small open field environment. As CREB1 is involved in neural plasticity, I wished to assay for the impact on behavioural sensitization, a paradigm which reveals long-lived neural change. Experiments to this effect showed no perturbation of behavioural sensitization to the effects of cocaine in the mutant. In addition, mutant mice also showed a similar response to the rewarding effects cocaine as witnessed in the control mice, however, the CREB1 mutants demonstrated a perturbed drug-environment contextual memory, which was not retained in long-term place preference experiments. Operant conditioning studies for intravenous self administration of cocaine revealed that CREB1 mutants displayed a dose-specific diminished drive to self-administer cocaine, whereas in contrast, self administration of a natural reward was no different to control mice. These data suggest that there is a specific role for CREB1 in telencephalic glutamatergic neurons regulating the motivational and associative properties of cocaine. / Together, these data provide evidence that CREB1 functions as a key molecular substrate in long lived drug-context environment associations and neural change underlying the developing addicted state, warranting future investigation for its properties in producing drug related functional and behavioural change.

Conceptual design is a series of complex cognitive processing tasks and research seeking to further understand design cognition will benefit by considering literature from the field of psychology. This thesis presents two research projects, which sought to understand and mitigate design biases in conceptual design through the application of theories from biological and cognitive psychology. The first of these puts forward a novel model of design creativity based on connectionist theory and a neurological phenomenon known as long-term potentiation. This model is applied to provide new insights into design fixation and develop interventions to assist designers overcome fixation. The second project seeks to establish that cognitive heuristics and biases predictably influence design cognition. Two studies are discussed that examined the role of confirmation bias in design. The first establishes that confirmation bias is present during concept generation; the second demonstrates that decision matrices can mitigate confirmation bias in concept evaluation.

Conceptual design is a series of complex cognitive processing tasks and research seeking to further understand design cognition will benefit by considering literature from the field of psychology. This thesis presents two research projects, which sought to understand and mitigate design biases in conceptual design through the application of theories from biological and cognitive psychology. The first of these puts forward a novel model of design creativity based on connectionist theory and a neurological phenomenon known as long-term potentiation. This model is applied to provide new insights into design fixation and develop interventions to assist designers overcome fixation. The second project seeks to establish that cognitive heuristics and biases predictably influence design cognition. Two studies are discussed that examined the role of confirmation bias in design. The first establishes that confirmation bias is present during concept generation; the second demonstrates that decision matrices can mitigate confirmation bias in concept evaluation.

Made available in DSpace on 2015-05-14T13:16:41Z (GMT). No. of bitstreams: 1 arquivototal.pdf: 1699049 bytes, checksum: 1479abcf9ed9ec58ea46e5f71d91ab6a (MD5) Previous issue date: 2010-09-16 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / This work aimed to evaluate if the lack of visual information can alter the perception of musical notes in blind adults when compared to adults with normal vision. The sample of this study was comprised of 30 adults (15 blinds (Experimental Group - EG) and 15 with normal vision (Control Group - CG)), 7 females and 8 males in each group from 18 to 30 years old, all with normal hearing acuity. All measurements were made by the forced-choice method between two alternatives. In this method, the volunteer had always to choose the certain stimulus informed previously by the experimenter (the test stimulus) between two stimuli. The other stimulus showed was a distracter stimulus. The measurements were made in 3 experimental sessions, one for each stimulus. In each experimental session, 20 pairs of stimuli were presented at random, one stimulus was the test stimulus and the other the distracter stimulus. The musical notes used as test stimulus were D, F and A in the first octave of the piano. The distracter stimulus were the musical notes that are neighboring the test note according to the standard musical notes scale (it means that when D was the test note, the distracter notes were C and E; to the F note, the distracters were E and G). Before the beginning of the experiment, the test stimulus of the session was presented for five consecutive times and the experiment only began when the experimenter was sure that the volunteer had understood all the instructions. The rate of discrimination (the number of rights divided per the number of presentations) for each musical note were gathered according to condition (CG and EG). The statistical analysis (One-Way ANOVA) did not show significant differences between the groups F (2, 27) = 2.17, p > 0.05 to discriminate musical notes. These results suggest that the congenital lack of vision do not cause changes in the ability to discriminate musical notes in blind adults. / A presente dissertação objetivou avaliar se a privação do sistema visual altera a percepção de notas musicais de adultos cegos quando comparados a adultos com visão normal. Participaram desse estudo 30 adultos (15 cegos (Grupo Experimental - GE) e 15 com visão normal (Grupo Controle - GC)), sendo 7 do sexo feminino e 8 do sexo masculino, em cada grupo, na faixa etária de 18 a 30 anos de idade, todos com acuidade auditiva normal. Todas as medidas foram realizadas com o método da escolha forçada entre duas alternativas. Neste método, o voluntário teve sempre de escolher entre dois estímulos o estímulo pré-determinado pelo pesquisador de estímulo teste . O outro estímulo apresentado era um estímulo distrator . Foram realizadas três sessões experimentais, uma para cada estímulo teste. Em cada sessão experimental foram apresentados aleatoriamente 20 pares de estímulos, sendo um deles o estímulo teste e o outro o estímulo distrator. As notas musicais utilizadas como teste foram Ré, Fá, Lá na primeira oitava do piano. Os estímulos distratores foram as notas que na escala padrão de notas musicais encontram-se vizinhas a nota de teste (ou seja, quando a nota de teste foi Ré, as notas distratoras foram Dó e Mi; para a nota Fá, as distratoras foram Mi e Sol; e para a nota teste Lá, as distratoras foram Sol e Si). Antes do início do experimento a nota teste, referente aquela sessão, foi apresentada cinco vezes consecutivas e o experimento só foi iniciado quando foi certificado que as instruções foram compreendidas pelo participante. Os índices de discriminação (número de acertos divididos pelo número de apresentações) para cada nota musical foram reunidas por condição (GC e GE). A análise estatística (ANOVA One-Way) não mostrou diferença significativa entre os grupos F (2, 27) = 2,17, p > 0,05 quanto a discriminação de notas musicais. Estes resultados sugerem que a privação visual congênita não causa alterações na habilidade de discriminação de notas musicais em adultos cegos.

Long-term potentiation (LTP) and depression (LTD) are activity dependent long-lasting changes in synaptic efficacy and have been proposed as mechanisms for learning and memory. Although the exact relationship of LTP and LTD to memory is not known, they do share some properties and mechanisms that relate to memory, such as the strengthening and weakening of synapses. LTP and LTD have been studied extensively in hippocampal brain-slice preparations, due to its relatively organized structure, ease of induction, and its critical function in memory storage. Less work has been done in the neocortex despite the belief that it is heavily involved in the storage of long-term memories. Activity dependent plasticity has also been demonstrated in the basal ganglia in vivo and in vitro, but the results have been somewhat inconsistent. The experiments presented in this thesis explore a novel form of neural plasticity in two excitatory pathways (corticostriatal and thalamocortical) of the basal ganglia motor loop in the intact brain in awake, freely behaving rats. In thalamocortical slice preparations, simultaneous presynaptic stimulation and postsynaptic depolarization can induce L TP in animals prior to the critical period. However the results presented in this thesis show that applied stimulation to the thalamocortical pathway failed to produce either LTP or LTD in the awake freely moving animal.Corticostriatal LTD has been shown in slice preparations following direct tetanic stimulation of the striatum. In the current experiment, cortical stimulation failed to induce LTD although there was an observable decrease in the evoked potential following low-frequency stimulation. Corticostriatal L TP has been shown to depend on the type of stimulation applied. High-frequency and theta burst stimulation produced long-lasting changes in response amplitude in the corticostriatal pathway, with theta burst stimulation appearing to be the more effective stimulation protocol for inducing LTP in both the early and late components. Paired stimulation of the substantia nigra pars compacta and cortex indicated a modulatory action of dopamine on corticostriatal synaptic plasticity. Pairing led to a stable increase in the amplitude of LTP of both early and late components. We also report that a temporal relationship exists in the striatum with respect to the release of nigral dopamine and cortical glutamate. Simultaneous stimulation produced a more robust L TP compared to the two other conditions in which there was an applied stimulation delay to either the corticostriatal or nigrostriatal pathway. The results demonstrate the mechanistic differences, not only between the thalamocortical and corticostriatal pathways, but also slice and anesthetized preparations. The results also emphasize the need for further study on mechanisms of L TP and LTD in the various excitatory and inhibitory pathways of the basal ganglia motor loop. / Thesis / Doctor of Philosophy (PhD)