Thesis (Ph. D.)--California Institute of Technology, 1993. UM #93-25,337. / Advisor names found in the Acknowledgments pages of the thesis. Title from home page. Viewed 02/18/2010. Includes bibliographical references.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references (leaves 82-86). Also available on the World Wide Web.

No description available.

For many organisms the sense of smell is critical to survival. Some olfactory stimuli elicit innate responses that are mediated through hardwired circuits that have developed over long periods of evolutionary time. Most olfactory stimuli, however, have no inherent meaning. Instead, meaning must be imposed by learning during the lifetime of an organism. Despite the dominance of olfactory stimuli on animal behavior, the mechanisms by which odorants elicit learned behavioral responses remain poorly understood. All odor-evoked behaviors are initiated by the binding of an odorant to olfactory receptors located on sensory neurons in the nasal epithelium. Olfactory sensory neurons transmit this information to the olfactory bulb via spatially organized axonal projections such that individual odorants evoke a stereotyped map of bulbar activity. A subset of bulbar neurons, the mitral and tufted cells, relay olfactory information to higher brain structures that have been implicated in the generation of innate and learned behavioral responses, including the cortical amygdala and piriform cortex. Anatomical studies have demonstrated that the spatial stereotypy of the olfactory bulb is maintained in projections to the posterolateral cortical amygdala, a structure that is involved in the generation of innate odor-evoked responses. The projections of mitral and tufted cells to piriform cortex however appear to discard the spatial order of the olfactory bulb: each glomerulus sends spatially diffuse, apparently random projections across the entire cortex. This anatomy appears to constrain odor-evoked responses in piriform cortex: electrophysiological and imaging studies demonstrate that individual odorants activate sparse ensembles that are distributed across the extent of cortex, and individual piriform neurons exhibit discontinuous receptive fields such that they respond to structurally and perceptually similar and dissimilar odorants. It is therefore unlikely that olfactory representations in piriform have inherent meaning. Instead, these representations have been proposed to mediate olfactory learning. In accord with this, lesions of posterior piriform cortex prevent the expression of a previously acquired olfactory fear memory and photoactivation of a random ensemble of piriform neurons can become entrained to both appetitive and aversive outcomes. Piriform cortex therefore plays a central role in olfactory fear learning. However, how meaning is imparted on olfactory representations in piriform remains largely unknown. We developed a strategy to manipulate the neural activity of representations of conditioned and unconditioned stimuli in the basolateral amygdala (BLA), a downstream target of piriform cortex that has been implicated in the generation of learned responses. This strategy allowed us to demonstrate that distinct neural ensembles represent an appetitive and an aversive unconditioned stimulus (US) in the BLA. Moreover, the activity of these representations can elicit innate responses as well as direct Pavlovian and instrumental learning. Finally activity of an aversive US representation in the basolateral amygdala is required for learned olfactory and auditory fear responses. These data suggest that both olfactory and auditory stimuli converge on US representations in the BLA to generate learned behavioral responses. Having identified a US representation in the BLA that receives convergent olfactory information to generate learned fear responses, we were then able to step back into the olfactory system and demonstrate that the BLA receives olfactory input via the monosynaptic projection from piriform cortex. These data suggest that aversive meaning is imparted on an olfactory representation in piriform cortex via reinforcement of its projections onto a US representation in the BLA. The work described in this thesis has identified mechanisms by which sensory stimuli generate appropriate behavioral responses. Manipulations of representations of unconditioned stimuli have identified a central role for US representations in the BLA in connecting sensory stimuli to both innate and learned behavioral responses. In addition, these experiments have suggested local mechanisms by which fear learning might be implemented in the BLA. Finally, we have identified a fundamental transformation through which a disordered olfactory representation in piriform cortex acquires meaning. Strikingly this transformation appears to occur within 3 synapses of the periphery. These data, and the techniques we employ, therefore have the potential to significantly impact upon our understanding of the neural origins of motivated behavior.

A Síndrome de Kallmann (SK), associação entre hipogonadismo hipogonadotrófico e distúrbio olfatório (hiposmia ou anosmia), é causada por uma deficiência da migração neuronal que envolve as células produtoras do hormônio liberador de gonadotrofinas e os neurônios olfatórios, com origem embriológica comum. O primeiro gene descrito, KAL1, codifica uma proteína chamada anosmina, que possui homologia com moléculas de adesão axonal envolvidas na migração neuronal. Dentre as anormalidades fenotípicas descritas na SK, destacam-se a malformação das estruturas do rinencéfalo (bulbos e sulcos olfatórios) e a presença, em parte dos pacientes, de uma alteração neurológica específica, os movimentos em espelho (ME). No presente trabalho estudamos 21 pacientes com SK, comparando com um grupo controle (n=16), utilizando técnicas qualitativas e quantitativas de imagem por Ressonância Magnética (RM), com os objetivos de (I) correlacionar as diferentes alterações radiológicas do encéfalo com os achados clínicos, laboratoriais e a presença de mutações gênicas; (II) caracterizar qualitativa e quantitativamente as alterações do rinencéfalo; e (III) investigar possíveis alterações associadas aos ME, dando atenção às duas principais hipóteses para sua causa, desenvolvimento anormal do trato corticoespinhal e deficiência do mecanismo inibitório contra-lateral via corpo caloso. Para estudo do rinencéfalo utilizamos especialmente imagens coronais ponderadas em T2 com cortes finos, avaliando subjetivamente e posteriormente medindo o volume dos bulbos olfatórios, comprimento e profundidade dos sulcos. Para estudo dos ME utilizamos a técnica de morfometria baseada em voxel (VBM), procurando alterações volumétricas da substancia branca (SB) e cinzenta (SC), seguida da avaliação de alterações da SB com as técnicas de relaxometria (RL) e cálculo da taxa de transferência de magnetização (TTM). Dezoito (85%) pacientes apresentaram graus variáveis de acometimento das estruturas olfatórias. Demonstramos que a aplasia dos bulbos e/ou sulcos olfatórios foi o achado mais comum na SK, e a presença de aplasia de bulbo olfatório teve excelente concordância com a presença de anosmia no teste olfativo. O VBM otimizado mostrou áreas alteradas da SC envolvendo o córtex motor de maneira diferente nos pacientes com e sem ME, compatíveis com uma resposta cortical hipertrófica à uma decussação deficiente do trato corticoespinhal nos pacientes com SK e ME. Ainda, as alterações da SC nos pacientes sem ME podem representar mecanismos mais complexos determinando a presença ou não do sinal. Apesar do nosso estudo de VBM não mostrar alteração significativa de volume da SB, as avaliações com RL e TTM mostraram áreas de alteração de sinal, demonstrando a presença de desmielinização e/ou desorganização axonal na SB dos pacientes com SK, envolvendo diferentemente o sistema motor dos pacientes com e sem ME, sendo compatível com os estudos prévios que sugerem a associação entre uma anomalia do trato corticoespinhal e uma deficiência no mecanismo inibitório inter-hemisférico como responsáveis pela persistência patológica dos ME. A análise da TTM demonstrou ainda alteração em topografia da decussação das pirâmides bulbares que pode representar o desarranjo primário desta região, com as alterações das fibras a montante, superiormente (evidenciadas na RL e TTM), e do córtex motor (evidenciadas no VBM), possivelmente sendo secundárias e acometendo diferentemente os pacientes com e sem ME. / Kallmann syndrome (KS) is defined by the association of hypogonadotropic hypogonadism with olfaction disturbance (hyposmia or anosmia). It is caused by a neuronal migration arrest that involves both the gonadotropin releasing hormone (GnRH) and the olfactory neurons, which have a common embryonic origin. The first gene described, KAL1, encodes a protein named anosmin, which shows a strong homology to axonal adhesion molecules involved in neuronal migration and axonal pathfinding. Various phenotypic abnormalities have been described in KS, including olfactory bulbs and sulci aplasia or hypoplasia and specific neurologic disorders, such as mirror movements (MM). In this study we evaluated 21 patients with KS, comparing with a control group (n=16), using qualitative and quantitative techniques with Magnetic Resonance Imaging (MRI), with the following purposes: (I) correlate the brains radiologic alterations with the clinical, laboratorial and genetic findings; (II) characterize the rhinencephalon alterations; and (III) investigate MM etiology, addressing the two main hypotheses concerning its cause, abnormal development of the primary motor system, involving the ipsilateral corticospinal tract, and lack of contralateral motor cortex inhibitory mechanisms, mainly through the corpus callosum. For rhinencephalon evaluation, we specially used thin-section coronal T2-weighed images, which were reviewed and then objectively evaluated with the measurements of the olfactory bulbs and sulci. To study MM we used the voxel-based morphometry (VBM), to determine white (WM) and gray matter (GM) volume changes, and T2 relaxometry (T2R) and magnetization transfer ratio (MTR), searching for signal intensity changes in the WM. Eighteen (85%) patients presented different degrees of olfactory structures abnormalities, with the bulbs and/or sulci aplasia being the most common finding, and presence olfactory bulb aplasia showed excellent agreement with anosmia as determined by the smell identification clinical test. The optimized VBM study did not show significant white matter changes in patients with KS but showed gray matter alterations in keeping with a hypertrophic response to a deficient pyramidal decussation in patients with MM. In addition, gray matter alterations were observed in patients without MM, which can represent more complex mechanisms determining the presence or absence of this symptom. Even if the VBM did not show significant volume changes in WM, the evaluation with the T2R and MTR showed WM signal intensity alterations, differently involving patients with and without MM, in keeping with demyelinization and/or axonal disorder, in accordance with the involvement of a corticospinal tract anomaly and a deficient inhibitory interhemispheric mechanism in the etiology of MM. The MTR analysis also showed a different alteration in the pyramidal decussation, which can represent a primary disorder in this region, with all other alterations in the superior WM fibers and motor cortex possibly being secondary to this disarrangement, and involving patients with and without MM in a different manner.

The current work explores the behavioural and anatomical consequences of unilateral neonatal bulbectomy (OBX) in male and female rats at postnatal day 1 (PI) and P10. In adulthood the animals underwent a battery of motor and cognitive tests, and diffuse effects of early brain injury on the development of behavior were found. Disturbing olfactory sense input during development affected motor output. Rats normally display an equal distribution of right or left paw preference. In this study, both OBX sexes showed a shifted paw preference to the ipsilesional side, and forelimb deficits were found in a skilled reaching task. Lesion animals also showed enhanced performance on a visually driven spatial cognitive test. Cross-modal compensatory changes may be responsible. Morphological changes within the cerebral cortex are described, including bulbar changes, enlarged but fewer glomeruli, smaller accessory olfactory bulb, decreased downstream connectivity, and a rostral shift of the forebrain toward the olfactory bulb. Changes to the lateral cortex were found in both intact and lesion hemispheres, along with dendritic changes in the forelimb reaching area. Cellular regeneration within the lesion bulb was indicated. Changed shape and relative size increases compared to the intact bulb were found. BrdU labeling showed increased mitotic activity in P10 lesion animals. These findings demonstrate that the impact of olfactory injury during early development goes well beyond odor perception and discrimination, and that olfactory inputs during development significantly contribute to the development of the neocortex. / xix, 195 leaves : ill. (some col.) ; 29 cm.

A Síndrome de Kallmann (SK), associação entre hipogonadismo hipogonadotrófico e distúrbio olfatório (hiposmia ou anosmia), é causada por uma deficiência da migração neuronal que envolve as células produtoras do hormônio liberador de gonadotrofinas e os neurônios olfatórios, com origem embriológica comum. O primeiro gene descrito, KAL1, codifica uma proteína chamada anosmina, que possui homologia com moléculas de adesão axonal envolvidas na migração neuronal. Dentre as anormalidades fenotípicas descritas na SK, destacam-se a malformação das estruturas do rinencéfalo (bulbos e sulcos olfatórios) e a presença, em parte dos pacientes, de uma alteração neurológica específica, os movimentos em espelho (ME). No presente trabalho estudamos 21 pacientes com SK, comparando com um grupo controle (n=16), utilizando técnicas qualitativas e quantitativas de imagem por Ressonância Magnética (RM), com os objetivos de (I) correlacionar as diferentes alterações radiológicas do encéfalo com os achados clínicos, laboratoriais e a presença de mutações gênicas; (II) caracterizar qualitativa e quantitativamente as alterações do rinencéfalo; e (III) investigar possíveis alterações associadas aos ME, dando atenção às duas principais hipóteses para sua causa, desenvolvimento anormal do trato corticoespinhal e deficiência do mecanismo inibitório contra-lateral via corpo caloso. Para estudo do rinencéfalo utilizamos especialmente imagens coronais ponderadas em T2 com cortes finos, avaliando subjetivamente e posteriormente medindo o volume dos bulbos olfatórios, comprimento e profundidade dos sulcos. Para estudo dos ME utilizamos a técnica de morfometria baseada em voxel (VBM), procurando alterações volumétricas da substancia branca (SB) e cinzenta (SC), seguida da avaliação de alterações da SB com as técnicas de relaxometria (RL) e cálculo da taxa de transferência de magnetização (TTM). Dezoito (85%) pacientes apresentaram graus variáveis de acometimento das estruturas olfatórias. Demonstramos que a aplasia dos bulbos e/ou sulcos olfatórios foi o achado mais comum na SK, e a presença de aplasia de bulbo olfatório teve excelente concordância com a presença de anosmia no teste olfativo. O VBM otimizado mostrou áreas alteradas da SC envolvendo o córtex motor de maneira diferente nos pacientes com e sem ME, compatíveis com uma resposta cortical hipertrófica à uma decussação deficiente do trato corticoespinhal nos pacientes com SK e ME. Ainda, as alterações da SC nos pacientes sem ME podem representar mecanismos mais complexos determinando a presença ou não do sinal. Apesar do nosso estudo de VBM não mostrar alteração significativa de volume da SB, as avaliações com RL e TTM mostraram áreas de alteração de sinal, demonstrando a presença de desmielinização e/ou desorganização axonal na SB dos pacientes com SK, envolvendo diferentemente o sistema motor dos pacientes com e sem ME, sendo compatível com os estudos prévios que sugerem a associação entre uma anomalia do trato corticoespinhal e uma deficiência no mecanismo inibitório inter-hemisférico como responsáveis pela persistência patológica dos ME. A análise da TTM demonstrou ainda alteração em topografia da decussação das pirâmides bulbares que pode representar o desarranjo primário desta região, com as alterações das fibras a montante, superiormente (evidenciadas na RL e TTM), e do córtex motor (evidenciadas no VBM), possivelmente sendo secundárias e acometendo diferentemente os pacientes com e sem ME. / Kallmann syndrome (KS) is defined by the association of hypogonadotropic hypogonadism with olfaction disturbance (hyposmia or anosmia). It is caused by a neuronal migration arrest that involves both the gonadotropin releasing hormone (GnRH) and the olfactory neurons, which have a common embryonic origin. The first gene described, KAL1, encodes a protein named anosmin, which shows a strong homology to axonal adhesion molecules involved in neuronal migration and axonal pathfinding. Various phenotypic abnormalities have been described in KS, including olfactory bulbs and sulci aplasia or hypoplasia and specific neurologic disorders, such as mirror movements (MM). In this study we evaluated 21 patients with KS, comparing with a control group (n=16), using qualitative and quantitative techniques with Magnetic Resonance Imaging (MRI), with the following purposes: (I) correlate the brains radiologic alterations with the clinical, laboratorial and genetic findings; (II) characterize the rhinencephalon alterations; and (III) investigate MM etiology, addressing the two main hypotheses concerning its cause, abnormal development of the primary motor system, involving the ipsilateral corticospinal tract, and lack of contralateral motor cortex inhibitory mechanisms, mainly through the corpus callosum. For rhinencephalon evaluation, we specially used thin-section coronal T2-weighed images, which were reviewed and then objectively evaluated with the measurements of the olfactory bulbs and sulci. To study MM we used the voxel-based morphometry (VBM), to determine white (WM) and gray matter (GM) volume changes, and T2 relaxometry (T2R) and magnetization transfer ratio (MTR), searching for signal intensity changes in the WM. Eighteen (85%) patients presented different degrees of olfactory structures abnormalities, with the bulbs and/or sulci aplasia being the most common finding, and presence olfactory bulb aplasia showed excellent agreement with anosmia as determined by the smell identification clinical test. The optimized VBM study did not show significant white matter changes in patients with KS but showed gray matter alterations in keeping with a hypertrophic response to a deficient pyramidal decussation in patients with MM. In addition, gray matter alterations were observed in patients without MM, which can represent more complex mechanisms determining the presence or absence of this symptom. Even if the VBM did not show significant volume changes in WM, the evaluation with the T2R and MTR showed WM signal intensity alterations, differently involving patients with and without MM, in keeping with demyelinization and/or axonal disorder, in accordance with the involvement of a corticospinal tract anomaly and a deficient inhibitory interhemispheric mechanism in the etiology of MM. The MTR analysis also showed a different alteration in the pyramidal decussation, which can represent a primary disorder in this region, with all other alterations in the superior WM fibers and motor cortex possibly being secondary to this disarrangement, and involving patients with and without MM in a different manner.