O núcleo dorsal da rafe (NDR) é a principal fonte de projeções serotonérgicas que inervam o sistema límbico. Estudos mostram que o NDR é uma estrutura complexa, formada por distintas sub-regiões topograficamente organizadas e que apresentam diferentes propriedades neuroquímicas e funcionais. Tem sido proposto que duas vias serotonérgicas oriundas do NDR, o trato prosencefálico e o trato periventricular, modulam diferentemente a expressão de comportamentos defensivos associados aos transtornos de ansiedade generalizada e de pânico. O presente trabalho investigou se as respostas defensivas de esquiva e de fuga evocadas no modelo do labirinto em T elevado (LTE), relacionadas à ansiedade generalizada e ao pânico, respectivamente, recrutam diferentes sub-regiões do NDR. Na primeira etapa do trabalho, usando a técnica de imunoistoquímica para detecção da proteína Fos e da enzima triptofano hidroxilase, avaliamos a expressão da proteína Fos por neurônios serotonérgicos e não-serotonérgicos em diferentes sub-regiões do NDR, bem como em estruturas mesencefálicas vizinhas ao NDR, ou seja, o núcleo mediano da rafe (NMR) e substância cinzenta periaquedutal (SCP) de ratos em decorrência da expressão dos comportamento de esquiva inibitória ou fuga no LTE. Nossos resultados mostraram que os comportamentos de fuga e de esquiva evocados no LTE recrutam distintas populações neuronais do NDR, do NMR, bem como da SCP. Enquanto neurônios serotonérgicos localizados no nível médio e caudal do NDR, mais precisamente, nas sub-regiões dorsal (DRD), caudal (DRC) e interfascicular (DRI), bem como do NMR, estão envolvidos com a aquisição do comportamento de esquiva inibitória, neurônios não serotonérgicos das asas laterais do NDR/SCP ventrolateral, bem como das colunas, dorsomedial e dorsolateral da SCP participam da expressão da fuga. Na segunda parte deste trabalho, avaliamos os efeitos da administração do agonista de receptores AMPA/cainato, ácido caínico, no DRD, DRC e asas laterais do NDR sobre os comportamentos defensivos avaliados no LTE. Os resultados mostraram que a injeção de ácido caínico, tanto no DRD, quanto no DRC, facilita a aquisição da esquiva inibitória e também prejudica a expressão do comportamento de fuga. Já, a estimulação das asas laterais do NDR com ácido caínico induz a expressão do comportamento de fuga, sem alterar o comportamento de esquiva. Efeito oposto sobre o comportamento de fuga foi observado com a administração nesta região de cloreto de cobalto, um inibidor da transmissão sináptica. Nossos resultados mostraram ainda que a administração de ácido caínico nas asas laterais aumenta a distância percorrida pelos animais em uma arena circular, resultado indicativo da evocação da resposta de fuga. Por fim, avaliamos a o envolvimento da neurotransmissão mediada por receptores GABAA e por receptores CRF1 nas asas laterais do NDR, na expressão do comportamento de fuga expressa no LTE. Os resultados mostram que o bloqueio dos receptores GABAA nas asas laterais facilitou a expressão da fuga. Por outro lado a administração de antalarmina, antagonista de receptores CRF1 não alterou a expressão da resposta de fuga, porém prejudicou a aquisição da esquiva inibitória. Em conjunto, os resultados da primeira etapa indicam o envolvimento de diferentes sub-populações neuronais do NDR na expressão dos comportamentos de esquiva e fuga avaliados no LTE. Nossos resultados também apontam o envolvimento de neurônios serotonérgicos do NMR na expressão da esquiva inibitória, bem como a participação da SCP na resposta de fuga. Os resultados da segunda etapa indicam que neurônios serotonérgicos localizados no DRD e DRC possam dar origem aos tratos prosencefálico e periventricular abordados pela teoria de Deakin & Graeff (1991). Embora as asas laterais do NDR estejam marcantemente envolvidas na expressão/regulação da resposta de fuga, populações neuronais específicas dessa região também estão envolvidas na modulação do comportamento de esquiva inibitória. / The dorsal raphe nucleus (DRN) is the main source of serotonergic projections that innervate the limbic system. A wealth of evidence indicates that the DRN is a complex structure composed by topographically organized sub-regions with distinct functional and neurochemical properties. It have been proposed that two serotonergic pathways originating in the DRN, the forebrain and periventricular tracts, distinctly modulate defensive behaviors associated with generalized anxiety disorder and panic disorder. The present study addressed the hypothesis that the two defensive responses evoked by the elevated T maze (ETM), i.e. escape and inhibitory avoidance which have been related to generalized anxiety and panic disorders, respectively, would recruit different subregions of the DRN. In the first part of this work, the number of doubly-immunostained cells for Fos protein and tryptophan hydroxylase, a marker of serotonergic neurons, was assessed within the rat DRN, median raphe nucleus (MRN) and PAG following inhibitory avoidance and escape performance in the ETM. Our results showed that these two defensive responses recruited distinct neuronal populations within the DRN, MRN and PAG. While serotonergic neurons located at the middle and caudal level of the DRN, specifically within the sub-regions dorsal (DRD), caudal (DRC) and interfascicular (DRI), and the MRN are implicated in the acquistion of inhibitory avoidance, nonserotonergic neurons in lateral wings (lwDR) of the DRN /ventrolateralPAG and the dorsal columns of PAG are implicated in the escape expression. In the second part of this study, we evaluated the effects caused by the administration of AMPA/kainate receptor agonist, kainic acid, into the DRD, DRC and lwDR of rats tested in the ETM. The results showed that injection of kainic acid into DRD and DRC facilitated inhibitory avoidance acquisition and impaired escape expression. On the other hand, stimulation of the lwDR by kainic acid facilitated escape expression, without interfering with inhibitory avoidance acquisition. Opposite effect on escape behavior was observed in this region followed injection of cobalt chloride, a synaptic transmission inhibitor. Our results also showed that administration of higher doses of kainic acid into the lwDR promptly evoked a vigorous escape reaction in animals tested in a circular arena. Finally, we evaluated the involvement of GABAA and CRF1 receptor-mediated neurotransmission in the lwDR in the regulation of the escape behavior measured by the ETM. Our results showed that the GABAA receptor antagonist bicuculine injected into the lwDR favored escape expression, without affecting inhibitory avoidance acquisition. On the other hand, local microinjection of the CRF1 receptor antagonist antalarmin impaired the acquisition of inhibitory avoidance, without changing escape expression. Together, our immunohistochemical results indicate the involvement of distinct DRN neuronal subpopulations in the regulation of escape and inhibitory avoidance responses. Our results also suggested that, while serotonergic neurons within the DRD, DRC, DRI and MRN are involved in inhibitory avoidance acquisition, non-serotonergic neurons of the vlPAG, dlPAG and dmPAG are involved in escape expression. The behavioral results with kainic acid indicated that the DRC and DRD may be the origin of the forebrain and periventricular tracts addressed by Deakin & Graeffs theory (1991). Although the lwDR are markedly implicated in escape regulation, specific neuronal populations within this region may also modulate inhibitory avoidance behavior.

Doctor of Philosophy (PhD) / Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

Doctor of Philosophy (PhD) / Schizophrenia is a severe mental illness that affects approximately 1% of the population worldwide, and which typically has a devastating effect on the lives of its sufferers. The characteristic symptoms of the disease include hallucinations, delusions, disorganized thought and reduced emotional expression. While many of the early theories of schizophrenia focused on its psychosocial foundations, more recent theories have focused on the neurobiological underpinnings of the disease. This thesis has four primary aims: 1) to use magnetic resonance imaging (MRI) to identify the structural brain abnormalities present in patients suffering from their first episode of schizophrenia (FES), 2) to elucidate whether these abnormalities were static or progressive over the first 2-3 years of patients’ illness, 3) to identify the relationship between these neuroanatomical abnormalities and patients’ clinical profile, and 4) to identify the normative relationship between longitudinal changes in neuroanatomy and electrophysiology in healthy participants, and to compare this to the relationship observed between these two indices in patients with FES. The aim of Chapter 2 was to use MRI to identify the neuroanatomical changes that occur over adolescence in healthy participants, and to identify the normative relationship between the neuroanatomical changes and electrophysiological changes associated with healthy periadolescent brain maturation. MRI and electroencephalographic (EEG) scans were acquired from 138 healthy participants between the ages of 10 and 30 years. The MRI scans were segmented into grey matter (GM) and white matter (WM) images, before being parcellated into the frontal, temporal, parietal and occipital lobes. Absolute EEG power was calculated for the slow-wave, alpha and beta frequency bands, for the corresponding cortical regions. The age-related changes in regional tissue volumes and regional EEG power were inferred with a regression model. The results indicated that the healthy participants experienced accelerated GM loss, EEG power loss and WM gain in the frontal and parietal lobes between the ages of 10 and 20 years, which decelerated between the ages of 20 and 30 years. A linear relationship was also observed between the maturational changes in regional GM volumes and EEG power in the frontal and parietal lobes. These results indicate that the periadolescent period is a time of great structural and electrophysiological change in the healthy human brain. The aim of Chapter 3 was to identify the GM abnormalities present in patients with FES, both at the time of their first presentation to mental health services (baseline), and over the first 2-3 years of their illness (follow-up). MRI scans were acquired from 41 patients with FES at baseline, and 47 matched healthy control subjects. Of these participants, 25 FES patients and 26 controls returned 2-3 years later for a follow-up scan. The analysis technique of voxel-based morphometry (VBM) was used in conjunction with the Statistical Parametric Mapping (SPM) software package in order to identify the regions of GM difference between the groups at baseline. The related analysis technique of tensor-based morphometry (TBM) was used to identify subjects’ longitudinal GM change over the follow-up interval. Relative to the healthy controls, the FES patients were observed to exhibit widespread GM reductions in the frontal, parietal and temporal cortices and cerebellum at baseline, as well as more circumscribed regions of GM increase, particularly in the occipital lobe. Furthermore, the FES patients lost considerably more GM over the follow-up interval than the controls, particularly in the parietal and temporal cortices. These results indicate that patients with FES exhibit significant structural brain abnormalities very early in the course of their illness, and that these abnormalities progress over the first few years of their illness. Chapter 4 employed the same methodology to investigate the white matter abnormalities exhibited by the FES subjects relative to the controls, both at baseline and over the follow-up interval. Compared to controls, the FES patients exhibited volumetric WM deficits in the frontal and temporal lobes at baseline, as well as volumetric increases at the fronto-parietal junction bilaterally. Furthermore, the FES patients lost considerably more WM over the follow-up interval than did the controls in the middle and inferior temporal cortex bilaterally. While there is substantial evidence indicating that abnormalities in the maturational processes of myelination play a significant role in the development of WM abnormalities in FES, the observed longitudinal reductions in WM were consistent with the death of a select population of temporal lobe neurons over the follow-up interval. The aim of Chapter 5 was to investigate the clinical correlates of the GM abnormalities exhibited by the FES patients at baseline. The volumes of four distinct cerebral regions where 31 patients with FES exhibited reduced GM volumes relative to 30 matched controls were calculated and correlated with patients’ scores on three primary symptom dimensions: Disorganization, Reality Distortion and Psychomotor Poverty. The results indicated that the greater the degree of atrophy exhibited by the FES patients in three of these four ‘regions-of-reduction’, the less severe their degree of Reality Distortion. These results suggest that an excessive amount of GM atrophy may in fact preclude the formation of hallucinations or highly systematized delusions in patients with FES. The aim of Chapter 6 was to identify the relationship between the longitudinal changes in brain structure and brain electrophysiology exhibited by 19 FES patients over the first 2-3 years of their illness, and to compare it to the normative relationship between the two indices reported in Chapter 2. The methodology employed for the parcellation of the MRI and EEG data was identical to Chapter 2. The results indicated that, in contrast to the healthy controls, the longitudinal reduction in GM volume exhibited by the FES patients was not associated with a corresponding reduction in EEG power in any brain lobe. In contrast, EEG power was observed to be maintained or even to increase over the follow-up interval in these patients. These results were consistent with the FES patients experiencing an abnormal elevation of neural synchrony. Such an abnormality in neural synchrony could potentially form the basis of the dysfunctional neural connectivity that has been widely proposed to underlie the functional deficits present in patients with schizophrenia. The primary aim of Chapter 7 was to assimilate the findings from the preceding empirical chapters with the theoretical framework provided in the literature, into an integrated and testable model of schizophrenia. The model emphasized dysfunctions in brain maturation, specifically in the normative processes of synaptic ‘pruning’ and axonal myelination, as playing a key role in the development of disintegrated neural activity and the subsequent onset of schizophrenic symptoms. The model concluded with the novel proposal that disintegrated neural activity arises from abnormal elevations in the synchrony of synaptic activity in patients with first-episode schizophrenia.

O núcleo dorsal da rafe (NDR) é a principal fonte de projeções serotonérgicas que inervam o sistema límbico. Estudos mostram que o NDR é uma estrutura complexa, formada por distintas sub-regiões topograficamente organizadas e que apresentam diferentes propriedades neuroquímicas e funcionais. Tem sido proposto que duas vias serotonérgicas oriundas do NDR, o trato prosencefálico e o trato periventricular, modulam diferentemente a expressão de comportamentos defensivos associados aos transtornos de ansiedade generalizada e de pânico. O presente trabalho investigou se as respostas defensivas de esquiva e de fuga evocadas no modelo do labirinto em T elevado (LTE), relacionadas à ansiedade generalizada e ao pânico, respectivamente, recrutam diferentes sub-regiões do NDR. Na primeira etapa do trabalho, usando a técnica de imunoistoquímica para detecção da proteína Fos e da enzima triptofano hidroxilase, avaliamos a expressão da proteína Fos por neurônios serotonérgicos e não-serotonérgicos em diferentes sub-regiões do NDR, bem como em estruturas mesencefálicas vizinhas ao NDR, ou seja, o núcleo mediano da rafe (NMR) e substância cinzenta periaquedutal (SCP) de ratos em decorrência da expressão dos comportamento de esquiva inibitória ou fuga no LTE. Nossos resultados mostraram que os comportamentos de fuga e de esquiva evocados no LTE recrutam distintas populações neuronais do NDR, do NMR, bem como da SCP. Enquanto neurônios serotonérgicos localizados no nível médio e caudal do NDR, mais precisamente, nas sub-regiões dorsal (DRD), caudal (DRC) e interfascicular (DRI), bem como do NMR, estão envolvidos com a aquisição do comportamento de esquiva inibitória, neurônios não serotonérgicos das asas laterais do NDR/SCP ventrolateral, bem como das colunas, dorsomedial e dorsolateral da SCP participam da expressão da fuga. Na segunda parte deste trabalho, avaliamos os efeitos da administração do agonista de receptores AMPA/cainato, ácido caínico, no DRD, DRC e asas laterais do NDR sobre os comportamentos defensivos avaliados no LTE. Os resultados mostraram que a injeção de ácido caínico, tanto no DRD, quanto no DRC, facilita a aquisição da esquiva inibitória e também prejudica a expressão do comportamento de fuga. Já, a estimulação das asas laterais do NDR com ácido caínico induz a expressão do comportamento de fuga, sem alterar o comportamento de esquiva. Efeito oposto sobre o comportamento de fuga foi observado com a administração nesta região de cloreto de cobalto, um inibidor da transmissão sináptica. Nossos resultados mostraram ainda que a administração de ácido caínico nas asas laterais aumenta a distância percorrida pelos animais em uma arena circular, resultado indicativo da evocação da resposta de fuga. Por fim, avaliamos a o envolvimento da neurotransmissão mediada por receptores GABAA e por receptores CRF1 nas asas laterais do NDR, na expressão do comportamento de fuga expressa no LTE. Os resultados mostram que o bloqueio dos receptores GABAA nas asas laterais facilitou a expressão da fuga. Por outro lado a administração de antalarmina, antagonista de receptores CRF1 não alterou a expressão da resposta de fuga, porém prejudicou a aquisição da esquiva inibitória. Em conjunto, os resultados da primeira etapa indicam o envolvimento de diferentes sub-populações neuronais do NDR na expressão dos comportamentos de esquiva e fuga avaliados no LTE. Nossos resultados também apontam o envolvimento de neurônios serotonérgicos do NMR na expressão da esquiva inibitória, bem como a participação da SCP na resposta de fuga. Os resultados da segunda etapa indicam que neurônios serotonérgicos localizados no DRD e DRC possam dar origem aos tratos prosencefálico e periventricular abordados pela teoria de Deakin & Graeff (1991). Embora as asas laterais do NDR estejam marcantemente envolvidas na expressão/regulação da resposta de fuga, populações neuronais específicas dessa região também estão envolvidas na modulação do comportamento de esquiva inibitória. / The dorsal raphe nucleus (DRN) is the main source of serotonergic projections that innervate the limbic system. A wealth of evidence indicates that the DRN is a complex structure composed by topographically organized sub-regions with distinct functional and neurochemical properties. It have been proposed that two serotonergic pathways originating in the DRN, the forebrain and periventricular tracts, distinctly modulate defensive behaviors associated with generalized anxiety disorder and panic disorder. The present study addressed the hypothesis that the two defensive responses evoked by the elevated T maze (ETM), i.e. escape and inhibitory avoidance which have been related to generalized anxiety and panic disorders, respectively, would recruit different subregions of the DRN. In the first part of this work, the number of doubly-immunostained cells for Fos protein and tryptophan hydroxylase, a marker of serotonergic neurons, was assessed within the rat DRN, median raphe nucleus (MRN) and PAG following inhibitory avoidance and escape performance in the ETM. Our results showed that these two defensive responses recruited distinct neuronal populations within the DRN, MRN and PAG. While serotonergic neurons located at the middle and caudal level of the DRN, specifically within the sub-regions dorsal (DRD), caudal (DRC) and interfascicular (DRI), and the MRN are implicated in the acquistion of inhibitory avoidance, nonserotonergic neurons in lateral wings (lwDR) of the DRN /ventrolateralPAG and the dorsal columns of PAG are implicated in the escape expression. In the second part of this study, we evaluated the effects caused by the administration of AMPA/kainate receptor agonist, kainic acid, into the DRD, DRC and lwDR of rats tested in the ETM. The results showed that injection of kainic acid into DRD and DRC facilitated inhibitory avoidance acquisition and impaired escape expression. On the other hand, stimulation of the lwDR by kainic acid facilitated escape expression, without interfering with inhibitory avoidance acquisition. Opposite effect on escape behavior was observed in this region followed injection of cobalt chloride, a synaptic transmission inhibitor. Our results also showed that administration of higher doses of kainic acid into the lwDR promptly evoked a vigorous escape reaction in animals tested in a circular arena. Finally, we evaluated the involvement of GABAA and CRF1 receptor-mediated neurotransmission in the lwDR in the regulation of the escape behavior measured by the ETM. Our results showed that the GABAA receptor antagonist bicuculine injected into the lwDR favored escape expression, without affecting inhibitory avoidance acquisition. On the other hand, local microinjection of the CRF1 receptor antagonist antalarmin impaired the acquisition of inhibitory avoidance, without changing escape expression. Together, our immunohistochemical results indicate the involvement of distinct DRN neuronal subpopulations in the regulation of escape and inhibitory avoidance responses. Our results also suggested that, while serotonergic neurons within the DRD, DRC, DRI and MRN are involved in inhibitory avoidance acquisition, non-serotonergic neurons of the vlPAG, dlPAG and dmPAG are involved in escape expression. The behavioral results with kainic acid indicated that the DRC and DRD may be the origin of the forebrain and periventricular tracts addressed by Deakin & Graeffs theory (1991). Although the lwDR are markedly implicated in escape regulation, specific neuronal populations within this region may also modulate inhibitory avoidance behavior.

Thesis named Calculation of advanced diffusion parameters in brain grey matter from DKI MRI images deals with processing of diffusion-weighted images from DKI. The thesis contains review of literature on principle of diffusion, influence of diffusion on MRI, calculation of DTI and DKI parameters and clinical application of diffusion-weighted maps with focus on grey matter. The thesis focuses on software tools for processing and pre-processing DTI and DKI. The practical part consisted of two sections. Two different softwares were used to calculate maps of diffusion parameters. Diffusion parameters from anatomical structure sunstantia nigra were compared between group of healthy controls and patients with Parkinson’s disease. This comparison did not show any statisticaly significant difference. In the second step, a script for creating diffusion maps in software Diffusinal Kurtosis Estimator was made.

No description available.

In der vorliegenden Arbeit wurde durch die Kombination zweier nichtinvasiver MR-Methoden in vivo untersucht, ob sich die funktionelle Sprachlateralisierung in einer strukturellen Asymmetrie der weißen Substanz widerspiegelt. Dafür wurden die Ergebnisse einer Patientengruppe mit Temporallappenepilepsie mit den Ergebnissen einer gesunden Kontrollgruppe verglichen. Es konnte gezeigt werden, dass mittels BOLD MRT eine Sprachlateralisierung in der grauen Substanz nachgewiesen werden kann, die mit einem strukturellen Korrelat in der weißen Substanz der sprachdominanten Hemisphäre einhergeht. Dieses Korrelat konnte als Asymmetrie der Mikrostruktur der weißen Substanz in DTI-Messungen belegt werden. Darüber hinaus konnte bewiesen werden, dass Patienten mit einer Temporallappenepilepsie im Vergleich zu gesunden Probanden eine atypische Lateralisierung der Sprachaktivierung im Broca-Areal aufweisen, die von einer gleichsinnig atypischen strukturelle Asymmetrie der weißen Substanz im Broca-Areal begleitet wird. Die These, dass eine funktionelle Sprachlateralisierung mit einer mikrostrukturellen Veränderung der weißen Substanz assoziiert ist, wird durch die vorliegende Arbeit sowohl für die gesunden Kontrollprobanden als auch für die Patienten mit einer fokalen Epilepsie bestätigt. Die Ergebnisse der vorliegenden Arbeit zeigen, dass DTI-Messungen eine sinnvolle Ergänzung zu BOLD MRT-Messungen in der Bestimmung der sprachrelevanten Areale darstellen können. Sprachlateralisierung könnte mit ihrer Hilfe in Zukunft exakt und nichtinvasiv bestimmt werden. Es stellte sich jedoch auch heraus, dass das in der vorliegenden Arbeit angewendete Verfahren in der Praxis sehr aufwendig ist, ohne eine entschieden höhere Aussagekraft über die Sprachlateralisierung zu erbringen. In dieser Form wird die nichtinvasive Bildgebung den Wada-Test als Goldstandard für den klinischen Alltag noch nicht ersetzen können.

Made available in DSpace on 2016-06-02T19:22:50Z (GMT). No. of bitstreams: 1 2381.pdf: 1192808 bytes, checksum: b6bdb4da58bced09244d3a1f38c4a657 (MD5) Previous issue date: 2009-04-24 / Universidade Federal de Sao Carlos / The exposure of animals to aversive situations, such as elevated plus-maze (EPM), activates serotonergic pathways with projections into structures involved in the defense system, such as the amygdala, septum, hypothalamus, hippocampus and periaqueductal grey matter (PAG), producing behavioral changes that can be characterized as anxiety. However the serotonin (5-HT) presents a dual role in this modulation. Thus, while the stimulation of the receptor subtype 5-HT1A and 5-HT2 prosencephalic in structures such as amygdala and hippocampus result in potentiation of responses of anxiety in rodents, the activation of these receptors in the PAG, often tends to reduce behaviors related to anxiety . This study focused the role of 5-HT3 receptors in the PAG in the anxiety in the mice EPM test. In experiments 1 and 2, mice received infusions intra-PAG of ondansetron (0, 0.3, 1.0, 3.0 nmol/0.1 μL) and mCPBG (0, 40, 80 and 160 nmol/0.1 μL), 5-HT3 receptors antagonist and agonist, respectively. As the mCPBG not changed any of the conventional indices (% open-arm entries and % open-arm time) and risk assessment, we investigated in experiment 3 the possibility of interaction between 5-HT3 and 5-HT2 receptors. For this, we perform combined microinfusions of intra-PAG ondansetron and mCPP, an agonist of 5-HT2B/2C receptors, on behavior of maze-naïve mice. The results showed that intra-PAG infusions of ondansetron (3.0 nmol) increased the behavioral indices of anxiety. None of the doses of intra-PAG infusions of mCPBG modified the conventional and ethological indices of anxiety. The anxiolytic-like effect produced by intra-PAG infusions of mCPP (0.03 nmol) was blocked by infusions of ondansetron (1.0 nmol) in the same mesencephalic structure. All effects were observed in the absence of significant changes in locomotor activity (closed-arm entries). Our results indicate that there is a possible interaction between 5-HT3 and 5-HT2B/2C receptors modulation into the PAG of anxiety in mice. / A exposição de animais a situações aversivas, tais como o labirinto em cruz elevado (LCE), ativa vias serotoninérgicas com projeções para estruturas envolvidas no sistema de defesa tais como, amídala, septo, hipotálamo, hipocampo e substância cinzenta periaquedutal (SCP), produzindo alterações comportamentais que podem ser caracterizadas como ansiedade. Entretanto, a serotonina (5-HT) apresenta um papel dual nesta modulação. Assim, enquanto a estimulação de receptores do subtipo 5-HT1A ou 5-HT2 em estruturas prosencefálicas como, amídala e hipocampo resultam na potencialização de respostas de ansiedade em roedores, a ativação dos mesmos receptores na SCP, freqüentemente tende a diminuir comportamentos relacionados à ansiedade. Este estudo investigou o papel dos receptores 5-HT3 da SCP na modulação da ansiedade em camundongos avaliados no LCE. Nos Experimentos 1 e 2, camundongos receberam microinjeções intra-SCP de ondansetron (0, 0,3, 1,0, 3,0 nmol/0,1 μl) e mCPBG (0, 40, 80 e 160 nmol/0,1 μl), antagonista e agonista dos receptores 5-HT3, respectivamente. Como o mCPBG não alterou nenhum dos índices convencionais de ansiedade (porcentagem de entrada e tempo gasto nos braços abertos) e de avaliação de risco, verificamos no experimento 3 a possibilidade de interação entre receptores 5-HT3 e 5-HT2. Para isso, realizamos microinjeções combinadas de ondansetron e mCPP, um agonista dos receptores 5-HT2B/2C. Os resultados mostraram que microinjeções de ondansetron (3,0 nmol) aumentaram os índices convencionais de ansiedade. Nenhuma das doses de mCPBG intra-SCP, alteraram os índices convencionais e etológicos de ansiedade. O efeito ansiolítico produzido pela administração intra-SCP do mCPP (0,03 nmol), foi bloqueado pela infusão de ondansetron (1,0 nmol) na mesma estrutura mesencefálica. Todos os efeitos foram observaA exposição de animais a situações aversivas, tais como o labirinto em cruz elevado (LCE), ativa vias serotoninérgicas com projeções para estruturas envolvidas no sistema de defesa tais como, amídala, septo, hipotálamo, hipocampo e substância cinzenta periaquedutal (SCP), produzindo alterações comportamentais que podem ser caracterizadas como ansiedade. Entretanto, a serotonina (5-HT) apresenta um papel dual nesta modulação. Assim, enquanto a estimulação de receptores do subtipo 5-HT1A ou 5-HT2 em estruturas prosencefálicas como, amídala e hipocampo resultam na potencialização de respostas de ansiedade em roedores, a ativação dos mesmos receptores na SCP, freqüentemente tende a diminuir comportamentos relacionados à ansiedade. Este estudo investigou o papel dos receptores 5-HT3 da SCP na modulação da ansiedade em camundongos avaliados no LCE. Nos Experimentos 1 e 2, camundongos receberam microinjeções intra-SCP de ondansetron (0, 0,3, 1,0, 3,0 nmol/0,1 μl) e mCPBG (0, 40, 80 e 160 nmol/0,1 μl), antagonista e agonista dos receptores 5-HT3, respectivamente. Como o mCPBG não alterou nenhum dos índices convencionais de ansiedade (porcentagem de entrada e tempo gasto nos braços abertos) e de avaliação de risco, verificamos no experimento 3 a possibilidade de interação entre receptores 5-HT3 e 5-HT2. Para isso, realizamos microinjeções combinadas de ondansetron e mCPP, um agonista dos receptores 5-HT2B/2C. Os resultados mostraram que microinjeções de ondansetron (3,0 nmol) aumentaram os índices convencionais de ansiedade. Nenhuma das doses de mCPBG intra-SCP, alteraram os índices convencionais e etológicos de ansiedade. O efeito ansiolítico produzido pela administração intra-SCP do mCPP (0,03 nmol), foi bloqueado pela infusão de ondansetron (1,0 nmol) na mesma estrutura mesencefálica. Todos os efeitos foram observados sem alteração da atividade locomotora (entrada nos braços fechados). Os nossos resultados sugerem uma possível interação entre receptores 5-HT3 e 5-HT2B/2C da SCP na modulação da ansiedade em camundongos.dos sem alteração da atividade locomotora (entrada nos braços fechados). Os nossos resultados sugerem uma possível interação entre receptores 5-HT3 e 5-HT2B/2C da SCP na modulação da ansiedade em camundongos.

L’apnée obstructive du sommeil (AOS) est l’un des troubles du sommeil les plus fréquents chez l’adulte et sa prévalence augmente avec l’âge. Elle se caractérise par des arrêts répétés de la respiration au cours du sommeil, menant à la présence de fragmentation du sommeil et à de l’hypoxémie intermittente. Lorsque non traité, ce trouble peut mener à diverses conséquences non négligeables sur la santé des individus qui en sont atteints, incluant sur la santé du cerveau. L’AOS est d’ailleurs de plus en plus reconnue comme étant un possible facteur de risque de déclin cognitif et de démence. Dans ce contexte, quelques études transversales ont caractérisé le volume de la substance grise cérébrale chez des adultes vieillissants atteints d’AOS, avec des résultats variables. En effet, certaines études ont noté de plus grands volumes de substance grise chez les personnes avec une AOS plus sévère, alors que d’autres ont retrouvé des plus petits volumes chez cette même population. Ce qui explique la variabilité entre les études demeure à ce jour mal compris, bien que certaines hypothèses aient émergé. Ainsi, cette thèse vise à évaluer l’association entre la sévérité de l’AOS et le volume de substance grise cérébrale chez des personnes d’âge moyen et âgées de manière transversale et longitudinale. La première étude de cette thèse se base sur des techniques de neuroimagerie afin d’évaluer les liens entre la sévérité de l’AOS et le volume de la substance grise cérébrale des sous-régions du lobe temporal médian, soit l’hippocampe, le cortex entorhinal et le cortex parahippocampique. Celles-ci ont été ciblées puisqu’elles peuvent être affectées tôt dans la progression de la pathologie de la maladie d’Alzheimer (MA). De plus, nous avons testé l’effet d’une correction de la portion d’eau libre sur les volumes cérébraux. Finalement, nous avions comme objectif de mieux comprendre si certaines caractéristiques démographiques ou cliniques de nos participants pouvaient avoir un impact sur les associations observées. Nous avons observé qu’une AOS plus sévère était associée à des volumes de substance grise plus grands de certaines sous-régions du lobe temporal médian (hippocampe et cortex entorhinal), mais seulement chez des groupes de participants spécifiques, soit les femmes, les participants plus âgés et ceux présentant un trouble cognitif léger de type amnésique. Le fait d’apporter une correction pour la portion d’eau libre aux volumes mesurés a rendu non significatives les associations observées. Il est donc possible que la présence accrue d’eau extracellulaire, suggérant de l’œdème cérébral, puisse expliquer la présence de plus grands volumes chez les participants présentant une AOS plus sévère. La deuxième étude visait quant à elle à évaluer les changements structurels des sous-régions du lobe temporal médian associés à la sévérité de l’AOS chez des personnes d’âge moyen et âgées sur une période d’environ 2 ans. Nous avons démontré que chez nos participants n’ayant pas utilisé un traitement pour l’AOS, la présence d’interaction entre la sévérité de l’AOS et l’âge permettait d’expliquer les changements annuels de volume de substance grise. De fait, les participants plus jeunes de notre échantillon (< 65 ans) avec une AOS plus sévère présentaient un plus grand taux de changement annuel de volume de substance grise, soulignant la présence d’hypertrophie dans ce sous-groupe. Ceci a été mis en lumière pour l’ensemble des sous-régions du lobe temporal médian. Chez les participants âgés entre 65 et 75 ans, aucune association entre la sévérité de l’AOS et les changements de volume au fil du temps n’a pu être soulignée. Les participants plus âgés (> 75 ans) avec une plus grande sévérité d’AOS présentaient quant à eux une plus grande atrophie au fil du temps dans certaines régions, soit l’hippocampe et le cortex entorhinal. Ces résultats supportent donc une hypothèse biphasique des changements au niveau de la substance grise cérébrale chez les gens présentant de l’AOS, avec une première phase caractérisée par des augmentations de volume chez les adultes plus jeunes, menant éventuellement à de l’atrophie chez les personnes plus âgées. Cette thèse permet d’avoir un portrait plus clair sur la nature des changements et des mécanismes impliqués dans l’association entre la sévérité de l’AOS et les volumes de substance grise. L’un des apports importants est l’utilisation d’une nouvelle méthodologie afin d’obtenir une portion d’eau libre, ce qui a permis de mieux comprendre l’apport potentiel de mécanismes pouvant sous-tendre les changements structuraux observés, notamment l’œdème cérébral. De plus, l’évaluation des caractéristiques individuelles des participants a permis d’expliquer partiellement les incongruences entre les études précédentes. Dans le cadre des études incluses dans cette thèse, nous avons observé des changements plus marqués chez les femmes. Nous avons également pu démontrer que l’âge des individus atteints d’AOS pouvait influencer significativement le patron de changements observés. Les résultats de cette thèse pourraient donc permettre de mieux cibler les personnes avec AOS qui pourraient le plus bénéficier d’un traitement pour maintenir leur santé cérébrale. / Obstructive sleep apnea (OSA) is one of the most common sleep disorders in adults, and its prevalence increases with age. It is characterized by repeated pauses in breathing during sleep, leading to sleep fragmentation and intermittent hypoxemia. If left untreated, this disorder can have numerous consequences, including on the brain’s health. OSA is increasingly recognized as a risk factor for cognitive decline and dementia. In this context, cross-sectional studies have characterized brain gray matter volume in aging adults with OSA, with variable results. Indeed, some studies have noted greater gray matter volumes in people with more severe OSA, while others have found smaller volumes in this same population. What explains the variability between studies remains poorly understood, although some hypotheses have emerged. Thus, this thesis aims to assess the association between OSA severity and cerebral gray matter volume in middle-aged and elderly individuals using cross-sectional and longitudinal designs. The first study in this thesis uses neuroimaging techniques to assess the links between OSA severity and cerebral gray matter volume of the medial temporal lobe subregions, i.e. the hippocampus, entorhinal cortex and parahippocampal cortex. These were chosen as they can be affected early in the progression of Alzheimer's disease (AD) pathology. We also corrected our brain volumes for free-water portion. Finally, we aimed to better understand whether certain demographic or clinical characteristics of our participants might have an impact on the associations observed. We noted that more severe OSA was associated with larger gray matter volumes in certain subregions of the medial temporal lobe (hippocampus and enthorinal cortex), but only in specific groups of participants: women, older participants and those with amnestic mild cognitive impairment. Correcting our volumes for free-water portion rendered the associations nonsignificant. It is therefore possible that the presence of extracellular water, suggestive of cerebral edema, could explain the presence of larger volumes in participants with more severe OSA. The second study aimed to assess longitudinal structural changes associated with OSA severity in middle-aged and elderly people over a period of around 2 years. We found that in participants who did not use treatment for OSA, the presence of interactions between OSA severity and age were associated with the annual changes in gray matter volume. Indeed, younger participants (< 65 years old) in our sample with more severe OSA showed a greater rate of annual change in gray matter volume, highlighting the presence of hypertrophy in this subgroup. This was underlined in all medial temporal lobe subregions. In participants aged between 65 and 75, no association between OSA severity and volume changes over time could be highlighted. Older participants (>75 years old) with greater OSA severity showed greater hippocampal and entorhinal cortex atrophy over time. These results therefore support a biphasic hypothesis of changes in cerebral gray matter in people with OSA, with an initial phase characterized by volume increases in younger adults, eventually leading to atrophy in older people. This thesis provides a clearer picture of the nature of the changes and mechanisms involved in the association between OSA severity and gray matter volumes. An important contribution is the use of a new methodology to obtain a free-water portion, which allows to better understand the potential contribution of mechanisms that may underlie the structural changes observed, notably cerebral edema. In addition, the assessment of participants' individual characteristics helped to partially explain incongruities between previous studies. Indeed, in the studies included in this thesis, we observed more marked changes in certain subgroups of participants, notably women. We were also able to demonstrate that the age of individuals with OSA could significantly influence the pattern of changes observed, either gray matter hypertrophy or atrophy. The results of this thesis could therefore make it possible to target specific subgroups of individuals suffering from OSA who may be at greater risk of displaying changes in gray matter structure, and thus promote screening and treatment when necessary.

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