Major depressive disorder (MDD) is a heritable and highly debilitating condition with antidepressants, first-line treatment, demonstrating low to modest response rates. No current biological mechanism substantially explains MDD but both neurostructural and neurochemical pathways have been suggested. Further explication of these may aid in identifying subgroups of MDD that are better defined by their aetiology. Specifically, genetic stratification provides an array of tools to do this, including the intermediate phenotype approach which was applied in this thesis. This thesis explores genetic overlap with regional brain volume and MDD and the genetic and non-genetic components of antidepressant response. The first study utilised the most recent published data from ENIGMA (Enhancing Neuroimaging Genetics through Meta-analysis) Consortium's genome-wide association study (GWAS) of regional brain volume to examine shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. This was explored using linkage disequilibrium score regression (LDSC), polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX (Breaking Up Heterogeneous Mixture Based On Cross-locus correlations). Results indicated that hippocampal volume was positively genetically correlated with MDD (rg= 0.46, P= 0.02), although this did not survive multiple comparison testing. Additionally, there was evidence for genetic subgrouping in Generation Scotland: Scottish Family Health Study (GS:SFHS) MDD cases (P=0.00281), however, this was not replicated in two other independent samples. This study does not support a shared architecture for regional brain volumes and MDD, however, provided some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. To explore antidepressant treatment resistance, the second study utilised prescription data in (GS:SFHS) to define a measure of (a) treatment resistance (TR) and (b) stages of resistance (SR) by inferring antidepressant switching as non-response. GWAS were conducted separately for TR in GS:SFHS and the GENDEP (Genome-based Therapeutic Drugs for Depression) study and then meta-analysed (meta-analysis n=4,213, cases=358). For SR, a GWAS on GS:SFHS only was performed (n=3,452). Additionally, gene-set enrichment, polygenic risk scoring (PRS) and genetic correlation analysis were conducted. No significant locus, gene or gene-set was associated with TR or SR, however power analysis indicated that this analysis was underpowered. Pedigree-based correlations identified genetic overlap with psychological distress, schizotypy and mood disorder traits. Finally, the role of neuroticism, psychological resilience and coping styles in antidepressant resistance was investigated. Univariate, moderation and mediation models were applied using logistic regression and structural equation modelling techniques. In univariate models, neuroticism and emotion-orientated coping demonstrated significant negative association with antidepressant resistance, whereas resilience, task-orientated and avoidance-orientated coping demonstrated significant positive association. No moderation of the association between neuroticism and TR was detected and no mediating effect of coping styles was found. However, resilience was found to partially mediate the association between neuroticism and TR. Whilst the first study does not indicate a genetic overlap between regional brain volumes and MDD, it demonstrates the utility of the intermediate approach in complex disease. Antidepressant resistance was associated with neuroticism both genetically and phenotypically, indicating its role as an intermediate phenotype. Nonetheless, larger sample sizes are needed to adequately address the components of antidepressant resistance. Further work in antidepressant non-response may help to identify biological mechanisms responsible in MDD pathology and help stratify individuals into more tractable groups.

Made available in DSpace on 2014-12-17T15:36:58Z (GMT). No. of bitstreams: 1 RovenaCGJE_DISSERT.pdf: 2142357 bytes, checksum: bbf33b27b7a838600336db16673db325 (MD5) Previous issue date: 2010-04-23 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The parabrachial complex (PB) is an area of the brainstem responsible for the processing and transmission of essential physiologic information for the survival of the organisms. This region is subdivided in approximately nine subregions, considering morphology, cytoarchitectural and functional characteristic. Its neurons have an extensive network of connections with other regions of the nervous system. The objective in this work was to map the retinal projection to the PB and make a citoarchitectonic and neurochemical characterization of this region in the common marmoset (Callithrix jacchus), a primate of the New World. The retinal projections were mapped by anterograde transport of the choleric toxin subunit b (CTb). The citoarchitecture was described through the Nissl method, and the neurochemical characterization was made through immunohistochemical technique to the some neurotransmitters and neuroactives substances present in this neural center. In marmoset PB, in the coronal sections labeled by Nissl method, we found a similar pattern to that evidenced in other animal species. The immunoreactivity against CTb was verified in the PBMv in fibers/terminal, characterizing such as retinal innervations in this area. The immunohistochemical technique reveled that the PB contain cells, fibers and/or terminals immunoreactives to the neuronal nuclear protein, Choline acetyl transferase, nitric oxide synthase, serotonin, enkephalin, substance P, Calcium-binding proteins (calbindin, calretinin e parvalbumin), and glial fibrillary acidic protein. The histochemical technique reveled cells and fibers NADPH-diaphorase reactive. Each one of those substances presented a characteristic pattern of demarcation in PB, and some serve as specific markers of subregions / O complexo parabraquial (PB) ? uma regi?o do tronco encef?lico respons?vel pelo processamento e transmiss?o de informa??es fisiol?gicas essenciais para a sobreviv?ncia dos organismos. Essa regi?o ? subdividida em aproximadamente nove regi?es, considerando caracter?sticas morfol?gicas, citoarquitet?nicas e funcionais. Seus neur?nios possuem uma ampla rede de conex?es com as demais regi?es do sistema nervoso. O objetivo deste trabalho foi mapear a proje??o retiniana para o PB e fazer uma caracteriza??o citoarquitet?nica e neuroqu?mica desta regi?o no Callithrix jacchus (sag?i), um primata do Novo Mundo. As proje??es retinianas foram mapeadas por transporte anter?grado da subunidade B da toxina col?rica (CTb). A citoarquitetura foi descrita atrav?s do m?todo de Nissl e a caracteriza??o neuroqu?mica foi feita atrav?s de t?cnicas imunoistoqu?micas para alguns neurotransmissores e subst?ncias neuroativas presentes neste centro neural. No PB do sagui, nas sec??es coronais coradas pelo m?todo de Nissl, foi poss?vel encontrar um padr?o similar ao que ? evidenciado em outras esp?cies animais. A imunorreatividade contra CTb foi encontrada em fibras terminais do PBMv, caracterizando desta forma uma inerva??o retiniana nessa ?rea. A t?cnica imunoistoqu?micas revelou que o PB cont?m c?lulas, fibras e/ou terminais imunorreativos a prote?na nuclear neuronal, colina acetiltransferase, ?xido n?trico sintetase, serotonina, encefalina, subst?ncia P, prote?nas ligantes de c?lcio (calbindina, calretinina e parvalbumina), e a prote?na ac?dica fibrilar glial. A partir de t?cnicas histoqu?micas verificou-se c?lulas e fibras reativas a NADPH-diaforase. Cada uma dessas subst?ncias apresentou um padr?o caracter?stico de marca??o no PB e algumas serviram como marcadores espec?ficos de subregi?es

A utilização experimental de CS é apontada como uma perspectiva benéfica no tratamento da lesão medular devido estas células produzirem fatores neurotróficos e citocinas inflamatórias que influenciam o ambiente do sistema nervoso. Ratos machos foram submetidos à lesão medular contusa de intensidade moderada (25mm) ao nível do 11o segmento torácico. As CS cultivadas a partir do nervo ciático foram pré-tratadas ou não com as citocinas inflamatórias TGF-1 (5ng/ml) ou TNF- (30ng/ml) e inoculadas no local da lesão imediatamente após o trauma. O grupo controle e o grupo lesão receberam inoculação do meio de cultura. Após a cirurgia os ratos foram submetidos à análise do comportamento motor durante 8 semanas. O BBB mostrou melhora do comportamento motor ao longo do período analisado para o grupo tratado com as CS. Este efeito não foi potenciado pelo pré-tratamento das CS com as citocinas inflamatórias. As medulas espinais foram processadas e receberam coloração pelo Violeta de Cresilo ou imunomarcação com a GAP-43, o glutamato, o NPY, a substância P, a GFAP, o FGF-2 e do NG2. Os tratamentos realizados neste desenho experimental não alteraram as respostas neuroprotetivas. Segundo análise estereológica não foram encontradas diferenças no número estimado de neurônios remanescentes e no volume de tecido preservado entre os grupos que receberam lesão medular. A lesão promoveu uma diminuição da imunorreatividade da GAP-43 no corno anterior, que foi revertida quando a lesão recebeu tratamento com as CS prétratadas ou não com a citocina TGF-1. O resultado do tratamento com as CS foi o de aumento na imunorreatividade do glutamato nas células no corno anterior e no funículo lateral quando comparado com o grupo lesão. Para o NPY no corno anterior houve aumento da imunorreatividade do grupo tratado com as CS apenas em comparação ao grupo controle. Já no funículo lateral a lesão aumentou a imunorreatividade NPY em comparação ao grupo controle, inclusive quando houve tratamento com as CS, mas este deixou de existir quando houve prétratamento das CS com as citocinas. Referente ao FGF-2, no funículo lateral e no fascículo grácil houve aumento da imunorreatividade no grupo tratado com as CS, acrescidas ou não de TGF-1, apenas em comparação ao grupo controle. Porém, o tratamento com as CS aumentou a imunorreatividade do FGF-2 na região do fascículo grácil. A imunorreatividade do FGF-2 aumentou na região de epicentro da lesão, e este efeito foi mantido nos grupos tratados com as CS, acrescidas ou não de TGF-1. Houve significante aumento da imunorreatividade da GFAP no corno anterior e no funículo lateral quando os grupos lesados foram tratados com as CS e/ou citocinas comparado ao grupo controle. Na região do epicentro, a lesão promoveu aumento da imunorreatividade da GFAP, que foi potencializado quando houve tratamento com as CS. A lesão promoveu aumento da imunorreatividade do NG2 no epicentro, inclusive quando houve tratamento com as CS. O melhor desempenho motor observado no grupo que recebeu inoculação de CS provavelmente está relacionado a fatores como respostas plásticas e neuroquímicas no tecido preservado da medula espinal. / The experimental use of Schwann cells is indicated on spinal cord treatment due to the ability of these cells to produce neurotrophic factors and inflammatory cytokines, influencing nervous system environment. Male rats were submitted to a moderate spinal cord contusion (25mm) at 11th thoracic level. Culture Schwann cells were obtained from sciatic nerves and pre-treated or not with inflammatory cytokines TGF-1 (5ng/ml) or TNF- (30ng/ml) and then were inoculated in lesion site just after trauma. Sham and lesion groups received culture medium inoculation. After surgery, rats were submitted to behavior analyses during 8 weeks. BBB showed motor recovery in the Schwann cell group. This effect was not potentiated by pretreated of Schwann cells with inflammatory cytokines. The spinal cords were processed for Cresil Violet or immunolabeling to GAP-43, glutamate, NPY, substance P, GFAP, FGF-2 and NG2. Stereological analyses showed no differences in the estimated number of remaining neurons and in the volume of the preserved tissue among the lesioned groups. The injury reduced GAP-43 immunoreactivity in ventral horn, which was reverted when injury was treated with Schwann cells pre-treated or not with TGF-1. Schwann cell treatment enhanced glutamate immunoreactivity in the ventral horn and lateral funiculus compared with lesioned group. In ventral horn, NPY immunoreactivity was enhanced in Schwann cells group compared with sham group. In lateral funiculus, the injury or the treatment with Schwann cells increased NPY immunoreactivity, comparing with sham group. FGF-2 of lateral funiculus and gracile fasciculus enhanced in Schwann cells group. Treatment with Schwann cells enhanced FGF-2 immunoreactivity in gracile fasciculus. Injury enhanced FGF-2 immunoreactivity in epicenter region, also observed in the groups treated by Schwann cells. In ventral horn and lateral funiculus when the lesioned groups were treated by Schwann cells and/or cytokines there was significant increase in GFAP immunoreactivity compared with sham group. In epicenter, the injury promoted GFAP immunoreactivity increase that was potentiated by Schwann cells treatment. The injury produced NG2 increase in epicenter, included by Schwann cells treatment. The motor recovery showed in Schwann cell group is probably related to neurochemical plasticity in spinal cord preserved tissue.

Factors that confer predisposition and vulnerability for alcoholism and other substance abuse disorders may be described usefully within the gene-environment interplay framework. Thus, it is postulated that heritability provides a major contribution not only to alcohol but also to other substances of abuse. Studies of evoked potential amplitude reduction have provided a highly suitable and testable method for the assessment of both environmentally-determined and heritable characteristics pertaining to substance use and dependence. The different personal attributes that may co-exist with parental influence or exist in a shared, monozygotic relationship contribute to the final expression of addiction. In this connection, it appears that personality disorders are highly prevalent co-morbid conditions among addicted individuals, and, this co-morbidity is likely to be accounted for by multiple complex eti-ological relationships, not least in adolescent individuals. Co-morbidity associated with deficient executive functioning may be observed too in alcohol-related aggressiveness and crimes of violence. The successful intervention into alcohol dependence and craving brought about by baclofen in both human and animal studies elucidates glutamatergic mechanisms in alcoholism whereas the role of the dopamine transporter, in conjunction with both the noradrenergic and serotonergic transporters, are implicated in cocaine dependence and craving. The role of the cannabinoids in ontogeny through an influence upon the expression of key genes for the development of neurotransmitter systems must be considered. Finally, the particular form of behaviour/ characteristic outcome due to childhood circumstance may lie with biological, gene-based determinants, for example individual characteristics of monoamine oxidase (MAO) activity levels, thereby rendering simple predictive measures both redundant and misguiding.

No description available.

No description available.

The study proposes an ecosystemic approach as an intervention for attentional difficulties and heightened motor activity, traditionally known as AD/HD. A literature study of AD/HD is presented first as a psycho-educational frame of reference. The focus then shifts to the symtoms of AD/DH to move closer to the possible underlying causes of these symptoms. In doing so, the focus changes from AD/HD as a diagnosis to attentional difficulties and heightened motor activity as presenting symptoms. Attention and motor activity as constructs are investigated in terms of their neuro-anatomical, neuro-chemical and neuro-physiological aspects. Furthermore, neurodevelopment, physiological stress, neurodevelopmental delay, information processing systems, sensory-motor subsystems and integration as constructs are investigated to understand their role in attention and modulation of motor activity. The study of attention and motor activity and their associated neurological factors motivates an alternative, ecosystemic method of intervention. The proposed approach includes an investigation into internal and external biochemical ecosystems such as environmental pollutants, deficiencies of essential nutrients and genetic deficiencies of the immune system. Other aspects such as time, maturation and neurodevelopment are also considered as well as the gentle interplay between these aspects. The therapeutic intervention includes sound therapy, neurodevelopmental movement activities, EEG neurofeedback and nutrition. Experimental research with a sample population of 12 diagnosed grade 4 and 5 AD/HD learners over a 11 week period was conducted. Statistically significant improvements in aspects of attention were noted using 2 standardised instruments and verification through parent interviews in the first and second experimental groups. Statistically significant improvements were noted in aspects of motor activity (a decline in hyperactive behaviour) in the second experimental group with verification from teacher interviews. Additionally, children in the first experimental group improved significantly more than children in the control group with regards to mathematic skills. The second experimental group showed significant improvement with large effect sizes on reading, mathematic skills and spelling. In conclusion, the statistically significant results obtained with the proposed approach motivates implementation, with improvements in attention, motor activity control and academic performance as a prospect. / Psychology of Education / D. Ed.(Psychology of Education)

The study proposes an ecosystemic approach as an intervention for attentional difficulties and heightened motor activity, traditionally known as AD/HD. A literature study of AD/HD is presented first as a psycho-educational frame of reference. The focus then shifts to the symtoms of AD/DH to move closer to the possible underlying causes of these symptoms. In doing so, the focus changes from AD/HD as a diagnosis to attentional difficulties and heightened motor activity as presenting symptoms. Attention and motor activity as constructs are investigated in terms of their neuro-anatomical, neuro-chemical and neuro-physiological aspects. Furthermore, neurodevelopment, physiological stress, neurodevelopmental delay, information processing systems, sensory-motor subsystems and integration as constructs are investigated to understand their role in attention and modulation of motor activity. The study of attention and motor activity and their associated neurological factors motivates an alternative, ecosystemic method of intervention. The proposed approach includes an investigation into internal and external biochemical ecosystems such as environmental pollutants, deficiencies of essential nutrients and genetic deficiencies of the immune system. Other aspects such as time, maturation and neurodevelopment are also considered as well as the gentle interplay between these aspects. The therapeutic intervention includes sound therapy, neurodevelopmental movement activities, EEG neurofeedback and nutrition. Experimental research with a sample population of 12 diagnosed grade 4 and 5 AD/HD learners over a 11 week period was conducted. Statistically significant improvements in aspects of attention were noted using 2 standardised instruments and verification through parent interviews in the first and second experimental groups. Statistically significant improvements were noted in aspects of motor activity (a decline in hyperactive behaviour) in the second experimental group with verification from teacher interviews. Additionally, children in the first experimental group improved significantly more than children in the control group with regards to mathematic skills. The second experimental group showed significant improvement with large effect sizes on reading, mathematic skills and spelling. In conclusion, the statistically significant results obtained with the proposed approach motivates implementation, with improvements in attention, motor activity control and academic performance as a prospect. / Psychology of Education / D. Ed.(Psychology of Education)

Made available in DSpace on 2014-12-17T15:36:41Z (GMT). No. of bitstreams: 1 RovenaCGJE_TESE.pdf: 3622694 bytes, checksum: f04b7feec9686941d276f158d103c97b (MD5) Previous issue date: 2013-06-21 / Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior / The circadian timing system (CTS) is responsible for the generation and synchronization and the suprachiasmatic nucleus (SCN) of the hypothalamus has been described as the major circadian pacemaker in many mammalian species. The internal temporal organization managed by SCN is disturbed with aging bringing many pathological disorders that range from loss of complex cognitive performance to simple physiological functions. Therefore, our aim was perform a comparative study of the morphological aspects and neurochemical composition in the SCN of marmosets (Callithrix jacchus) adults and older using immunohistochemical techniques. We found morphometric and neurochemical changes in th SCN o folder animals in comparison to adults, among these a possible decreased in retinal projection to the SCN of older animals, found through a decline in CTB immunostaining, which can occur due atrophy and/or decreasing of fibers from the retinohypothalamic tract (RHT). The Kl?ver-Barrera histological technique strongly suggests a decrease in those fibers from RHT. Also, by means of a morphometric study, it is found a atrophy and numerical decline of neurons in SCN of aged animals, investigated by Nissl technique, and immunostaining with NeuN and calbindin. Relative optical density (ROD) analysis were used to evaluate the expression of some neurochemical components in SCN, such as GFAP expression, which was increased in older, result that indirectly reinforces that morphological changes occurs due the aging; the vasoactive intestinal polipeptide (VIP) showed no expression alteration in SCN of older animals; the serotonin (5-HT) was descreased in the dorsomedial portion of the SCN, and neurpeptide Y (NPY) apparently also decrease due to the increase of age. Many of these modifications were seen in other animals, such as rodents, human primates and non-human primates. These data about marmoset comes to add new information of the effect of aging on structures responsibles for the circadian rhytmicity, and that some behavioral changes controlled by th SCN, and founded in aged animals, may be caused by these morphological and neurochemical changes. Although some results have been quantitatively negative, qualitatively all analysis show significant change comparing adult and older animals, perhaps due to a low sampling number. In conclusion, the marmoset presents several morphological and neurochemical changes in the SCN of aged animals compared to adults, which may result in behavioral changes that favor pathology aging related / O sistema de temporiza??o circadiana (STC) ? respons?vel pela gera??o e sincroniza??o dos ritmos circadianos e o n?cleo supraquiasm?tico (NSQ) do hipot?lamo tem sido descrito como o principal marca-passo circadiano em diversas esp?cies de mam?feros. A organiza??o temporal interna comandada pelo NSQ ? perturbada com o avan?o da idade trazendo in?meros transtornos patol?gicos que v?o desde a perda do desempenho cognitivo complexo a fun??es fisiol?gicas simples. Portanto, nosso objetivo foi fazer um estudo comparativo dos aspectos morfol?gicos e da composi??o neuroqu?mica no NSQ de saguis (Callithrix jacchus) adultos e idosos atrav?s de t?cnicas imunoistoqu?mica. Encontramos modifica??es morfom?tricas e neuroqu?micas no NSQ de animais idosos quando comparado aos adultos, dentre essas uma poss?vel diminui??o da proje??o da retina ao NSQ de animais idosos, encontrada atrav?s da diminui??o na imunomarca??o a CTB, que pode ocorrer devido uma atrofia e/ou diminui??o nas fibras provenientes do tracto retinohipotal?mico (TRH). A t?cnica histol?gica de Kl?ver-Barrera sugere realmente haver uma diminui??o dessas fibras que do TRH. Tamb?m ? visto, atrav?s de um estudo morfom?trico, diminui??o e atrofia no n?mero de neur?nios do NSQ de animais idosos, investigados por meio da t?cnica de Nissl, imunomarca??o a NeUN e a calbindina. An?lises por densidade ?ptica relativa (DOR) auxiliaram na avalia??o da express?o de alguns componentes neuroqu?micos do NSQ, como a express?o de GFAP, que foi aumentada em idosos, dado que indiretamente refor?a estar ocorrendo altera??es morfol?gicas decorrentes do envelhecimento; o polipet?deo intestinal vasoativo (VIP) que n?o mostrou altera??o na sua express?o no NSQ de aniamis idosos, a serotonina (5-HT) que se mostrou diminu?da na por??o dorsomedial do NSQ, e o neuropept?deo Y que aparentemente tamb?m diminuiu sua express?o em decorr?ncia do aumento da idade. V?rias dessas modifica??es foram vistas em outros animais roedores, primatas humanos e n?o humanos, o sagui vem adicionar novas informa??es sobre o efeito do envelhecimento nas estruturas respons?veis pela ritmicidade circadiana e que algumas altera??es comportamentais comandadas pelo STC e vistas em animais idosos podem ser provocadas por essas mudan?as morfol?gicas e neuroqu?micas. Embora alguns resultados tenham sido quantitativamente negativos, qualitativamente todas as an?lises mostram subst?ncial mudan?a ao se comparar animais adultos e idosos, talvez em decorr?ncia de um baixo n?mero de amostragem. Em conclus?o, o sagui mostra in?meras altera??es morfol?gicas e neuroqu?micas no NSQ de animais idosos quando comparado aos adultos, o que podem resultar em altera??es comportamentais que favorecem patologias relacionadas ao envelhecimento

The trigeminal ganglion (TG) is a complex sensory structure and multiple lines of evidence suggest that significant differences exist in anatomical, neurochemical and physiological properties between it and its equivalent structure in the somatosensory system, the dorsal root ganglion (DRG). This is likely to be a reflection, first on the unique areas of tissue innervation of the TG and second, on the unusual responses to injury which give rise to distinct pain symptoms such as toothache, migraine and temporomandibular joint disorders. In an attempt to address this disparity in knowledge, we have carried out an in-depth in vivo study investigating neurochemical populations and cell size distributions of sensory neurons within the rat TG. We have performed a detailed analysis of expression patterns for receptor components of important inflammatory mediators, NGF (TrkA), TNFα (p55) and IL-6 (gp130), along with the thermo-transducers TRPV1 and TRPM8. For each analysis we have compared our findings with those of the rat DRG. We have shown a significantly larger population of NF200+ neurons within the TG (51%) compared to the DRG (40%), and most interestingly, the majority of NF200+ neurons in the TG were within the small to medium cell size range, conferring a nociceptive phenotype. We have for the first time, determined expression of p55 and gp130 protein levels within neurochemically defined subpopulations of the TG. We show that a large proportion (33%) of TG neurons, in particular 27% of NF200+ neurons co-express p55, and thereby have the potential to respond directly to TNFα. Furthermore, we have observed gp130 protein expression to be ubiquitous within the TG, suggesting all neurons, including non-nociceptors, could respond to IL-6. In addition, we have utilised biochemical and electrophysiological techniques in vitro to measure the functional outcome of exposure of TG neurons to IL-6. We have demonstrated that IL-6 activates the JAK/STAT signalling pathway, preferentially within NF200+ neurons. Furthermore, we have shown that IL-6 sensitises the response of TG neurons to the TRPV1 agonist capsaicin, altering the gating properties and prolonging the opening time of the channel. Taken together, our findings support the emerging picture of a complex combinatorial pattern of co-expression of sensory neurochemicals, transducers and receptor components that help to define TG neuronal modality and function. We would advocate caution in making generalisations across sensory ganglia in particular in extrapolating data from the DRG to the trigeminal ganglion.