Caffeine is used for the treatment of apnea of prematurity. The objective of this study was to determine the long term neuropathological and neurobehavioral effects of caffeine on the immature rat brain. Newborn rats were injected with either caffeine, or normal saline from postnatal days 3 to 7, equivalent to the human premature infant of 28-36 weeks. Behavioral tests revealed no abnormality in caffeine treated animals compared to controls. Fluro-Jade B stain of P4 rat brains showed that caffeine caused significant neuronal cell death in some areas of the brain, compared to controls, but this alteration was transient and not present at P8. Anti-NeuN stain at P21 showed significant neuronal cell loss in CA1 and hypothalamus regions in the caffeine group, but not at P160. Anti-Neurofilament M stain at P8, P21 and P160 showed no differences between the control and caffeine groups. We conclude that use of caffeine has no significant effect on the behavioral tests measured in our newborn rat pups. While caffeine caused neuronal cell death at P4, and neuronal cell loss in CA1 and hypothalamus regions at P21, there was no long-lasting effect on neuropathological outcome. However, given these latter findings, the use of caffeine in the premature infant must still be done with caution. / Medical Sciences

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2009. / Title from first page of PDF file (viewed June 16, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 118-130).

Thesis (Ph.D.)--Kent State University, 2006. / Title from PDF t.p. (viewed Sept. 19, 2006). Advisor: Eric Glasgow. Keywords: oxytocin; isotocin; vasopressin; vasotocin; hypothalamo-neurohypophysial system; hypothalamus; development; autism; Prader-Willi Syndrome; single-minded; orthopedia; arylhydrocarbon nuclear translocator; Brn2; POU; zebrafish; behavior; paraventricular nucleus; supraoptic nucleus; preoptic nucleus; diencephalon; suprachiasmatic nucleus; thyroid transcription factor; sonic hedgehog; NK 2 transcription factor related; distal-less homeobox gene; homeobox; homeodomain; morpholino Includes bibliographical references (p. 230-266).

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed June 11, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 171-178).

Introdução: Neurocisticercose (NCC) é a doença parasitária do sistema nervoso central (SNC) mais freqüente no mundo, afetando mais de 50 milhões de pessoas. No entanto, alguns de seus achados clínicos, tais como comprometimento cognitivo, é um aspecto pouco estudado na literatura e ainda permanece mal caracterizado. Objetivos: Avaliar o desempenho cognitivo de pacientes portadores de NCC e comparar o desempenho deste grupo em testes de avaliação cognitiva com o desempenho de indivíduos saudáveis (GC) e de indivíduos com epilepsia criptogênica (GE). O estudo objetivou também relacionar os achados com o tipo morfológico, número, localização dos cisticercos e fase de desenvolvimento do parasita. Métodos: 32 pacientes (média de idade = 45,2 ± 10,2 anos) com diagnóstico de NCC, com ou sem tratamento específico e em ambas as fases de desenvolvimento do parasita (formas ativa e inativa) foram submetidos a uma avaliação cognitiva, constituída de dez testes (memória, habilidades visuoespaciais, cálculo, abstração, praxias e gnosias e o Mini Exame do Estado Mental - MEEM), sendo comparados a 32 GC e 24 GE emparelhados por idade, gênero e nível educacional. Resultados: Pacientes com NCC apresentam prejuízo cognitivo, em comparação aos controles saudáveis em tarefas de memória visual, memória lógica imediata e recente. Pacientes com NCC e aqueles do GC apresentaram um desempenho cognitivo superior, em comparação ao GE; nos testes que envolveram a atenção e a memória operacional e na praxia reflexiva. Não houve diferença estatisticamente significativa no desempenho cognitivo nos três grupos estudados nos testes cognitivos que avaliaram a praxia construcional e ideomotora, cálculo e capacidade de abstração e julgamento. Não foi encontrada correlação entre alterações nos testes cognitivos dos pacientes com NCC e número de lesões e a fase de desenvolvimento do parasita. Em relação ao tipo morfológico, foi observado que os indivíduos que apresentavam a forma racemosa obtiveram um desempenho inferior no teste do Mini Exame do estado mental (MEEM), quando comparados aos que apresentavam a forma cística simples. Em relação à localização dos cisticercos, pode-se notar que os indivíduos com lesões de localização parenquimatosa demonstraram escores inferiores no teste de Faces Famosas e no teste de memória lógica recente, quando comparados àqueles com lesões ventriculares e no espaço subaracnóide. Conclusões: O declínio cognitivo foi uma manifestação clínica muito freqüente em nossa amostra de pacientes com NCC. Estes dados podem fornecer um conhecimento mais abrangente das manifestações clínicas presentes na NCC / Introduction: Neurocysticercosis (NCC) is the most frequent parasitic disease of the central nervous system (CNS), affecting more than 50 million people. However, some its clinical findings, such as cognitive impairment, are is an aspect little studied in the literature and remain poorly characterized. Aim: Assess the cognitive performance of patients with NCC and compare the performance of this group healthy controls (HC) and cryptogenic epilepsy (CE) patients. The study also aimed to relate the findings with the morphological type, number, location of cysticerci and development phase of the parasite. Methods: thirty-two patients (mean age = 45.2 ± 10.2 years) with diagnosis of NCC, with or without specific treatment and in both stages of parasite development (active and inactive forms) underwent a cognitive evaluation, constituted of ten tests. They were then compared to HC 32 and 24 CE, matched for age, gender and educational level. Results: NCC patients presented cognitive impairment compared to healthy controls in tasks of visual memory, immediate and recent logical memory. NCC patients and the HC presented a higher cognitive performance, compared to CE, in tests involving attention, working memory and reflective praxis. There was no statistically significant difference in cognitive performance among the three groups on cognitive tests that assessed ideomotor and constructional praxis, calculation and capacity for abstraction and trial. No correlation was found between changes in cognitive tests of patients NCC and number of lesions and stage of parasite development. Regarding to the morphological type, it was observed that individuals with the racemose form a lower performance in tests of the Mini Mental State Examination (MMSE), when compared to those who had the simple cystic form. Regarding location of cysticerci, it was noted that individuals with parenchymal lesions showed lower scores in the Famous Faces Test and recent test of logical memory when compared to those with lesions in the ventricular and subarachnoid space. Conclusions: The cognitive decline was a very frequent clinical manifestation in our sample of patients NCC. This data provide a better understanding of the broader clinical manifestations in patients with NCC

Serotonin (5HT) is a monoamine neurotransmitter that modulates a wide range of brain functions via the actions at 5HT receptors and 5HT transporters. Dysregulation of 5HT transmission underlies many neurological and psychiatric disorders, such as depression and anxiety disorders. To advance the research in serotonergic neurotransmission and dysfunction, we have focused on two distinct approaches- 1) investigation of basic biology of synaptic function and 2) small molecule drug discovery. We have first developed a novel fluorescent tracer of 5HT, providing a molecular tool to study the serotonergic system in the CNS with subcellular and cellular resolution in vitro and in vivo. Next, we have developed novel small molecules to activate the serotonin 2A receptor (5HT2A agonists). By exploring new scaffolds, we expect to expand the pharmacophore space for 5HT2A agonists to allow exploration of 5HT2A as molecular target for treating neuropsychiatric disorders, and guide structure-based discovery of more selective 5HT2A agonists with desirable pharmacological properties as potential drug candidates.

Traumatic brain injury (TBI) is a prevalent CNS neurodegenerative condition that results in lasting neurological dysfunction, including potentially debilitating cognitive impairments. Despite the advancements in understanding the complex damage that can culminate in cellular dysfunction and loss, no therapeutic treatment has been effective in clinical trials, highlighting that new approaches are desperately needed. A therapy that limits cell death while simultaneously promoting reparative mechanisms, including post-traumatic neurogenesis, in the injured brain may have maximum effectiveness in improving recovery of function after TBI. Insulin-like growth factor-1 (IGF-1) is a potent growth factor that has previously been shown to promote recovery of function after TBI, but no studies have evaluated the efficacy of IGF-1 to promote cell survival and modulate neurogenesis following brain injury. Systemic infusion of IGF-1 resulted in undetectable levels of IGF-1 in the brain, but did promote increased cortical activation of Akt, a pro-survival downstream mediator of IGF-1 signaling, in mice subjected to controlled cortical impact (CCI), a well-established model of contusion TBI. However, systemic infusion of IGF-1 did not promote recovery of motor function in mice after CCI. A one week central infusion of IGF-1 elevated brain levels of IGF-1, increased Akt activation and improved motor and cognitive function after CCI. Central infusion of IGF-1 also significantly increased immature neuron density at 7 d post-injury for a range of doses and when administered with a clinically relevant delayed onset of 6 hr post-injury. To mitigate potential side effects of central infusion, an alternative conditional astrocyte-specific IGF-1 overexpressing mouse model was utilized to evaluate the efficacy of IGF-1 to promote post-traumatic neurogenesis. Overexpression of IGF-1 did not protect against acute immature neuron loss, but did increase immature neuron density above uninjured levels at 10 d post-injury. The increase in immature neuron density appeared to be driven by enhanced neuronal differentiation. In wildtype mice, immature neurons exhibited injury-induced reductions in dendritic arbor complexity following severe CCI, a previously unknown pathological phenomenon. Overexpression of IGF-1 in brain-injured mice promoted the restoration of dendritic arbor complexity to the dendritic morphology observed in uninjured mice. Together, these findings provide strong evidence that treatment with IGF-1 promotes the recovery of neurobehavioral function and enhances post-traumatic neurogenesis in a mouse model of contusion TBI.

Lead is a central nervous system poison. Healthy People 2010 established a target blood lead level (BLL) for children of 0 μg/dL by 2010, but is silent with regard to any changes in BLLs standards for working age adults. In this paper, the relation of BLL to performance on two neurobehavioral tests was assessed in working age adults (N = 4909; Age 20 to 59 years; 51.4% Female) employing data from the Third National Health and Nutrition Survey (NHANES 111). Multiple linear regression analyses indicated a significant effect of BLL on time taken to complete an attention demanding cognitive task (Symbol Digit Substitution Task, SDST) but not accuracy of performance of the SDST or simple reaction time, after controlling for confounding variables of age, sex, race-ethnicity, and education. Persons with BLL ≥5 μg /dL took longer (multivariate adjusted mean = 23.6 Sec, SE = 0.30) compared to individuals with BLLs <5 μg /dL (mean = 22.5 Sec, SE = 0.14). The results suggest that lead burden in working age persons impairs central nervous processes involving executive mental functions (decision speed and attention). The findings, if confirmed by case control and or cohort studies would indicate a need to reconsider currently accepted lead levels in working age adults.

Introdução: Neurocistcercose (NC) é a doença parasitária do SNC mais frequente no mundo. Afeta mais de 50 milhões de pessoas. No entanto, algumas de suas manifestações clínicas, como comprometmento cognitivo e demência, ainda permanecem caracterizadas de modo incompleto, sem que haja estudos controlados disponíveis na literatura até o momento. Objetvos: Investigar a frequência e o perfil clínico do comprometimento cognitivo associado à NC ativa, comparando o desempenho em testes de avaliação cognitiva de pacientes com a doença ao de controles saudáveis (CS) e de pacientes com epilepsia criptogênica (EC). Métodos: Quarenta pacientes (idade média = 39,25 ± 10,50 anos), com diagnóstco de NC ativa segundo critérios absolutos à ressonância magnética (RM) de crânio e sem tratamento antiparasitário prévio foram submetdos à avaliação cognitiva e funcional extensas, sendo comparados a 49 CS e 28 pacientes com EC emparelhados por idade, nível educacional e frequência de crises epilépticas (grupo EC). Resultados: Pacientes com NC apresentaram comprometimento significativo em relação ao grupo CS nos testes que avaliam funções executivas, memória verbal e não verbal, praxia construtiva e fluência verbal (p<0,05). Demência foi diagnosticada em 12,5% dos pacientes com NC de acordo com os critérios do DSM-IV. Os doentes do grupo NC apresentaram desempenho significativamente inferior em testes de memória operacional, memória episódica verbal, funções executivas, nomeação, praxia construtiva e orientação visual-espacial, quando comparados àqueles do grupo EC. Não se encontrou correlação entre as alterações nos testes cognitivos nos pacientes com NC e os achados à RM (carga de doença, tipo e localização das lesões). Conclusões: Comprometimento cognitivo foi muito frequente na amostra de pacientes com NC avaliada, sendo que demência foi identificada em uma proporção significativa dos doentes. Estes dados aumentam o nosso conhecimento sobre a apresentação clínica da NC e sobre seu potencial impacto na saúde pública. / Introducton: Neurocysticercosis (NCYST) is the most frequent CNS parasitic disease worldwide, afecting more than 50 million people. However, some of its clinical findings, such as cognitive impairment and dementia, remain poorly characterized, with no controlled studies conducted so far. We investigated the frequency and the clinical profile of cognitive impairment and dementia in a sample of NCYST patents in comparison to cognitvely healthy controls (HC) and to cryptogenic epilepsy (CE) patents. Methods: Forty treatment-naïve NCYST patients aged 39.25 ± 10.50 years and fulfilling absolute criteria for definitive active NCYST on magnetic resonance imaging (MRI), underwent a comprehensive cognitive and functional evaluation and were compared to 49 HC and 28 CE patients of similar age, educational level, and seizure frequency. Results: NCYST patients displayed significant impairment in executive functions, verbal and non-verbal memory, constructive praxis, and verbal fluency when compared to HC (p<0.05). Dementia was diagnosed in 12.5% of NCYST patients according to the DSM-IV criteria. When compared to CE patients, NCYST patients presented altered working and episodic verbal memory, executive functions, naming, verbal fluency, constructive praxis, and visual-spatal orientation. No correlation emerged between cognitive scores and number, localization or type of NCYST lesions on MRI. Conclusions: Cognitive impairment was ubiquitous in this sample of active NCYST patients. Antepileptic drug use and seizure frequency could not account for these features. Dementia was present in a signifcant proportion of patients. These data broaden our knowledge on the clinical presentations of NCYST and its impact in public health

Les microglies, les cellules de l’immunité innée, résidentes du cerveau, sont impliquées dans la réponse inflammatoire cérébrale et le modelage des réseaux neuronaux au cours du développement. La perturbation de leurs activités par des stimuli environnementaux pouvant conduire à des altérations psychopathologiques, dans cette thèse, nous avons étudié le rôle des microglies dans les effets neurobiologiques et comportementaux d’un stimulus inflammatoire. Les travaux précédents ont révélé que l’administration de lipopolysaccharide (LPS), une endotoxine bactérienne, provoque des comportements de type dépressifs. Le rôle des microglies dans ces altérations a fait l’objet de la première étude de cette thèse (Chapitre 2). Afin de dépléter les microglies du cerveau, des souris adultes ont reçu par voie d’administration intra-hippocampique des liposomes contenant du clodronate, provoquant ainsi l’apoptose des microglies phagocytaires. L’administration de LPS active dans l’hippocampe la synthèse de cytokines pro-inflammatoires [interleukine (IL)-1b et facteur de nécrose tumorale (TNF)-a] et anti-inflammatoires (IL-10), et de l'indoleamine 2,3-dioxygénase, une enzyme impliquée dans le métabolisme du tryptophane aux activités pro-dépressives. La déplétion des microglies phagocytaires atténue les effets du LPS, à l’exception de l’IL-1b, dont l’expression est exacerbée. De plus, l’administration de clodronate prévient les effets du LPS sur les comportements de type dépressif. Dans leur ensemble, ces résultats ont révélé que les microglies phagocytaires sont impliquées dans les effets inflammatoires et comportementaux de type dépressif induits par le LPS. Nous avons ensuite étudié le rôle des microglies dans les effets comportementaux d’une inflammation maternelle précoce provoquée lors de la colonisation du cerveau fœtal par les microglies (Chapitres 3 & 4). Ainsi, nous avons administré au jour gestationnel (JG)9.5 du LPS à des souris gestantes et évalué la trajectoire développementale pré- et post-natale des microglies et du comportement de la progéniture (Chapitre 3). L’administration de LPS à JG9.5 provoque une réduction du pourcentage représenté par les microglies matures aux JG14.5 et 18.5 et des déficits comportementaux persistants à l’âge adulte avec un dimorphisme sexuel prononcé. Nous avons alors recherché à identifier les mécanismes moléculaires impliqués dans les effets du LPS administré à JG9.5, en étudiant la piste de l’action des cytokines inflammatoires (Chapitre 4). Pour cela, nous nous sommes focalisé sur l’IL-1b, la cytokine inflammatoire effectrice principale de l’activité microgliale. L’expression de l'IL-1b et des cytokines associées (IL-6, TNFa et IL-10) augmente dans le plasma maternel, le placenta et le cerveau fœtal, 2 et 4 heures après l’administration de LPS. Ces changements sont accompagnés d'un phénotype microglial immature à JG18.5 et d’une réduction de la population microgliale totale au jour postnatal (JPN)9. À l’âge adulte (JPN65), nous avons observé une modification morphologique de la microglie dans plusieurs structures cérébrales. Enfin, les souris adultes, prénatalement traitées au LPS, développent des altérations des comportements de type sociaux et des comportements répétitifs. Les altérations du nombre de microglies induites par le LPS sont corrélées aux troubles comportementaux, et ce, de façon spécifique en fonction du sexe des souris. Enfin, la co-administration de l'antagoniste du récepteur de l'IL-1 et de LPS chez les femelles gestantes au JG9.5 réduit, voire prévient les effets inflammatoires et comportementaux du LPS. [...] / Recent research on microglia has uncovered a multitude of activities that extends the role of these cells well beyond their traditional function as immune sentinels. The most prominent of these newly described activities is an intricate role in neuronal network remodeling notably upon environmental challenge or during brain development, the disruption of which can result in long lasting consequences relevant to several psychopathologies. We sought, in the current thesis, to identify some of the mechanisms involved. Our initial approach was to target the immune function of microglia, based on our previous findings linking systemic immunogenic challenge with lipopolysaccharide (LPS) in mice with the development of despair-like behavior/depression. Here, we sought to identify immune mediators activated in microglia following a single systemic challenge with LPS (Chapter 2). These studies were conducted in adult mice in which phagocytic microglia were depleted using a single injection of liposomal clodronate in the CA3 region of the hippocampus. LPS challenge significantly upregulated the expression of both pro-inflammatory [interleukin (IL)-1b and tumor necrosis factor (TNF)-a] and anti-inflammatory (IL-10) cytokines compared to saline treated animals. In addition, LPS highly increased the expression of indoleamine 2,3-dioxygenase (IDO), an important rate limiting enzyme for metabolizing tryptophan in the brain and an established indicator of the activation of this depression mediating pathway. Clodronate-mediated depletion attenuated all of these effects apart from IL-1b expression which was further exacerbated. Behavioral assessment of the mice demonstrated a significant LPS-induced increase of immobility in the forced swim test (FST), which was prevented by clodronate. This experimental approach provided a snapshot of the role of inflammation in the development of brain dysfunction mediated by microglia. In subsequent studies (chapter 3 & 4), and in order to perform a more comprehensive, longer-term investigation of microglia activity in neurodevelopment, we utilized a prenatal infection model using LPS to activate maternal immunity at a relatively early [Gestational Day (GD)9.5] time point when microglia colonize the fetal brain to assess the impact on microglial population during development and the subsequent behavior of the progeny (Chapter 3). The results demonstrated LPS reduced the percentage of mature microglial population at GD14.5 and GD18.5 representing mid to late gestation. In addition, prenatal LPS had a significant effect on the offspring’s neonatal as well as adult behavior, with a clear divergence along sex lines in adulthood. In the final study (Chapter 4), we sought to investigate the mechanisms underlying the changes we noted in microglial development and the sexually dimorphic behavioral deficits. For this, we focused on the role played by pro-inflammatory cytokines, particularly IL-1b which represents the main effector of microglial activation following infection or injury. Detailed analysis of the expression of IL-1b and other related cytokines (IL-6, TNF-a and IL-10) revealed an increased expression of these mediators in maternal plasma, placenta and fetal brain, 2 and 4 hours after the prenatal LPS treatment. These changes were accompanied with a decreased percentage of mature microglia in the brain of embryos at GD18.5 and of total microglia population at post-natal day (PND)9. In the adult offspring (PND65), we detected an increased density and altered microglial morphology in specific higher-order structures implicated in complex behaviors, as well as altered social preference and memory and increased repetitive actions. [...]