Thesis (Ph. D.)--Leland Stanford Jr. University. / Cover title. Reprinted from Archiv. für die ges. physiologie, bd. 101; and American Journal of Physiology, vol. X, no. 7.

Based on evidence of abnormalities in axon thickness and neuronal disorganization, autism spectrum disorder (ASD) is commonly considered to be a condition resulting from neuronal dysfunction. Yet, recent findings suggest that non-neuronal cell types also contribute to ASD pathology. To investigate the role of glial cells in ASD, a combination of protein and gene expression analyses were used to determine levels of two glial markers, glial fibrillary acidic protein (GFAP) and myelin oligodendrocyte glycoprotein (MOG), in the postmortem brain tissue from control and ASD donors. Levels of GFAP immunoreactivity (ir) were significantly elevated (P = 0.008) in anterior cingulate cortex (Brodmann area 24; BA24) white matter of ASD donors compared to control donors. In contrast, GFAP-ir levels were similar in BA24 gray matter from ASD and control donors. MOG-ir was also similar in both BA24 white and gray matter from ASD and control donors. In anterior prefrontal cortex (BA10), there were no significant differences in GFAP-ir or MOG-ir in either white or gray matter comparing ASD to control donors. Levels of expression of the genes GFAP and MOG also showed no differences between control and ASD donors in BA24 and BA10 white and gray matter. Collectively, these data imply that ASD is associated with an activation of white matter astrocytes in the anterior cingulate cortex as a result of a yet undefined cellular insult. Research is needed to investigate the molecular pathways that underlie this astrocyte reaction and such research may yield important clues regarding the etiology of ASD.

Animals rely on information provided by their senses to perform the complicated series of motor actions that allow them to obtain food and shelter, locate mates, and avoid predators. Interpreting sensory information and using it to guide behavior is one of the principle roles of the nervous system. In the insect brain, a system of midline neuropils called the central complex is thought to be the site at which sensory information is integrated and converted into the signals that initiate or modify motor outputs. This dissertation addresses three important questions for understanding how the central complex processes sensory information and influences behavior. These questions are: 1. What kind of sensory information is represented in the central complex? 2. What is the relationship of central complex neuropils to other brain regions? 3. Are such regions simply relay stations, or do they support computations that contribute to phenomena cautiously ascribed to the central complex, such as visual learning and memory? Using the flesh fly, Neobellieria bullata, intracellular recordings and dye fills were conducted to explore the sensory parameters that are relayed to the central complex. The results of these experiments along with previously published observations suggest that the sensory information relayed to the central complex differs from species to species and is likely matched to the behavior of each. Reconstructions of neurons labeled during intracellular recordings, cobalt injections, Golgi impregnations, immunohistochemistry, and Bodian staining were used to further explore the relationship between the central complex and the superior protocerebrum. These studies suggest that the superior protocerebrum is a complicated computation center, more intricately related to the central complex than has been previously assumed. These results are used to propose a network model for how one circuit in the central complex may perform some of the functions the central complex has experimentally been shown to mediate. The differences between this model and the elaboration of the central complex in vivo suggest that circuits within the central complex also support a variety of other computations. Finally, future experiments are described, investigating the role of the central complex in orientation of migrating monarch butterflies.

O objetivo deste estudo é descrever a organização anatômica da glândula pineal do macaco Cebus apella, analisando seus aspectos macroscópicos e microscópicos, vistos sob a óptica da microscopia de luz, microscopia eletrônica de transmissão e microanálise por difração de RX. Para desenvolver este trabalho utilizamos 12 exemplares de macaco Cebus apella, cedidos pelo IBAMA ? MG. Para a análise macroscópica utilizamos 12 animais, os quais foram empregados para estudos relacionados à topografia e sintopia do corpo pineal. Desse grupo, 07 espécimes foram utilizados para a microscopia de luz, 01 espécime para microscopia eletrônica de transmissão e 01 espécime para microscopia eletrônica de varredura, preparados conforme técnicas histológicas de rotina. A glândula pineal do macaco Cebus apella apresentou-se como um pequeno órgão de forma e dimensões variáveis, medindo de 2,5 mm a 4,0 mm de comprimento e de 2,0 mm a 3,5 mm de largura. Está localizada caudalmente ao esplênio do corpo caloso, em correspondência ao recesso pineal, podendo ser classificada como subcalosa e do tipo A, segundo Vollrath (1981). É revestida externamente por uma cápsula de tecido conjuntivo, rica em fibras colágenas, derivada da pia-máter. No parênquima glandular verificam-se três tipos de células: pinealócitos, células da glia e mastócitos. De acordo com as características morfológicas dos núcleos, identificamos pinealócitos do tipo I e pinealócitos do tipo II. Concreções arredondadas e em forma de mórula são vistas no parênquima glandular, nas quais a microanálise por difração de RX demonstrou dois componentes principais: o fósforo e o alumínio / The objective of this study is to describe the anatomical organization of the pineal gland of the Cebus apella monkey, analyzing its macrocospic and microscopical aspects, seen under the optics of the light microscopy, electronic microscopy of transmission and microanalysis by emission of X-Ray. In the development of this study 12 units of Cebus apella monkey, supplied by IBAMA ? MG, were used. For the macrocospic analysis we used 12 animals, which had been used for topography and related to pineal body related studies. From this group, seven specimens were used on the light microscopy, one specimen on electronic microscopy of transmission and one specimen on electronic microscopy of scanning. All the specimens were prepared according to histological techniques of routine. The pineal gland of the Cebus apella monkey presented itself as a small organ of variable forms and lengths, measuring 2,5mm to 4,0mm in length and 2,0mm to 3,5mm in width. It is caudally located to the esplenium of the calosus body, in relation to the pineal recess, being classified as subcalosus and type A according to Vollrath (1981). It is externally covered by a conjunctive tissue capsule, rich in collagen fibers, derived from the piamater. In the glandular parenchyma three types of cells are verified: pinealocytes, cells of the glia and mast cells. According to the morphologic characteristics of the cores, we identify pinealocytes of type I and pinealocytes of type II. Corpora arenaceae round and in morula shape are seen in the glandular parenchyma in which the microanalysis by emission of X-Ray showed two main components: the phosphorus and the aluminum

O conhecimento de diversos aspectos da Neuroanatomia de primatas não humanos - que atualmente é falho, pela falta de trabalhos a respeito - é importante não apenas pela importância intrínseca desse conhecimento como até pelo fato de contribuir para um melhor entendimento da própria evolução do grupo, o que representa um fator relevante para a sua preservação e proteção. O objetivo deste trabalho é efetuar estudos morfológicos da hipófise do macaco Cebus apella a fim de conhecer melhor esta estrutura, e oferecer subsídios para análises comparativas mais amplas. Utilizamos 11 animais sendo 7 deles constantes do acervo de pesquisa da Universidade Federal de Uberlândia e, os outros 4 exemplares, doados pelo IBAMA-MG. A preparação das peças anatômicas foi levada a efeito mediante cuidadosa dissecção dos espécimes, cujos encéfalos foram retirados das caixas cranianas, preservando-se ao máximo todas as suas estruturas. As hipófises, depois de registrada sua macroscopia, foram submetidas aos métodos histológicos de rotina para observações em microscopia de luz e eletrônica de transmissão. Dos resultados obtidos podemos citar que a hipófise, neste animal, é uma glândula intracraniana alojada na sela turcica, fixada à base do cérebro pelo infundíbulo, sendo este muito curto. Ela exibe forma odontóide, exibindo-se aparentemente, como uma massa única, pois macroscopicamente apenas é possível, a identificação de uma divisão discreta em um lobo anterior e outro posterior, além do infundíbulo. As análises histológicas mostram esta glândula dividida em três lobos: anterior (adenohipófise), intermédio e posterior (neurohipófise). À microscopia eletrônica de transmissão foi possível identificar e classificar 4 tipos celulares em relação á adenohipófise: células do tipo I, II, III e IV. O aspecto do núcleo dessas células, exibindo freqüentemente, invaginações profundas de sua membrana, confere à hipófise do macaco Cebus apella, características peculiares, o que nos instiga a realizar novas pesquisas sobre o assunto / The knowledge of many aspects of Neuroanatomy of non-human primates - which is currently poor due to the lack of studies on the subject - is very important not only for the intrinsic significance of the knowledge itself but also because it contributes for a better understanding of the evolution of the group, which represents a relevant factor for its preservation and protection. The objective of this study is to perform morphological researches on the hypophysis of the Cebus apella monkey in order to understand this structure better and to provide basis for wider comparative analyses. Eleven animals were used on this study. Seven of them were properties of the research collection of the Federal University of Uberlândia and the other four were donated by the IBAMA-MG. The preparation of the anatomical parts was carefully done through dissection of the specimens, whose encephalus were removed from their skulls preserving all their structures. The hypophysis, after having their macroscopy registered, were submitted to histological methods of routine for observation in light microscopy and electronic microscopy of transmission. We could conclude from the obtained results that the hypophysis, on this particular animal, is a intracranial gland lodged in the sela turcica fixed to the base of the brain by the infundibulum which is very short. It has in dens shape and it presents itself as a single mass, because, macroscopically, it is only possible the identification of a discrete division in an anterior lobe and another posterior one besides the infundibulum. The histological analyses show this gland divided in three lobes: anterior (adenohypophysis), intermediary and posterior (neurohypophysis). Through the electronic microscopy of transmission it was possible to identify and classify four cellular types related to the adenohypophysis: types I, II, III and IV. The aspect of the cores of these cells, frequently showing deep invaginations of their membranes, confers to hypophysis of the Cebus apella monkey, peculiar characteristics, which instigates us to carry on performing new studies on the subject

Introduction. Callous-unemotional (CU) traits predict socially debilitating outcomes including Antisocial Personality Disorder and violent crime in adulthood. Despite significant research, the etiology of CU traits is not well understood. This dissertation incorporates genetic, physiological, neuroanatomical, and self-report measures to investigate the etiology of CU traits. Specifically, this project focuses on measures previously found to associate with impaired fear-processing observed in individuals high on CU. Brain morphometry for paralimbic regions of interest (ROIs) and electromyographic facial eyeblink reflex to startle and fear-potentiated startle probes were investigated as potential endophenotypes for CU traits. Methods. Two genetically informative (ages 9-20) twin samples (N=1696 individuals; 848 twin pairs) were used to estimate the changing heritable and environmental influences on CU over the age range of 9-20 using age-moderated biometric structural equation modeling (SEM). To determine potential endophenotypes, shared genetic variance with CU was examined for baseline and fear-potentiated startle reflex and morphometric measures of brain ROIs. Results. The heritability of CU increases over the ages of 9-20, from approximately 34% at age 9 to 47% at age 20. Therefore, environmental mechanisms for CU are most influential at younger ages. Although there were no significant associations after correction for multiple testing, there was some evidence to suggest potential positive associations between CU traits and baseline and fear-potentiated startle in younger (9-14) females. There was also evidence suggesting potential negative associations between CU traits and right anterior cingulate cortex thickness as well as right posterior cingulate cortex thickness in females only. There was no genetic covariance between CU and any of the examined physiological or neuroanatomical phenotypes. Discussion. These results suggest that middle childhood may be the most salient time for environmental interventions associated with preventing or ameliorating CU traits. Furthermore, these results suggest that the cingulate cortex may play a role in the development of CU traits, possibly in females specifically. The cingulate cortex may influence CU traits through its roles in emotional processing, learning, and memory. Larger samples will likely be needed to determine the genetic relationship between CU traits and the structural development of the cingulate cortex.

Aim To determine the neural correlates of Bipolar Disorder (BD) using functional Magnetic Resonance Imaging (fMRI) in different phases of the illness. Methods Five fMRI studies were conducted in adult female BD patients and healthy matched comparison subjects. The first two studies examined patients with bipolar depression and hypomania using captioned-pictures to characterize mood-state related patterns of activation. The subsequent three studies investigated BD euthymia using emotional words and faces to identify a potential trait-marker. Results During depression, bipolar patients demonstrated additional subcortical activation in the thalamus, amygdala, hypothalamus and medial globus pallidus. In hypomania, patients again had additional subcortical activation involving the caudate and the thalamus. In both studies patients had prefrontal cortex activation, but the pattern differed from that in healthy subjects. These studies suggested a pattern of mood-state related subcortical recruitment for emotional processing in BD. The next set of studies examined euthymic BD patients to partition trait and state-markers. The first study used implicit positive and negative word-associated affect and found diminished responses to positive and negative affective words as compared to healthy subjects in both cortical and subcortical brain regions, in particular the cingulate, thalamus and caudate. The second study used the emotional Stroop task to elicit implicit affective processing and euthymic patients had less cortical and subcortical activation in response to affect, in particular decreased left ventral prefrontal cortex (BA47) activation. The final study used explicit emotional processing of fear and disgust to examine affective responses, and showed that patients were generally less responsive to disgust, but had comparatively greater activations to fear. Conclusions BD patients have a likely deficit in the ventral prefrontal cortex that is evident in euthymia. Prefrontal cognitive appraisal of emotions is constrained in euthymic, depressed and hypomanic phases, reflected in subcortical changes that suggest additional processing. The likely cause for this is a functional prefrontal cortex deficit that results in compensatory changes in emotional processing systems. Treatment probably stabilizes these systems without normalizing them. Our studies demonstrate the benefits of examining BD in its different phases, and future studies should attempt to emulate this in medication-free patients.

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a gradual deterioration of the patients’ ability to independently perform day to day activities. Researchers have discovered significant changes in neuroanatomy, cognition and behavior that are related to the disease process of AD and researchers continue to uncover new variables, such as the presence of vascular risk factors, which may further increase our ability to understand and characterize the disease. The purpose of this study is to identify the neuroanatomical, cognitive and behavioral variables that best predict impairment of instrumental activities of daily living in individuals with probable AD. Reduced white matter integrity in the dorsolateral prefrontal cortex as well as the presence of vascular risk factors significantly predicted impairments in activities of daily living (ADLs). Executive functioning skills, typically described as frontal lobe system behaviors, were positively associated with ADLs. Further, executive functions fully mediated the relationship between frontal lobe white matter integrity and ADLs. A better understanding of the variables responsible for diminished ADLs in AD will allow researchers and clinicians to better target prevention and intervention strategies and ultimately help individuals with AD to maintain their independence for a longer duration.

Charting out the complete brain microstructure of a mammalian species is a grand challenge. Recent advances in serial sectioning microscopy such as the Knife- Edge Scanning Microscopy (KESM), a high-throughput and high-resolution physical sectioning technique, have the potential to finally address this challenge. Nevertheless, there still are several obstacles remaining to be overcome. First, many of these serial sectioning microscopy methods are still experimental and are not fully automated. Second, even when the full raw data have been obtained, morphological reconstruction, visualization/editing, statistics gathering, connectivity inference, and network analysis remain tough problems due to the unprecedented amounts of data. I designed a general data acquisition and analysis framework to overcome these challenges with a focus on data from the C57BL/6 mouse brain. Since there has been no such complete microstructure data from any mammalian species, the sheer amount of data can overwhelm researchers. To address the problems, I constructed a general software framework for automated data acquisition and computational analysis of the KESM data, and conducted two scientific case studies to discuss how the mouse brain microstructure from the KESM can be utilized. I expect the data, tools, and studies resulting from this dissertation research to greatly contribute to computational neuroanatomy and computational neuroscience.

Thesis (Ph. D.)--University of Queensland, 2003. / Includes bibliographical references.